US 20160302417A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2016/0302417 A1 Eckelbarger et al. (43) Pub. Date: Oct. 20, 2016

(54) MOLECULES HAVING PESTICIDAL C07D 331/04 (2006.01) UTILITY. AND INTERMEDIATES, C07D 295/32 (2006.01) COMPOSITIONS, AND PROCESSES, C07D 305/08 (2006.01) RELATED THERETO C07D 205/04 (2006.01) C07D 309/14 (2006.01) (71) Applicant: Dow AgroSciences LLC, Indianapolis, C07D 333/48 (2006.01) IN (US) C07D 261/72 (2006.01) C07D 207/273 (2006.01) (72) Inventors: Joseph D. Eckelbarger, Carmel, IN C07D 263/26 (2006.01) (US); Daniel I. Knueppel, Zionsville, C07D 277/36 (2006.01) IN (US); Ronald J. Heemstra, Fishers, C07D 307/33 (2006.01) IN (US); Ronald Ross, JR., Zionsville, C07D 233/80 (2006.01) IN (US); Kyle A. DeKorver, C07C 237/42 (2006.01) Grandville, MI (US); Kaitlyn Gray, (52) U.S. CI. Indianapolis, IN (US); Peter Vednor, CPC ...... A0IN 53/00 (2013.01); CO7C 237/42 Carmel, IN (US); Timothy P. Martin, (2013.01); CO7C 255/46 (2013.01); CO7D Noblesville, IN (US), Ricky Hunter, 333/36 (2013.01); CO7D 331/04 (2013.01); Westfield, IN (US); David A. Demeter. CO7D 295/32 (2013.01); CO7D 305/08 Fishers, N(US), Tony K. Trullinger. (2013.01); CO7D 205/04 (2013.01); CO7D Westfield, IN (US); Erich Baum, 309/14 (2013.01); CO7D 333/48 (2013.01); Greenwood, IN (US); Zoltan L. Benko, CO7D 261/12 (2013.01); CO7D 207/273 Indianapolis, IN (US); Nakyen Choy, (2013.01); CO7D 263/26 (2013.01); CO7D Carmel, IN (US); Gary Crouse, 277/36 (2013.01); CO7D 307/33 (2013.01); Noblesville, IN (US); John F. Daeuble, CO7D 233/80 (2013.01); CO7C 2101/02 SR. Carmel, IN (US). Fangzheng Li. (2013.01); CO7C 2101/04 (2013.01); CO7C Carmel,Indianapolis, IN (US); IN (US); Jeff Nissen,Michelle Riener, 2101/08 (2013.01); CO7C 2101/14 (2013.01) Newtonville, MA (US); Tom Sparks, (57) ABSTRACT Greenfield, IN (US); Frank Wessels, Indianapolis, IN (US); Maurice Yap, This disclosure relates to the field of molecules having Zionsville, IN (US) pesticidal utility against pests in Phyla Arthropoda, Mol lusca, and Nematoda, processes to produce such molecules, (73) Assignee: Dow AgroSciences LLC, Indianapolis, intermediates used in such processes, pesticidal composi IN (US) tions containing such molecules, and processes of using such pesticidal compositions against such pests. These pes (21) Appl. No.: 15/092,641 ticidal compositions may be used, for example, as acari - cides, insecticides, miticides, molluscicides, and nemati (22) Filed: Apr. 7, 2016 cides. This document discloses molecules having the Related U.S. Application Data following formula (“Formula One”). (60) Provisional application No. 62/148,809, filed on Apr. 17, 2015, provisional application No. 62/148,814, Formula One filed on Apr. 17, 2015, provisional application No. R 12

62/148,830, filed on Apr. 17, 2015, provisional ap plication No. 62/148,837, filed on Apr. 17, 2015, R13 provisional application No. 62/148,818, filed on Apr. R15 17, 2015, provisional application No. 62/148,824, ! filed on Apr. 17, 2015. SR 16 Publication Classification R 14 Q2 (51) Int. Cl. A0IN 53/00 (2006.01) C07C 255/46 (2006.01) C07D 333/36 (2006.01) US 2016/0302417 A1 Oct. 20, 2016

MOLECULES HAVING PESTICIDAL [0006] It is noted that gastropods (slugs and snails) are UTILITY. AND INTERMEDIATES, pests of less economic importance than other arthropods or COMPOSITIONS, AND PROCESSES, nematodes, but in certain places, they may reduce yields RELATED THERETO substantially, severely affecting the quality of harvested products, as well as, transmitting human, animal, and plant CROSS-REFERENCES TO RELATED diseases. While only a few dozen species of gastropods are APPLICATIONS serious regional pests, a handful of species are important [0001] This application claims the benefit of, and priority pests on a worldwide scale. In particular, gastropods affect from, U.S. provisional application Ser. Nos. 62/148,830; a wide variety of agricultural and horticultural crops, such 62/148,837; 62/148,809; 62/148,814; 62/148,818; and as, arable, pastoral, and fiber crops; vegetables; bush and 62/148,824; all of which were filed on Apr. 17, 2015. The tree fruits; herbs; and ornamentals (Speiser). entire contents of all of the above-identified applications are [0007] Termites cause damage to all types of private and hereby incorporated by reference into this application. public structures, as well as to agricultural and forestry resources. In 2005, it was estimated that termites cause over FIELD OF THIS DISCLOSURE US$50 billion in damage worldwide each year (Korb). [0008] Consequently, for many reasons, including those [0002] This disclosure relates to the field of molecules mentioned above, there is an on-going need for the costly having pesticidal utility against pests in Phyla Arthropoda, (estimated to be about US$256 million per pesticide in Mollusca, and Nematoda, processes to produce such mol 2010), time-consuming (on average about 10 years per ecules, intermediates used in such processes, pesticidal pesticide), and difficult, development of new pesticides compositions containing such molecules, and processes of (CropDife America). using such pesticidal compositions against such pests. These pesticidal compositions may be used, for example, as aca CERTAIN REFERENCES CITED IN THIS ricides, insecticides, miticides, molluscicides, and nemati DISCLOSURE cides. [0009| CropLi?e America, The Cost of New Agrochemical BACKGROUND OF THIS DISCLOSURE Product Discovery, Development & Registration, and [0003] “Many of the most dangerous human diseases are Research & Development predictions for the Future, transmitted by insect vectors” (Rivero et al.). “Historically, 2010. malaria, dengue, yellow fever, plague, filariasis, louse-borne [0010) Drewes, M., Tietjen, K., Sparks, T. C., High typhus, trypanomiasis, leishmaniasis, and other vector borne Throughput Screening in Agrochemical Research, Mod diseases were responsible for more human disease and death ern Methods in Crop Protection Research, Part I, Meth in the 17th through the early 20th centuries than all other ods for the Design and Optimization of New Active causes combined” (Gubler). Vector-borne diseases are Ingredients, Edited by Jeschke, P., Kramer, W., Schirmer, responsible for about 17% of the global parasitic and infec U., and Matthias W., p. 1-20, 2012. tious diseases. Malaria alone causes over 800,000 deaths a [0011] Gubler, D., Resurgent Vector-Borne Diseases as a year, 85% of which occur in children under five years of age. Global Health Problem, Emerging Infectious Diseases, Each year there are about 50 to about 100 million cases of Vol. 4, No. 3, p. 442-450, 1998. dengue fever. A further 250,000 to 500,000 cases of dengue [0012] Korb, J., Termites, Current Biology, Vol. 17, No. hemorrhagic fever occur each year (Matthews). Vector con 23, 2007. trol plays a critical role in the prevention and control of [0013] Matthews, G., Integrated Vector Management: infectious diseases. However, insecticide resistance, includ Controlling Vectors of Malaria and Other Insect Vector ing resistance to multiple insecticides, has arisen in all insect Borne Diseases, Ch. 1, p. 1, 2011. species that are major vectors of human diseases (Rivero et [0014] Nicol, J., Turner S., Coyne, L., den Nijs, L., Hock al.). Recently, more than 550 arthropod species have devel sland, L., Tahna-Maafi, Z., Current Nematode Threats to oped resistance to at least one pesticide (Whalon et al.). World Agriculture, Genomic and Molecular Genetics of Furthermore, the cases of insect resistance continue to Plant-Nematode Interactions, p. 21-43, 2011. exceed by far the number of cases of herbicide and fungicide [0015] Pimental, D., Pest Control in World Agriculture, resistance (Sparks et al.). Agricultural Sciences—Vol. II, 2009. [0004] Each year insects, plant pathogens, and weeds, destroy more than 40% of all food production. This loss [0016] Rivero, A., Vezilier, J., Weill, M., Read, A., Gan occurs despite the application of pesticides and the use of a don, S., Insect Control of Vector-Borne Diseases: When is wide array of non-chemical controls, such as, crop rotations, Insect Resistance a Problem? Public Library of Science and biological controls. If just some of this food could be Pathogens, Vol. 6, No. 8, p. 1-9, 2010. saved, it could be used to feed the more than three billion [0017| Sparks T. C., Nauen R., IRAC; Mode of action people in the world who are malnourished (Pimental). classification and insecticide resistance management, [0005] Plant parasitic nematodes are among the most Pesticide Biochemistry and Physiology (2014) available widespread pests, and are frequently one of the most insidi online 4 December 2014. ous and costly. It has been estimated that losses attributable [0018] Speiser, B., Molluscicides, Encyclopedia of Pest to nematodes are from about 9% in developed countries to Management, Ch. 219, p. 506-508, 2002. about 15% in undeveloped countries. However, in the [0019] Whalon, M., Mota-Sanchez, D., Hollingworth, R., United States of America a survey of 35 States on various Analysis of Global Pesticide Resistance in Arthropods, crops indicated nematode-derived losses of up to 25% Global Pesticide Resistance in Arthropods, Ch. 1, p. 5-33, (Nicol et al.). 2008.

US 2016/0302417 A1 Oct. 20, 2016

methyl, chlorquinox, chlorsulfuron, chlorthal, chlorthiamid, diflufenican, diflufenicanil, diflufenzopyr, diflumetorim, chlorthiophos, chlortoluron, chlozolinate, chltosan, chole dikegulac, dilor, dimatif, dimefluthrin, dimefox, dimefuron, calciferol, choline chloride, chromafenozide, cicloheximide, dimehypo, dimepiperate, dimetachlone, dimetan, dimethac cimectacarb, cimetacarb, cinerin I, cinerin II, cinerins, cini arb, dimethachlone, dimethachlor, dimethametryn, dimeth don-ethyl, cinmethylin, cinosulfuron, cintofen, ciobutide, enamid, dimethenamid-P dimethipin, dimethirimol, dime thoate, dimethomorph, dimethrin, dimethyl carbate, cisanilide, cismethrin, clacyfos, clefoxydim, clempirin, clen dimethyl disulfide, dimethyl phthalate, dimethylvinphos, pyrin, clethodim, climbazole, cliodinate, clodinafop, cloeth dimetilan, dimexano, dimidazon, dimoxystrobin, dimpylate, ocarb, clofencet, clofenotane, clofentezine, clofenvinfos, dimuron, dinex, dingjunezuo, diniconazole, diniconazole clofibric acid, clofop, clomazone, clomeprop, clonitralid, M, dinitramine, dinitrophenols, dinobuton, dinocap, cloprop, cloproxydim, clopyralid, cloquintocet, cloransu dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, lam, closantel, clothianidin, clotrimazole, cloxyfonac, dinoprop, dinosam, dinoseb, dinosulfon, dinotefuran, cloxylacon, clozylacon, CMA, CMMP CMP CMU, codle dinoterb, dinoterbon, diofenolan, dioxabenzofos, dioxacarb, lure, colecalciferol, colophonate, copper 8-quinolinolate, dioxathion, dioxation, diphacin, diphacinone, diphenadione, copper acetate, copper acetoarsenite, copper arsenate, cop diphenamid, diphenamide, diphenyl sulfone, diphenylam per carbonate, basic, copper hydroxide, copper naphthenate, ine, diphenylsulphide, diprogulic acid, dipropalin, dipropet copper oleate, copper oxychloride, copper silicate, copper ryn, dipterex, dipymetitrone, dipyrithione, diguat, disodium tetraborate, disosultap, disparlure, disugran, disul, disul sulfate, copper sulfate, basic, copper zinc chromate, cou firam, disulfoton, ditalimfos, dithianon, dithicrofos, dithio machlor, coumafène, coumafos, coumafuryl, coumaphos, ether, dithiométon, dithiopyr, diuron, dixanthogen, d-limo coumatetralyl, coumethoxystrobin, coumithoate, coumox nene, DMDS, DMPA, DNOC, dodemorph, dodicin, dodine, ystrobin, CPMC, CPMF, CPPC, credazine, cresol, cresylic dofenapyn, doguadine, dominicalure, doramectin, DPC, dra acid, crimidine, crotamiton, crotoxyfos, crotoxyphos, crufo zoxolon, DSMA, d-trans-allethrin, d-trans-resmethrin, dufu mate, cryolite, cue-lure, cufraneb, cumyleron, cumyluron, lin, dymron, EBEP, EBP. ebufos, ecdysterone, echlomezol, cuprobam, cuprous oxide, curcumenol, CVMP. cyanamide, EDB, EDC, EDDP edifemphos, eglinazine, emamectin, cyanatryn, cyanazine, cyanofenphos, cyanogen, cyanophos, EMPC, empenthrin, enadenine, endosulfan, endothal, cyanthoate, cyantraniliprole, cyanuric acid, cyazofamid, endothall, endothion, endrin, enestroburin, enilconazole, cybutryne, cyclafuramid, cyclanilide, cyclaniliprole, enoxastrobin, ephirsulfonate, EPN, epocholeone, cyclethrin, cycloate, cycloheximide, cycloprate, cyclopro epofenonane, epoxiconazole, eprinomectin, epronaz, EPTC, thrin, cyclopyrimorate, cyclosulfamuron, cycloxydim, erbon, ergocalciferol, erlujixiancaoan, esdépalléthrine, cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyflu esfenvalerate, ESP, esprocarb, etacelasil, etaconazole, eta thrin, cyhalofop, cyhalothrin, cyhexatin, cymiazole, phos, etem, ethaboxam, ethachlor, ethalfluralin, ethametsul cymoxanil, cyometrinil, cypendazole, cypermethrin, cyper furon, ethaprochlor, ethephon, ethidimuron, ethiofencarb, quat, cyphenothrin, cyprazine, cyprazole, cyproconazole, ethiolate, ethion, ethiozin, ethiprole, ethirimol, ethoate cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyro methyl, ethobenzanid, ethofumesate, ethohexadiol, ethop rop, ethoprophos, ethoxyfen, ethoxyquin, ethoxysulfuron, mazine, cythioate, cytrex, daimuron, dalapon, daminozide, ethychlozate, ethyl formate, ethyl pyrophosphate, ethylan, dayoutong, dazomet, DBCP, d-camphor, DCB, DCIP. ethyl-DDD, ethylene, ethylene dibromide, ethylene dichlo DCPA, DCPTA, DCU, DDD, DDPP DDT. DDVP. debac ride, ethylene oxide, ethylicin, ethylmercury 2,3-dihydroxy arb, decafentin, decamethrin, decarbofuran, deet, dehy propyl mercaptide, ethylmercury acetate, ethylmercury bro droacetic acid, deiquat, delachlor, delnav, deltamethrin, mide, ethylmercury chloride, ethylmercury phosphate, demephion, demephion-O, demephion-S, demeton, deme etinofen, ETM, etnipromid, etobenzanid, etofemprox, etox ton-methyl, demeton-O, demeton-O-methyl, demeton-S, azole, etridiazole, etrimfos, étrimphos, eugenol, EXD, demeton-S-methyl, demeton-S-methyl sulphone, demeton famoxadone, famphur, fenac, fenamidone, fenaminosulf, S-methylsulphon, DEP depallethrine, derris, desmedipham, fenaminstrobin, fenamiphos, fenapanil, fenarimol, fenasu desmetryn, desmetryne, d-fanshiluquebingjuzhi, diafenthi lam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin uron, dialifor, dialifos, diallate, diamidafos, dianat, diato oxide, fenchlorazole, fenchlorphos, fenclofos, fenclorim, maceous earth, diatomite, diazinon, dibrom, dibutyl phtha fenethacarb, fenfluthrin, fenfuram, fenhexamid, fenidin, late, dibutyl succinate, dicamba, dicapthon, dichlobenil, fenitropan, fenitrothion, fénizon, fenjuntong, fenobucarb, dichlofenthion, dichlofluanid, dichlone, dichloralurea, femolovo, fenoprop, fenothiocarb, fenoxacrim, fenoxanil, dichlorbenzuron, dichlorfenidim, dichlorflurenol, dichlo fenoxaprop, fenoxaprop-P, fenoxasulfone, fenoxycarb, fen rflurenol, dichlormate, dichlormid, dichloromethane, diclo piclonil, fempirithrin, fempropathrin, fempropidin, fempropi romezotiaz, dichlorophen, dichlorprop, dichlorprop-P. morph, fenpyrazamine, fempyroximate, fenguinotrione, fen dichlorvos, dichlozolin, dichlozoline, diclobutrazol, diclo ridazon, fenson, fensulfothion, fenteracol, fenthiaprop, cymet, diclofop, diclomezine, dicloran, diclosulam, dicofol, fenthion, fenthion-ethyl, fentiaprop, fentin, fentrazamide, dicophane, dicoumarol, dicresyl, dicrotophos, dicryl, fentrifanil, fenuron, fenuron-TCA, fenvalerate, ferbam, fer dicumarol, dicyclanil, dicyclonon, dieldrin, dienochlor, imzone, ferric phosphate, ferrous sulfate, fipronil, flamprop, diethamquat, diethatyl, diethion, diéthion, diethofencarb, flamprop-M, flazasulfuron, flocoumafen, flometoquin, floni dietholate, diéthon, diethyl pyrocarbonate, diethyltolu camid, florasulam, fluacrypyrim, fluazifop, fluazifop-P, flu amide, difenacoum, difenoconazole, difenopenten, difenox azimam, fluazolate, fluazuron, flubendiamide, flubenzimine, uron, difenzoquat, difethialone, diflovidazin, diflubenzuron, flubrocythrinate, flucarbazone, flucetosulfuron, fluchloralin, US 2016/0302417 A1 Oct. 20, 2016 flucofuron, flucycloxuron, flucythrinate, fludioxonil, fluéné looplure, lufenuron, lùxiancaolin, Ivdingjunzhi, Ivfumijvzhi, thyl, fluenetil, fluensulfone, flufenacet, flufenerim, flufeni lvXiancaolin, lythidathion, M-74, M-81, MAA, magnesium can, flufenoxuron, flufenoxystrobin, flufenprox, flufenpyr, phosphide, malathion, maldison, maleic hydrazide, malono flufenzine, flufiprole, fluhexafon, flumethrin, flumetover, ben, maltodextrin, MAMA, mancopper, mancozeb, mande flumetralin, flumetsulam, flumezin, flumiclorac, flumiox strobin, mandipropamid, maneb, matrine, mazidox, MCC, azin, flumipropyn, flumorph, fluometuron, fluopicolide, flu MCP, MCPA, MCPA-thioethyl, MCPB, MCPP mebenil, opyram, fluorbenside, fluoridamid, fluoroacetamide, fluoro mecarbam, mecarbinzid, mecarphon, mecoprop, mecoprop acetic acid, fluorochloridone, fluorodifen, fluoroglycofen, P. medimeform, medinoterb, medlure, mefenacet, fluoroimide, fluoromide, fluoromidine, fluoronitrofen, fluo mefenoxam, mefenpyr, mefluidide, megatomoic acid, melis roxypyr, fluothiuron, fluotrimazole, fluoxastrobin, syl alcohol, melitoxin, MEMC, menazon, MEP mepanipy flupoxam, flupropacil, flupropadine, flupropanate, flupyra rim, meperfluthrin, mephenate, mephosfolan, mepiquat, difurone, flupyrsulfuron, fluquinconazole, fluralaner, flura mepronil, meptyldinocap, mercaptodimethur, mercapto zole, flurecol, flurenol, fluridone, flurochloridone, fluromi phos, mercaptophos thiol, mercaptothion, mercuric chloride, dine, fluroxypyr, flurprimidol, flursulamid, flurtamone, mercuric oxide, mercurous chloride, merphos, merphos flusilazole, flusulfamide, flutenzine, fluthiacet, fluthiamide, oxide, mesoprazine, mesosulfuron, mesotrione, mesulfen, flutianil, flutolanil, flutriafol, fluvalinate, fluxapyroxad, flux mesulfenfos, mesulphen, metacresol, metaflumizone, meta ofenim, folpel, folpet, fomesafen, fonofos, foramsulfuron, laxyl, metalaxyl-M, metaldehyde, metam, metamifop, met forchlorfenuron, formaldehyde, formetanate, formothion, amitron, metaphos, metaxon, metazachlor, metazosulfuron, formparanate, fosamine, fosetyl, fosmethilan, fospirate, fos metazoxolon, metconazole, metepa, metflurazon, methaben thiazate, fosthietan, frontalin, fthalide, fuberidazole, fucao jing, fucaomi, fujunmanzhi, fulumi, fumarin, funaihecaol zthiazuron, methacrifos, methalpropalin, metham, methami ing, fuphenthiourea, furalane, furalaxyl, furamethrin, dophos, methasulfocarb, methazole, methfuroxam, methi furametpyr, furan tebufenozide, furathiocarb, furcarbanil, benzuron, methidathion, methiobencarb, methiocarb, furconazole, furconazole-cis, furethrin, furfural, furilazole, methiopyrisulfuron, methiotepa, methiozolin, methiuron, furmecyclox, furophanate, furyloxyfen, gamma-BHC, methocrotophos, métholcarb, methometon, methomyl, gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid, methoprene, methoprotryn, methoprotryne, methoduin-bu gibberellin A3, gibberellins, gliftor, glitor, glucochloralose, tyl, methothrin, methoxychlor, methoxyfenozide, methoxy glufosinate, glufosinate-P. glyodin, glyoxime, glyphosate, phenone, methyl apholate, methyl bromide, methyl eugenol, glyphosine, gossyplure, grandlure, griseofulvin, guanoctine, methyl iodide, methyl isothiocyanate, methyl parathion, guazatine, halacrinate, halauxifen, halfemprox, halofenozide, methylacetophos, methylchloroform, methyldithiocarbamic halosafen, halosulfuron, haloxydine, haloxyfop, haloxyfop acid, methyldymron, methylene chloride, methyl-isofen P. haloxyfop-R, HCA, HCB, HCH, hemel, hempa, HEOD, phos, methylmercaptophos, methylmercaptophos oxide, heptachlor, heptafluthrin, heptenophos, heptopargil, her methylmercaptophos thiol, methylmercury benzoate, meth bimycin, herbimycin A, heterophos, hexachlor, hexachloran, ylmercury dicyandiamide, methylmercury pentachlorophe hexachloroacetone, hexachlorobenzene, hexachlorobutadi noxide, methylneodecanamide, methylnitrophos, methyltri ene, hexachlorophene, hexaconazole, hexaflumuron, azothion, metiozolin, metiram, metiram-zinc, hexafluoramin, hexaflurate, hexalure, hexamide, hexazi metobenzuron, metobromuron, metofluthrin, metolachlor, none, hexylthiofos, hexythiazox, HHDN, holosulf, homo metolcarb, metometuron, metominostrobin, metosulam, brassinolide, huancaiwo, huanchongjing, huangcaoling, metoxadiazone, metoxuron, metrafenone, metriam, huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, metribuzin, metrifonate, metriphonate, metsulfovax, metsul hydrogen cyanamide, hydrogen cyanide, hydroprene, furon, mevinphos, mexacarbate, miechuwei, mieshuan, mie hydroxyisoxazole, hymexazol, hyduincarb, IAA, IBA, IBP. wenjuzhi, milbemectin, milbemycin oxime, milneb, icaridin, imazalil, imazamethabenz, imazamox, imazapic, mimaznan, mipafox, MIPC, mirex, MNAF, moguchun, imazapyr, imazaquin, imazethapyr, imazosulfuron, imiben molinate, molosultap, momfluorothrin, monalide, moni conazole, imicyafos, imidacloprid, imidaclothiz, iminocta suron, monoamitraz, monochloroacetic acid, monocroto dine, imiprothrin, inabenfide, indanofan, indaziflam, indox phos, monolinuron, monomehypo, monosulfiram, monosul acarb, inezin, infusorial earth, iodobonil, iodocarb, furon, monosultap, monuron, monuron-TCA, morfamquat, iodofemphos, iodomethane, iodosulfuron, iofensulfuron, moroxydine, morphothion, morzid, moxidectin, MPMC, ioxynil, ipazine, IPC, ipconazole, ipfencarbazone, iproben MSMA, MTMC, muscalure, myclobutanil, myclozolin, fos, iprodione, iprovalicarb, iprymidam, ipsdienol, ipsenol, myricyl alcohol, N-(ethylmercury)-p-toluenesulphonanilide, IPSP, IPX, isamidofos, isazofos, isobenzan, isocarbamid, NAA, NAAm, nabam, naftalofos, naled, naphthalene, naph isocarbamide, isocarbophos, isocil, isodrin, isofenphos, thaleneacetamide, naphthalic anhydride, naphthalophos, isofenphos-methyl, isofetamid, isolan, isomethiozin, isono naphthoxyacetic acids, naphthylacetic acids, naphthylin ruron, isopamphos, isopolinate, isoprocarb, isoprocil, iso dane-1,3-diones, naphthyloxyacetic acids, naproanilide, propalin, isopropazol, isoprothiolane, isoproturon, isopyra napropamide, napropamide-M, naptalam, natamycin, zam, isopyrimol, isothioate, isotianil, isouron, isovaledione, NBPOS, neburea, neburon, nendrin, neonicotine, nichlorfos, isoxaben, isoxachlortole, isoxadifen, isoxaflutole, isoxapy niclofen, niclosamide, nicobifen, nicosulfuron, nicotine, rifop, isoxathion, isuron, ivermectin, ixoxaben, izopamfos, nicotine sulfate, nifluridide, nikkomycins, NIP. nipyra izopamphos, japonilure, japothrins, jasmolin I, jasmolin II, clofen, nipyralofen, nitenpyram, nithiazine, nitralin, nitrapy jasmonic acid, jiahuangchongzong, jiajizengxiaolin, jiaxi rin, nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene, angjunzhi, jiecaowan, jiecaoxi, jingammycin A, jodfemphos, nitrothal-isopropyl, nobormide, nonanol, norbormide, norea, juvenile hormone I, juvenile hormone II, juvenile hormone norflurazon, mornicotine, noruron, novaluron, noviflumuron, III, kadethrin, kappa-bifenthrin, kappa-tefluthrin, karbuti NPA, nuarimol, nuranone, OCH, octachlorodipropyl ether, late, karetazan, kasugamycin, kejunlin, kelevan, ketospira octhilinone, o-dichlorobenzene, oftirace, omethoate, o-phe dox, kieselguhr, kinetin, kinoprene, kiralaxyl, kresoxim nylphenol, orbencarb, orfralure, orthobencarb, ortho-dichlo methyl, kuicaoxi, lactofen, lambda-cyhalothrin, latilure, robenzene, orthosulfamuron, oryctalure, orysastrobin, lead arsenate, lenacil, lepimectin, leptophos, lianbenjingzhi, oryzalin, osthol, osthole, ostramone, ovatron, ovex, oxabe lime sulfur, lindane, lineatin, linuron, lirimfos, litlure, trinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl, US 2016/0302417 A1 Oct. 20, 2016 oxapyrazon, oxapyrazone, oxasulfuron, oxathiapiprolin, propyl, pyribencarb, pyribenzoxim, pyributicarb, pyriclor, oxaziclomefone, oxine-copper, oxine-Cu, oxolinic acid, pyridaben, pyridafol, pyridalyl, pyridaphenthion, pyrida oxpoconazole, oxycarboxin, oxydemeton-methyl, phenthione, pyridate, pyridinitril, pyrifenox, pyrifluqui oxydeprofos, oxydisulfoton, oxyenadenine, oxyfluorfen, mazon, pyriftalid, pyrimétaphos, pyrimethanil, pyrimicarbe, oxymatrine, oxytetracycline, oxythioquinox, PAC, pyrimidifen, pyriminobac, pyriminostrobin, pyrimiphos paclobutrazol, paichongding, palléthrine, PAP para-dichlo éthyl, pyrimiphos-methyl, pyrimisulfan, pyrimitate, pyrin robenzene, parafluron, paraquat, parathion, parathion uron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen, methyl, parinol, Paris green, PCNB, PCP, PCP-Na, p-di pyrisoxazole, pyrithiobac, pyrolan, pyroquilon, pyroxasul chlorobenzene, PDJ, pebulate, pédinex, pefurazoate, fone, pyroxsulam, pyroxychlor, pyroxyfur, qincaosuan, pelargonic acid, penconazole, pencycuron, pendimethalin, qingkuling, quassia, quinacetol, quinalphos, quinalphos penfenate, penflufen, penfluron, penoxalin, penoxsulam, methyl, quinazamid, quinclorac, quinconazole, quinmerac, pentachlorophenol, pentachlorophenyl laurate, pentano quinoclamine, quinomethionate, quinonamid, quinothion, chlor, penthiopyrad, pentmethrin, pentoxazone, perchlorde quinoxyfen, quintio?os, quintozene, quizalofop, quizalofop cone, perfluidone, permethrin, pethoxamid, PHC, phe P. quwenzhi, quyingding, rabenzazole, rafoxanide, R-dini namacril, phenamacril-ethyl, phénaminosulf, phenazine conazole, rebemide, reglone, renriduron, rescalure, res oxide, phénétacarbe, phenisopham, phenkapton, phenmed methrin, rhodethanil, rhodojaponin-III, ribavirin, ipham, phenmedipham-ethyl, phenobenzuron, phenothiol, rimsulfuron, rizazole, R-metalaxyl, rodéthanil, ronnel, rote phenothrin, phenproxide, phenthoate, phenylmercuriurea, none, ryania, sabadilla, saflufenacil, saijunmao, saisentong, phenylmercury acetate, phenylmercury chloride, phenyl salicylanilide, salifluofen, sanguinarine, santonin, S-bioal mercury derivative of pyrocatechol, phenylmercury nitrate, lethrin, schradan, scilliroside, sebuthylazine, sechumeton, phenylmercury salicylate, phorate, phosacetim, phosalone, sedaxane, selamectin, semiamitraz, sesamex, sesamolin, phosametime, phosazetim, phosazetin, phoscyclotin, phosdi sesone, sethoxydim, sevin, shuangjiaancaolin, shuangji phen, phosethyl, phosfolan, phosfolan-methyl, phosglycin, anancaolin, S-hydroprene, siduron, sifumijvzhi, siglure, phosmet, phosnichlor, phosphamide, phosphamidon, phos silafluofen, silatrane, silica aerogel, silica gel, silthiofam, phine, phosphinothricin, phosphocarb, phosphorus, phostin, silthiopham, silthiophan, silvex, simazine, simeconazole, phoxim, phoxim-methyl, phthalide, phthalophos, simeton, simetryn, simetryne, sintofen, S-kinoprene, slaked phthalthrin, picarbutrazox, picaridin, picloram, picolinafen, picoxystrobin, pimaricin, pindone, pinoxaden, piperalin, lime, SMA, S-methoprene, S-metolachlor, sodium arsenite, piperazine, piperonyl butoxide, piperonyl cyclonene, pip sodium azide, sodium chlorate, sodium cyanide, sodium erophos, piproctanly, piproctanyl, piprotal, pirimetaphos, fluoride, sodium fluoroacetate, sodium hexafluorosilicate, pirimicarb, piriminil, pirimioxyphos, pirimiphos-ethyl, sodium naphthenate, sodium o-phenylphenoxide, sodium pirimiphos-methyl, pival, pivaldione, plifenate, PMA, PMP. orthophenylphenoxide, sodium pentachlorophenate, sodium polybutenes, polycarbamate, polychlorcamphene, poly pentachlorophenoxide, sodium polysulfide, sodium silico ethoxyquinoline, polyoxin D, polyoxins, polyoxorim, poly fluoride, sodium tetrathiocarbonate, sodium thiocyanate, thialan, potassium arsenite, potassium azide, potassium solan, sophamide, spinetoram, spinosad, spirodiclofen, cyanate, potassium ethylxanthate, potassium naphthenate, spiromesi?en, spirotetramat, spiroxamine, stirofos, strepto potassium polysulfide, potassium thiocyanate, pp'-DDT. mycin, strychnine, sulcatol, sulcofuron, sulcotrione, sulfal prallethrin, precocene I, precocene II, precocene III, preti late, sulfentrazone, sulfiram, sulfluramid, sulfodiazole, sul lachlor, primidophos, primisulfuron, probenazole, prochlo formeturon, sulfosate, sulfosulfuron, sulfotep, sulfotepp, raz, proclonol, procyazine, procymidone, prodiamine, pro sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sul fenofos, profluazol, profluralin, profluthrin, profoxydim, furyl fluoride, Sulglycapin, sulphosate, sulprofos, sultropen, profurite-aminium, proglinazine, prohexadione, prohydro swep, tau-fluvalinate, tavron, tazimcarb, TBTO, TBZ, TCA, jasmon, promacyl, promecarb, prometon, prometryn, prom TCBA, TCMTB, TCNB, TDE, tebuconazole, tebufenozide, etryne, promurit, pronamide, propachlor, propafos, propami tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthi dine, propamocarb, propanil, propaphos, propaquizafop, uron, tecloftalam, tecnazene, tecoram, tedion, teflubenzuron, propargite, proparthrin, propazine, propetamphos, propham, tefluthrin, tefuryltrione, tembotrione, temefos, temephos, propiconazole, propidine, propineb, propisochlor, propoxur, tepa, TEPP, tepraloxydim, teproloxydim, terallethrin, terba propoxycarbazone, propyl isome, propyrisulfuron, propyz cil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthyla zine, terbutol, terbutryn, terbutryne, terraclor, terramicin, amide, produinazid, prosuler, prosulfalin, prosulfocarb, pro terramycin, tetcyclacis, tetrachloroethane, tetrachlorvin sulfuron, prothidathion, prothiocarb, prothioconazole, pro phos, tetraconazole, tetradifon, tetradisul, tetrafluron, thiofos, prothoate, protrifenbute, proxan, prymidophos, tetramethrin, tetra methylfluthrin, tetramine, tetranactin, tet prynachlor, psoralen, psoralene, pydanon, pyflubumide, raniliprole, tetrapion, tetrasul, thallium sulfate, thallous sul pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyra fate, thenylchlor, theta-cypermethrin, thiabendazole, thia clostrobin, pyraflufen, pyrafluprole, pyramat, pyrameto cloprid, thiadiazine, thiadifluor, thiamethoxam, thiameturon, thiapronil, thiazafluron, thiazfluron, thiazone, thiazopyr, thi strobin, pyraoxystrobin, pyrasulfotole, pyraziflumid, pyra crofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone, zolate, pyrazolynate, pyrazon, pyrazophos, pyrazosulfuron, thifensulfuron, thi?luzamide, thimerosal, thimet, thioben pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I, pyre carb, thiocarboxime, thiochlorfemphim, thiochlorphen thrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz phime, thiocyanatodinitrobenzenes, thiocyclam, thiodan, US 2016/0302417 A1 Oct. 20, 2016 thiodiazole-copper, thiodicarb, thiofanocarb, thiofanox, [0026] (b) (3S,6S,7R,8R)-8-benzyl-3-(3-((isobutyryloxy) thiofluoximate, thiohempa, thiomersal, thiometon, thion methoxy)-4-methoxypicolinamido)-6-methyl-4,9-dioxo azin, thiophanate, thiophanate-ethyl, thiophanate-methyl, 1,5-dioxonan–7-yl isobutyrate (hereafter “AI-2”) thiophos, thioquinox, thiosemicarbazide, thiosultap, thio tepa, thioxamyl, thiram, thiuram, thuringiensin, tiabenda zole, tiadinil, tiafenacil, tiaojiean, TIBA, ti?atol, tiocarbazil, tioclorim, tioxazafen, tioxymid, tirpate, TMTD, tolclofos methyl, tolfenpyrad, tolprocarb, tolpyralate, tolyfluanid, tolylfluanid, tolylmercury acetate, tomarin, topramezone, toxaphene, TPN, tralkoxydim, tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin, tretamine, triacon tanol, triadimefon, triadimenol, triafamone, triallate, tri H3C–O O O O O CH3 allate, triamiphos, triapenthenol, triarathene, triarimol, tria / \ CH3, sulfuron, triazamate, triazbutil, triaziflam, triazophos, O ... wO triazothion, triazoxide, tribasic copper chloride, tribasic cop FN HNIII, , . per sulfate, tribenuron, tribufos, tributyltin oxide, tricamba, O trichlamide, trichlopyr, trichlorfon, trichlormetaphos-3, trichloronat, trichloronate, trichlorotrinitrobenzenes, trichlo O rphon, triclopyr, triclopyricarb, tricresol, tricyclazole, tricy clohexyltin hydroxide, tridemorph, tridiphane, trietazine, trifenmorph, trifenofos, trifloxystrobin, trifloxysulfuron, tri fludimoxazin, triflumezopyrim, triflumizole, triflumuron, trifluralin, triflusulfuron, trifop, trifopsime, triforine, trihy [0027] (3) a molecule known as Lotilaner that has the droxytriazine, trimedlure, trimethacarb, trimeturon, trinex following structure apac, triphenyltin, triprene, tripropindan, triptolide, tritac, trithialan, triticonazole, tritosulfuron, trunc-call, tuoyelin, uniconazole, uniconazole-P. urbacide, uredepa, Valerate, validamycin, validamycin A, valifenalate, valone, vamido thion, vangard, vaniliprole, vernolate, vinclozolin, vitamin D3, warfarin, xiaochongliulin, xinjunan, xiwojunan, xiwo junzhi, XMC, xylachlor, xylenols, xylylcarb, xymiazole, yishijing, Zarilamid, Zeatin, Zengxiaoan, Zengxiaolin, Zeta cypermethrin, zinc naphthenate, zinc phosphide, zinc thiaz ole, zinc thiozole, zinc trichlorophenate, zinc trichlorophe noxide, zineb, ziram, zolaprofos, zoocoumarin, Zoxamide, Zuoanjunzhi, Zuocaoan, Zuojunzhi, Zuomihuanglong, Cº-chlorohydrin, Cº-ecdysone, Cº-multistriatin, Cº-naphthale and neacetic acids, and fl-ecdysone; [0028] (4) the following molecules in Table A [0024] (2) the following molecules [0025] (a) N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl) TABLE A N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide (hereafter “AI-1”) Structure of Mii - active ingredients

M?? Structure

M1 RI RŠ *>Šen rº2 || N N R = CH, N R1 = H, Me US 2016/0302417 A1 Oct. 20, 2016

TABLE A-continued methoxyfenozide, noviflumuron, spinetoram, spinosad, and sulfoxaflor (hereafter “AIGA-2”). Structure of M?? - active ingredients [0031] Additionally, another particularly preferred selec tion of active ingredients are acequinocyl, acetamiprid, M?? Structure acetoprole, avermectin, azinphos-methyl, bifenazate, bifen M2 X thrin, carbaryl, carbofuran, chlorfenapyr, chlorfluazuron, 2^ chromafenozide, clothianidin, cyfluthrin, cypermethrin, del N S. tamethrin, diafenthiuron, emamectin benzoate, endosulfan, F esfenvalerate, ethiprole, etoxazole, fipronil, flonicamid, flu acrypyrim, gamma-cyhalothrin, halofenozide, indoxacarb, lambda-cyhalothrin, lufenuron, malathion, methomyl, R novaluron, permethrin, pyridalyl, pyrimidifen, spirodi O clofen, tebufenozide, thiacloprid, thiamethoxam, thiodicarb, X = F, Cl tolfenpyrad, and zeta-cypermethrin (hereafter “AIGA-3”). R = H, F [0032] The term “alkenyl” means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or M3 Br unbranched, substituent consisting of carbon and hydrogen, N. 20 for example, vinyl, allyl, butenyl, pentenyl, and hexenyl. H.C.’ N H | N [0033] The term “alkenyloxy” means an alkenyl further N / consisting of a carbon-oxygen single bond, for example, N allyloxy, butenyloxy, pentenyloxy, hexenyloxy. C| [0034] The term “alkoxy” means an alkyl further consist O ing of a carbon-oxygen single bond, for example, methoxy, Cl Cl s? \ ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tertbu S toxy. [0035] The term “alkyl” means an acyclic, saturated, Cl branched or unbranched, substituent consisting of carbon

and hydrogen, for example, methyl, ethyl, propyl, isopropyl, M4 butyl, and tertbutyl. [0036] The term “alkynyl” means an acyclic, unsaturated (at least one carbon-carbon triple bond), branched or unbranched, substituent consisting of carbon and hydrogen, for example, ethynyl, propargyl, butynyl, and pentynyl. [0037] The term “alkynyloxy” means an alkynyl further consisting of a carbon-oxygen single bond, for example, pentynyloxy, hexynyloxy, heptynyloxy, and octynyloxy. [0038] The term “aryl” means a cyclic, aromatic substitu ent consisting of hydrogen and carbon, for example, phenyl, naphthyl, and biphenyl. M5 [0039] The term “biopesticide” means a microbial biologi cal pest control agent that, in general, is applied in a similar manner to chemical pesticides. Commonly they are bacte rial, but there are also examples of fungal control agents, including Trichoderma spp. and Ampelomyces quisqualis. One well-known biopesticide example is Bacillus species, a bacterial disease of Lepidoptera, Coleoptera, and Diptera. Biopesticides include products based on entomopathogenic fungi (e.g. Metarhizium anisopliae), entomopathogenic M6 nematodes (e.g. Steinernema feltiae), and entomopathogenic viruses (e.g. Cydia pomonella granulovirus). Other examples of entomopathogenic organisms include, but are not limited to, baculoviruses, protozoa, and Microsporidia. For the avoidance of doubt, biopesticides are active ingre dients. [0040] The term “cycloalkenyl” means a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent consisting of carbon and hydrogen, for [0029] As used in this disclosure, each of the above is an example, cyclobutenyl, cyclopentenyl, cyclohexenyl, nor active ingredient. For more information consult the “Com bornenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl, hexa pendium of Pesticide Common Names” located at Alan hydronaphthyl, and octahydronaphthyl. wood.net and various editions, including the on-line edition, [0041] The term “cycloalkenyloxy” means a cycloalkenyl of “The Pesticide Manual” located at bepcdata.com. further consisting of a carbon-oxygen single bond, for [0030] A particularly preferred selection of active ingre example, cyclobutenyloxy, cyclopentenyloxy, norbornemy dients are 1,3 dichloropropene, chlorpyrifos, hexaflumuron, loxy, and bicyclo[2.2.2]octenyloxy. US 2016/0302417 A1 Oct. 20, 2016

[0042] The term “cycloalkyl” means a monocyclic or [0053] The phrase “MoA Material” means an active ingre polycyclic, saturated substituent consisting of carbon and dient having a mode of action (“MoA”) as indicated in IRAC hydrogen, for example, cyclopropyl, cyclobutyl, cyclopen MoA Classification v. 7.3, located at irac-online.org., which tyl, norbornyl, bicyclo[2.2.2]octyl, and decahydronaphthyl. describes the following groups. [0043] The term “cycloalkoxy” means a cycloalkyl further [0054] (1) Acetylcholinesterase (AChE) inhibitors, consisting of a carbon-oxygen single bond, for example, includes the following active ingredients alanycarb, aldi cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, norborny carb, bendiocarb, benfuracarb, butocarboxim, butoxycar loxy, and bicyclo[2.2.2]octyloxy. boxim, carbaryl, carbofuran, carbosulfan, ethiofencarb, [0044] The term “halo” means fluoro, chloro, bromo, and fenobucarb, formetanate, furathiocarb, isoprocarb, methio iodo. carb, methomyl, metolcarb, oxamyl, pirimicarb, propoxur, [0045] The term “haloalkoxy” means an alkoxy further thiodicarb, thiofanox, triazamate, trimethacarb, XMC, consisting of from one to the maximum possible number of xylylcarb, acephate, azamethiphos, azinphos-ethyl, azim identical or different, halos, for example, fluoromethoxy, phos-methyl, cadusafos, chlorethoxyfos, chlorfenvinphos, trifluoromethoxy, 2,2-difluoropropoxy, chloromethoxy, chlormephos, chlorpyrifos, chlorpyrifos-methyl, couma trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and pentafluo phos, cyanophos, demeton-S-methyl, diazinon, dichlorvos/ roethoxy. DDVP, dicrotophos, dimethoate, dimethylvinphos, disulfo [0046] The term “haloalkyl” means an alkyl further con ton, EPN, ethion, ethoprophos, famphur, fenamiphos, sisting of from one to the maximum possible number of fenitrothion, fenthion, fosthiazate, heptenophos, imicyafos, identical or different, halos, for example, fluoromethyl, isofenphos, isopropyl O-(methoxyaminothio-phosphoryl) trifluoromethyl, 2,2-difluoropropyl, chloromethyl, trichlo salicylate, isoxathion, malathion, mecarbam, methami romethyl, and 1,1,2,2-tetrafluoroethyl. dophos, methidathion, mevinphos, monocrotophos, naled, [0047] The term “heterocyclyl" means a cyclic substituent omethoate, oxydemeton-methyl, parathion, parathion that may be aromatic, fully saturated, or partially or fully methyl, phenthoate, phorate, phosalone, phosmet, phos unsaturated, where the cyclic structure contains at least one phamidon, phoxim, pirimiphos-methyl, profenofos, pro carbon and at least one heteroatom, where said heteroatom petamphos, prothiofos, pyraclofos, pyridaphenthion, is nitrogen, sulfur, or oxygen. Examples are: quinalphos, sulfotep, tebupirimfos, temephos, terbufos, tet [0048] (1) aromatic heterocyclyl substituents include, but rachlorvinphos, thiometon, triazophos, trichlorfon, vamido are not limited to, benzofuranyl, benzoisothiazolyl, benzo thion. isoxazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, cin [0055] (2) GABA-gated chloride channel antagonists, nolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl, includes the following active ingredients chlordane, endo isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazoli sulfan, ethiprole, and fipronil. nyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyra [0056] (3) Sodium channel modulators, includes the fol zolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazoli lowing active ingredients acrinathrin, allethrin, d-cis-trans nyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, allethrin, d-trans allethrin, bifenthrin, bioallethrin, bioal thiazolyl, thienyl, triazinyl, and triazolyl; lethrin S-cyclopentenyl, bioresmethrin, cycloprothrin, cyflu [0049) (2) fully saturated heterocyclyl substituents thrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, include, but are not limited to, piperazinyl, piperidinyl, gamma-cyhalothrin, cypermethrin, alpha-cypermethrin, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropy beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, ranyl, tetrahydrothiophenyl, tetrahydrothiophenyl-oxide, cyphenothrin [(1R)-trans-isomers], deltamethrin, empen tetrahydrothiophenyl-dioxide; thrin [(EZ)-(1R)-isomers], esfenvalerate, etofemprox, fen [0050] (3) partially or fully unsaturated heterocyclyl sub propathrin, fenvalerate, flucythrinate, flumethrin, tau-flu stituents include, but are not limited to, 4,5-dihydro-isox valinate, halfemprox, imiprothrin, kadethrin, permethrin, azolyl, 4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl, phenothrin [(1R)-trans-isomer], prallethrin, pyrethrins (py 2,3-dihydro-[1,3,4]-oxadiazolyl, 2,5-dioxoimidazolidinyl, rethrum), resmethrin, silafluofen, tefluthrin, tetramethrin, 2,4-dioxo-1,3-diazaspiro[4.4|nonanylisoxazolidinonyl, tetramethrin [(1R)-isomers], tralomethrin, and transfluthrin, oxazolidinonyl, imidazolidinonyl, isoxazolidinonyl, pyrro and methoxychlor. lidinonyl, 1,2,3,4-tetrahydro-quinolinyl, and thioxothiazoli [0057] (4) Nicotinic acetylcholine receptor (nAChR) ago dinonyl; and nists, includes the following active ingredients [0051] (4) Additional examples of heterocyclyls include [0058] (4A) acetamiprid, clothianidin, dinotefuran, imi the following: dacloprid, nitenpyram, thiacloprid, thiamethoxam, [0059] (4B) nicotine, [0060] (4C) sulfoxaflor, [0061] (4D) flupyradifurone, [0062] (4E) triflumezopyrim and dicloromezotiaz. [0063) (5) Nicotinic acetylcholine receptor (nAChR) allosteric activators, includes the following active ingredi ents spinetoram and spinosad. [0064] (6) Chloride channel activators, includes the fol thietanyl thietanyl-oxide and thietanyl-dioxade. lowing active ingredients abamectin, emamectin benzoate, lepimectin, and milbemectin. [0065] (7) Juvenile hormone mimics, includes the follow [0052] The term “locus” means a habitat, breeding ground, ing active ingredients hydroprene, kinoprene, methoprene, plant, seed, soil, material, or environment, in which a pest is fenoxycarb, and pyriproxyfen. growing, may grow, or may traverse. For example, a locus [0066] (8) Miscellaneous nonspecific (multi-site) inhibi may be: where crops, trees, fruits, cereals, fodder species, tors, includes the following active ingredients methyl bro vines, turf, and/or ornamental plants, are growing; where mide, chloropicrin, sulfuryl fluoride, borax, and tartar domesticated animals are residing; the interior or exterior emetic. surfaces of buildings (such as places where grains are [0067] (9) Modulators of Chordotonal Organs, includes stored); the materials of construction used in buildings (such the following active ingredients pymetrozine and flonic as impregnated wood); and the soil around buildings. amid. US 2016/0302417 A1 Oct. 20, 2016

[0068] (10) Mite growth inhibitors, includes the following [0086] The term “pest” means an organism that is detri active ingredients clofentezine, hexythiazox, diflovidazin, mental to humans, or human concerns (such as, crops, food, and etoxazole. livestock, etc.), where said organism is from Phyla Arthro [0069] (11) Microbial disruptors of insect midgut mem poda, Mollusca, or Nematoda. Particular examples are ants, branes, includes the following active ingredients Bacillus thuringiensis subsp. Israelensis, Bacillus thuringiensis aphids, bed bugs, beetles, bristletails, caterpillars, cock subsp. aizawai, Bacillus thuringiensis subsp. Kurstaki, roaches, crickets, earwigs, fleas, flies, grasshoppers, grubs, Bacillus thuringiensis subsp. tenebrionenis, Bt crop proteins hornets, killer bees, leafhoppers, lice, locusts, maggots, (Cry1Ab, Cry1Ac, Cry1|a, Cry1A.105, Cry2Ab, Vip3A, mites, moths, nematodes, planthoppers, psyllids, sawflies, mCry3A, Cry3 Ab, Cry3Bb, Cry34Ab1/Cry35Ab1), and scales, silverfish, slugs, snails, spiders, springtails, stink Bacillus sphaericus. bugs, symphylans, termites, thrips, ticks, wasps, whiteflies, [0070) (12) Inhibitors of mitochondrial ATP synthase, and wireworms. includes the following active ingredients tetradifon, [0087] Additional examples are pests in propargite, azocyclotin, cyhexatin, fenbutatin oxide, and [0088] (1) Subphyla Chelicerata, Myriapoda, and diafenthiuron. Hexapoda. [0071] (13) Uncouplers of oxidative phosphorylation via disruption of the proton gradient, includes the following [0089) (2) Classes of Arachnida, Symphyla, and Insecta. active ingredients chlor?enapyr, DNOC, and sulfluramid. [0090] (3) Order Anoplura. A non-exhaustive list of par [0072] (14) Nicotinic acetylcholine receptor (nAChR) ticular genera includes, but is not limited to, Haematopinus channel blockers, includes the following active ingredients spp., Hoplopleura spp., Linognathus spp., Pediculus spp., bensultap, cartap hydrochloride, thiocyclam, and thiosultap Polyplax spp., Solenopotes spp., and Neohaematopinis spp. sodium. A non-exhaustive list of particular species includes, but is [0073] (15) Inhibitors of chitin biosynthesis, type 0, not limited to, Haematopinus asini, Haematopinus suis, includes the following active ingredients bistrifluron, chlo Linognathus setosus, Linognathus ovillus, Pediculus rfluazuron, diflubenzuron, flucycloxuron, flufenoxuron, humanus capitis, Pediculus humanus humanus, and Pthirus hexaflumuron, lufenuron, novaluron, noviflumuron, pubis. teflubenzuron, and triflumuron. [0091] (4) Order Coleoptera. A non-exhaustive list of [0074] (16) Inhibitors of chitin biosynthesis, type 1, particular genera includes, but is not limited to, Acanthos includes the following active ingredient buprofezin. celides spp., Agriotes spp., Anthonomus spp., Apion spp., [0075] (17) Moulting disruptor, Dipteran, includes the Apogonia spp., Araecerus spp., Aulacophora spp., Bruchus following active ingredient cyromazine. spp., Cerosterna spp., Cerotoma spp., Ceutorhynchus spp., [0076] (18) Ecdysone receptor agonists, includes the fol Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio lowing active ingredients chromafenozide, halofenozide, spp., Cyclocephala spp., Diabrotica spp., Dinoderus spp., methoxyfenozide, and tebufenozide. Gnathocerus spp., Hemicoelus spp., Heterobostruchus spp., [0077] (19) Octopamine receptor agonists, includes the Hypera spp., Ips spp., Lyctus spp., Megascelis spp., following active ingredient amitraz. Meligethes spp., Mezium spp., Niptus spp., Otiorhynchus [0078] (20) Mitochondrial complex III electron transport spp., Pantomorus spp., Phyllophaga spp., Phyllotreta spp., inhibitors, includes the following active ingredients hydram Ptinus spp., Rhizotrogus spp., Rhynchites spp., Rhynchopho ethylnon, acequinocyl, and fluacrypyrim. rus spp., Scolytus spp., Sphenophorus spp., Sitophilus spp., [0079) (21) Mitochondrial complex I electron transport Tenebrio spp., and Tribolium spp. A non-exhaustive list of inhibitors, includes the following active ingredients fenaza particular species includes, but is not limited to, Acanthos quin, fenpyroximate, pyrimidifen, pyridaben, tebufenpyrad, celides obtectus, Agrilus planipennis, Ahasverus advena, tolfenpyrad, and rotenone. Alphitobius diaperinus, Anoplophora glabripennis, Antho [0080) (22) Voltage-dependent sodium channel blockers, nomus grandis, Anthrenus verbasci, Anthrenus falvipes, includes the following active ingredients indoxacarb and Ataenius spretulus, Atomaria linearis, Attagenus unicolor, metaflumizone. Bothynoderes punctiventris, Bruchus pisorum, Callosobru [0081) (23) Inhibitors of acetyl CoA carboxylase, includes chus maculatus, Carpophilus hemipterus, Cassida vittata, the following active ingredients spirodiclofen, spiromesi?en, Cathartus quadricollis, Cerotoma trifurcata, Ceutorhynchus and spirotetramat. assimilis, Ceutorhynchus mapi, Conoderus scalaris, [0082) (24) Mitochondrial complex IV electron transport Conoderus stigmosus, Conotrachelus menuphar, Cotinis inhibitors, includes the following active ingredients, alu nitida, Crioceris asparagi, Cryptolestes ferrugineus, Cryp minium phosphide, calcium phosphide, phosphine, zinc tolestes pusillus, Cryptolestes turcicus, Cylindrocopturus phosphide, and cyanide. adspersus, Deporaus marginatus, Dermestes lardarius, Der [0083) (25) Mitochondrial complex II electron transport mestes maculatus, Epilachna varivestis, Euvrilletta peltata, inhibitors, includes the following active ingredients cyen Faustinus cubae, Hylobius pales, Hylotrupes bajulus, opyrafen and cyflumetofen. and Hypera postica, Hypothenemus hampei, Lasioderma serri [0084] (28) Ryanodine receptor modulators, includes the come, Leptinotarsa decemlineata, Limonius canus, Liogenys following active ingredients chlorantraniliprole, cyantra fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus, niliprole, and flubendiamide. Lophocateres pusillus, Lyctus planicollis, Maecolaspis jol [0085] Groups 26 and 27 are unassigned in this version of iveti, Melanotus communis, Meligethes aeneus, Melolontha the classification scheme. Additionally, there is a Group UN melolontha, Necrobia rufipes, Oberea brevis, Oberea lin that contains active ingredients of unknown or uncertain earis, Oryctes rhinoceros, Oryzaephilus mercator, Oryzae mode of action. This group includes the following active philus surinamensis, Oulema melanopus, Oulema oryzae, ingredients, azadirachtin, benzoximate, bifenazate, bro Phyllophaga cuyabana, Polycaon stoutti, Popillia japonica, mopropylate, chinomethionat, cryolite, dicofol, pyridalyl, Prostephanus truncatus, Rhyzopertha dominica, Sitona lin and pyrifluquinazon. eatus, Sitophilus granarius, Sitophilus oryzae, Sitophilus US 2016/0302417 A1 Oct. 20, 2016 zeamais, Stegobium paniceum, Tenebroides mauritanicus, hirsutus, Macrosiphum euphorbiae, Macrosiphum grana Tribolium castaneum, Tribolium confusum, Trogoderma rium, Macrosiphum rosae, Macrosteles quadrilineatus, granarium, Trogoderma variabile, Xestobium rufovillosum, Mahanarva frimbiolata, Megacopta cribraria, Metopolo and Zabrus tenebrioides. phium dirhodum, Mictis longicomis, Myzus persicae, [0092] (5) Order Dermaptera. A non-exhaustive list of Nephotettix cincticeps, Neurocolpus longirostris, Nezara particular species includes, but is not limited to, Forficula viridula, Nilaparvata lugens, Parlatoria pergandii, Parla auricularia. toria ziziphi, Peregrinus maidis, Phylloxera vitifoliae, [0093] (6) Order Blattaria. A non-exhaustive list of par Physokermes piceae, Phytocoris califormicus, Phytocoris ticular species includes, but is not limited to, Blattella relativus, Piezodorus guildinii, Poecilocapsus lineatus, germanica, Blattella asahinai, Blatta orientalis, Blatta lat Psallus vaccinicola, Pseudacysta perseae, Pseudococcus eralis, Parcoblatta pennsylvanica, Periplaneta americana, brevipes, Quadraspidiotus pemiciosus, Rhopalosiphum Periplaneta australasiae, Periplaneta brunnea, Periplaneta maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoris fuliginosa, Pycnoscelus surinamensis, and Supella longi castanea, Schizaphis graminum, Sitobion avenae, Sogatella palpa. furcifera, Trialeurodes vaporariorum, Trialeurodes [0094) (7) Order Diptera. A non-exhaustive list of particu abutiloneus, Unaspis yanonensis, and Zulia entrerriana. lar genera includes, but is not limited to, Aedes spp., [0096] (9) Order Hymenoptera. A non-exhaustive list of Agromyza spp., Anastrepha spp., Anopheles spp., Bactro particular genera includes, but is not limited to, Acromyrmex cera spp., Ceratitis spp., Chrysops spp., Cochliomyia spp., spp., Atta spp., Camponotus spp., Diprion spp., Dolichove Contarinia spp., Culex spp., Culicoides spp., Dasineura spula spp., Formica spp., Monomorium spp., Neodiprion spp., Delia spp., Drosophila spp., Fannia spp., Hylemya spp., Paratrechina spp., Pheidole spp., Pogonomyrmex spp., spp., Liriomyza spp., Musca spp., Phorbia spp., Pollenia Polistes spp., Solenopsis spp., Technomyrmex, spp., spp., Psychoda spp., Simulium spp., Tabanus spp., and Tetramorium spp., Vespula spp., Vespa spp., and Xylocopa Tipula spp. A non-exhaustive list of particular species spp. A non-exhaustive list of particular species includes, but includes, but is not limited to, Agromyza frontella, Anas is not limited to, Athalia rosae, Atta texana, Caliroa cerasi, trepha suspensa, Anastrepha ludens, Anastrepha obliqua, Cimbex americana, Iridomyrmex humilis, Linepithema Bactrocera cucurbitae, Bactrocera dorsalis, Bactrocera humile, Mellifera Scutellata, Monomorium minimum, invadens, Bactrocera zonata, Ceratitis capitata, Dasineura Monomorium pharaonis, Neodiprion sertifer, Solenopsis brassicae, Delia platura, Fannia canicularis, Fannia sca invicta, Solenopsis geminata, Solenopsis molesta, Solenop laris, Gasterophilus intestinalis, Gracillia perseae, Haema sis richtery, Solenopsis xyloni, Tapinoma sessile, and Was tobia irritans, Hypoderma lineatum, Liriomyza brassicae, mannia auropunctata. Melophagus ovinus, Musca autumnalis, Musca domestica, [0097] (10) Order Isoptera. A non-exhaustive list of par Oestrus ovis, Oscinella frit, Pegomya betae, Piophila casei, ticular genera includes, but is not limited to, Coptotermes Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, spp., Comitermes spp., Cryptotermes spp., Heterotermes Rhagoletis mendax, Sitodiplosis mosellana, and Stomoxys spp., Kalotermes spp., Incisitermes spp., Macrotermes spp., calcitrans. Marginitermes spp., Microcerotermes spp., Procomitermes [0095] (8) Order Hemiptera. A non-exhaustive list of par spp., Reticulitermes spp., Schedorhinotermes spp., and Zoo ticular genera includes, but is not limited to, Adelges spp., termopsis spp. A non-exhaustive list of particular species Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., includes, but is not limited to, Coptotermes acinaciformis, Ceroplastes spp., Chionaspis spp., Chrysomphalus spp., Coptotermes curvignathus, Coptotermes frenchi, Copto Coccus spp., Empoasca spp., Euschistus spp., Lepidosaphes termes formosanus, Coptotermes gestroi, Cryptotermes bre spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., vis, Heterotermes aureus, Heterotermes tenuis, Incisitermes Nephotettix spp., Nezara spp., Nilaparvata spp., Philaenus minor, Incisitermes snyderi, Microtermes obesi, Nasuti spp., Phytocoris spp., Piezodorus spp., Planococcus spp., termes comiger, Odontotermes formosanus, Odontotermes Pseudococcus spp., Rhopalosiphum spp., Saissetia spp., obesus, Reticulitermes banyulensis, Reticulitermes grassei, Theriodphis spp., Toumeyella spp., Toxoptera spp., Trialeu Reticulitermes flavipes, Reticulitermes hageni, Reticuli rodes spp., Triatoma spp., and Unaspis spp. A non-exhaus termes hesperus, Reticulitermes santonensis, Reticulitermes tive list of particular species includes, but is not limited to, speratus, Reticulitermes tibialis, and Reticulitermes virgini Acrosternum hilare, Acyrthosiphon pisum, Aleyrodes prole Cº?.S. tella, Aleurodicus dispersus, Aleurothrixus floccosus, [0098] (11) Order Lepidoptera. A non-exhaustive list of Amrasca biguttula biguttula, Aonidiella aurantii, Aphis gos particular genera includes, but is not limited to, Adoxophyes sypii, Aphis glycines, Aphis pomi, Aulacorthum solani, Bac spp., Agrotis spp., Argyrotaenia spp., Cacoecia spp., Calop tericera cockerelli, Bagrada hilaris, Bemisia argentifolii, tilia spp., Chilo spp., Chrysodeixis spp., Collas spp., Cram Bemisia tabaci, Blissus leucopterus, Boisea trivittata, bus spp., Diaphania spp., Diatraea spp., Earias spp., Ephes Brachycorynella asparagi, Brevennia rehi, Brevicoryne tia spp., Epimecis spp., Feltia spp., Gortyna spp., brassicae, Cacopsylla pyri, Cacopsylla pyricola, Calocoris Helicoverpa spp., Heliothis spp., Indarbela spp., Lithocol norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimex letis spp., Loxagrotis spp., Malacosoma spp., Nemapogon lectularius, Dagbertus fasciatus, Dichelops furcatus, Diu spp., Peridroma spp., Phyllonorycter spp., Pseudaletia spp., raphis noxia, Diaphorina citri, Dysaphis plantaginea, Dys Plutella spp., Sesamia spp., Spodoptera spp., Synanthedon dercus suturellus, Edessa meditabunda, Eriosoma lanige spp., and Yponomeuta spp. A non-exhaustive list of particu rum, Eurygaster maura, Euschistus conspersus, Euschistus lar species includes, but is not limited to, sp. Achaea janata, heros, Euschistus servus, Halyomorpha halys, Helopeltis Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, antonii, Helopeltis theivora, Icerya purchasi, Idioscopus Amorbia cuneana, Amyelois transitella, Anacamptodes nitidulus, Laodelphax striatellus, Leptocorisa oratorius, defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia Leptocorisa varicomis, Lygus hesperus, Maconellicoccus gemmatalis, Archips argyrospila, Archips rosana, Argyro US 2016/0302417 A1 Oct. 20, 2016

taenia citrana, Autographa gamma, Bonagota Cranaodes, Frankliniella occidentalis, Frankliniella schultzei, Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Frankliniella tritici, Frankliniella williamsi, Heliothrips Carposina niponensis, Chlumetia trans versa, Choris haemorrhoidalis, Rhipiphorothrips cruentatus, Scirtothrips toneura rosaceana, Cnaphalocrocis medinalis, Conopomor citri, Scirtothrips dorsalis, Taeniothrips rhopalantennalis, pha cramerella, Corcyra cephalonica, Cossus cossus, Cydia Thrips hawaiiensis, Thrips nigropilosus, Thrips orientalis, caryana, Cydia funebrana, Cydia molesta, Cydia nigricana, Thrips palmi, and Thrips tabaci. Cydia pomonella, Darna diducta, Diaphania nitidalis, Dia [0104] (17) Order Thysanura. A non-exhaustive list of traea saccharalis, Diatraea grandiosella, Earias insulana, particular genera includes, but is not limited to, Lepisma spp. Earias vittella, Ecdytolopha aurantianum, Elasmopalpus and Thermobia spp. lignosellus, Ephestia cautella, Ephestia elutella, Ephestia [0105] (18) Order Acarina. A non-exhaustive list of par kuehniella, Epinotia aporema, Epiphyas postvittana, Eri ticular genera includes, but is not limited to, Acarus spp., onota thrax, Estigmene acrea, Eupoecilia ambiguella, Aculops spp., Argus spp., Boophilus spp., Demodex spp., Euxoa auxiliaris, Galleria mellonella, Grapholita molesta, Dermacentor spp., Epitrimerus spp., Eriophyes spp., Ixodes Hedylepta indicata, Helicoverpa armigera, Helicoverpa spp., Oligonychus spp., Panonychus spp., Rhizoglyphus zea, Heliothis virescens, Hellula undalis, Keiferia lycoper spp., and Tetranychus spp. A non-exhaustive list of particu sicella, Leucinodes orbonalis, Leucoptera coffeella, Leucop lar species includes, but is not limited to, Acarapis woodi, tera malifoliella, Lobesia botrana, Loxagrotis albicosta, Acarus siro, Aceria mangiferae, Aculops lycopersici, Aculus Lymantria dispar, Lyonetia derkella, Mahasena corbetti, pelekassi, Aculus schlechtendali, Amblyomma americanurn, Mamestra brassicae, Manduca sexta, Maruca testulalis, Brevipalpus obovatus, Brevipalpus phoenicis, Dermacentor Metisa plana, Mythimna unipuncta, Neoleucinodes elegan variabilis, Dermatophagoides pteronyssinus, Eotetranychus talis, Nymphula depunctalis, Operophtera brumata, carpini, Liponyssoides sanguineus, Notoedres cati, Oligony Ostrinia nubilalis, Oxydia vesulia, Pandemis cerasana, chus coffeae, Oligonychus ilicis, Ornithonyssus bacoti, Pandemis heparana, Papilio demodocus, Pectinophora gos Panonychus citri, Panonychus ulmi, Phyllocoptruta sypiella, Peridroma saucia, Perileucoptera coffeella, Phtho oleivora, Polyphagotarsonemus latus, Rhipicephalus san rimaea operculella, Phyllocnistis citrella, Phyllonorycter guineus, Sarcoptes scabiei, Tegolophus perseaflorae, Tet blancardella, Pieris rapae, Plathypena scabra, Platynota ranychus urticae, Tyrophagus longior, and Varroa destruc idaeusalis, Plodia interpunctella, Plutella xylostella, Poly tor. chrosis viteana, Prays endocarpa, Prays oleae, Pseudaletia [0106] (19) Order Araneae. A non-exhaustive list of par unipuncta, Pseudoplusia indudens, Rachiplusia nu, Scir ticular genera includes, but is not limited to, Loxosceles spp., pophaga incertulas, Sesamia inferens, Sesamia nonagri Latrodectus spp., and Atrax spp. A non-exhaustive list of oides, Setora nitens, Sitotroga cerealella, Sparganothis particular species includes, but is not limited to, Loxosceles pilleriana, Spodoptera exigua, Spodoptera frugiperda, recluse, Latrodectus mactans, and Atrax robustus. Spodoptera eridania, Thecla basilides, Tinea pellionella, [0107] (20) Class Symphyla. A non-exhaustive list of Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera particular species includes, but is not limited to, Scutigerella coffeae, and Zeuzea pyrina. immaculate. [0099] (12) Order Mallophaga. A non-exhaustive list of [0108) (21) Subclass Collembola. A non-exhaustive list of particular genera includes, but is not limited to, Anaticola particular species includes, but is not limited to, Bourletiella spp., Bovicola spp., Chelopistes spp., Goniodes spp., Mena hortensis, Onychiurus armatus, Onychiurus fimetarius, and canthus spp., and Trichodectes spp. A non-exhaustive list of Sminthurus viridis. particular species includes, but is not limited to, Bovicola [0109] (22) Phylum Nematoda. A non-exhaustive list of bovis, Bovicola caprae, Bovicola ovis, Chelopistes melea particular genera includes, but is not limited to, Aph gridis, Goniodes dissimilis, Goniodes gigas, Menacanthus elenchoides spp., Belonolaimus spp., Criconemella spp., stramineus, Menopon gallinae, and Trichodectes canis. Ditylenchus spp., Globodera spp., Heterodera spp., [0100] (13) Order Orthoptera. A non-exhaustive list of Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., particular genera includes, but is not limited to, Melanoplus Pratylenchus spp., and Radopholus spp. A non-exhaustive spp. and Pterophylla spp. A non-exhaustive list of particular list of particular species includes, but is not limited to, species includes, but is not limited to, Acheta domesticus, Dirofilaria immitis, Globodera pallida, Heterodera gly Anabrus simplex, Gryllotalpa africana, Gryllotalpa austra cines, Heterodera zeae, Meloidogyne incognita, Meloid lis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla, ogyne javanica, Onchocerca volvulus, Pratylenchus pen Locusta migratoria, Microcentrum retinerve, Schistocerca etrans, Radopholus similis, and Rotylenchulus reniformis. gregaria, and Scudderia furcata. [0110] (23) Phylum Mollusca. A non-exhaustive list of [0101) (14) Order Psocoptera. A non-exhaustive list of particular species includes, but is not limited to, Arion particular species includes, but is not limited to, Liposcelis vulgaris, Cornu aspersurn, Deroceras reticulatum, Limax decolor, Liposcelis entomophila, Lachesilla quercus, and flavus, Milax gagates, and Pomacea canaliculata. Trogium pulsatorium. [0111] A particularly preferred pest group to control is [0102) (15) Order Siphonaptera. A non-exhaustive list of sap-feeding pests. Sap-feeding pests, in general, have pierc particular species includes, but is not limited to, Cerato ing and/or sucking mouthparts and feed on the sap and inner phyllus gallinae, Ceratophyllus niger, Ctenocephalides plant tissues of plants. Examples of sap-feeding pests of canis, Ctenocephalides felis, and Pulex irritans. particular concern to agriculture include, but are not limited [0103] (16) Order Thysanoptera. A non-exhaustive list of to, aphids, leafhoppers, moths, scales, thrips, psyllids, particular genera includes, but is not limited to, Caliothrips mealybugs, stinkbugs, and whiteflies. Specific examples of spp., Frankliniella spp., Scirtothrips spp., and Thrips spp. A Orders that have sap-feeding pests of concern in agriculture non-exhaustive list of particular species includes, but is not include but are not limited to, Anoplura and Hemiptera. limited to, Frankliniella bispinosa, Frankliniella fusca, Specific examples of Hemiptera that are of concern in

US 2016/0302417 A1 Oct. 20, 2016

(0192] (P) R* is selected from the group consisting of -continued (Cs-Cs)cycloalkyl, azetidinyl, morpholinyl, oxetanyl, pyra nyl, tetrahydrothiophenyl, thietanyl, thietanyl-oxide, and thietanyl-dioxide, wherein each cycloalkyl, azetidinyl, mor pholinyl, oxetanyl, pyranyl, tetrahydrothiophenyl, thietanyl, thietanyl-oxide, and thietanyl-dioxide, may be optionally substituted with one or more substituents selected from the group consisting of H, F, CN, C(=O)C)(C1-C4)alkyl, C(=O)(Cs-Ca)cyclopropyl, C(=O)(C1-C4)haloalkyl, and C(=O)(C1-C4)alkyl(C1-C4)alkoxy; and [0193] (Q) Q' and Q are O. [0195] In yet other embodiments, 1-3 may be prepared Preparation of Cyclopropyl Carboxylic Acids from the aryl ketone 1.5-1, wherein R', Rº, Rº, Rº, and Rº are as previously disclosed, and Rº is methyl. The aceto [0194| Stilbenes 1-1, wherein R', Rº, Rº, Rt. R*, R*, and phenome 1.5-1 may be reacted in a first step with a stabilized R” are as previously disclosed, may be treated with a base phosphonate carbanion, generated by treating a phospho such as sodium hydroxide in the presence of a carbene nate, such as ethyl 2-(diethoxyphosphoryl)-acetate with a source such as chloroform or bromoform and a phase strong base like sodium hydride or potassium tert-butoxide transfer catalyst such as N-benzyl-N,N-diethylethan in a polar aprotic solvent, such as tetrahydrofuran at a aminium chloride in a polar protic solvent such as water at temperature from about 0°C. to about 5° C. (Scheme 1.5, temperatures from about 0°C. to about 40° C. to provide step a). This reaction, like many others involving the treat diaryl cyclopropanes 1-2, wherein R', Rº, Rº, Rt. R*, R*, ment of aldehydes or ketones with stabilized phosphonate R7, Rº, and Rº are as previously disclosed (Scheme 1, step carbanions to give olefins, will be readily recognized by one a). Treatment of diaryl cyclopropanes 1-2 with a transition skilled in the art as the Horner-Wadsworth-Emmons olefi nation. In a second step, the Cº.,5-unsaturated ester 1.5-2, metal such as ruthenium(III) chloride in the presence of a wherein R*, R*, R*, R*, R*, and Rº are as defined above, may stoichiometric oxidant such as sodium periodate in a solvent be treated with a reducing agent, for example a metal mixture preferably water, ethyl acetate, and acetonitrile at hydride like diisobutylaluminum hydride, in an aromatic temperatures from about 0°C. to about 40°C. may provide hydrocarbon solvent like toluene at a temperature from cyclopropyl carboxylic acids 1-3, wherein R', Rº, Rº, Rº, about -78° C. to about 22° C. to give the intermediate R*, R*, R7, Rº, and Rº are as previously disclosed (Scheme primary alcohol 1.5-3 (Scheme 1.5, step b), wherein R', Rº, 1, step b). R*, R*, R*, and Rº are as defined above and Rº' is as previously disclosed. Protection of the primary alcohol 1.5-3 is required for the successful completion of subsequent Scheme 1 chemical transformations, and a wide variety of protecting group strategies could be utilized. For example, treating the alcohol 1.5–3 with 3,4-dihydro-2-H-pyran in the presence of a catalytic amount of an organic acid, such as para-toluene sulfonic acid monohydrate, in an aprotic solvent like diethyl ether from a temperature of about 0° C. to about ambient temperature affords the tetrahydro-2-H-pyran (THP) pro tected alcohol 1.5-4 (Scheme 1.5, step c), wherein R', Rº, R*, R*, R*, R* and Rº are as defined above. The THP protected styryl intermediate may be converted to the THP protected cyclopropane intermediate 1.5-5, wherein R', Rº, R*, R*, R*, R* and Rº are as defined above and R7 and Rº are as previously disclosed, by treatment with carbene source such as chloroform in the presence of a base, such as sodium or potassium hydroxide, and a catalyst such as tetrabuty lammonium hexafluorophosphate at a temperature from about 25 to about 45° C. (Scheme 1.5, step d). Deprotection

of the THP-protected cyclopropane intermediate 1.5-5, wherein R', Rº, Rº, Rt. R*, Rº, R7, Rº, and Rº are as defined above, can be achieved by treatment with a catalytic amount of an organic acid, such as para-toluenesulfonic acid mono hydrate, in polar, protic solvent, such as methanol, at a temperature of about 22°C. to give the cyclopropyl metha nol intermediate 1.5-6 (Scheme 1.5, step e). Oxidation of the primary alcohol intermediate 1.5-6, wherein R', Rº, Rº, R*, R*, Rº, R7, Rº, and Rº are as defined above, can be achieved using a wide range of reagents and conditions known in the art (Figadere, B. and Franck, X., “Carboxylic Acids: Syn thesis from Alcohols” Science of Synthesis 2006, (20a) pp US 2016/0302417 A1 Oct. 20, 2016

173-204), many of which offer differential functional group -continued compatibility and selectivity. For example, treating the alco R7 R8 hol intermediate 1.5-6 with solutions of chromium trioxide in solutions of dilute sulfuric acid and acetone, Jones reagent, affords the cyclopropyl carboxylic acid 1-3, wherein R', Rº, Rº, Rt. R*, Rº, R7, Rº, and Rº are as defined above (Scheme 1.5, step f).

1.5-6

Preparation of Stilbenes [0196) Stilbenes 1-1 may be prepared by several different methods as outlined in Scheme 2. Phenyl carbonyls 2-1, wherein R*, R*, R*, R*, R*, and Rº are as previously disclosed, may be treated with alkoxy benzyl phosphonates 2-2 in the presence of a base such as sodium methoxide in a polar aprotic solvent such as N,N-dimethylformamide at temperatures from about -10° C. to about 30° C. and subsequently heated to 40° C. to about 80° C. to provide stilbenes 1-1 (Scheme 2, step a).

1.5-5 US 2016/0302417 A1 Oct. 20, 2016 17

-continued O Scheme 2.5 1-1

2-4

R2

BreI

OYC-coalkyl

2-5

Preparation of Cyclopropyl Amides (0199] Cyclopropyl amides 3-3, wherein R', Rº, Rºº, R, [0197] Aryl halides 2-3, wherein R*, R*, R*, R*, and Rº R*, R. R*, R*, R10. R", R12, R13, R14, Q°, R15, and R'" are are as previously disclosed, may be treated with vinylben as previously disclosed, may be prepared by treatment with zenes 2-4, wherein R* and Rº are as previously disclosed, in amines or amine salts 3-2, wherein R*, R*, R**, R*, R*, the presence of a transition metal catalyst such as palladium Q°, and Rº, and R'" are as previously disclosed, and activated carboxylic acids 3-1, wherein A is an activating (II) acetate and a bisphosphine ligand such as 1,1'-bis group, and R', Rº, Rº, Rt. R*, R*, R7, Rº, and Rº are as (diphenylphosphino)ferrocene in a basic solvent such as previously disclosed, with a base, such as triethylamine, triethylamine at temperatures from about 60° C. to about diisopropylethylamine, 4-methylmorpholine, or 4-dimethyl 100° C. to provide stilbenes 1-1 (Scheme 2, step b). Alter aminopyridine in an anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, dim natively, aryl halides 2-3 may be treated with vinylboronates ethylformamide, or any combination thereof, at tempera 2-5, wherein R* and Rº are as previously disclosed, in the tures between about 0°C. and about 120° C. (Scheme 3, step presence of a transition metal catalyst such as tetrakis a). (triphenylphosphine)palladium(0) and a base such as potas [0200] Activated carboxylic acids 3-1 may be an acid halide, such as an acid chloride, an acid bromide, or an acid sium carbonate in a solvent mixture such as 1,2-dimethoxy fluoride; a carboxylic ester, such as a para-nitrophenyl ester, ethane and water attemperatures from about 60° C. to about a pentafluorophenyl ester, an ethyl (hydroxyiminio)cyano 100° C. to provide stilbenes 1-1 (Scheme 2, step c). acetate ester, a methyl ester, an ethyl ester, a benzyl ester, an N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-yl [0198] In yet another embodiment, stilbenes 1-1 may also ester, or a hydroxypyridyltriazol-1-yl ester; an O-acylisou be prepared by the Wittig olefination method (Chalal, M.; rea; an acid anhydride; or a thioester. Acid chlorides may be Vervandier-Fasseur, D.; Meunier, P.; Cattey, H.; Hierso, prepared from the corresponding carboxylic acids by treat J.-C. Tetrahedron 2012, 68, 3899-3907) as outlined in ment with a dehydrating chlorinating reagent, such as oxalyl Scheme 2.5. Phenyl carbonyls 2-1, wherein R', Rº, Rº, Rº, chloride or thionyl chloride. Activated carboxylic esters 3-1 may be prepared from carboxylic acids in situ with a and Rº are as previously disclosed and Rº is H, may be uronium salt, such as 1-[bis(dimethylamino)methylene)-1H treated with alkoxy benzyl triphenylphosphonium chlorides 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate 2.5-2 in the presence of a base such as n-butyl lithium in a (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluro polar aprotic solvent such as tetrahydrofuran attemperatures nium hexafluorophosphate (HBTU), or (1-cyano-2-ethoxy from about —78° C. to ambient temperature to provide 2-oxoethylidenaminooxy)dimethylamino-morpholino-car stilbenes 1-1 (Scheme 2.5, step a). benium hexafluorophosphate (COMU). Activated US 2016/0302417 A1 Oct. 20, 2016

carboxylic esters 3-1 may also be prepared from carboxylic -continued acids in situ with a phosphonium salt such as benzotriazol R 12 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop). Activated carboxylic esters 3-1 may also be pre pared from carboxylic acids in situ with a coupling reagent such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide, or dicyclohexylcarbodiimide in the presence of a triazole such as hydroxybenzotriazole monohydrate (HOBt) or 1-hy droxy-7-azabenzotriazole (HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimide such as 1-(3 R 14 Q2 dimethylamino propyl)-3-ethylcarbodiimide or dicyclohex ylcarbodiimide. Activated carboxylic esters 3-1 may also be prepared from carboxylic acids in situ with a coupling reagent such as 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in the presence of a triazole such as 1-hydroxy-7-azabenzotriazole (HOAt). Activated carbox ylic esters 3-1 may also be prepared from carboxylic acids in situ with a coupling reagent such as 2,4,6-tripropyl-1,3, [0204] Cyclopropyl amides 4-3, wherein R*, R*, R*, R*, 5,2,4,6-trioxatriphosphiname 2,4,6-trioxide (T3PR) in the R*, R*, R7, R*, R*, Q', R19, R", R12, R13, R14, R15, and R'" presence of a base such as pyridine. are as previously disclosed, may be prepared by treatment [0201] Cyclopropyl amides 3-3, wherein R* is thietanyl with amines or amine salts 4-2, wherein R* and R'" are as or tetrahydrothiophenyl and Rºº is as previously disclosed, previously disclosed, and activated carboxylic acids 4-1, may be oxidized to the corresponding sulfoxide or sulfone wherein A is an activating group, and R', R*, R*, R*, R*, R*, by treatment with about one equivalent of meta-chloroper R7, Rº, Rº, Q', R'", R'', Rºº, Rºº, and Rºº are as previously oxybenzoic acid in a polar aprotic solvent such as dichlo disclosed, are as previously disclosed, with a base, such as romethane (sulfoxide) or about two equivalents of meta triethylamine, diisopropylethylamine, 4-methylmorpholine, chloroperoxybenzoic acid (sulfone) attemperatures between or 4-dimethylaminopyridine in an anhydrous aprotic solvent about 0° C. to about 40° C. (0202) Alternatively, cyclopropylamides 3-3, wherein R* such as dichloromethane, tetrahydrofuran, 1,2-dichloroeth is thietanyl or tetrahydrothiophenyl and R* is as previously ane, dimethylformamide, or any combination thereof, at disclosed, may be oxidized to the corresponding sulfoxide or temperatures between about 0° C. and about 120° C. sulfone by treatment with one equivalent of sodium perbo (Scheme 4, step a). rate in a protic solvent such as acetic acid (sulfoxide) or two [0205] Activated carboxylic acids 4-1 may be an acid equivalents of sodium perborate (sulfone). The oxidation halide, such as an acid chloride, an acid bromide, or an acid may be performed at temperatures between about 40°C. to fluoride; a carboxylic ester, such as a para-nitrophenyl ester, about 100° C. using about 1.5 equivalents of sodium per a pentafluorophenyl ester, an ethyl (hydroxyiminio)cyano borate to provide chromatographically separable mixtures of acetate ester, a methyl ester, an ethyl ester, a benzyl ester, an sulfoxide and sulfone cyclopropyl amides 3-3. N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-yl [0203] Cyclopropyl amides 3-3, wherein R* is N02 may be ester, or a hydroxypyridyltriazol-1-yl ester; an O-acylisou reduced to the corresponding NH, by treatment with an acid rea; an acid anhydride; or a thioester. Acid chlorides may be source, such as ammonium chloride, and iron in a protic prepared from the corresponding carboxylic acids by treat solvent, such as methanol, water, or any combination ment with a dehydrating chlorinating reagent, such as oxalyl thereof, at temperatures from about 20° C. to about 60° C. chloride or thionyl chloride. Activated carboxylic esters 4-1 may be prepared from carboxylic acids in situ with a uronium salt, such as 1-[bis(dimethylamino)methylene)-1H Scheme 3 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluro nium hexafluorophosphate (HBTU), or (1-cyano-2-ethoxy 2-oxoethylidenaminooxy)dimethylamino-morpholino-car benium hexafluorophosphate (COMU). Activated carboxylic esters 4-1 may also be prepared from carboxylic acids in situ with a phosphonium salt such as benzotriazol 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop). Activated carboxylic esters 4-1 may also be pre pared from carboxylic acids in situ with a coupling reagent such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide, or dicyclohexylcarbodiimide in the presence of a triazole such as hydroxybenzotriazole monohydrate (HOBt) or 1-hy droxy-7-azabenzotriazole (HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimide such as 1-(3 dimethylamino propyl)-3-ethylcarbodiimide or dicyclohex ylcarbodiimide. Activated carboxylic esters 4-1 may also be prepared from carboxylic acids in situ with a coupling reagent such as 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in the presence of a triazole such as 1-hydroxy-7-azabenzotriazole (HOAt). Activated carbox ylic esters 4-1 may also be prepared from carboxylic acids in situ with a coupling reagent such as 2,4,6-tripropyl-1,3, US 2016/0302417 A1 Oct. 20, 2016

5,2,4,6-trioxatriphosphiname 2,4,6-trioxide (T3PR) in the uronium salt, such as 1-[bis(dimethylamino)methylene)-1H presence of a base such as pyridine. 1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluro nium hexafluorophosphate (HBTU), or (1-cyano-2-ethoxy Scheme 4 2-oxoethylidenaminooxy)dimethylamino-morpholino-car benium hexafluorophosphate (COMU). Activated R 12 carboxylic esters 5-2 may also be prepared from carboxylic acids in situ with a phosphonium salt such as benzotriazol R7 R8 R!! R13 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate 5 Q1 R (PyBop). Activated carboxylic esters 5-2 may also be pre R6 A. pared from carboxylic acids in situ with a coupling reagent R4 N R9 | such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide, or R10 R 14 O dicyclohexylcarbodiimide in the presence of a triazole such as hydroxybenzotriazole.monohydrate (HOBt) or 1-hy R3 R! droxy-7-azabenzotriazole (HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimide such as 1-(3 R2 dimethylamino propyl)-3-ethylcarbodiimide or dicyclohex 4-1 &l ylcarbodiimide. Activated carboxylic esters 5-2 may also be + –º prepared from carboxylic acids in situ with a coupling reagent such as 2-chloro-1,3-dimethylimidazolidinium R15 hexafluorophosphate (CIP) in the presence of a triazole such º as 1-hydroxy-7-azabenzotriazole (HOAt). Activated carbox R16 ylic esters 5-2 may also be prepared from carboxylic acids 4-2 in situ with a coupling reagent such as 2,4,6-tripropyl-1,3, R 12 5,2,4,6-trioxatriphosphiname 2,4,6-trioxide (T3PR) in the presence of a base such as pyridine. R!! R13 R15 N Sp16 Scheme 5 R12 R 14 O R13 H N

R14 Q2 \\ O

+ A.Js X [0206] Cyclopropyl amides 5-3, wherein R*, R*, R*, R*, 5-2 R*, R*, R7, Rº, Rº, Q, R”, R*, R*, R*, R*, and Q” are aS previously disclosed, and X is (C1-C4)haloalkyl or (C1-C4) alkyl(C1-C4)alkoxy, may be prepared by treatment of amines 5-1, wherein R', Rº, Rº, Rt. R*, R*, R7, Rº, Rº, Q', R”, R*, R**, R*, R**, and Q are as previously disclosed, and activated carboxylic acids 5-2, wherein A is an activat ing group, and X is (C1-C4)alkyl, (C1-C4)haloalkyl, or (C1-C4)alkyl(C1-C4)alkoxy, with a base, such as triethylam ine, diisopropylethylamine, 4-methylmorpholine, or 4-dim ethylaminopyridine in an anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane, dim ethylformamide, or any combination thereof, at tempera tures between about 0°C. and about 120° C. (Scheme 5, step a). 5-3 [0207] Activated carboxylic acids 5-2 may be an acid halide, such as an acid chloride, an acid bromide, or an acid [0208] Cyclopropyl amides 6-3, wherein R', Rº, Rt. R*, fluoride; a carboxylic ester, such as a para-nitrophenyl ester, R*, R7. R*, R*, Q', R19, R", R12, R13, R14, R15, R16, and Q” a pentafluorophenyl ester, an ethyl (hydroxyiminio)cyano are as previously disclosed, may be prepared by treatment of acetate ester, a methyl ester, an ethyl ester, a benzyl ester, an aryl bromide 6-1, wherein R*, R*, R*, R*, R*, R7, Rº, Rº, Q', N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-yl R”, R*, R*, R*, R*, R*, R*, and Q are as previously ester, or a hydroxypyridyltriazol-1-yl ester; an O-acylisou disclosed, and (C1-C4)alkenyl stannane 6-2 wherein each rea; an acid anhydride; or a thioester. Acid chlorides may be alkenyl may be optionally substituted with one or more F. prepared from the corresponding carboxylic acids by treat with a palladium source, such as bis(triphenylphosphine) ment with a dehydrating chlorinating reagent, such as oxalyl palladium(II) dichloride in an aprotic solvent such as 1,4 chloride or thionyl chloride. Activated carboxylic esters 5-2 dioxane, at temperatures between about 20° C. and about may be prepared from carboxylic acids in situ with a 120° C. (Scheme 6, step a). US 2016/0302417 A1 Oct. 20, 2016 20

Scheme 6 R 12 R13 R15

N ~ R16 R 14 Q2

Bugsn + Yc-coalkeny 6-2

R12

R13 R15

N ~ R16 R14 Q2 (C1-C6)alkenyl

[0209] In some embodiments, 1-3 may be prepared from the o,5-unsaturated aldehyde 7-1, wherein R', Rº, Rº, R*, previously disclosed, in a polar solvent selected from the R’, R*, and Rº are as previously. It will be understood by one group consisting of acetone, acetonitrile, methanol, ethanol, skilled in the art that compound 7-1 may be synthesized via nitromethane, N,N-dimethylformamide, dimethyl sulfoxide, Aldol condensation (see Yoshikawa, M.; Kamei, T. PCT Int. ethyl acetate, tetrahydrofuran and 1,4-dioxane, in the pres Appl. 2010.123006, 2010) of an appropriately substituted, ence of an aqueous mineral acid selected from the group commercially available aldehyde and acetaldehyde. Treat consisting of nitric acid, hydrochloric acid, hydrobromic ment of 7-1 with a (C-C.)alkyl orthoformate, in the pres acid, and sulfuric acid (Scheme 7, step c) at ambient ence of an acid whose pH is 0-5 such as hydrobromic acid, temperature. The cyclopropyl acid 1-3, wherein R', Rº, Rº, N-bromosuccinimide, hydrochloric acid, N-chlorosuccinim R*, R*, R*, R7, Rº, and Rº are as previously disclosed, may ide, and pyridinium p-toluenesulfonate (PPTS), in a (C-C2) be obtained by oxidation of the aldehyde 7-4 with oxidants alkanol solvent, at a temperature from 0°C. to ambient and such sodium permanganate or potassium permanganate, or under ambient pressure provides the acetal 7-2, wherein R*, under Pinnick oxidation conditions in a polar aprotic solvent R*, R*, R*, R*, R*, and Rº are as previously disclosed and selected from the group consisting of acetone, acetonitrile, R* is a (C-C.)alkyl or Rº and Rº taken together can form a N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, cyclic acetal (Scheme 7, step a). The acetal 7-2 may be converted to the cyclopropyl acetal 7-3, wherein R', Rº, Rº, tetrahydrofuran and 1,4-dioxane at a temperature from about R*, R*, R*, R7, Rº, Rº, and Rº are as previously disclosed, 0° C. to about ambient temperature (Scheme 7, step d). by treatment with a carbene source such as a haloform, for Standard safety precautions should be exercised because an example, bromoform or chloroform, in the presence of an exotherm may occur when conducting this reaction. inorganic base, such as sodium or potassium hydroxide or sodium or potassium carbonate, and a phase-transfer catalyst such as benzyl triethylammonium chloride, (-)-N-dodecyl Scheme 7 N-methylephedrinium bromide, tetramethylammonium bro mide, tetrapropylammonium bromide, tetrabutylammonium R5 R6 O tetrafluoroborate, tetramethylammonium chloride or tetra butylammonium hexafluorophosphate at a temperature from about ambient temperature up to below the boiling point of the haloform (Scheme 7, step b). Caution: Step B is an exothermic reaction and careful control of the exotherm should be exercised when conducting this reaction. The cyclopropyl acetal 7-3 may be transformed into the aldehyde 7-1 7-4, wherein R*, R*, R*, Rt. R*, R*, R7, Rº, and Rº are as US 2016/0302417 A1 Oct. 20, 2016

-continued -continued R5 R6 OR6

R4 S OR" b R9 –º R3 R! R2 7-2

EXAMPLES [0211] These examples are for illustration purposes and are not to be construed as limiting this disclosure to only the embodiments disclosed in these examples. [0212] Starting materials, reagents, and solvents that were obtained from commercial sources were used without fur ther purification. Anhydrous solvents were purchased as Sure/SealTM from Aldrich and were used as received. Melt ing points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated Melting Point System from Stanford Research Systems and are uncorrected. Examples using “room temperature” were conducted in climate controlled laboratories with tempera tures ranging from about 20° C. to about 24°C. Molecules are given their known names, named according to naming programs within ISIS Draw, ChemDraw, or ACD Name Pro. If such programs are unable to name a molecule, such molecule is named using conventional naming rules. "H [0210] It will be understood by those skilled in the art that, NMR spectral data are in ppm (Ö) and were recorded at 300, in some embodiments, the cyclopropyl acid 1-3, wherein R*, 400, 500, or 600 MHz; **C NMR spectral data are in ppm R*, R*, R*, R*, R*, R7, Rº, and Rº are as previously (6) and were recorded at 75, 100, or 150 MHz, and *F NMR disclosed, may be resolved into its (R,R) and (S,S) spectral data are in ppm (Ö) and were recorded at 376 MHz, enantiomers via a known method such as that in Kovalenko unless otherwise stated. V. N., Kulinkovich O. G. Tetrahedron: Asymmetry 2011, 22, Example 1 26 (Scheme 8, step a). Preparation of trans-2,2-dichloro-3-(3,5-dichloro phenyl)cyclopropanecarboxylic acid (C1)

Scheme 8 [0213]

Cl C|

Cl OH

Cl US 2016/0302417 A1 Oct. 20, 2016 22

[0214) Ruthenium(III) chloride (0.080 g, 0.39 mmol) was Example 2 added to a stirred mixture of trans-1,3-dichloro-5-(-2,2 Preparation of trans-2,2-dichloro-3-(4-(trifluorom dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene (C22) ethyl)phenyl)cyclopropanecarboxylic acid (C4) (2.8 g., 7.7 mmol) and sodium periodate (33 g, 160 mmol) in water:ethyl acetate:acetonitrile (8:1:1, 155 mL) at 23° C. [0220) The resulting biphasic brown mixture was vigorously stirred at 23°C. for 5 hours. The reaction mixture was diluted with C| Cl water (1000 mL) and extracted with dichloromethane (4×200 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue OH was diluted with a sodium hydroxide solution (1 M, 100 mL) and washed with diethyl ether (4×50 mL). The aqueous layer was adjusted to pH 2, using concentrated hydrochloric acid, and extracted with dichloromethane (3×50 mL). The com bined organic layers were dried over magnesium sulfate, filtered, and concentrated to afford the title product as a light brown powder (0.78 g, 34%); mp 117-120° C.; H NMR [0221) To a stirred mixture of trans-1-(2,2-dichloro-3-(4 (400 MHz, DMSO-de) 8 13.38 (brs, 1H), 7.52-7.65 (m,3H), (trifluoromethyl)phenyl)cyclopropyl)-4-methoxybenzene 3.57 (d. J–8.5 Hz, 1H), 3.50 (d. J–8.5 Hz, 1H), IR (thin film) (C25) (3.50 g, 9.60 mmol) and sodium periodate (30.8 g. 3083 (s), 3011 (s), 1731 (s), 1590 (w), 1566 (s), 1448 (w), 144 mmol) in water:ethyl acetate:acetonitrile (8:1:1, 200 1431 (m), 1416 (m) cm ". mL) was added ruthenium(III) chloride (0.100 g, 0.400 [0215] The following compounds were prepared in like mmol) at 23° C. The resulting mixture was vigorously manner to the procedure outlined in Example 1: stirred at 23°C. for about 5 hours. The reaction mixture was diluted with dichloromethane and washed with water. The trans-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclo combined organic layers were dried over sodium sulfate, propanecarboxylic acid (C2) filtered, and concentrated. Purification by flash column chromatography provided the title compound as an off-white [0216] solid (0.630 g, 38%); mp 100-102°C.; H NMR (400 MHz, DMSO-d.) 8 13.43 (brs, 1H), 7.77-7.73 (m, 2H), 7.67-7.64 (m, 2H), 3.55 (d. J–8.8 Hz, 1H), 3.44 (d. J–8.8 Hz, 1H): Cl C| O ESIMS m/z 347 (IM-HIT). [0222] The following compounds were prepared in like Cl OH manner to the procedure outlined in Example 2: trans-2,2-Dichloro-3-(3-(trifluoromethyl)phenyl) cyclopropane carboxylic acid (C5) Cl [0223) Cl

C| Cl O [0217] Isolated as a yellow powder (1.5g, 39%); ‘H NMR F (400 MHz, CDC13) & 7.31 (d. J–0.7 Hz, 2H), 3.40 (d. J–8.2 F Hz, 1H), 2.86 (d. J–8.3 Hz, 1H); "C NMR (101 MHz, OH CDC1,) b 171,05, 134.55, 132.44, 131.75, 128.89, 61.18, F 39.26, 37.14, ESIMS m/z 333 (IM-HIT). trans-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopro panecarboxylic acid (C3) [0224) Isolated as an off-white solid (0.81 g, 33%); mp [0218] 86-88° C.; H NMR (400 MHz, DMSO-d.) 8 13.37 (brs, 1H), 7.83 (s, 1H), 7.76-7.69 (m, 2H), 7.65-7.59 (m, 1H), 3.59-3.51 (m, 2H), ESIMS m/z 297 (IM-HIT). Cl C| O trans-2,2-Dichloro-3-(3-chloro-4-(trifluoromethoxy) phenyl)cyclopropanecarboxylic acid (C6) Cl OH [0225]

Cl C| Cl

[0219) Isolated as a pale yellow solid (3.2 g, 51%). "H C| OH NMR (400 MHz, CDC1,) 67.47 (d. J–8.3 Hz, 1H), 7.37 (d. J=1.6 Hz, 1H), 7.12 (ddd, J–8.3, 2.1, 0.6 Hz, 1H), 3.43 (d. J–8.3 Hz, 1H), 2.86 (d. J–8.3 Hz, 1H); **C NMR (101 MHz, CDC1,) b 171.52, 132.91, 132.76, 132.29, 130.66, 130.62, 128.02, 61.48, 39.65, 37.13; ESIMS m/z 298 (IM-HIT).

US 2016/0302417 A1 Oct. 20, 2016 26

trans-1,2-Dichloro-4-(2,2-dichloro-3-(4-methoxy [0265] The following compounds were prepared in like phenyl)cyclopropyl)benzene (C24) manner to the procedure outlined in Example 4: [0261) trans-1-(2,2-Dichloro-3-(4-methoxyphenyl)cyclopro pyl)-3-(trifluoromethyl)benzene (C26)

O CI Cl O NCH, [0266]

Cl /\

Cl

[0262) Isolated as an orange-red oil (7.6 g. 99%); ‘H NMR (400 MHz, CDC1,) 67.47 (d. J–4.9 Hz, 1H), 7.45 (bs, 1H), 7.30-7.23 (m, 2H), 7.21 (dd, J–8.2, 1.9 Hz, 1H), 6.96-6.90 (m, 2H), 3.83 (s, 3H), 3.11 (app. q, J–8.8 Hz, 2H), “C NMR [0267] Isolated as a brown liquid (3.5 g. 67%); ‘H NMR (300 MHz, CDC13) & 7.62-7.50 (m, 4H), 7.29 (d. J–9.0 Hz, (101 MHz, CDC1,) b 159.39, 134.90, 132.62, 131.99, 130. 2H), 6.94 (d. J–9.0 Hz, 2H), 7.35-7.25 (m, 3H), 7.97-6.88 90, 130.40, 129.90, 128.33, 125.81, 113.98, 64.94, 55.33, (m, 1H), 3.83 (s, 3H), 3.19 (m, 2H), ESIMS m/z 361 39.52, 38.75. (IM+H]"). Example 4 trans-2-Chloro-4-(2,2-dichloro-3-(4-methoxyphenyl) cyclopropyl)-1-(trifluoromethoxy)benzene (C27) Preparation of trans-1-(2,2-dichloro-3-(4-(trifluo romethyl)phenyl)cyclopropyl)-4-methoxybenzene [0268] (C25) O [0263] Cl C| NoH, Cl /\ CI Cl ^CH3 F

FSls O

F O [0269) Isolated as an off-white solid (2.5 g. 65%); H F NMR (400 MHz, CDC1,) 67.57 (d. J–2.0 Hz, 1H), 7.44 (d. F J–8.8 Hz, 1H), 7.35-7.25 (m, 3H), 7.97-6.88 (m, 1H), 3.84 (s, 3H), 3.15-3.05 (m, 2H), ESIMS m/z 411 ([M+H]"). [0264] To a stirred solution of (E)-1-methoxy-4-(4-(trif trans-1,2,4-Trichloro-5-(2,2-dichloro-3-(4-methoxy luoromethyl)styryl)benzene (C46) (4.00 g, 14.0 mmol) and phenyl)cyclopropyl)benzene (C28) N-benzyl-N,N-diethylethanaminium chloride (0.320 g, 14.0 mmol) in chloroform (23.1 g, 288 mmol), was added aque [0270) ous sodium hydroxide (50%, 8.64 g, 216 mmol) in water (17 mL) at 23° C., and the resulting mixture was vigorously stirred at 23° C. for 16 hours. The reaction mixture was O diluted with water and extracted with dichloromethane. The CI Cl O NoH, combined organic layers were dried over sodium sulfate, Cl /\ filtered, and concentrated. Purification by flash column chromatography provided the title compound as an off-white solid (3.70 g. 68%); ‘H NMR (300 MHz, CDC1,) 6 7.65 (d. Cl Cl J=8.4 Hz, 2H), 7.49 (d. J–8.4 Hz, 2H), 7.29 (d, J–8.4 Hz, 2H), 6.94 (d. J–8.4 Hz, 2H), 3.83 (s, 3H), 3.19 (s. 2H); [0271) Isolated as a brown liquid (2.0 g, 58%). EIMS m/z ESIMS m/z 361 (IM+H]"). 394 (IMI").

US 2016/0302417 A1 Oct. 20, 2016 29

[0299| Isolated as an off-white solid (1.5 g, 45%); H [0306) Isolated as an off-white solid (6.0 g, 53%); mp NMR (400 MHz, CDC13) & 7.27 (d. J–8.0 Hz, 4H), 6.90 (d. 91-94°C.; H NMR (400 MHz, CDC1,) 67.56 (d, J-20 Hz, J=8.0 Hz, 4H), 4.04 (q, J–6.8 Hz, 4H), 3.09 (s, 2H), 1.42 (t, 1H), 7.46-7.42 (m, 2H), 7.39 (d, J–8.4 Hz, 1H), 7.29 (dd, J–6.8 Hz, 6H), ESIMS m/z 351 (IM+HI*). J=8.4, 2.1 Hz, 1H), 7.04 (d. J–16.2 Hz, 1H), 6.93-6.88 (m, 2H), 6.85 (d. J–16.3 Hz, 1H), 3.84 (s, 3H); *C NMR (101 Example 5 MHz, CDC1,) & 159.75, 137.86, 132.72, 130.58, 130.49, Preparation of (E)-1,3-dichloro-5-(4-methoxystyryl) 130.12, 129.33, 127.96, 127.77, 125.37, 123.98, 114.24, benzene (C43) 55.35; EIMS m/z 279 ([M]*). [0300] O Example 6 NoH, Preparation of (E)-1-methoxy-4-(4-(trifluoromethyl) Cl S. styryl)benzene (C46) [0307| O O NoH, Cl S

F [0301] Sodium methoxide powder (98%, 0.63 g, 11 mmol) was added to a stirred solution of 3,5-dichlorobenzaldehyde F (2.0 g, 11 mmol) and diethyl 4-methoxybenzylphosphonate F (2.0 mL, 11 mmol) in dry N,N-dimethylformamide (38 mL) at 23°C. The resulting heterogeneous dark blue mixture was [0308] To a stirred solution of diethyl 4-methoxybenzyl heated to 80° C., resulting in a dark brown mixture, and phosphonate (8.89 g, 34.0 mmol) in N,N-dimethylforma stirred for 24 hours. The cooled reaction mixture was diluted mide (30 mL) was added sodium methoxide powder (1.86 g, with water (500 mL) and extracted with diethyl ether (3×100 34.0 mmol). The reaction mixture was stirred at room mL). The combined organic layers were diluted with hexane temperature for 1 hour. The reaction mixture was cooled to (150 mL) and washed with water (300 mL). The organic 0° C. and 4-(trifluoromethyl)benzaldehyde (5.00 g, 28.0 layer was dried over magnesium sulfate, filtered, and con mmol) in N,N-dimethylformamide (30 mL) was added centrated to afford the title product as a light brown oil (2.4 dropwise. The reaction mixture was stirred at 60° C. for 2 g, 75%); ‘H NMR (400 MHz, CDC13) & 7.44 (m, 2H), 7.34 hours. The reaction mixture was poured in ice cold water, (d. J–2 Hz, 2H), 7.20 (t, J–2 Hz, 1H), 7.06 (d. J–16.5 Hz, filtered, and dried to afford the title compound as an off 1H), 6.91 (m, 2H), 6.82 (d. J–16.5 Hz, 1H), 3.84 (s, 3H), IR white solid (3.60 g, 80%), 1H NMR (300 MHz, CDC1,) 6 (thin film) 2934 (w), 2835 (w), 1724 (w), 1637 (w), 1605 7.61-7.52 (m, 4H), 7.47 (d. J–9.0 Hz, 2H), 7.14 (d. J–16.5 (m), 1581 (m), 1558 (m), 1511 (s) cm ". Hz, 1H), 6.97 (d. J–16.5 Hz, 1H), 6.91 (d. J–9.0 Hz, 2H), [0302] The following compounds were prepared in like 3.84 (s, 3H); ESIMS m/z 279 (IM+H]"). manner to the procedure outlined in Example 5: [0309] The following compounds were prepared in like (E)-1,2,3-Trichloro-5-(4-methoxystyryl)benzene manner to the procedure outlined in Example 6: (C44) (E)-1-(4-Methoxystyryl)-3-(trifluoromethyl)benzene [0303) O (C47)

NoH, Cl S

Cl

Cl [0304) Isolated as an off-white solid (3.7 g, 31%): 'H [0311) Isolated as an off-white solid (4.0 g, 85%); H NMR (400 MHz, CDC1,) 67.49-7.46 (m, 2H), 7.47-7.39 (m, NMR (400 MHz, CDC1,) 8 7.72 (s, 1H), 7.64 (d. J–6.8 Hz, 2H), 7.04 (d. J–16.3 Hz, 1H), 6.93-6.89 (m, 2H), 6.78 (d. 1H), 7.50-7.44 (m, 4H), 7.12 (d. J–16.0 Hz, 1H), 6.98 (d, J–16.3 Hz, 1H), 3.84 (s, 3H); *C NMR (101 MHz, CDC1,) J–16.0 Hz, 1H), 6.91 (d. J–8.8 Hz, 2H), 3.84 (s, 3H); ESIMS ô 159.46, 135.08, 134.23, 130.91, 129.85, 129.16, 125.42, 114,02, 64.67, 55.32, 39.62, 38.48; EIMS m/z 313 ([M]"). (E)-2-Chloro-4-(4-methoxystyryl)-1-(trifluo (E)-1,2-Dichloro-4-(4-methoxystyryl)benzene (C45) romethoxy)benzene (C48) [0305 O [0312] NoH, O O NoH, Cl S F C| S

Cl

US 2016/0302417 A1 Oct. 20, 2016

dried in a vacuum oven at 40° C. to provide the title trans-N-Cyclopropyl-3-(2,2-dichloro-3-(3,5-dichlo compound as a light brown solid (0.421 g, 93%); mp rophenyl)cyclopropanecarboxamido)benzamide (F3) 234-236° C.; H NMR (400 MHz, DMSO-de) 8 13.47 (s, 1H), 10.90 (s, 1H), 8.16 (d. J–2.3 Hz, 1H), 7.78 (dd, J–8.7, [0358] 2.4 Hz, 1H), 7.59 (m, 4H), 3.56 (dd, J-49.8, 8.5 Hz, 2H), C| ClQ H 1.09 (m, 1H); *C NMR (101 MHz, DMSO-de) & 16626, N 165.77, 162.61, 137.57, 137.27, 134.04, 132.18, 131.44, 131.22, 127.88, 127.66, 126.40, 125.92, 122.88, 121.17, Cl NH N7 102.37, 62.11, 38.41, 36.83; ESIMS m/z 454 (IM+HI*). O Example 13 C| Preparation of trans-2-chloro-N-cyclopropyl-5-(2,2 dichloro-3-(3,5-dichlorophenyl)cyclopropanecarbox [0359] Isolated as a white solid (0.200 g. 66%). amido) benzamide (F1) trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-di [0353] F chloro-3-(3,5-dichlorophenyl)cyclopropanecarbox F amido)benzamide (F4)

Cl ClQ F [0360) C| H N Cl ClQ 2% N H C| N N7 C| N O H O

C| Cl [0354) 5-Amino-N-cyclopropyl-2-(trifluoromethyl)benz amide (C69) (0.129 g, 0.528 mmol) and 4-dimethylamin [0361) Isolated as a brown semi-solid (0.071 g, 55%). opyridine (0.0700 g, 0.572 mmol) were sequentially added to a stirred mixture of trans-2,2-dichloro-3-(3,5-dichloro trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophe phenyl)cyclopropanecarboxylic acid (C1) (0.132 g, 0.440 nyl)cyclopropanecarboxamido)-N-(3,3-difluorocy mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide clobutyl)benzamide (F5) (0.127 g, 0.660 mmol) in 1,2-dichloroethane (4.40 mL) at room temperature. The reaction was stirred at room tem [0362] Cl perature for 20 hours. Dichloromethane was added and the C| CIQ mixture was washed with saturated aqueous sodium bicar H N bonate and hydrochloric acid (1 N). The organic phase was Cl N dried over magnesium sulfate, filtered, and concentrated to H F give the title compound as a yellow solid (0.0870 g, 36%). O [0355] The following compounds were prepared in like F manner to the procedure outlined in Example 13: Cl trans-N-Cyclopropyl-5-(2,2-dichloro-3-(3,5-dichlo rophenyl)cyclopropanecarboxamido)-2-(trifluorom [0363) Isolated as a tan powder (0.200 g, 74%). ethyl)benzamide (F2) trans-2-Chloro-5-(2,2-dichloro-3-(3,4,5-trichloro [0356] phenyl)cyclopropanecarboxamido)-N-(3,3-difluoro cyclobutyl)benzamide (F6) Cl Cl ClQ [0364] Cl H C| CIQ N H N C| NH N7 Cl N O H F O F Cl

C| Cl

[0357) Isolated as a white solid (0.087 g, 17%). [0365) Isolated as an off-white powder (0.092 g, 67%).

US 2016/0302417 A1 Oct. 20, 2016 40

[0453) Isolated as a white solid (0.052 g, 39%). [0460) Isolated as a white powder (0.067 g. 60%): trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-di chloro-3-(3,4-dichloro-5-methylphenyl)cyclopropan trans-tert-Butyl 3-(2-chloro-5-(2,2-dichloro-3-(3,5 ecarboxamido)benzamide (F51) dichlorophenyl)cyclopropanecarboxamido)ben [0454) zamido)azetidine-1-carboxylate (F54) [0461) Cl CI Cl O N

C| N H H N O h C| C| Nº O Srºk.CH CH3 O CH3 3 Cl [0455) Isolated as a white foam (0.087 g. 69%). Example 14 Preparation of trans-2-Chloro-5-(2,2-dichloro-3-(3, [0462) Isolated as a light green powder (0.805 g, 60%): 5-dichlorophenyl)cyclopropanecarboxamido)-N morpholinobenzamide (F52) Example 15 [0456] Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,5 dichlorophenyl)cyclopropanecarboxamido)-N-(tetra C| Cl O hydro-2H-pyran-4-yl)benzamide (F55) R [0463] Cl NH sº

O º C|

H CH3 N C| N H [0457] To a solution of morpholin-4-amine (0.0200 g, 0.198 mmol) in dichloromethane (2 mL) was added in sequence 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide º O O (0.0480 g, 0.248 mmol), 4-dimethylaminopyridine (0.0240 g, 0.198 mmol), and 2-chloro-5-(2,2-dichloro-3-(3,5-dichlo C| rophenyl)cyclopropanecarboxamido)benzoic acid (C67) (0.0750 g, 0.165 mmol). The reaction was stirred at room temperature for 16 hours. Purification by flash chromatog [0464] To a solution of 2-chloro-5-(2,2-dichloro-3-(3,5 raphy using 0-100% ethyl acetate/hexanes as eluent pro dichlorophenyl)cyclopropanecarboxamido)benzoic acid vided the title compound as a white solid (0.0378 g, 43%). [0458] The following compounds were prepared in like (C67) (0.200 g, 0.441 mmol) in dichloromethane (2.2 mL) manner to the procedure outlined in Example 14: stirred at 0° C., was added N,N-dimethylformamide (1 trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophe drop), followed by oxalyl chloride (0.0579 mL, 0.661 nyl)cyclopropanecarboxamido)-N-(oxetan-3-yl)ben mmol). The ice bath was removed and the reaction was zamide (F53) allowed to warm to room temperature over 90 minutes. The [0459) reaction was then concentrated to yield a cream colored foam (0.210 g). Half of the isolated acid chloride (0.100 g, 0.212 mmol) was dissolved in dichloromethane (2 mL) and the solution was added to a cooled solution of tetrahydro H N 2H-pyran-4-amine (0.0290 g, 0.254 mmol) and triethylam h ine (0.0440 mL, 0.318 mmol) dissolved in dichloromethane rivy (2 mL). The ice bath was removed and the reaction was allowed to stir at room temperature for 16 hours. Purification by flash column chromatography using 0-40% ethyl acetate/ CH3 hexanes as eluent provided the title compound as a white solid (0.0339 g, 29%). US 2016/0302417 A1 Oct. 20, 2016 41

Example 16 romethane (2.5 mL) was added meta-chloroperoxybenzoic acid (0.140 g, 0.626 mmol). The reaction was stirred at room Preparation of diastereoisomers of trans-2-chloro-5 temperature for 3 hours. Saturated aqueous sodium carbon (2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropan ate was added and the mixture was extracted with ethyl ecarboxamido)-N-(1-oxidothietan-3-yl)benzamide acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concen (F56) and (F57) trated. Purification by flash column chromatography using [0465] 0-15% methanol/dichloromethane provided the title com pounds as a faint yellow solid (0.0460 g, 30%). F56 Example 18 Cl C| Cl O Preparation of trans-N-(azetidin-3-yl)-2-chloro-5-(2, H N 2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecar boxamido) benzamide (F59) Cl NH `S O §Neº [0469) Cl

Cl C| F57 C| H C| Cl O H N Cl NH NºS O Ö". Ö Cl Cl [0470] Trifluoroacetic acid (0.082 mL, 1.1 mmol) was added to a stirred mixture of trans-tert-butyl 3-(2-chloro-5 [0466] To a solution of trans-2-chloro-5-(2,2-dichloro-3 (2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarbox (3,4,5-trichlorophenyl)cyclopropanecarboxamido)-N-(thi amido)benzamido)azetidine-1-carboxylate (F54) (0.065 g, etan-3-yl)benzamide (F17) (0.150 g, 0.268 mmol) in dichlo 0.11 mmol) in dichloromethane (1.4 mL) at 23° C. The romethane (2.68 mL) was added meta-chloroperoxybenzoic resulting homogeneous colorless solution was stirred at 23° acid (0.0630 g, 0.282 mmol). The reaction was stirred at C. for 3 hours. The reaction mixture was diluted with room temperature for 3 hours. Saturated aqueous sodium saturated aqueous sodium bicarbonate solution (50 mL) and bicarbonate was added and the mixture was extracted with extracted with dichloromethane (9×15 mL). The combined ethyl acetate. The combined organic phases were washed organic layers were dried over magnesium sulfate, filtered, with brine, dried over magnesium sulfate, filtered, and and concentrated to afford the desired product as a white concentrated. Purification by flash column chromatography powder (0.047 g, 87%). using 0-15% methanol/dichloromethane as eluent provided the title compound (F56) as a white solid (0.0390 g, 24%) and (F57) as a white solid (0.0200 g, 12%). Example 19 Example 17 Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,5 dichlorophenyl)cyclopropanecarboxamido)-N-(1-(2, Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,4, 2,2-trifluoroacetyl)azetidin-3-yl)benzamide (F60) 5-trichlorophenyl)cyclopropanecarboxamido)-N-(1, 1-dioxidothietan-3-yl)benzamide (F58) [0471) [0467] Clº Cl O Cl Cl { H N Cl NH NºN i F

H =O) O Sr*. C| N O º - O Cl C| ºC| \, [0472] Trifluoroacetic acid (0.13 mL, 1.7 mmol) was added to a stirred mixture of trans-tert-butyl 3-(2-chloro-5 [0468] To a solution of trans-2-chloro-5-(2,2-dichloro-3 (2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarbox (3,4,5-trichlorophenyl)cyclopropanecarboxamido)-N-(thi amido)benzamido)azetidine-1-carboxylate (F54) (0.10 g, etan-3-yl)benzamide (F17) (0.140 g, 0.250 mmol) in dichlo 0.17 mmol) in dichloromethane (1.6 mL) at 23° C. The US 2016/0302417 A1 Oct. 20, 2016 42 resulting homogeneous colorless solution was stirred at 23° The combined aqueous phases were neutralized with satu C. for 4 hours. The reaction mixture was concentrated and rated aqueous sodium bicarbonate and extracted with dichlo the residue was reconstituted in dichloromethane (1.6 mL). romethane. The combined organic phases were dried over Triethylamine (0.034 mL, 0.25 mmol) and 2-methoxyacetic magnesium sulfate, filtered, and concentrated to provide the acid (0.020 mL, 0.25 mmol) were added followed by title compound as a faint yellow solid (0.136 g, 73%); H 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydro NMR (400 MHz, CDC1,) 6 7.40 (d. J–8.5 Hz, 1H), 6.74 (d. chloride (0.063 g, 0.33 mmol), 4-dimethylaminopyridine J=2.4 Hz, 1H), 6.70 6.64 (m, 1H), 5.86 (s, 1H), 4.09 (s. 2H), (0.030 g, 0.25 mmol). The resulting homogeneous bright 2.90 2.80 (m, 1H), 0.91 0.82 (m, 2H), 0.66 0.57 (m, 2H), IR yellow solution was stirred at 23° C. for 72 hours. The (thin film) 3333, 3249, 1627 cm-"; EIMS m/z 244 ([M]"). reaction mixture was concentrated and the residue was purified by reverse phase flash column chromatography [0477] The following compounds were prepared in like using 5-100% acetonitrile/water as eluent to provide the title manner to the procedure outlined in Example 21: product as white powder (0.042 g, 42%). 5-Amino-2-chloro-N-(1-cyanocyclopropyl)benzamide Example 20 (C70) Preparation of [0478] 5-amino-2-chloro-N-cyclopropylbenzamide (C68) [0473] N Cl § 2. H2N H N O

O [0479. Isolated as a yellow solid (0.326 g, 75%); ‘H NMR (400 MHz, DMSO-de) & 9.23 (s, 1H), 7.08 (d. J–8.6 Hz, [0474] 2-Chloro-N-cyclopropyl-5-nitrobenzamide (C79) 1H), 6.64-6.53 (m, 2H), 5.44 (s, 2H), 1.55 (dd, J–8.2, 5.5 Hz, (0.130 g, 0.540 mmol) was dissolved in ethyl acetate (2.5 2H), 1.19 (dd, J–8.0, 5.4 Hz, 2H), IR (thin film)3468, 3261, mL). Ethanol (2.5 mL) was added to dissolve the material. 2243, 1655 cm-"; EIMS m/z 236 ([M]). Iron (0.181 g, 3.24 mmol) was added followed by water (0.5 mL) then acetic acid (0.866 mL, 15.1 mmol), and the Example 22 mixture stirred at room temperature for 5 days. The reaction was filtered through Celite R, diluted with water, and Preparation of 5-amino-2-chloro-N-(3,3-difluorocy extracted with ethyl acetate. The combined organic phases clobutyl)benzamide (C71) were dried over magnesium sulfate, filtered, and concen trated to provide the title compound as a yellow solid (0.112 g, 88%); H NMR (400 MHz, CDC1,) 6 7.10 (d. J–8.6 Hz, [0480] 1H), 6.96 (d. J–2.9 Hz, 1H), 6.63 (dd, J–8.6, 2.9 Hz, 1H), 6.44 (s, 1H), 3.78 (s, 2H), 2.95-2.82 (m, 1H), 0.89-0.82 (m, C| 2H), 0.66-0.60 (m, 2H), EIMS m/z 211 ([M]"). H Example 21 N H2N Preparation of O F 5-amino-N-cyclopropyl-2-(trifluoromethyl)benzamide F (C69) [0475] [0481] 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.840 g, 4.40 mmol) and 4-dimethylamin opyridine (0.460 g, 3.80 mmol) were sequentially added to F a stirred mixture of 5-amino-2-chlorobenzoic acid (0.500 g, F 2.90 mmol), 3,3-difluorocyclobutylamine hydrochloride F (0.500 g, 3.50 mmol), and triethylamine (0.490 mL, 3.50 H mmol) in dichloromethane (15 mL) at 23°C. The resulting N heterogeneous gray mixture was stirred at 23° C. for 96 hours. The reaction mixture was concentrated and the resi H2N N7 due was purified by reverse phase flash column chromatog O raphy using 5-100% acetonitrile/water as eluent. The residue was slurried in dichloromethane and vacuum filtered to [0476] To a solution of N-cyclopropyl-5-nitro-2-(trifluo afford the desired product as a tan powder (0.530 g, 70%): romethyl)benzamide (0.189 g, 0.689 mmol) in methanol (2.3 *H NMR (400 MHz, DMSO-de) 58.77 (d. J–7 Hz, 1H), 7.06 mL) and water (1.1 mL) was added iron powder (0.192 g, (m, 1H), 6.56-6.61 (m, 2H), 5.41 (brs, 2H), 4.17 (m, 1H), 3.45 mmol) and ammonium chloride (0.111 g, 2.07 mmol). 2.89-3.01 (m, 2H), 2.56-2.70 (m, 2H), IR (thin film) 3482 The reaction was heated at 60° C. for 2 hours. The reaction (w), 3372 (w), 3251 (w), 2917 (m), 2850 (m), 1697 (w), was filtered through Celite R. The filtrate was diluted with 1631 (s), 1599 (s), 1577 (m), 1540 (s), 1478 (s) cm "; dichloromethane and extracted with hydrochloric acid (1 N). ESIMS m/z 261 (IM+H]*). US 2016/0302417 A1 Oct. 20, 2016

Example 23 [0488] Isolated as a white powder (0.680 g, 71%); mp 166-168° C.; H NMR (400 MHz, DMSO-de) & 8.94 (br d, Preparation of 5-amino-2-chloro-N-(tetrahydrothio J–7.5 Hz, 1H), 7.06 (d. J–8.7 Hz, 1H), 6.52-6.61 (m, 2H), phen-3-yl)benzamide (C72) 5.41 (br's, 2H), 5.12 (h, J–7.5 Hz, 1H), 3.38-3.47 (m, 2H), [0482] 3.20-3.27 (m, 2H), IR (thin film) 3424 (w), 3303 (m), 2943 (w), 1639 (s), 1598 (m), 1578 (m), 1523 (s), 1474 (m) cm '; Cl ESIMS m/z 243 (IM+H]").

H 5-Amino-2-chloro-N-cyclobutylbenzamide (C75) N H2N S [0489) O

C| [0483] 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.15 g. 6.00 mmol) and 4-dimethylamin H opyridine (0.590 g, 4.80 mmol) were sequentially added to N a stirred mixture of 5-amino-2-chlorobenzoic acid (0.690 g, 4.00 mmol) and tetrahydrothiophen-3-amine (0.450 g, 4.40 ºrO ºn mmol) in dichloromethane (16 mL) at 23°C. The resulting homogeneous gray solution was stirred at 23° C. for 16 hours. The reaction mixture was concentrated, and the [0490) Isolated as an off-white powder (); mp 130-132° residue was purified by reverse phase flash column chroma C.; H NMR (400 MHz, DMSO-de) & 8.49 (br d, J–8 Hz, tography using 5-100% acetonitrile/water as eluent provided the title compound as a light brown oil (0.780 g, 76%). "H 1H), 7.04 (d, J–8.4 Hz, 1H), 6.52-6.59 (m, 2H), 5.36 (br's, NMR (400 MHz, CDC1,) 6 7.14 (d, J-9 Hz, 1H), 7.00 (d. 2H), 4.31 (m, 1H), 2.13–2.23 (m, 2H), 1.91-2.02 (m, 2H), J=3 Hz, 1H), 6.66 (dd, J–9, 3 Hz, 1H), 6.56 (brs, 1H), 4.91 1.58-1.69 (m, 2H), IR (thin film) 3447 (w), 3334 (m), 3283 (m. 1H), 3.78 (brs, 2H), 3.15 (dd, J-11, 5 Hz, 1H), 2.78-3.02 (m), 2991 (w), 2942 (w), 2861 (w), 1618 (s), 1601 (s), 1541 (m, 3H), 2.29 (m, 1H), 2.08 (m, 1H); IR (thin film).3340 (w), (s), 1476 (m), 1428 (m) cm '; ESIMS m/z 225 ([M+H]"). 3230 (m), 2935 (w), 1634 (s), 1599 (s), 1575 (m), 1520 (s), 1474 (s), 1432 (m) cm '; ESIMS m/z 257 (IM+H]"). [0484] The following compounds were prepared in like Example 24 manner to the procedure outlined in Example 23: Preparation of 5-amino-2-chloro-N-(3,3-difluorocy 5-Amino-2-chloro-N-(1-cyanocyclobutyl)benzamide clobutyl)-N-methylbenzamide (C76) (C73) [0491] [0485]

C| Cl

N Nº § 2. H2N H2N O F O F

[0486) Isolated as a brown glass (0.276 g, 27%); ‘H NMR [0492] To a solution of 2-chloro-N-(3,3-difluorocyclobu (400 MHz, CDC1,) 69.33 (brs, 1H), 8.09 (m, 1H), 7.09 (d. tyl)-N-methyl-5-nitrobenzamide (C82) (0.513 g, 1.68 J=9 Hz, 1H), 6.62 (m, 1H), 5.46 (brs, 2H), 2.57-2.71 (m, 2H), 2.33-2.47 (m, 2H), 1.98-2.11 (m, 2H), IR (thin film) mmol) in ethyl acetate (10 mL) under a nitrogen blanket was 3353 (w), 3222 (w), 2951 (w), 2236 (w), 1647 (s), 1600 (s), added palladium on carbon (0.179 g, 0.0840 mmol). The 1523 (s), 1476 (s), 1435 (m) cm "; ESIMS m/z 250 (IM+ reaction was placed under a balloon of hydrogen and stirred H]*). vigorously for 5 hours. The reaction was filtered through 5-Amino-2-chloro-N-(thietan-3-yl)benzamide (C74) Celite R washing with ethyl acetate. The filtrates were con [0487] centrated to yield the title compound as a white solid (0.394 g, 85%); ‘H NMR (400 MHz, CDCls) b rotamers 7.14 (dd. J=8.6, 5.6 Hz, 1H), 6.64 (ddd, J–8.5, 7.5, 2.8 Hz, 1H), 6.54 Cl (dd, J–14.9, 2.8 Hz, 1H), 5.03-4.82 (m, 0.5H), 4.22-4.06 (m, H 0.5H), 3.77 (s, 2H), 3.09 (s, 1.5H), 3.04-2.91 (m, 1H), 2.85 N (s, 1.5H), 2.92-2.59 (m, 3H); "F NMR (376 MHz, CDC1,) S ö rotamers —83.92 (d. J–1992 Hz), -84.69 (d, J–201.6 Hz), ºrO so –99.42 (d. J–201.6 Hz), -99.78 (d. J–199.1 Hz); ESIMS m/z 275 (IM+H]*). US 2016/0302417 A1 Oct. 20, 2016 44

Example 25 Example 26 Preparation of Preparation of 2-chloro-N-cyclopropyl-5-nitrobenzamide (C79) 5-amino-2-chloro-N-(3-cyanocyclopentyl)benzamide (C77) [0498)

[0493) Cl

H O N C| sº N7 H O O N H2N EN [0499] 2-Chloro-5-nitrobenzoic acid (0.250 g, 1.24 mmol) O and 4-dimethylaminopyridine (0.197 g, 1.61 mmol) were sequentially added to a stirred mixture of cyclopropanamine (0.103 mL, 1.49 mmol) and 1-ethyl-3-(3-dimethylaminopro [0494] 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide pyl)-carbodiimide (0.357 g, 1.86 mmol) in 1,2-dichloroeth hydrochloride (0.490 g, 2.50 mmol) and 4-dimethylamin ane (12 mL) at room temperature. The reaction was stirred at room temperature for 20 hours. The reaction was diluted opyridine (0.270 g, 2.20 mmol) were sequentially added to with dichloromethane and washed with saturated aqueous a stirred mixture of 5-amino-2-chlorobenzoic acid (0.290 g, sodium bicarbonate and hydrochloric acid (1 N). The 1.70 mmol), 3-aminocyclopentanecarbonitrile hydrochlo organic phase was dried over magnesium sulfate, filtered, ride (0.250 g, 1.70 mmol), and triethylamine (0.280 mL, and concentrated to provide the title compound as a white 2.00 mmol) in dichloromethane (11 mL) at 23° C. The solid (0.142 g, 45%); mp 173-176° C.; H NMR (400 MHz, resulting homogeneous light tan solution was stirred at 23° CDC1,) 6 8.49 (d. J–2.7 Hz, 1H), 8.21 (dd, J–8.8, 2.7 Hz, C. for 72 hours. The reaction mixture was concentrated, and 1H), 7.59 (d, J–8.8 Hz, 1H), 6.26 (s, 1H), 3.02-2.89 (m, 1H), 0.98-0.90 (m, 2H), 0.72-0.64 (m, 2H), ESIMS m/z 241 the residue was purified by reverse phase flash column (IM+H]"). chromatography using 5-100% acetonitrile/water as eluent [0500] The following compounds were prepared in like to provide the title compound as an off-white powder (0.350 manner to the procedure outlined in Example 26: g, 78%); mp 117-119° C.; H NMR (400 MHz, DMSO-d.) ö 8.46 (br d, J–7 Hz, 1H), 7.05 (d. J–8.2 Hz, 1H), 6.53-6.59 N-Cyclopropyl-5-nitro-2-(trifluoromethyl)benzamide (m, 2H), 5.37 (brs, 2H), 4.19 (m, 1H), 3.01 (p, J–8 Hz, 1H), (C80) 2.39 (m, 1H), 2.02 (m, 1H), 1.83-1.95 (m, 2H), 1.61-1.78 [0501) (m, 2H), IR (thin film) 3444 (m), 3360 (m), 3237 (m), 3064 (w), 2951 (w), 2875 (w), 2238 (m), 1626 (s), 1599 (s), 1577 F (m), 1544 (s), 1475 (s), 1437 (s) cm '; ESIMS m/z 264 F (IM+H]"). [0495] The following compounds were prepared in like F manner to the procedure outlined in Example 25: O { sº V 5-Amino-2-chloro-N-(4,4-difluorocyclohexyl)benz O- O amide (C78) [0502) Isolated as a white solid (0.189 g, 31%): "H NMR [0496] (400 MHz, CDC1,) 58.40-8.33 (m, 2H), 7.93-7.87 (n, 1H), 5.98 (s, 1H), 2.96-2.88 (m, 1H), 0.96-0.89 (m, 2H), 0.70-0. 64 (m, 2H), EIMS m/z 274 ([M]*). Cl Example 27 H N Preparation of H2N 2-chloro-N-(1-cyanocyclopropyl)-5-nitrobenzamide O F (C81) F [0503]

C| [0497] Isolated as a gray powder (0.560 g, 67%); mp 132° N C. (dec.); ‘H NMR (400 MHz, DMSO-de) & 8.28 (br d, J–8 Hz, 1H), 7.04 (d. J–8 Hz, 1H), 6.51-6.60 (m, 2H), 5.37 (br O § 2. s, 2H), 3.90 (m, 1H), 1.80-2.09 (m, 6H), 1.50-1.63 (m, 2H): sº IR (thin film) 3430 (w), 3298 (m), 2948 (w), 1634 (s), 1602 O- O (m), 1579 (m), 1533 (s), 1478 (m) cm "; ESIMS m/z 289 (IM+H]"). US 2016/0302417 A1 Oct. 20, 2016

[0504] 2-Chloro-5-nitrobenzoic acid (0.500 g, 2.48 mmol) (dd, J–15.0, 7.3 Hz, 1H), 3.16-2.97 (m, 2H), 2.88-2.77 (m, and 4-dimethylaminopyridine (0.394 g, 3.22 mmol) were 2H), ESIMS m/z 291 (IM+H]"). added to a solution of 1-aminocyclopropanecarbonitrile hydrochloride (0.353 g, 2.98 mmol), diethylisopropylethyl Example 28 amine (0.520 mL, 2.98 mmol) and 1-ethyl-3-(3-dimethyl Preparation of 2-chloro-N-(3,3-difluorocyclobutyl) aminopropyl)-carbodiimide (0.713 g, 3.72 mmol) in 1,2 N-methyl-5-nitrobenzamide (C83) dichloroethane (9.92 mL) at room temperature. The reaction was stirred at room temperature overnight. The reaction [0508 mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate followed by hydro chloric acid (1 N). The organic phases was dried over Cl magnesium sulfate, filtered, and concentrated to provide the title compound as a white solid (0.444 g. 64%); ‘H NMR O Nº (400 MHz, DMSO-de) & 9.62 (s, 1H), 8.37 (d. J–2.7 Hz, SN, 1H), 8.31 (dd, J–8.8, 2.8 Hz, 1H), 7.85 (d. J–8.8 Hz, 1H), 1.59 (dd, J–8.3, 5.4 Hz, 2H), 1.34 (dd, J–8.4, 5.5 Hz, 2H); O O F IR (thin film)3271, 3103, 2247, 1664 cm-"; ESIMS m/z 266 F (IM+H]"). [0505] The following compounds were prepared in like [0509] To a solution of 2-chloro-N-(3,3-difluorocyclobu manner to the procedure outlined in Example 27: tyl)-5-nitrobenzamide (C82) (0.490 g, 1.69 mmol) in dry N,N-dimethylformamide (8 mL) cooled in an ice bath was 2-Chloro-N-(3,3-difluorocyclobutyl)-5-nitrobenz added sodium hydride (0.0940 g, 2.36 mmol). The slurry amide (C82) was stirred for 30 minutes and then iodomethane (0.264 mL, 4.2.1 mmol) was added. The reaction was stirred for 3 hours. [0506] The reaction was cooled in an icebath and quenched by the slow addition of water. The reaction was extracted with ethyl acetate (30 mL). The organic layer was washed with water Cl (2x20 mL) and brine (20 mL). The organic layer was poured through a phase separator to dry and concentrated to provide O { the title compound as a light yellow solid (0.513 g, quant): *H NMR (400 MHz, CDCl3) 6 rotamers 8.29-8.13 (m, 2H), sy 7.66-7.58 (m, 1H), 5:00-4.85 (m, 0.5H), 4.05-3.92 (m, O- O F 0.5H), 3.16 (s, 1.5H), 3.10-2.95 (m, 1H), 2.87 (s, 1.5H) F 2.95-2.66 (m, 2H); *F NMR (376 MHz, CDC1,) 6 rotamers –84.01 (d, J–199.7 Hz), -84.85 (d. J–202.6 Hz), -99.36 (d. J–202.5 Hz), -99.67 (d. J–199.7 Hz); ESIMS m/z 305 [0507) Isolated as a white foam (0.103 g, 71%): "H NMR (IM+H]"). (400 MHz, Acetone-de) & 8.36 (d, J–2.8 Hz, 1H), 8.30 (dd. [0510] The following molecules in Table 1 may be pre J–8.8, 2.8 Hz, 1H), 8.26 (s, 1H), 7.79 (d. J–8.7 Hz, 1H), 4.41 pared according to the procedures disclosed above. TABLE P1

Structure and preparation method for prophetic molecules

No. Structure Prep”

P1 C| 13, 15 Cl O /* NH % F N H O

Cl

P2 Cl 13, 15 C| O /* NH % F N H O

Cl US 2016/0302417 A1 Oct. 20, 2016

TABLE P1-continued

Structure and preparation method for prophetic molecules

No. Structure Prep”

P3 C| Cl Cl 13, 15

O

A * * *O P4 Br } Cº. 13, 15 O

C|

P5 Clº Cl O C| 13, 15 H N F N H F O F

Cl

P6 Clº Cl O Cl 13, 15 H N F N H F O F C|

P7 Cl 13, 15 C| Cl O N C| F A * * *s } O F F

P8 Cl 13, 15 C| Cl O N Br O F º F

US 2016/0302417 A1 Oct. 20, 2016 50

TABLE P1-continued

tructure and preparation method for prophetic molecules

No. Structure Prep” P27 13, 15

P28 13, 15

P29 13, 15

NH

P30 13, 15

Cl

P31 13, 15

P32 13, 15

h

Cl US 2016/0302417 A1 Oct. 20, 2016

TABLE P1-continued

Structure and preparation method for prophetic molecules

No. Structure Prep”

P33 C| Cl C| O 13, 15 O CH H 2 tº N O C| N H O

Cl

P34 Cly Cl O Cl 13, 15 O R Cl N >N H O syO

C|

P35 Cly Cl O Cl 13, 15 S {{ Cl N >N H S O O

C|

P36 CI Cl Cl 13, 15 O O H N Cl N H S O

C|

P37 Clv Øl O Cl 13, 15 O H N Cl N H O O

P38 Clº Cl O C| 13, 15 O { C| SN NH O

Cl US 2016/0302417 A1 Oct. 20, 2016 52

TABLE P1-continued Structure and preparation method for prophetic molecules

No. Structure Prep”

P39 CI Cl Cl 13, 15 O O N Cl N >N H NH O O CH3 CH3 C|

P40 Clº Cl O C| 13, 15 O N C| N SN H NH O O

Cl

P41 Clv Cl O Cl 13, 15 O N Cl N >N H O O sº

P42 C| 13, 15 Clº Cl O O F NH sº C| NH F O

Cl

P43 Clº Cl O Cl O 13, 15 H />CH, N N Cl N H H O

C|

P44 CI Cl Cl 13, 15 O O N Cl N >N H N O F F F US 2016/0302417 A1 Oct. 20, 2016 53

TABLE P1-continued

Structure and preparation method for prophetic molecules

No. Structure Prep”

P45 C| Cl O C| 13, 15 O H N C| h N O / \ O CH3

Cl

P46 C| Cl O Cl 13, 15 O H N C| N

H O 2-ch O

C|

P47 Cl C| Cl 13, 15 O O H N Cl N H N O F F F C|

P48 C| Cl C| 13, 15 O O H N C| h N O \ CH3

Cl

P49 Clº Cl O Cl 13, 15 O H N C| N H N–CH, O

C|

Prep” means prepare according to Example or Scheme

US 2016/0302417 A1 Oct. 20, 2016

[0633] The following compounds were prepared in like silica gel:potassium fluoride. Purification by flash column manner to the procedure outlined in Example 26: chromatography using 0-35% ethyl acetate in hexanes as the eluent afforded the title compound as a pale yellow foam (R)-2-Chloro-5-nitro-N-(3-oxo-2-(2,2,2-trifluoro (0.091 g, 61%). ethyl)isoxazolidin-4-yl)benzamide (C108) [0634) Cl Example 30

O N Preparation of trans-5-(3-(4-aminophenyl)-2,2-di chlorocyclopropane-1-carboxamido)-2-chloro-N-(3, 3-difluorocyclobutyl)benzamide (F70)

[0641] Cl C| Cl O H [0635) Isolated as an orange foam (0.355 g, 70%): "H N NMR (300 MHz, DMSO-de) & 9.44 (d. J–7.7 Hz, 1H), h W ) 8.35-8.29 (m, 2H), 7.92-7.81 (m, 1H), 5.15-5.02 (m, 1H), O F 4.72 (t, J–8.6 Hz, 1H), 4.48-4.35 (m, 2H), 4.22 (t, J–8.6 Hz, F 1H); "F NMR (376 MHz, DMSO-d.) 6–69.11; ESIMS m/z H2N 368 (IM+H]"). [0636] The following compounds were prepared in like [0642] To a slurry of trans-2-chloro-5-(2,2-dichloro-3-(4 manner to the procedure outlined in Example 28: nitrophenyl)cyclopropane-1-carboxamido)-N-(3,3-difluoro 2-Chloro-N-(1-cyanocyclopropyl)-N-methyl-5-ni cyclobutyl)benzamide (F69) (60 mg, 0.116 mmol) in metha trobenzamide (C109) nol (1.0 mL) and water (0.36 mL) was added iron powder (32.3 mg, 0.578 mmol) and ammonium chloride (19 mg, [0637] Cl 0.347 mmol). The slurry was stirred at 55° C. for 3 hours. The reaction mixture was filtered through a pad of Celite R N washing with ethyl acetate, and the filtrate was concentrated. Os Nº * Nt Purification by flash column chromatography using 0-100% | ethyl acetate/hexanes as the eluent provided the title com O O pound as an orange foam (0.049 g, 82%). [0638] Isolated as a white solid (0.280 g, 87%); ‘H NMR Example 31 (400 MHz, DMSO-de) & 8.40 (d. J–2.8 Hz, 1H), 8.30 (dd. J–8.8, 2.8 Hz, 1H), 7.87 (d. J–8.8 Hz, 1H), 2.84 (s, 3H), Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,5 1.73-138 (m, 4H); ESIMS m/z 280 (IM+HI*). dichloro-phenyl)-3-methylcyclopropane-1-carbox Example 29 amido)-N-(3,3-difluorocyclobutyl)-benzamide (F61) Preparation of trans-2-chloro-N-(1-cyanocyclopro [0643] pyl)-5-(2,2-dichloro-3-(3-chloro-4-vinylphenyl)cy clopropane-1-carboxamido)benzamide (F67) [0639] Cly Cl O Cl NH *N Cl N H O [0644] To a solution of 5-amino-2-chloro-N-(3,3-difluo rocyclobutyl)benzamide (C71) (0.0623 g, 0.239 mmol) and trans-2,2-dichloro-3-(3,5-dichlorophenyl)-3-methylcyclo [0640] A solution of trans-5-(3-(4-bromo-3-chlorophe propanecarboxylic acid (C2) (0.075 g, 0.239 mmol) in ethyl nyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro acetate (3 mL) were added pyridine (0.058 mL, 0.717 mmol) N-(1-cyanocyclopropyl)benzamide (F66) (0.1 g, 0.178 followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphori mmol), dichlorobis(triphenylphosphine)palladium(II) name-2,4,6-trioxide (T3PR, 50% solution in ethyl acetate, (0.025 g, 0.036 mmol), and tributyl(vinyl)stannane (0.156 304 mg, 0.478 mmol), and the resulting pale-yellow solution mL, 0.169 mmol), in 1,4-dioxane (1 mL) was sealed under was stirred at room temperature for approximately 14 hours. an atmosphere of nitrogen and heated to 90° C. for 1 hour The solution was concentrated under a stream of nitrogen, via microwave irradiation. The reaction was diluted with and purified by silica gel flash column chromatography with ethyl acetate, then filtered through 15 g of 10:1 silica a mobile phase of hexanes/ethyl acetate. The pure fractions gel:potassium carbonate, rinsing with ethyl acetate. The were combined and concentrated under vacuum on a rotary solution was concentrated, and the resulting crude material evaporator to provide the title compound as a white foam was loaded onto a preload cartridge containing 5 g of 5:1 (0.080 g, 59%).

US 2016/0302417 A1 Oct. 20, 2016

[0661) Isolated as a colorless oil (0.076 g. 68%). (C67) (0.150 g, 0.33 mmol) and 3-aminocyclobutan-1-one hydrochloride (0.055 g, 0.36 mmol) in ethyl acetate (3.3 trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-di mL) stirred at 23°C., were added pyridine (0.080 mL, 0.99 chloro-3-(4-(difluoromethyl)-3-fluorophenyl)cyclo mmol), followed by a 50% solution 2,4,6-tripropyl-1,3,5,2, propane-1-carboxamido)benzamide (F90) 4,6-trioxatriphosphiname 2,4,6-trioxide (T3PR) in ethyl [0662] C| acetate (300 pull, 0.50 mmol). The reaction mixture was CI Cl O heated to 50° C. and stirred for 18 hours. The reaction mixture was concentrated, and the residue was purified by N reverse phase flash column chromatography using 5-100% F N H acetonitrile/water as eluent to provide the title product as O white powder (0.031 g, 18%). F [0670] The following compounds were prepared in like manner to the procedure outlined in Example 32: F trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluoro [0663) Isolated as a colorless oil (0.041 g, 38%). phenyl)cyclopropane-1-carboxamido)-N-(4-oxocy clohexyl)benzamide (F81) trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-di chloro-3-(3-(difluoromethyl)-phenyl)cyclopropane [0671] 1-carboxamido)benzamide (F91) C| H [0664] C| N CI Cl O Cly Cl O N C. F § 2.N H N O O.O F H F O Cl

[0665) Isolated as a colorless oil (0.072 g, 69%). [0672) Isolated as white film (0.106 g, 22%). trans-2-Chloro-N-(1-cyanocyclopropyl)-5-(2,2-di chloro-3-(4-(difluoromethyl)-phenyl)cyclopropane Example 33 1-carboxamido)benzamide (F92) Preparation of trans-2-chloro-N-(1-(cyclopropan [0666] C| CI Cl O ecarbonyl)-azetidin-3-yl)-5-(2,2-dichloro-3-(3,5 N dichlorophenyl)cyclopropane-1-carboxamido)benz

N amide (PF9) H O F

F

[0667) Isolated as a colorless oil (0.093 g, 89%). Example 32 Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,5 dichloro-phenyl)cyclopropane-1-carboxamido)-N [0674] Trifluoroacetic acid (0.13 mL, 1.7 mmol) was (3-oxocyclobutyl)benzamide (F68) added to a stirred mixture of trans-tert-butyl 3-(2-chloro-5 (2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarbox [0668] Cl amido)-benzamido)azetidine-1-carboxylate (F54) (0.10 g, 0.17 mmol) in dichloromethane (1.6 mL) at 23° C. The H resulting homogeneous colorless solution was stirred at 23° N C. for 4 hours. The reaction mixture was concentrated, and H the residue was reconstituted in dichloromethane (1.6 mL). C| N \\ Triethylamine (0.050 mL, 0.25 mmol), cyclopropanecarbo nyl chloride (0.018 mL, 0.20 mmol), and 4-dimethylamin º O O opyridine (0.024 g, 0.20 mmol) were added sequentially. Cl The resulting homogeneous colorless solution was stirred at 23°C. for 72 hours. The reaction mixture was concentrated, and the residue was purified by reverse phase flash column [0669] To a mixture of 2-chloro-5-(2,2-dichloro-3-(3,5 chromatography using 5-100% acetonitrile/water as eluent dichlorophenyl)cyclopropane-carboxamido)benzoic acid to provide the title product as a white foam (0.070 g, 74%).

US 2016/0302417 A1 Oct. 20, 2016 67

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophe [0698) Isolated as a white solid (0.042 g, 51%). nyl)cyclopropane-1-carbox-amido)-N-(5-(morpholi nomethyl)-2-oxooxazolidin-3-yl)benzamide (PF41) trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophe nyl)cyclopropane-1-carbox-amido)-N-((R)-2-ethyl [0691] 3-oxoisoxazolidin-4-yl)benzamide (PF45) [0699) O C| O Cl Cl N J. Cl O Cl NH SN' So Cl C| O # \ C| N N O H Cº. H ON O / \ C| ºO CH3

[0692] Isolated as a white solid (0.059 g, 36%). Cl trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophe nyl)cyclopropane-1-carbox-amido)-N-(1-((2,2,2 [0700) Isolated as a white solid (0.060 g, 63%). trifluoroethyl)carbamoyl)cyclopropyl)benzamide (PF42) Example 35 [0693) Preparation of trans-2-chloro-5-(2,2-dichloro-3-(3,4, 5-trichloro-phenyl)cyclopropane-1-carboxamido)-N (1-oxidotetrahydrothiophen-3-yl)-benzamide (PF18) Cl O O Cl < ...Cl H [0701] N F N N C| O F Cl Cl ? H N Cl Cl N H S = O O [0694) Isolated as a white solid (0.091 g, 64%). trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophe Cl nyl)cyclopropane-1-carbox-amido)-N-(1-(ethylcar Cl bamoyl)cyclopropyl)benzamide (PF43) [0695) [0702] To a solution of trans-2-chloro-5-(2,2-dichloro-3 (3,4,5-trichlorophenyl)cyclopropanecarboxamido)-N-(tetra hydrothiophen-3-yl)benzamide (F8) (0.150 g, 0.27 mmol) in Cl glacial acetic acid (2.6 mL) was added sodium perborate O O C| C| N tetrahydrate (0.0630 g, 0.282 mmol). The reaction was 2^ heated to 60° C. and stirred for 4 hours. Saturated aqueous Cl NH NH CH3 sodium bicarbonate was added, and the mixture was extracted with dichloromethane. The combined organic O phases were dried over magnesium sulfate, filtered, and concentrated. The residue was slurried in hexane and vacuum filtered to provide the title compound as a tan C| powder (0.068 g. 44%). [0696) Isolated as a white solid (0.085 g, 62%). Example 36 trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophe Preparation of trans-2,2-dichloro-3-(3,5-dichloro nyl)cyclopropane-1-carbox-amido)-N-(2-oxo-3-(2,2, phenyl)cyclopropane carboxylic acid (C1) 2-trifluoroethyl)imidazolidin-1-yl)benzamide (PF44) [0703) [0697)

Cl C|

Cl US 2016/0302417 A1 Oct. 20, 2016

[0704] Sodium permanganate (40% aqueous) (84 g, 236 trans-2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cy mmol) was added dropwise to a stirred mixture of trans-2, clopropane-1-carboxylic acid (C16) 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carbalde hyde (C115) (58.7 g, 196 mmol) in acetone (982 mL) at 15° [0710) C. The resulting mixture was stirred at 20° C. for 2 hours. The reaction mixture was diluted with isopropyl alcohol (20 mL) and concentrated to remove the acetone. Celite R and Cl C| O aqueous hydrochloric acid (1 N, 295 mL, 295 mmol) were added to the brown residue. The resulting mixture was diluted with ethyl acetate (500 mL) and filtered through Celite R. The filtrate was washed with brine (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting slurry was diluted with heptane F cº (~200 mL) and allowed to solidify at 20°C. The solid was collected, washed with heptane and dried to afford the title [0711] Isolated as a white solid (165 g, 71%): 1H NMR product as a white solid (54.68 g, 91%). "H NMR (300 MHz, (400 MHz, CDC13) & 11.57 (s, 1H), 7.42 (dd, J–8.2, 7.6 Hz, CDC1,) 6 7.36 (t, J–1.9 Hz, 1H), 7.17 (dd, J–1.9, 0.7 Hz, 1H), 7.11-6.98 (m, 2H), 3.46 (d, J–8.2 Hz, 1H), 2.85 (d, 2H), 3.48-3.37 (m, 1H), 2.87 (d. J–8.3 Hz, 1H); *C NMR J-83 Hz, 1H): "F NMR (376 MHz, CDC1,) 8 –114.07; (400 MHz, CDC1,) b 135.44, 135.28, 128.66, 127.30, 39.68, ESIMS m/z 282 (IM-HIT). 36.88, ESIMS m/z =298.9 (IM-HDT. trans-2,2-Dichloro-3-(3-chloro-5-cyanophenyl)cy [0705] The following compounds were prepared in like clopropane-1-carboxylic acid (C110) manner to the procedure outlined in Example 36: [0712] trans-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclo propane-1-carboxylic acid (C2) Cl C| O [0706) N

C| C| O

C| OH sºCl [0713] Isolated as a white solid (2.92 g, 60%); mp 173 C| 175° C.: "H NMR (500 MHz, DMSO-d.) 8 13.42 (s, 1H), Cl 8.03 (t, J–1.7 Hz, 1H), 7.98 (t, J–1.9 Hz, 2H), 3.65 (d. J–8.6 Hz, 1H), 3.57 (d. J–8.6 Hz, 1H); ESIMS m/z 290 ([M]). [0707) Isolated as a white solid (2.78 g, 95%); ‘H NMR Example 37 (400 MHz, DMSO-de) 8 13.41 (s, 1H), 7.81 (d. J–0.6 Hz, 2H), 3.62 (d. J–8.6 Hz, 1H), 3.52 (d. J–8.6 Hz, 1H); ESIMS Preparation of trans-2,2-dibromo-3-(3,5-dichloro m/z 332 (IM—HIT). phenyl)cyclopropane-1-carboxylic acid (C111) [0714] trans-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopro pane-1-carboxylic acid(C3) Br Br O [0708]

C| C| O

ºCl C| [0715] To a solution of trans-2,2-dibromo-3-(3,5-dichlo rophenyl)cyclopropane-1-carbaldehyde (C120) (1.67 g, 4.48 mmol) in acetonitrile (15.4 mL) and water (2.5 mL) was [0709) Isolated as a white solid (124 g, 82%); mp 133 added sodium hydrogen sulfite (3.26 g, 31.4 mmol). The 135° C.: "H NMR (500 MHz, DMSO-d.) 8 13.39 (s, 1H), resultant solution was cooled to 0°C., and sodium chlorite 7.76 (d. J–2.0 Hz, 1H), 7.64 (d. J–8.3 Hz, 1H), 7.44 (dd. (3.54 g, 17.9 mmol) was added slowly. The mixture was J–8.4, 2.1 Hz, 1H), 3.49 (s. 2H). "C NMR (126 MHz, stirred while slowly warming to room temperature over DMSO-de) & 166.34, 133.35, 130.47, 130.33, 130.09, 129. night. The mixture was then diluted with aqueous hydro 77, 128.81, 61.43, 37.00, 36.06. chloric acid solution (1 N) until the pH was equal to or less US 2016/0302417 A1 Oct. 20, 2016 69 than 3. The mixture was then repeatedly extracted with ethyl [0720) Isolated as a clear colorless oil (0.088 g, 57%); H acetate, and the combined extracts were dried over sodium NMR (400 MHz, Acetone-de) & 7.60-7.27 (m, 3H), 2.81 (s, sulfate, filtered, and concentrated in vacuo. Purification of 1H), 1.77 (s, 3H); *C NMR (101 MHz, Acetone-de) & the crude solid by flash column chromatography using 166.50, 141.92, 134.78, 129.66, 128.50, 128.26, 127.93, 0-100% ethyl acetate/hexanes as eluent provided the title 67.25, 42.16, 41.58, 30.43, 30.24, 30.05, 29.97, 29.85, compound as a light brown solid (0.91 g, 52%); ‘H NMR 29,77, 29.66, 29.57, 29.47, 29.28, 28.71, 20.20, ESIMS m/z (400 MHz, CDC1,) 67.36 (t, J–1.9 Hz, 1H), 7.17 (dd, J–1.9, 0.8 Hz, 2H), 3.39 (d. J–8.2 Hz, 1H), 2.91 (d. J–8.2 Hz, 1H); 313 (IM—HIT). *C NMR (101 MHz, CDC1,) 8 172.15, 136.91, 135.25, trans-2,2-Dichloro-3-(4-nitrophenyl)cyclopropane-1 128.64, 127.29, 40.29, 37.32, 26.57, ESIMS m/z 386 (IM— H]-). carboxylic acid (C114) Example 38 [0721] Preparation of trans-2,2-dichloro-3-(3,5-dichloro phenyl)-3-methylcyclopropane-1-carboxylic acid Cl C| O (C112) [0716] OH

Cl C| O OSN + H3C Cl OH O

[0722) Isolated as a pink solid (0.158 g, 48%): "H NMR (400 MHz, CDC13) & 8.26 (d. J–8.3 Hz, 2H), 7.47 (d. J–8.4 Cl Hz, 2H), 3.57 (d. J–83 Hz, 1H), 2.98 (d. J–8.3 Hz, 1H); *C NMR (101 MHz, CDC1,) b 171.34, 147.88, 139.21, 129.75, [0717) trans-2,2-Dichloro-3-(3,5-dichlorophenyl)-3 123.85, 61.33, 40.14, 37.43, IR (thin film) 2923, 2603, 1709, methylcyclopropyl)methanol (C136) (1.16 g, 3.87 mmol) 1601, 1520, 1446 cm-"; ESIMS m/z 273.9 (IM—HIT). was added to a stirring solution of Jones reagent (4.02 g, 18.6 mmol) in acetone (20 mL) at 5° C. The mixture was Example 39 stirred for 2 hours at 0-5°C. and then for 12 hours at room temperature. The resulting brown suspension was cooled to Preparation of trans-2,2-dichloro-3-(3,5-dichloro 5° C. and quenched with isopropyl alcohol (20 mL), fol phenyl)cyclopropane-1-carbaldehyde (C115) lowed by water (100 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts [0723] were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure on a rotary evaporator. The crude product was C| Cl purified by C-18 flash chromatography with acetonitrile/ water as eluent to give trans-2,2-dichloro-3-(3,5-dichloro phenyl)-3-methylcyclopropanecarboxylic acid (0.727 g 59%) as a white solid: "H NMR (400 MHz, Acetons dº) b 7.49 (dd, J–18.6, 1.9 Hz, 3H), 3.11 (s, 1H), 1.78 (s, 3H); **C NMR (101 MHz, Acetone-de) & 166.55, 146.09, 135.70, 129.69, 128.49, 128.26, 66.75, 41.87, 39.59, 30.41, 30.21, 30.02, 29.83, 29.64, 29.55, 29.45, 29.25, 20.18; ESIMS m/z 313 (IM—HIT). [0718] The following compounds were prepared in like manner to the procedure outlined in Example 38: [0724] Aqueous hydrochloric acid (2 N, 237 mL) was added to a stirred solution of 1,3-dichloro-5-((trans-2,2 cis-2,2-Dichloro-3-(3,5-dichlorophenyl)-3-methylcy dichloro-3-(diethoxymethyl)cyclopropyl)benzene (C121) clopropane-1-carboxylic acid (C113) (85.7 g, 227 mmol) in acetonitrile (1184 mL). The mixture [0719) was stirred at 20°C. for 16 hours. The resulting mixture was diluted with water (200 mL) and concentrated to remove the acetonitrile. The resulting aqueous mixture was extracted Cl C| with hexanes (600 mL). The organic layer was washed water (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash col umn chromatography using 0-20% ethyl acetate/hexanes as eluent to afford the title product as a yellow oil (58.7 g, 86%, purity 95%). "H NMR (400 MHz, CDC1,) 69.54 (d. J–40 Cl OH Hz, 1H), 7.46-7.09 (m, 3H) 3.51 (d. J–8.0 Hz, 1H), 2.92 (dd, J–8.0, 40 Hz, 1H); *C NMR (126 MHz, CDC1,) 6 193.41, 135.33, 135.09, 128.78, 127.34, 42.89, 39.31, IR Cl (thin film) 3078, 2847, 1714, 1590, 1566, 1417, 1387. [0725] The following compounds were prepared in like manner to the procedure outlined in Example 39: US 2016/0302417 A1 Oct. 20, 2016 70

trans-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopro 1.9, 14, 0.5 Hz, 1H), 7.52 (td, J–1.8, 0.7 Hz, 1H), 7.48 (td, pane-1-carbaldehyde (C116) 1.5, 0.7 Hz, 1H), 3.56 (dq, J–8.0, 0.6 Hz, 1H), 2.98 (dd, 8.0, 3.7 Hz, 1H). [0726) C| Cl O Example 40 Preparation of trans-2,2-dibromo-3-(3,5-dichloro phenyl)cyclopropane-1-carbaldehyde (C120) [0734] ºC| [0727) Isolated as orange oil (143 g, 98%): "H NMR (400 MHz, CDC1,) 6 9.53 (d. J–4.1 Hz, 1H), 7.47 (d. J–8.3 Hz, 1H), 7.37 (dd, J–2.2, 0.7 Hz, 1H), 7.12 (ddd, J–8.3, 2.2, 0.7 Hz, 1H), 3.51 (dd, J–7.9, 0.8 Hz, 1H), 2.90 (dd, J–8.0, 4.1 Hz, 1H). trans-2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cy clopropane-1-carbaldehyde (C117) [0735] To a solution of (E)-1,3-dichloro-5-(3,3-diethoxy | 0.728| C| Cl O prop-1-en-1-yl)benzene (C126) (500 mg, 1.817 mmol) in bromoform (12.1 mL) were added tetrabutylammonium hexafluorophosphate(V) (70.4 mg, 0.182 mmol) followed by solid sodium hydroxide (Careful! Add slowly! 1454 mg, 36.3 mmol). The mixture was heated to 90°C. while stirring overnight. The mixture was then diluted with dichlorometh ane and water and extracted with additional dichlorometh >F * ane. The organic layer was then dried over sodium sulfate and concentrated. Purification by flash column chromatog [0729) Isolated as an orange oil (230 g, 97%); ‘H NMR raphy using 0-100% ethyl acetate/hexanes as eluent pro (300 MHz, CDC1,) 8 9.52 (d. J–4.2 Hz, 1H), 736-7.30 (m, vided the resulting elutant, which was then dissolved in 1H), 7.19-7.16 (m, 1H), 7.15 (d. J–12 Hz, 1H), 3.51 (dt, acetone (4 mL) and aqueous hydrochloric acid (2 N, 1 mL, J–7.9, 0.7 Hz, 1H), 2.88 (dd, J–7.9, 4.2 Hz, 1H). 2 mmol). The mixture was stirred overnight. The mixture was diluted with saturated sodium bicarbonate solution until trans-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclo the pH of the solution was greater than 7. The mixture was propane-1-carbaldehyde (C118) then extracted with diethyl ether and ethyl acetate, and the combined organic layers were dried over sodium sulfate and [0730) C| Cl concentrated providing the dark brown product (0.03 g, 4%): *H NMR (400 MHz, CDC1,) 69.48 (d. J–4.0 Hz, "H), 7.37 (t, J–1.9 Hz, 1H), 7.17 (dd, J–1.9, 0.7 Hz, 2H), 3.60-3.36 (m, 1H), 2.90 (dd, J–7.9, 4.0 Hz, 1H); "C NMR (101 MHz, CDC1,) b 194.74, 136.55, 135.31, 128.76, 127.34, 42.34, 39.84, 26.05; ESIMS m/z 343 (IM-CHOIT). Example 41 Preparation of 1,3-dichloro-5-(trans-2,2-dichloro-3 (diethoxy-methyl)cyclopropyl)benzene (C121) [0731) Isolated as a yellow solid (2.8 g. 69%); ‘H NMR (400 MHz, CDC1,) 69.55 (d. J–3.9 Hz, 1H), 7.30 (d. J–0.7 [0736] Hz, 2H), 3.48 (dt, J–8.0, 0.8 Hz, 1H), 2.92 (dd, J–7.9, 3.9 Hz, 1H). Cl C| trans-3-Chloro-5-(2,2-dichloro-3-formylcyclopropyl) CH3 benzonitrile (C119) Cl CH3 [0732]0732 Clº Cl O

N

[0737] A 1 L 4-neck flask equipped with a mechanical stirrer, condenser, temperature probe and nitrogen inlet was sºCl charged with (E)-1,3-dichloro-5-(3,3-diethoxyprop-1-en-1 yl)benzene (C126) (40 g, 138 mmol) and CHC1s (447 mL). [0733) Isolated as a yellow solid (2.9 g, 77%); ‘H NMR Tetrabutylammonium hexafluorophosphate(V) (1.081 g, (300 MHz, CDCl3) & 9.59 (d. J–3.6 Hz, 1H), 7.65 (ddd, 2.76 mmol) was added. The light yellow solution was heated

US 2016/0302417 A1 Oct. 20, 2016

[0759| Ethyl 2-(diethoxyphosphoryl)acetate (7.41 g, 33.1 [0763| 3,4-Dihydro-2H-pyran (1.05, 12.45 mmol) was mmol) was added dropwise to a stirred mixture of sodium added dropwise to a stirred solution of (E)-3-(3,5-dichloro hydride (60% oil dispersion) (1.32 g, 33.1 mmol) in anhy drous tetrahydrofuran (50 mL) at 5°C. Upon completion of phenyl)but-2-en-1-ol (C132) (1.59 g, 7.32 mmol) and the addition, the resulting solution was stirred for another 30 p-toluenesulfonic acid monohydrate (0.07 g., 0.366 mmol) in minutes at 0°C., followed by the addition of 3,5-dichloro anhydrous ether (50 mL) at 0°C. The solution was allowed acetophenone (5.0 g, 26.5 mmol) dissolved in tetrahydro to warm to room temperature and stirred for another 12 furan (10 mL). The resulting pale yellow oil suspension was hours. The reaction mixture was quenched with water (100 stirred at room temperature for 12 hours. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ether (3×50 mL). The combined mL). The aqueous mixture was extracted with ethyl ether organic extracts were washed with water and brine, dried (3×50 mL). The combined organic extracts were washed over anhydrous magnesium sulfate, filtered, and concen with water and brine, dried over anhydrous magnesium trated under reduced pressure on a rotary evaporator to give sulfate, filtered, and concentrated under reduced pressure on (E)-2-((3-(3,5-dichlorophenyl)but-2-en-1-yl)oxy)tetra a rotary evaporator. The crude product was purified by silica gel flash chromatography (hexanes/ethyl acetate mobile hydro-2H-pyran (2.17 g, 93%) as a clear colorless oil. phase) to give ethyl-3-(3,5-dichlorophenyl)but-2-enoate [0764] The following compounds were prepared in like (5.69 g, 79%) as a mixture of E- (85%) and Z- (15%) manner to the procedure outlined in Example 45: 1SOImerS. Example 44 (E)-2-((3-(4-Nitrophenyl)allyl)oxy)tetrahydro-2H Preparation of (E)-3-(3,5-dichlorophenyl)but-2-en pyran (C134) 1-ol (C132) [0760) [0765)

Cl S O OH C| 2. OSN CH3 O [0761] Diisobutylaluminum hydride (1.5 M solution in toluene, 33 mL, 48.3 mmol) was added dropwise to a stirred solution of ethyl-3-(3,5-dichlorophenyl)but-2-enoate (C131) (5.69 g, 21.95 mmol) in anhydrous toluene (50 mL) [0766) Isolated as a yellow oil (2.25 g, 97%); ‘H NMR at –78°C. Upon completion of the addition, the yellowish (400 MHz, CDC1,) 58.26-8.09 (m, 2H), 7.57-744 (m, 2H), solution was stirred at –78°C. for another 2 hours and then 6.79-6.63 (m, 1H), 6.51 (ddd, J–16.0, 5.8, 5.2 Hz, 1H), 4.71 allowed to warm to room temperature. After 11 hours, the (dd, J–4.2, 3.0 Hz, 1H), 4.46 (ddd, J–13.9, 5.2, 1.7 Hz, 1H), reaction mixture was carefully quenched with aqueous 4.20 (ddd, J–13.9, 5.9, 1.6 Hz, 1H), 3.91 (ddd, J–11.2, 8.2, hydrochloric acid (1 N, 50 mL) and extracted with toluene 3.3 Hz, 1H), 3.65-3.47 (m, 1H), 1.96-1.36 (m, 6H); "C (3×50 mL). The combined organic extracts were washed NMR (101 MHz, CDC1,) b 146.95, 143.36, 131.36, 129.36, with water and brine, dried over anhydrous magnesium 126.93, 123.98, 98.33, 67.10, 62.34, 30.58, 25.41, 19.44; IR sulfate, filtered, and concentrated under reduced pressure on a rotary evaporator. The crude product was purified by silica (thin film) 2939, 2849, 1595, 1513, 1339 cm-". gel flash chromatography (hexanes/ethyl acetate mobile phase) to give (Z)-3-(3,5-dichlorophenyl)but-2-en-1-ol Example 46 (0.316 g. 6.3%) as a clear colorless oil and (E)-3-(3,5 dichlorophenyl)but-2-en-1-ol (1.59 g, 32%) as a clear col orless oil. Preparation of trans-2-((2,2-dichloro-3-(3,5-dichlo rophenyl)-3-methylcyclopropyl)methoxy)tetrahydro Example 45 2H-pyran (C135) Preparation of (E)-2-((3-(3,5-dichlorophenyl)but-2 en-1-yl)oxy)tetrahydro-2H-pyran (C133) [0767] [0762]

CH3 Cl S US 2016/0302417 A1 Oct. 20, 2016 74

[0768| Powdered sodium hydroxide (2.92 g, 73 mmol) and tetrabutylammonium hexafluorophosphate(V) (0.037 g. was added portionwise to a stirring solution of (E)-2-((3-(3, 0.095 mmol) in chloroform (6.33 mL) was added powdered 5-dichlorophenyl)but-2-en-1-yl)oxy)tetrahydro-2H-pyran sodium hydroxide (1.139 g, 28.5 mmol), and the reaction (C133) (2.17 g, 7.3 mmol) and tetrabutylammonium mixture was vigorously stirred at room temperature for 18 hexafluorophosphate(V) (0.283 g, 0.730 mmol) in chloro form (20 mL). The resulting yellow suspension of solids was hours. The reaction mixture was diluted with water and heated to 55° C. for a total of 7 hours and stirred at room dichloromethane, and the layers were separated. The organic temperature for an additional 12 hours. The reaction mixture layer was concentrated and purified by flash column chro was quenched with water (100 mL) and extracted ether (with matography giving 2-((trans-2,2-dichloro-3-(4-nitrophenyl) 3×50 mL). The combined organic extracts were washed with cyclopropyl)methoxy)-tetrahydro-2H-pyran as a mixture of water and brine, dried over anhydrous magnesium sulfate, diastereomers. The mixture was dissolved in methanol (10 filtered, and concentrated under reduced pressure on a rotary mL). To the methanol solution was added p-toluenesulfonic evaporator. The crude product was purified by silica gel flash acid (0.020 g, 0.107 mmol), and the reaction mixture was chromatography (hexanes/ethyl acetate mobile phase) to stirred at room temperature for 18 hours. give trans-2-((2,2-dichloro-3-(3,5-dichlorophenyl)-3-meth ylcyclopropyl)methoxy)tetrahydro-2H-pyran (2.03 g, 69%) [0773] The reaction mixture was quenched with saturated as a clear colorless oil. sodium bicarbonate and extracted with ethyl acetate (2x). The combined organic layers were dried over sodium sul Example 47 fate, filtered, and concentrated giving the title compound as a yellow oil (310 mg, 53% over 2 steps): "H NMR (400 Preparation of trans-2,2-dichloro-3-(3,5-dichloro MHz, CDC1,) 58.22 (d. J–8.7 Hz, 2H), 7.52-7.34 (m, 2H), phenyl)-3-methylcyclopropyl)methanol (C136) 4.10 (ddd, J–12.4, 7.2, 5.3 Hz, 1H), 3.95 (ddd, J–12.0, 8.0, 5.0 Hz, 1H), 2.78 (d. J–8.3 Hz, 1H), 2.37 (td, J–8.2, 5.4 Hz, [0769) 1H); "C NMR (101 MHz, CDC1,) b 147.43, 14142, 129,77, 123.59, 63.74, 62.25, 38.50, 37.04; IR (thin film) 1598, 1514, 1345, 1046 cm-"; HRMS-ESI (m/z) [M+Na]” Cl C| calcd for CoEI,C1,NOANa, 283.9852, found, 283.9844. Example 49 Preparation of 1-bromo-2-chloro-4-(trans-2,2-di chloro-3-(4-methoxyphenyl)cyclopropyl)benzene Cl (C138) [0774] [0770] p-Toluenesulfonic acid monohydrate (0.101 g, 0.528 mmol) was added to a stirring solution of trans-2-((2, 2-dichloro-3-(3,5-dichlorophenyl)-3-methylcyclopropyl) O methoxy)tetrahydro-2H-pyran (C135) (2.03 g, 5.28 mmol) C| Cl O NoH, in methanol (20 mL). The mixture was stirred for 11 hours C| /\ at room temperature and then was concentrated under vacuum on a rotary evaporator. Purification by silica gel flash chromatography (hexanes/ethyl acetate mobile phase) gave trans-2,2-dichloro-3-(3,5-dichlorophenyl)-3-methylcy Br clopropyl)methanol (1.16 g, 70%) as a pale yellow oil. Example 48 [0775] To a stirred solution of (E)-1-bromo-2-chloro-4-(4 methoxystyryl)benzene (C142) (0.38 g, 1.174 mmol) and Preparation of trans-(2,2-dichloro-3-(4-nitrophenyl) tetrabutylammonium hexafluorophosphate(V) (0.045 g, cyclopropyl)-methanol (C137) 0.117 mmol) in chloroform (5.61 g, 3.77 mL, 47.0 mmol) was added aqueous sodium hydroxide (50%, 2.348 g, 29.4 [0771) mmol), and the resulting mixture was stirred vigorously at room temperature for 40 hours. The reaction mixture was diluted with water and was extracted with dichloromethane. C| Cl The combined organic layers were dried over sodium sul fate, filtered, and concentrated. Purification by flash column OH chromatography using 0-10% ethyl acetate/hexanes as the eluent provided the title compound as a colorless oil (0.362 g, 72%); H NMR (400 MHz, CDC1,) 8 7.62 (d. J–83 Hz, 9s N 1H), 7.46 (d. J–2.0 Hz, 1H), 7.29-7.23 (m, 2H), 7.13 (dd. J–8.3, 2.1 Hz, 1H), 6.93 (d. J–8.7 Hz, 2H), 3.83 (s, 3H), 3.12 O (d. J–8.7 Hz, 1H), 3.07 (d. J–8.7 Hz, 1H); "C NMR (101 MHz, CDCl3) & 159.43, 135.68, 134.63, 133.68, 130.80, 129.90, 128.49, 125.81, 121.83, 114.01, 64.86, 55.33, 39.54, [0772] To a stirred solution of (E)-2-((3-(4-nitrophenyl) 38.85; IR (thin film) 3356 (br), 3002, 2835, 1514, 1248 allyl)oxy)tetrahydro-2H-pyran (C134) (0.5 g, 1.899 mmol) cm ". US 2016/0302417 A1 Oct. 20, 2016

[0776] The following compounds were prepared in like [0782) Isolated as a yellow oil (0.37 g, 59%); ‘H NMR manner to the procedure outlined in Example 49: (400 MHz, CDC1,) 6 7.31-7.23 (m, 3H), 6.98 (d. J–11.6 Hz, 1H), 6.96-6.90 (m, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.13 (d, 2-Bromo-5-(trans-2,2-dichloro-3-(4-methoxyphenyl) J–8.8 Hz, 1H), 3.07 (d.J–8.8 Hz, 1H); "CNMR (101 MHz, cyclopropyl)-1,3-difluorobenzene (C139) CDC1,) b 15938, 152.57, 147,73, 129.93, 127.93, 125.93, 120.63, 117.66, 117.23, 113.97, 65.40, 56.57, 55.33, 40.10, [0777] 39.59; *F NMR (376 MHz, CDC1,) 8 –135.58. Example 50 O Preparation of (E)-1-bromo-2-chloro-4-(4-methox ystyryl)benzene (C142) Cl C| O NoH, [0783)

F C /\ O NCH, Br

F Cl S

[0778] Isolated as a yellow solid (3.44 g, 79%); mp Br 104.0-109.3° C.; H NMR (400 MHz, CDC1,) & 728-7.22 (m, 2H), 7.02-6.96 (m, 2H), 6.96-6.90 (m, 2H), 3.83 (s, 3H), [0784] To a stirred solution of diethyl (4-methoxybenzyl) 3.12 (d. J–8.7 Hz, 1H), 3.08 (d. J–8.7 Hz, 1H); "C NMR phosphonate (0.619 mL, 2.73 mmol) in N,N-dimethylfor (101 MHz, CDC13) & 161.10, 159.49, 129.86, 125.47, 114. mamide (3 mL) at 0°C. was added a solution of sodium 04, 112.79, 112.56, 112.53, 64.66, 55.33, 39.77, 39.01: "F methoxide (5.4 M in methanol, 0.844 mL, 4.56 mmol). NMR (376 MHz, CDC1,) 8 –104.75. 4-Bromo-3-chlorobenzaldehyde (0.5 g, 2.278 mmol) in N,N-dimethylformamide (1 mL) was added, and the reaction 2-Bromo-5-(trans-2,2-dichloro-3-(4-methoxyphenyl) mixture was heated to 65° C. for 4 hours. The reaction cyclopropyl)-1-fluoro-3-methoxybenzene (C140) mixture was allowed to cool to room temperature and was partitioned between water and ethyl acetate. The organic [0779) layer was dried over magnesium sulfate, filtered, and con centrated. Purification by flash column chromatography O using 0-10% ethyl acetate/hexanes as the eluent provided the Cl C| title compound as a yellow crystalline solid (0.484 g, 59%). O NCH, mp 77-88°C.; H NMR (400 MHz, CDC1,) 8 7.58-7.53 (m, O /\ 2H), 747-7.39 (m, 2H), 7.22 (dd, J–8.4, 2.1 Hz, 1H), 7.06 (d, J–16.2 Hz, 1H), 6.95-6.87 (n, 2H), 6.84 (d. J–16.3 Hz, 1H), 3.84 (s, 3H); EIMS m/z 324. Ho’ C Example 51 Br Preparation of (E)-2-bromo-1,3-difluoro-5-(4 F methoxystyryl)benzene (C143) and (E)-2-bromo-1 fluoro-3-methoxy-5-(4-methoxystyryl)benzene [0780) Isolated as a yellow oil (1.18 g, 76%); ‘H NMR (C144) (400 MHz, CDC13) & 7.30-7.26 (m, 2H), 6.96-6.91 (m, 2H), [0785] 6.80-6.74 (m, 1H), 6.70 (d, J-1.6 Hz, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.15-3.07 (m, 2H); "C NMR (101 MHz, CDC1,) 6 161.20, 159.43, 136.09, 135.99, 129.91, 125.85, 114.01, C143 109.29, 109,05, 108.20, 64.91, 56.79, 55.33, 39.59, 39.49; °F NMR (376 MHz, CDC1,) 8 –104.96. 1-Bromo-5-(trans-2,2-dichloro-3-(4-methoxyphenyl) cyclopropyl)-3-fluoro-2-methoxybenzene (C141)

[0781) Br

CI Cl NoH,

Br US 2016/0302417 A1 Oct. 20, 2016 76

[0786] To a stirred solution of diethyl (4-methoxybenzyl) Example 53 phosphonate (5.54 mL, 24.43 mmol) in N,N-dimethylfor Preparation of (E)-3-chloro-5-(4-methoxystyryl) mamide (27 mL) at 0°C. was added a solution of sodium benzaldehyde (C146) methoxide (5.4 M in methanol, 4.52 mL, 24.43 mmol). 4-Bromo-3,5-difluorobenzaldehyde (4.5 g. 20.36 mmol) in [0789) N,N-dimethylformamide (9 mL) was added, and the reaction mixture was heated to 65° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and con centrated. Purification by flash column chromatography using 0-10% ethyl acetate/hexanes as the eluent provided (E)-2-bromo-1,3-difluoro-5-(4-methoxystyryl)benzene (C143) as a white solid (3.28 g, 47%) and (E)-2-bromo-1 fluoro-3-methoxy-5-(4-methoxystyryl)benzene (C144) as a white solid (1.19 g, 16%). C143: mp 104.1-112.7° C.; "H [0790] To a stirred solution of 3-bromo-5-chlorobenzal NMR (400 MHz, CDC1,) 67.48-741 (m, 2H), 7.10-7.02 (m, dehyde (20.0 g, 91.32 mmol) in dimethylacetamide, 1-methoxy-4-vinylbenzene (18.3 g, 136.9 mmol) and trieth 3H), 6.94-6.88 (m, 2H), 6.82 (d, J–16.2 Hz, 1H), 3.84 (s, ylamine (50.5 mL, 273.96 mmol) were added, and the 3H); "F NMR (376 MHz, CDC1,) 8 –106.11; EIMS m/z reaction mixture was degassed with argon for 5 minutes. 324.0. C144: mp 118.5-123.0° C.; H NMR (400 MHz, Palladium(II) acetate (410 mg, 1.83 mmol) and tri-o-tolyl CDC1,) 6 7.45 (d. J–8.6 Hz, 2H), 7.06 (d. J–16.2 Hz, 1H), phosphine (1.11 g, 3.65 mmol) were added, and the resulting 6.91 (dd, J–9.1, 2.2 Hz, 3H), 6.86 (d, J–16.2 Hz, 1H), 6.78 reaction mixture was heated to 100° C. for 16 hours. The reaction mixture was poured into water and extracted with (t, J–1.5 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H); *F NMR (376 ethyl acetate. The combined organic layer was dried over MHz, CDCl3) 6–106.15, EIMS m/z 336.0. sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography using 5-10% ethyl acetate in petroleum Example 52 ether as the eluent to afford the title compound as a yellow solid (13.5g, 54%); ‘H NMR (300 MHz, CDC1,) 59.99 (s. Preparation of (E)-1-bromo-3-fluoro-2-methoxy-5 1H), 7.85 (s, 1H), 7.69 (s. 2H), 7.47 (d. J–8.4 Hz, 2H), 7.16 (4-methoxy-styryl)benzene (C145) (d, J–16.2 Hz, 1H), 6.94 (t, J–8.4 Hz, 3H), 3.84 (s, 3H): ESIMS m/z 273 (IM+H]*). [0791] The following compounds were prepared in like [0787] manner to the procedure outlined in Example 53: (E)-2-Chloro-5-(4-methoxystyryl)benzaldehyde O (C147) NoH, [0792] F S

H3C3 No C

Br

[0788] To a stirred solution of diethyl (4-methoxybenzyl) phosphonate (1.85 mL, 8.14 mmol) in N,N-dimethylforma [0793) Isolated as a pale yellow solid (11.8 g. 27%); H mide (9 mL) at 0° C. was added a solution of sodium NMR (300 MHz, CDC1,) b 10.45 (s, 1H), 8.02 (s, 1H), 7.62 methoxide (5.4 M in methanol, 1.38 mL, 7.47 mmol). (d, J–6.4 Hz, 1H), 7.46-7.40 (m, 3H), 7.12 (d. J–16.4 Hz, 3-Bromo-4,5-fluorobenzaldehyde (1.5 g. 6.79 mmol) in 1H), 6.95-6.90 (m, 3H), 3.95 (s, 3H); ESIMS m/z 273 N,N-dimethylformamide (3 mL) was added, and the reaction (IM+H]"). mixture was heated to 65° C. for 2 hours. The reaction (E)-3-Fluoro-5-(4-methoxystyryl)benzaldehyde mixture was allowed to cool to room temperature and was (C148) partitioned between water and ethyl acetate. The organic [0794) layer was dried over magnesium sulfate, filtered, and con centrated. Purification by flash column chromatography using 0-10% ethyl acetate as the eluent provided (E)-1 bromo-3-fluoro-2-methoxy-5-(4-methoxystyryl)benzene as a white solid (0.48 g. 20%): mp 78.0-84.8° C.; H NMR (400 MHz, CDC1,) 67.47 (d. J–8.7 Hz, 2H), 7.39 (d. J–12.5 Hz, 1H), 7.19 (dd, J–16.1, 1.7 Hz, 1H), 7.14 (d. J–8.1 Hz, 1H), 6.94-6.89 (m, 2H), 6.86 (d, J–16.2 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H); *F NMR (376 MHz, CDCl3) 6–135.86; EIMS m/z 336.0.

US 2016/0302417 A1 Oct. 20, 2016 79

(E)-1-(Difluoromethyl)-4-(4-methoxystyryl)benzene room temperature overnight. The reaction was concentrated (C161) under reduced pressure and the residue partitioned between ethyl acetate and hydrochloric acid (1 N). Phases were cut [0821] and the organic layer was washed with hydrochloric acid (1 N) followed by saturated aqueous sodium bicarbonate solu tion and then brine. The organic layer was concentrated and O the residue purified by column chromatography using 0-30% Ethyl acetate/hexanes to yield the title compound as a white S C NCH, solid (0.058 g, 21%): "H NMR (400 MHz, CDC1,) 58.57 (d. J–2.7 Hz, 1H), 8.26 (dd, J–8.8, 2.8 Hz, 1H), 7.63 (d. J–8.8 Hz, 1H), 6.53 (s, 1H), 3.70-3.52 (m, 1H), 2.05-1.91 (m, 1H), 1.62-1.48 (m, 1H), IR (thin film) 3268, 1661, 1538 cm '; ESIMS m/z 277 (IM+H]*). Example 57 [0822) Isolated as an off-white solid (15.4 g, 75%); H NMR (300 MHz, CDC13) & 7.57-7.45 (m, 6H), 7.12 (d. J–15.9 Hz, 1H), 7.00-6.89 (m, 3H), 6.64 (t, J–57 Hz, 1H), Preparation of (1R,3R)-2,2-dichloro-3-(3,5-dichlo 3.92 (s, 3H), ESIMS m/z 260.17 (IM+H]*). rophenyl)-cyclopropane-1-carboxylic acid (C164) Example 55 [0827) Preparation of 3-aminocyclobutan-1-one hydrochloride (C162) Cl C| O [0823] X2, Cl w" (R) (R) OH

Cl [0824] To a solution of tert-butyl (3-oxocyclobutyl)car bamate (1.0 g, 5.1 mmol) in dichloromethane (34 mL) at 23° [0828] 1% resolution; (R)-1-Phenylethanamine (6.49 g, C. was added a 4 M solution of hydrochloric acid in 53.0 mmol) was slowly added to a stirred solution of 1,4-dioxane (6.4 mL, 26 mmol). The reaction mixture was rac-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-car stirred at 23° C. for 24 hours. The reaction mixture was concentrated to provide the title compound as an off-white boxylic acid) (32.45 g, 106 mmol) in acetone (106 mL). The powder (0.620 g, 100%); ‘H NMR (400 MHz, DMSO-de) 6 resulting solution was stirred at 45° C. After a solid began 8.55 (br's, 3H), 3.92 (m, 1H), 3.44-3.34 (m, 2H), 3.32-3.22 to deposit, the mixture was placed at 5° C. for 4 hours. The (m, 2H). solid was collected, washed with minimal cold acetone and dried. The white solid salt was diluted with ethyl acetate Example 56 (100 mL) and washed with aqueous hydrochloric acid (1 N, 10 mL) and brine (30 mL). The organic layer was dried over Preparation of 2-chloro-N-(2,2-difluorocyclopro sodium sulfate, filtered and concentrated to afford the title pyl)-5-nitrobenzamide (C163) product as a white solid (10.33 g, 88% enantiomeric excess “ee”). [0825] [0829] 2" resolution; (R)-1-Phenylethanamine (3.4 g, 28 mmol) was slowly added to a stirred solution of rac-2,2' Cl dichloro-3-(3,5-dichlorophenyl)cyclopropane-carboxylic acid) (10.33 g, 88% ee) in acetone (100 mL). After 2 hours, H F a solid was collected, washed with minimal cold acetone and N dried. The solid was treated with aqueous hydrochloric acid O2N NA to afford the title compound as a white solid (7.84 g, 97% ee. O 24.2%); Specific Rotation: +47.4 (10 mg/mL in acetonitrile, 589 mm, 25.2° C.); ‘H NMR (300 MHz, CDC1,) 8 7.36 (t, J–1.9 Hz, 1H), 7.17 (dd, J–1.9, 0.7 Hz, 2H), 3.48-3.37 (m, [0826] To a solution of 2-chloro-5-nitrobenzoic acid (0.2 g, 0.992 mmol) in dry dichloromethane (4 mL) cooled in an 1H), 2.87 (d. J–83 Hz, 1H); "C NMR (400 MHz, DMSO ice bath was added 1 drop of N,N-dimethylformamide de) & 166.28, 136.40, 133.39, 127.27, 127.04, 61.36, 37.10, followed by oxalyl chloride (0.130 mL, 1.488 mmol). The 35.98; ESIMS m/z 298.9 (IM-HIT). reaction was warmed to room temperature and stirred for 30 [0830) ee was determined by Chiral HPLC method as min. Separately, 2,2-difluorocyclopropanamine hydrochlo follows: Column: CHIRALPAKR ZWDK(+), particle size 3 ride (0.257 g, 1.984 mmol) and triethylamine (0.691 mL, pum, dimension 3 mm ×150 mmL, DAIC 511584; Mobile 4.96 mmol) were slurried in dichloromethane (4 mL). The phase: 49% acetonitrile/49% methanol/water with 50 mM slurry was cooled in an ice bath and the acid chloride formic acid and diethylamine; Flow rate: 0.5 mL/min: Time: solution slowly added. The resulting mixture was warmed to 9 min; Temperature: 25° C. US 2016/0302417 A1 Oct. 20, 2016

[0831] The following compounds were prepared in like [0839] The mother liquor from 1" R,R-acid resolution manner to the procedure outlined in Example 57: (from example 33) was concentrated and dissolved in acetone (~100 mL) and warmed to 45° C. With swirling, (1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclo (S)-1-phenylethanamine (5.0 g, 41.2 mmol, 0.8 eq.) was propane-1-carboxylic acid (C165) added. The resulting solution was stirred at 45° C. After a solid began to deposit, the mixture placed at 5° C. for 2 [0832] hours. A solid was collected, washed with minimal cold acetone and vacuum-dried at 35° C. The solid was treated with HCl (aq) to provide the free S.S.-acid as a white solid Cl C| O (9.87 g. 85% ee, 59% yield). A second resolution of the 85% ee combined S.S.-acid (13.45 g, 41.7 mmol, 85% ee) using the same procedure with (S)-1-phenylethanamine (3.8 g. Cl w" X2.or (R) OH 31.3 mmol, 0.75 eq.) provided S.S.-acid as a white solid (8.53 g 99% ee, 26% yield). Specific Rotation: –51.9 (10 mg/mL in ACN, 589 mm, 25.2° C.). Analytical data are Cl consistent with racemic acid C1 [0840] ee was determined by Chiral HPLC method as follows: Column: CHIRALPAKR ZWDK(+), particle size 3 [0833) Isolated as a white solid (6.7 g, 30%, 96% ee). pum, dimension 3 mm ×150 mmL, DAIC 511584; Mobile Analytical data are consistent with racemic acid Cs. phase: 49% acetonitrile/49% methanol/water with 50 mM formic acid and diethylamine; Flow rate: 0.5 mL/min: Time: (1R,3R)-2,2-Dichloro-3-(3-chloro-4-fluorophenyl) 9 min; Temperature: 25° C. cyclopropane-1-carboxylic acid (C166) [0841] The following compounds were prepared in like [0834] manner to the procedure outlined in Example 58: (1S,3S)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclo propane-1-carboxylic acid (C169) [0842) Cly Cl O Cl *** OH wº’ (R) (R) Cl (S) wº F [0835) Isolated as a white solid (0.5 g, 13%, 99% ee). Analytical data are consistent with racemic acid C16. Cl (1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cy [0843) Isolated as a white solid (7 g, 35%, 98% ee). clopropane-1-carboxylic acid (C167) Analytical data are consistent with racemic acid Cs. [0836] Clv Cl O (1S,3S)-2,2-Dichloro-3-(3-chloro-4-fluorophenyl) cyclopropane-1-carboxylic acid (C170) 0844 Cl wºº X2.(R) (R) | | Cl C| O

Cl .**ls OH Cl (S) (S) Cl F [0837) Isolated as a white solid (2 g, 29%, 99% ee). Analytical data are consistent with racemic acid C2. [0845] Isolated as a white solid (0.64 g, 27%, 98% ee). Example 58 Analytical data are consistent with racemic acid C16. (1S,3S)-2,2-Dichloro-3-(3,5-dichlorophenyl)-cyclo (1S,3S)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclo propane-1-carboxylic acid (C168) propane-1-carboxylic acid (C171)

[0838] Cl C| O [0846] Cl C| O

Cl .**ls OH Cl .**ls OH (S) (S) (S) (S)

Cl

Cl Cl US 2016/0302417 A1 Oct. 20, 2016

[0847) Isolated as a white solid (0.75 g, 41%, 99% ee). the following examples. In the reporting of the results, the Analytical data are consistent with racemic acid C2. “BAW & CL Rating Table” was used (See Table Section). [0848] It is recognized that some reagents and reaction conditions may not be compatible with certain functional Bioassays on BAW ities that may be present in certain molecules of Formula One or certain molecules used in the preparation of certain [0854] Bioassays on BAW were conducted using a 128 molecules of Formula One. In such cases, it may be neces well diet tray assay. One to five second instar BAW larvae sary to employ standard protection and deprotection proto were placed in each well (3 mL) of the diet tray that had been cols comprehensively reported in the literature and well previously filled with approximately 1.5 mL of artificial diet known to a person skilled in the art. In addition, in some to which 50 pg/cm3 of the test molecule (dissolved in 50 pl. cases it may be necessary to perform further routine syn of 90:10 acetone-water mixture) had been applied (to each thetic steps not described herein to complete the synthesis of of eight wells) and then allowed to dry. Trays were covered desired molecules. A person skilled in the art will also with a clear self-adhesive cover, vented to allow gas recognize that it may be possible to achieve the synthesis of exchange, and held at 25°C., 14:10 light-dark for five to desired molecules by performing some of the steps of the seven days. Percent mortality was recorded for the larvae in synthetic routes in a different order to that described. A each well; activity in the eight wells was then averaged. The person skilled in the art will also recognize that it may be results are indicated in the table entitled “Table ABC: possible to perform standard functional group interconver Biological Results” (See Table Section). sions or substitution reactions on desired molecules to introduce or modify substituents. Bioassays on CL [0855] Bioassays on CL were conducted using a 128-well Biological Assays diet tray assay, one to five second instar CL larvae were [0849] The following bioassays against Beet Armyworm placed in each well (3 mL) of the diet tray that had been (Spodoptera exigua), Cabbage Looper (Trichoplusia ni), previously filled with 1 mL of artificial diet to which 50 Green Peach Aphid (Myzus persicae), and Yellow Fever ug/cm3 of the test molecule (dissolved in 50 pil of 90:10 Mosquito (Aedes aegypti), are included herein due to the acetone-water mixture) had been applied (to each of eight damage they inflict. Furthermore, the Beet Armyworm and wells) and then allowed to dry. Trays were covered with a Cabbage Looper are two good indicator species for a broad clear self-adhesive cover, vented to allow gas exchange, and range of chewing pests. Additionally, the Green Peach Aphid held at 25° C., 14:10 light-dark for five to seven days. is a good indicator species for a broad range of sap-feeding Percent mortality was recorded for the larvae in each well; pests. The results with these three indicator species along activity in the eight wells was then averaged. The results are with the Yellow Fever Mosquito show the broad usefulness indicated in the table entitled “Table ABC: Biological of the molecules of Formula One in controlling pests in Results” (See Table Section). Phyla Arthropoda, Mollusca, and Nematoda (Drewes et al.) Example B Example A Bioassays on Green Peach Aphid (Myzus persicae, Bioassays on Beet Armyworm (Spodoptera exigua, MYZUPE) (“GPA") LAPHEG) (“BAW”), and Cabbage Looper [0856] GPA is the most significant aphid pest of peach (Trichoplusia ni, TRIPNI) (“CL”) trees, causing decreased growth, shriveling of the leaves, and the death of various tissues. It is also hazardous because [0850] Beet armyworm is a serious pest of economic it acts as a vector for the transport of plant viruses, such as concern for alfalfa, asparagus, beets, citrus, corn, cotton, potato virus Y and potato leafroll virus to members of the onions, peas, peppers, potatoes, soybeans, sugar beets, sun nightshade/potato family Solanaceae, and various mosaic flowers, tobacco, and tomatoes, among other crops. It is viruses to many other food crops. GPA attacks such plants as native to Southeast Asia but is now found in Africa, Aus broccoli, burdock, cabbage, carrot, cauliflower, daikon, egg tralia, Japan, North America, and Southern Europe. The plant, green beans, lettuce, macadamia, papaya, peppers, larvae may feed in large swarms causing devastating crop sweet potatoes, tomatoes, watercress, and zucchini, among losses. It is known to be resistant to several pesticides. other crops. GPA also attacks many ornamental crops such [0851] Cabbage looper is a serious pest found throughout as carnation, chrysanthemum, flowering white cabbage, the world. It attacks alfalfa, beans, beets, broccoli, Brussel poinsettia, and roses. GPA has developed resistance to many sprouts, cabbage, cantaloupe, cauliflower, celery, collards, pesticides. Currently, it is a pest that has the third largest cotton, cucumbers, eggplant, kale, lettuce, melons, mustard, number of reported cases of insect resistance (Sparks et al.). parsley, peas, peppers, potatoes, soybeans, spinach, squash, Consequently, because of the above factors control of this tomatoes, turnips, and watermelons, among other crops. pest is important. Furthermore, molecules that control this This species is very destructive to plants due to its voracious pest (GPA), which is known as a sap-feeding pest, are useful appetite. The larvae consume three times their weight in in controlling other pests that feed on the sap from plants. food daily. The feeding sites are marked by large accumu [0857] Certain molecules disclosed in this document were lations of sticky, wet, fecal material, which may contribute tested against GPA using procedures described in the fol to higher disease pressure thereby causing secondary prob lowing example. In the reporting of the results, the “GPA & lems on the plants in the site. It is known to be resistant to YFM Rating Table” was used (See Table Section). several pesticides. [0858] Cabbage seedlings grown in 3-inch pots, with 2-3 [0852] Consequently, because of the above factors control small (3-5 cm) true leaves, were used as test substrate. The of these pests is important. Furthermore, molecules that seedlings were infested with 20-50 GPA (wingless adult and control these pests (BAW and CL), which are known as nymph stages) one day prior to chemical application. Four chewing pests, will be useful in controlling other pests that pots with individual seedlings were used for each treatment. chew on plants. Test molecules (2 mg) were dissolved in 2 mL of acetone/ [0853) Certain molecules disclosed in this document were methanol (1:1) solvent, forming stock solutions of 1000 ppm tested against BAW and CL using procedures described in test molecule. US 2016/0302417 A1 Oct. 20, 2016

[0859] The stock solutions were diluted 5x with 0.025% Agriculturally Acceptable Acid Addition Salts, Salt Tween 20 in water to obtain the solution at 200 ppm test Derivatives, Solvates, Ester Derivatives, Polymorphs, molecule. A hand-held aspirator-type sprayer was used for Isotopes, and Radionuclides spraying a solution to both sides of cabbage leaves until runoff. Reference plants (solvent check) were sprayed with [0864] Molecules of Formula One may be formulated into the diluent only containing 20% by volume of acetone/ agriculturally acceptable acid addition salts. By way of a methanol (1:1) solvent. Treated plants were held in a holding non-limiting example, an amine function can form salts with room for three days at approximately 25° C. and ambient hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, relative humidity (RH) prior to grading. Evaluation was benzoic, citric, malonic, salicylic, malic, fumaric, oxalic, conducted by counting the number of live aphids per plant succinic, tartaric, lactic, gluconic, ascorbic, maleic, aspartic, under a microscope. Percent control was measured using benzenesulfonic, methanesulfonic, ethanesulfonic, Abbott’s correction formula (W. S. Abbott, “A Method of hydroxyl-methanesulfonic, and hydroxyethanesulfonic Computing the Effectiveness of an Insecticide” J. Econ. acids. Additionally, by way of a non-limiting example, an Entomol. 18 (1925), pp. 265-267) as follows. Corrected 9% acid function can form salts including those derived from Control=100*(X–Y)/X where X=No. of live aphids on alkali or alkaline earth metals and those derived from solvent check plants and Y=No. of live aphids on treated ammonia and amines. Examples of preferred cations include plants. The results are indicated in the table entitled “Table sodium, potassium, and magnesium. ABC: Biological Results” (See Table Section). [0865) Molecules of Formula One may be formulated into salt derivatives. By way of a non-limiting example, a salt Example C derivative may be prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt. A free base may be regenerated by treating the salt with a suitable Bioassays on Yellow Fever Mosquito (Aedes dilute aqueous base solution such as dilute aqueous sodium aegypti, AEDSAE) (“YFM”) hydroxide, potassium carbonate, ammonia, and sodium bicarbonate. As an example, in many cases, a pesticide, such [0860] YFM prefers to feed on humans during the daytime as 2,4-D, is made more water-soluble by converting it to its and is most frequently found in or near human habitations. dimethylamine salt. YFM is a vector for transmitting several diseases. It is a [0866] Molecules of Formula One may be formulated into mosquito that can spread the dengue fever and yellow fever stable complexes with a solvent, such that the complex viruses. Yellow fever is the second most dangerous mos remains intact after the non-complexed solvent is removed. quito-borne disease after malaria. Yellow fever is an acute These complexes are often referred to as “solvates.” How viral hemorrhagic disease and up to 50% of severely affected ever, it is particularly desirable to form stable hydrates with persons without treatment will die from yellow fever. There water as the solvent. are an estimated 200,000 cases of yellow fever, causing [0867] Molecules of Formula One containing an acid 30,000 deaths worldwide each year. Dengue fever is a nasty, functionality may be made into ester derivatives. These ester viral disease; it is sometimes called “breakbone fever” or derivatives can then be applied in the same manner as the “break-heart fever” because of the intense pain it can pro molecules disclosed in this document are applied. duce. Dengue fever kills about 20,000 people annually. [0868] Molecules of Formula One may be made as various Consequently, because of the above factors control of this crystal polymorphs. pest is important. Furthermore, molecules that control this [0869] Polymorphism is important in the development of pest (YFM), which is known as a sucking pest, are useful in agrochemicals since different crystal polymorphs or struc controlling other pests that cause human and animal suffer tures of the same molecule can have vastly different physical 1ng. properties and biological performances. [0861) Certain molecules disclosed in this document were [0870] Molecules of Formula One may be made with tested against YFM using procedures described in the fol different isotopes. Of particular importance are molecules lowing paragraph. In the reporting of the results, the “GPA having *H (also known as deuterium) or *H (also known as & YFM Rating Table” was used (See Table Section). tritium) in place of "H. Molecules of Formula One may be [0862] Master plates containing 400 pig of a molecule made with different radionuclides. Of particular importance dissolved in 100 pull of dimethyl sulfoxide (DMSO) (equiva are molecules having "C (also known as radiocarbon). lent to a 4000 ppm solution) are used. A master plate of Molecules of Formula One having deuterium, tritium, or assembled molecules contains 15 pull per well. To this plate, 1°C may be used in biological studies allowing tracing in 135 pull of a 90:10 water/acetone mixture is added to each chemical and physiological processes and half-life studies, well. A robot is programmed to dispense 15 pull aspirations as well as, MoA studies. from the master plate into an empty 96-well shallow plate (“daughter” plate). There are 6 reps (“daughter” plates) Combinations created per master. The created “daughter” plates are then [0871] In another embodiment of this invention, mol immediately infested with YFM larvae. ecules of Formula One may be used in combination (such as, [0863] The day before plates are to be treated, mosquito in a compositional mixture, or a simultaneous or sequential eggs are placed in Millipore water containing liver powder application) with one or more active ingredients. to begin hatching (4 g. into 400 mL). After the “daughter” [0872] In another embodiment of this invention, mol plates are created using the robot, they are infested with 220 ecules of Formula One may be used in combination (such as, pull of the liver powder/larval mosquito mixture (about 1 in a compositional mixture, or a simultaneous or sequential day-old larvae). After plates are infested with mosquito application) with one or more active ingredients each having larvae, a non-evaporative lid is used to cover the plate to a MoA that is the same as, similar to, but more likely— reduce drying. Plates are held at room temperature for 3 days different from, the MoA of the molecules of Formula One. prior to grading. After 3 days, each well is observed and [0873] In another embodiment, molecules of Formula One scored based on mortality. The results are indicated in the may be used in combination (such as, in a compositional table entitled “Table ABC: Biological Results” (See Table mixture, or a simultaneous or sequential application) with Section). one or more molecules having acaricidal, algicidal, avicidal,

US 2016/0302417 A1 Oct. 20, 2016

obtain the desired granular particle size. Another form of surface-active agent, wherein the globules having a mean granules is a water emulsifiable granule (EG). It is a for particle diameter of less than 800 nanometers. mulation consisting of granules to be applied as a conven tional oil-in-water emulsion of the active ingredient(s), Other Formulation Components either solubilized or diluted in an organic solvent, after disintegration and dissolution in water. Water emulsifiable [0896] Generally, when the molecules disclosed in For granules comprise one or several active ingredient(s), either mula One are used in a formulation, such formulation can solubilized or diluted in a suitable organic solvent that is also contain other components. These components include, (are) absorbed in a water soluble polymeric shell or some but are not limited to, (this is a non-exhaustive and non other type of soluble or insoluble matrix. mutually exclusive list) wetters, spreaders, stickers, pen [0888] Dusts containing a pesticide are prepared by inti etrants, buffers, sequestering agents, drift reduction agents, mately mixing the pesticide in powdered form with a compatibility agents, anti-foam agents, cleaning agents, and suitable dusty agricultural carrier, such as kaolin clay, emulsifiers. A few components are described forthwith. ground volcanic rock, and the like. Dusts can suitably [0897] A wetting agent is a substance that when added to contain from about 1% to about 10% of the pesticide. Dusts a liquid increases the spreading or penetration power of the may be applied as a seed dressing or as a foliage application liquid by reducing the interfacial tension between the liquid with a dust blower machine. and the surface on which it is spreading. Wetting agents are [0889] It is equally practical to apply a pesticide in the used for two main functions in agrochemical formulations: form of a solution in an appropriate organic solvent, usually during processing and manufacture to increase the rate of petroleum oil, such as the spray oils, which are widely used wetting of powders in water to make concentrates for in agricultural chemistry. soluble liquids or suspension concentrates; and during mix [0890] Pesticides can also be applied in the form of an ing of a product with water in a spray tank to reduce the aerosol composition. In such compositions, the pesticide is wetting time of wettable powders and to improve the pen dissolved or dispersed in a carrier, which is a pressure etration of water into water-dispersible granules. Examples generating propellant mixture. The aerosol composition is of wetting agents used in wettable powder, suspension packaged in a container from which the mixture is dispensed concentrate, and water-dispersible granule formulations are: through an atomizing valve. sodium lauryl sulfate; sodium dioctyl sulfosuccinate; alkyl [0891] Pesticide baits are formed when the pesticide is phenol ethoxylates; and aliphatic alcohol ethoxylates. mixed with food or an attractant or both. When the pests eat [0898] A dispersing agent is a substance that adsorbs onto the bait, they also consume the pesticide. Baits may take the the surface of particles, helps to preserve the state of form of granules, gels, flowable powders, liquids, or solids. dispersion of the particles, and prevents them from reaggre Baits may be used in pest harborages. gating. Dispersing agents are added to agrochemical formu [0892] Fumigants are pesticides that have a relatively high lations to facilitate dispersion and suspension during manu vapor pressure and hence can exist as a gas in sufficient facture, and to ensure the particles redisperse into water in concentrations to kill pests in soil or enclosed spaces. The a spray tank. They are widely used in wettable powders, toxicity of the fumigant is proportional to its concentration suspension concentrates, and water-dispersible granules. and the exposure time. They are characterized by a good Surfactants that are used as dispersing agents have the capacity for diffusion and act by penetrating the pest’s ability to adsorb strongly onto a particle surface and provide respiratory system or being absorbed through the pest’s a charged or steric barrier to reaggregation of particles. The cuticle. Fumigants are applied to control stored product most commonly used surfactants are anionic, non-ionic, or pests under gas proof sheets, in gas sealed rooms or build mixtures of the two types. For wettable powder formula ings, or in special chambers. tions, the most common dispersing agents are sodium ligno [0893] Pesticides may be microencapsulated by suspend sulfonates. For suspension concentrates, very good adsorp ing the pesticide particles or droplets in plastic polymers of tion and stabilization are obtained using polyelectrolytes, various types. By altering, the chemistry of the polymer or such as sodium-naphthalene-sulfonate-formaldehyde-con by changing factors in the processing, microcapsules may be densates. Tristyrylphenol ethoxylate phosphate esters are formed of various sizes, solubility, wall thicknesses, and also used. Non-ionics such as alkylarylethylene oxide con degrees of penetrability. These factors govern the speed with densates and EO-PO block copolymers are sometimes com which the active ingredient within is released, which in turn, bined with anionics as dispersing agents for suspension affects the residual performance, speed of action, and odor concentrates. In recent years, new types of very high of the product. The microcapsules might be formulated as molecular weight polymeric surfactants have been devel suspension concentrates or water dispersible granules. oped as dispersing agents. These have very long hydropho [0894] Oil solution concentrates are made by dissolving bic ‘backbones’ and a large number of ethylene oxide chains pesticide in a solvent that will hold the pesticide in solution. forming the teeth’ of a “comb' surfactant. These high Oil solutions of a pesticide usually provide faster knock molecular weight polymers can give very good long-term down and kill of pests than other formulations due to the stability to suspension concentrates because the hydropho solvents themselves having pesticidal action and the disso bic backbones have many anchoring points onto the particle lution of the waxy covering of the integument increasing the surfaces. Examples of dispersing agents used in agrochemi speed of uptake of the pesticide. Other advantages of oil cal formulations are: sodium lignosulfonates; sodium naph solutions include better storage stability, better penetration thalene sulfonate formaldehyde condensates; tristyrylphe of crevices, and better adhesion to greasy surfaces. nol-ethoxylate-phosphate-esters; aliphatic alcohol [0895] Another embodiment is an oil-in-water emulsion, ethoxylates; alkyl ethoxylates; EO-PO block copolymers; wherein the emulsion comprises oily globules which are and graft copolymers. each provided with a lamellar liquid crystal coating and are [0899) An emulsifying agent is a substance that stabilizes dispersed in an aqueous phase, wherein each oily globule a suspension of droplets of one liquid phase in another liquid comprises at least one molecule which is agriculturally phase. Without the emulsifying agent, the two liquids would active, and is individually coated with a monolamellar or separate into two immiscible liquid phases. The most com oligolamellar layer comprising: (1) at least one non-ionic monly used emulsifier blends contain an alkylphenol or an lipophilic surface-active agent, (2) at least one non-ionic aliphatic alcohol with twelve or more ethylene oxide units hydrophilic surface-active agent, and (3) at least one ionic and the oil-soluble calcium salt of dodecylbenzenesulfonic US 2016/0302417 A1 Oct. 20, 2016

acid. A range of hydrophile-lipophile balance (“HLB”) val sorbic acid and its sodium or potassium salts; benzoic acid ues from about 8 to about 18 will normally provide good and its sodium salt; p-hydroxybenzoic acid sodium salt; stable emulsions. Emulsion stability can sometimes be methyl p-hydroxybenzoate; and 1,2-benzisothiazolin-3-one improved by the addition of a small amount of an EO-PO (BIT). block copolymer surfactant. [0906] The presence of surfactants often causes water [0900] A solubilizing agent is a surfactant that will form based formulations to foam during mixing operations in micelles in water at concentrations above the critical micelle production and in application through a spray tank. In order concentration. The micelles are then able to dissolve or to reduce the tendency to foam, anti-foam agents are often solubilize water-insoluble materials inside the hydrophobic added either during the production stage or before filling part of the micelle. The types of surfactants usually used for into bottles. Generally, there are two types of anti-foam solubilization are non-ionics, sorbitan monooleates, sorbitan agents, namely silicones and non-silicones. Silicones are monooleate ethoxylates, and methyl oleate esters. usually aqueous emulsions of dimethyl polysiloxane, while [0901] Surfactants are sometimes used, either alone or the non-silicone anti-foam agents are water-insoluble oils, with other additives such as mineral or vegetable oils as such as octanol and nonanol, or silica. In both cases, the adjuvants to spray-tank mixes to improve the biological function of the anti-foam agent is to displace the surfactant performance of the pesticide on the target. The types of from the air-water interface. surfactants used for bioenhancement depend generally on the nature and mode of action of the pesticide. However, [0907] “Green” agents (e.g., adjuvants, surfactants, sol they are often non-ionics such as: alkyl ethoxylates; linear vents) can reduce the overall environmental footprint of crop aliphatic alcohol ethoxylates; and aliphatic amine ethoxy protection formulations. Green agents are biodegradable and lates. generally derived from natural and/or sustainable sources, [0902] A carrier or diluent in an agricultural formulation is e.g. plant and animal sources. Specific examples are: veg a material added to the pesticide to give a product of the etable oils, seed oils, and esters thereof, also alkoxylated required strength. Carriers are usually materials with high alkyl polyglucosides. absorptive capacities, while diluents are usually materials with low absorptive capacities. Carriers and diluents are Applications used in the formulation of dusts, wettable powders, granules, and water-dispersible granules. [0908] Molecules of Formula One may be applied to any [0903] Organic solvents are used mainly in the formula locus. Particular loci to apply such molecules include loci tion of emulsifiable concentrates, oil-in-water emulsions, where alfalfa, almonds, apples, barley, beans, canola, corn, suspoemulsions, oil dispersions, and ultra-low volume for cotton, crucifers, flowers, fodder species (Rye Grass, Sudan mulations, and to a lesser extent, granular formulations. Grass, Tall Fescue, Kentucky Blue Grass, and Clover), Sometimes mixtures of solvents are used. The first main fruits, lettuce, oats, oil seed crops, oranges, peanuts, pears, groups of solvents are aliphatic paraffinic oils such as peppers, potatoes, rice, sorghum, soybeans, strawberries, kerosene or refined paraffins. The second main group (and sugarcane, sugarbeets, sunflowers, tobacco, tomatoes, wheat the most common) comprises the aromatic solvents such as (for example, Hard Red Winter Wheat, Soft Red Winter xylene and higher molecular weight fractions of C9 and C10 Wheat, White Winter Wheat, Hard Red Spring Wheat, and aromatic solvents. Chlorinated hydrocarbons are useful as Durum Spring Wheat), and other valuable crops are growing cosolvents to prevent crystallization of pesticides when the or the seeds thereof are going to be planted. formulation is emulsified into water. Alcohols are sometimes [0909) Molecules of Formula One may also be applied used as cosolvents to increase solvent power. Other solvents where plants, such as crops, are growing and where there are may include vegetable oils, seed oils, and esters of vegetable low levels (even no actual presence) of pests that can and seed oils. commercially damage such plants. Applying such molecules [0904] Thickeners or gelling agents are used mainly in the in such locus is to benefit the plants being grown in such formulation of suspension concentrates, oil dispersions, locus. Such benefits, may include, but are not limited to: emulsions and suspoemulsions to modify the rheology or helping the plant grow a better root system; helping the plant flow properties of the liquid and to prevent separation and better withstand stressful growing conditions; improving the settling of the dispersed particles or droplets. Thickening, health of a plant; improving the yield of a plant (e.g. gelling, and anti-settling agents generally fall into two increased biomass and/or increased content of valuable categories, namely water-insoluble particulates and water ingredients); improving the vigor of a plant (e.g. improved soluble polymers. It is possible to produce suspension con plant growth and/or greener leaves); improving the quality centrate and oil dispersion formulations using clays and of a plant (e.g. improved content or composition of certain silicas. Examples of these types of materials, include, but are ingredients); and improving the tolerance to abiotic and/or not limited to, montmorillonite, bentonite, magnesium alu biotic stress of the plant. minum silicate, and attapulgite. Water-soluble polysaccha rides in water based suspension concentrates have been used [0910] Molecules of Formula One may be applied with as thickening-gelling agents for many years. The types of ammonium sulfate when growing various plants as this may polysaccharides most commonly used are natural extracts of provide additional benefits. seeds and seaweeds or are synthetic derivatives of cellulose. [0911] Molecules of Formula One may be applied on, in, Examples of these types of materials include, but are not or around plants genetically modified to express specialized limited to, guar gum, locust bean gum; carrageenam; alg traits, such as Bacillus thuringiensis (for example, Cry1Ab, inates; methyl cellulose; sodium carboxymethyl cellulose Cry1Ac, Crylfa, Cry1A.105, Cry2Ab, Vip3A, mCry3A, (SCMC); and hydroxyethyl cellulose (HEC). Other types of Cry3Ab, Cry3Bb, Cry34Ab1/Cry35Ab1), other insecticidal anti-settling agents are based on modified starches, poly toxins, or those expressing herbicide tolerance, or those with acrylates, polyvinyl alcohol, and polyethylene oxide. “stacked” foreign genes expressing insecticidal toxins, her Another good anti-settling agent is xanthan gum. bicide tolerance, nutrition-enhancement, or any other ben [0905] Microorganisms can cause spoilage of formulated eficial traits. products. Therefore, preservation agents are used to elimi [0912] Molecules of Formula One may be applied to the nate or reduce their effect. Examples of such agents include, foliar and/or fruiting portions of plants to control pests. but are not limited to: propionic acid and its sodium salt; Either such molecules will come in direct contact with the US 2016/0302417 A1 Oct. 20, 2016

pest, or the pest will consume such molecules when eating dogs, and cats. Particular pests to control would be flies, the plant or while extracting sap or other nutrients from the fleas, and ticks that are bothersome to such animals. Suitable plant. formulations are administered orally to the animals with the [0913] Molecules of Formula One may also be applied to drinking water or feed. The dosages and formulations that the soil, and when applied in this manner, root and stem are suitable depend on the species. feeding pests may be controlled. The roots may absorb such molecules thereby taking it up into the foliar portions of the [0921] Molecules of Formula One may also be used for plant to control above ground chewing and sap feeding controlling parasitic worms, especially of the intestine, in pests. the animals listed above. [0914] Systemic movement of pesticides in plants may be utilized to control pests on one portion of the plant by [0922) Molecules of Formula One may also be employed applying (for example by spraying a locus) a molecule of in therapeutic methods for human health care. Such methods Formula One to a different portion of the plant. For example, include, but are limited to, oral administration in the form of. control of foliar-feeding insects may be achieved by drip for example, tablets, capsules, drinks, granules, and by irrigation or furrow application, by treating the soil with for dermal application. example pre- or post-planting soil drench, or by treating the seeds of a plant before planting. [0923] Molecules of Formula One may also be applied to [0915] Molecules of Formula One may be used with baits. invasive pests. Pests around the world have been migrating Generally, with baits, the baits are placed in the ground to new environments (for such pest) and thereafter becoming where, for example, termites can come into contact with, a new invasive species in such new environment. Such and/or be attracted to, the bait. Baits can also be applied to molecules may also be used on such new invasive species to a surface of a building, (horizontal, vertical, or slant surface) control them in such new environments. where, for example, ants, termites, cockroaches, and flies, [0924] Before a pesticide may be used or sold commer can come into contact with, and/or be attracted to, the bait. cially, such pesticide undergoes lengthy evaluation pro [0916] Molecules of Formula One may be encapsulated cesses by various governmental authorities (local, regional, inside, or placed on the surface of a capsule. The size of the capsules can range from nanometer size (about 100-900 state, national, and international). Voluminous data require nanometers in diameter) to micrometer size (about 10-900 ments are specified by regulatory authorities and must be microns in diameter). addressed through data generation and submission by the [0917| Molecules of Formula One may be applied to eggs product registrant or by a third party on the product regis of pests. Because of the unique ability of the eggs of some trant’s behalf, often using a computer with a connection to pests to resist certain pesticides, repeated applications of the World Wide Web. These governmental authorities then such molecules may be desirable to control newly emerged review such data and if a determination of safety is con larvae. cluded, provide the potential user or seller with product [0918] Molecules of Formula One may be applied as seed registration approval. Thereafter, in that locality where the treatments. Seed treatment may be applied to all types of product registration is granted and supported, such user or seeds, including those from which plants genetically modi seller may use or sell such pesticide. fied to express specialized traits will germinate. Represen tative examples include those expressing proteins toxic to [0925) Molecules according to Formula One may be tested invertebrate pests, such as Bacillus thuringiensis or other to determine its efficacy against pests. Furthermore, mode of insecticidal toxins, those expressing herbicide tolerance, action studies may be conducted to determine if said mol such as “Roundup Ready” seed, or those with “stacked” ecule has a different mode of action than other pesticides. foreign genes expressing insecticidal toxins, herbicide tol Thereafter, such acquired data may be disseminated, such as erance, nutrition-enhancement, drought tolerance, or any by the internet, to third parties. other beneficial traits. Furthermore, such seed treatments with molecules of Formula One may further enhance the [0926] The headings in this document are for convenience ability of a plant to withstand stressful growing conditions only and must not be used to interpret any portion hereof. better. This results in a healthier, more vigorous plant, which can lead to higher yields at harvest time. Generally, about 1 Tables gram of such molecules to about 500 grams per 100,000 seeds is expected to provide good benefits, amounts from [0927] about 10 grams to about 100 grams per 100,000 seeds is expected to provide better benefits, and amounts from about 25 grams to about 75 grams per 100,000 seeds is expected TABLE B to provide even better benefits. Molecules of Formula One may be applied with one or more active ingredients in a soil Weight Ratios amendment. Molecule of the Formula One:active ingredient [0919) Molecules of Formula One may be used for con trolling endoparasites and ectoparasites in the veterinary 100:1 to 1:100 medicine sector or in the field of non-human-animal keep ing. Such molecules may be applied by oral administration 50:1 to 1:50 in the form of, for example, tablets, capsules, drinks, gran 20:1 to 1:20 ules, by dermal application in the form of for example, 10:1 to 1:10 dipping, spraying, pouring on, spotting on, and dusting, and 5:1 to 1:5 by parenteral administration in the form of for example, an 3:1 to 1:3 injection. [0920) Molecules of Formula One may also be employed 2:1 to 1:2 advantageously in livestock keeping, for example, cattle, 1:1 chickens, geese, goats, pigs, sheep, and turkeys. They may also be employed advantageously in pets such as, horses, US 2016/0302417 A1 Oct. 20, 2016 87

TABLE C active 100 X, Y X, Y X, Y ingredient 50 X, Y X, Y X, Y X, Y X, Y (Y) Parts 20 X, Y X, Y X, Y X, Y X, Y by weight 15 X, Y X, Y X, Y X, Y X, Y 10 X, Y X, Y 5 X, Y X, Y X, Y X, Y 3 X, Y X, Y X, Y X, Y X, Y X, Y X, Y 2 X, Y X, Y X, Y X, Y X, Y 1 X, Y X, Y X, Y X, Y X, Y X, Y X, Y X, Y X, Y 1 2 3 5 10 15 20 50 100 molecule of Formula One (X) Parts by weight

TABLE 2

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F1 F F Clº Cl O F H N Cl NH N7 O

C| F2 Cly Cl O Cl H N Cl NH N7 O

C| F3 Cly Cl O H N Cl NH N7 O

C|

F4 Clº Cl O Cl N

Na / Cl US 2016/0302417 A1 Oct. 20, 2016 88

TABLE 2-continued

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F5 Cl 13 Cl C| O { Cl h F F

F6 Cl 13 Cl C| O N Cl } F F Cl

F7 Cl 13 Cl C| O N Cl } S

F8 Cl 13 Cl C| O N Cl h S

Cl

F9 13 Cl C|

Cl Cl F F Cl X

F10 13 Cl C| Cl h} NNX Cl US 2016/0302417 A1 Oct. 20, 2016

TABLE 2-continued

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F11 Cl 13 Cl C|

* * * *O { Cl h X Cl

F12 13 Cl C| O Cl N

Na / Cl N H O

C|

F13 Cl C| O Cl N 13

Nn / Cl N H O

Cl

C|

F14 Cl C| O Cl N 13

Na / Cl N H O

Cl

F15 Cl 13 Cl C| O H N Cl N H S O

C|

F16 Cl 13 Cl C| O N Cl h \\ Cl US 2016/0302417 A1 Oct. 20, 2016 90

TABLE 2-continued

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F17 CI Cl Cl 13 O N Cl N

H O \\

Cl

F18 13

F19 13 Cl C| O F ** *** -ºº º-, -º-Cl { } FF F

F20 13

F21 13

F22 13 US 2016/0302417 A1 Oct. 20, 2016 91

TABLE 2-continued

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F23 Clº Cl O Cl N 13

Na / N H O F

F F

F24 CI Cl Cl 13

H N

F O F

13 F25 CI Cl Cl N

Nn /

O

F26 Cly Cl O Cl 13 F H F N

F h F O F

C|

F27 CI Cl Cl N 13

F O H / F N N F H O US 2016/0302417 A1 Oct. 20, 2016 92

TABLE 2-continued

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F28 Cl 13 Cl Cl O H N Br N H F O F

Br

F29 Cl Cl O Cl N 13

Na / Br N H O

Br

F30 Cl 13 Cl C| O H N C| N H F O F F

C|

F31 Cl C| O Cl N 13

Nn / Cl N H O

F

C|

F32 Cl 13 Cl C| O CH3

N Cl N H F O F

C|

F33 13 Cl

Cl

Cl US 2016/0302417 A1 Oct. 20, 2016 93

TABLE 2-continued

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F34 Cl 13 Cl C| O CH3

N Cl N H F O F Cl

C|

F35 Clº Cl O Cl 13 H N Cl N H EN O

C|

F36 Cly Ql O Cl 13 H N Cl N H EN O

Cl

F37 Cly Cl O Cl 13 H N N H F O F

F38 CI Cl Cl N 13

F39 Cly Cl O Cl 13 H N Cl N H EN O

Cl US 2016/0302417 A1 Oct. 20, 2016 94

TABLE 2-continued

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F40 CI Cl Cl 13

* * * *O { Cl } `y O

CI Cl Cl 13

* * * *O { Cl } O

Cl

CI Cl Cl 13

& W ºr *O N Cl i O

Cl

Cl Cl 13

A * * *O N Cl } O F F

F44 CI Cl Cl 13

Cl

F Cl X

F45 CI Cl Cl 13 Cl hh N{ Cl OO FF US 2016/0302417 A1 Oct. 20, 2016 95

TABLE 2-continued

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F46 Cl 13 CI Cl O H N H3C N H F O F

C|

F47 CI Cl O Cl N 13

Nn / H3C N H O

C|

F48 Cl 13 CI Cl O H N Cl N H F O F H3C C|

F49 CI Cl O Cl N 13

Nm / Cl N H O H3C C|

F50 Cl 13 CI Cl O H N Cl N H F O F Cl CH3

F51 CI Cl O Cl N 13

Na / Cl N H O

Cl CH3 US 2016/0302417 A1 Oct. 20, 2016 96

TABLE 2-continued

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F52 Cl 14 Clv Cl O N Cl NH sº O º

C| F53 Clv Cl O Cl 14 H N Cl N H O O

C| F54 Cly Cl O Cl 14 H N Cl N H N O CH O 3 CH3 O CH3 C|

F55 Cl 15 CI Cl O H N Cl N H O O

C| F56 Cly Cl O Cl 16 H N Cl N H S O ÖN.9 Cl

C| F57 Cly Cl O Cl 16 H N Cl N H S O 㺠Cl US 2016/0302417 A1 Oct. 20, 2016 97

TABLE 2-continued

tructure and preparation method for F and PF Series molecules

No. Structure Prep.” Cly Cl O Cl 17 H N Cl NH \\ O \,WT Cl

Cl 18 Cl C| O

Cl h

F60 Cl 19 Cl C| O N Cl

Cl 31 Cl C| O N Cl }

Cl C| 31

Cl N h O Cl

31 Cl C|

Cl

Cl US 2016/0302417 A1 Oct. 20, 2016

TABLE 2-continued

Structure and preparation method for F and PF Series molecules

No. Structure Prep.”

F64 CI Cl O Cl 31 | H wº N Cl .** N H O

Cl

C|

F65 Cl 14 CI Cl O H N Cl N H O O

C|

F66 Cl 13 Cl Cl O 2.N

O

Br

C| F67 Cly Cl O C| 29 N NH * N H O

H2Cs Cl F68 Cly Cl O Cl 32 H N

Cl h O \\O

C| F69 Cly Cl O Cl 13 H N N H F O F Os