Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. egigSun Pengliag the on Mechanism Effects Cycloaddition Substituent 1,3-Dipolar of Study Theory Functional Density xdaoedrvtvssnhszdb iaiah ta.as hwdgo yooi ciiyaantthe against activity cytotoxic good showed also 6.50 mice. = al. (IC50 with et line experiments cell 1,2,4- Miralinaghi in tumor the activity by MCF-7 of retained breast synthesized use and few derivatives the lines a oxadiazole resistance, cell for drug cancer activity of colon good context and exhibited design. the have drug have in in groups compounds direction present, research 3-aryl-5-(3-chlorothiophene-2-yl)-1,2,4-oxadiazole new At a several become treatment. skeletons, has antitumor skeleton diverse oxadiazole of rich molecularly field and novel, the structures, with joined compounds. complex compounds lead skeletons, anti-tumor more molecular discover of diverse To studied. discovery with the easily products facilitates natural be and and of can properties properties library chemical the compounds a compounds, of synthesized diversity similar building face. the the synthesize the to on to point of chemistry focus from relationship combinatorial library to compound use diffusion structure-activity the can branching expanding uses method of usually synthetic aim the that this with synthesis compounds forward of of five-membered complexity chemistry. kind of and organic synthesis theoretical a the in to in significance refers role great important synthesis has an also plays but only not compounds, that heterocyclic reaction a is cycloaddition 1,3-Dipolar reaction. this of reaction course of the Introduction kind revealing for this basis for theoretical idea the necessary effective changing orbital the an Keywords: and molecular that provided synthesis occupied it showed organic Finally, highest of results the reaction. design The of the the level in of energy compounds. progress the the heterocyclic affects consequently, and of and compounds M062X, classical chloroxime synthesis a M052X, the the B3LYP, cycloaddition, on 1,3-dipolar the for substituents of using mechanism method the calculations effective on theory effects and substituent functional investigate density to functionals performed APFD we study, of this course In the revealing for basis theoretical necessary Abstract effective the an and provided synthesis it organic Finally, of reaction. design the the of in energy progress reaction the reaction. the of affects this consequently, compounds kind and synthesis chloroxime this orbital the the for molecular on for substituents idea occupied method the effective highest changing and the to that classical of showed functionals a level results APFD cycloaddition, and The M062X, 1,3-dipolar compounds. M052X, of B3LYP, heterocyclic mechanism the of the using on calculations theory effects functional substituent density investigate performed we study, this In Abstract 2020 29, May 2 1 hns cdm fSciences of Academy Chinese University Yunnan ,-ioa yladto ecin est ucinlter;Rato mechanism; Reaction theory; functional Density reaction; cycloaddition 1,3-dipolar 1 egLiu Meng , 2 e Pu Wei , μ M). 1 15 iJin Yi , ahe l eeoe eiso diaryl-5-amino-1,2,4-oxadiazole of series a developed al. et Gakh 1 hx Liu Shixi , 1 10-13 1 ieCao Qiue , mn h opud ihti skeleton, this with compounds the Among 9 14 eiso oe triaryl-1,2,4- novel of series A 1 n hntoDing Zhongtao and , 8 oevr thastens it Moreover, 1-4 Diversity-oriented 5-7 Because 1 Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. oecrepnigt h ievco one otecrepnigratnsadpout ntereaction. the vibration in The products and state. reactants transition constant corresponding the force the of to the vibrational authenticity pointed whether The the eigenvector determine confirm the obtained. to and to are eigenvalue analyzed corresponding coordinates negative were mode reaction one TS1–TS3, the has angle, states, with intrinsic bond only transition state the the matrix optimized of transition using the curves the level The of B3LYP/6-31G(d) of states methods. energy the (PCM) and at B3LYP/6-31G(d) model length calculated the continuum bond at polarizable was out and solution (IRC) carried in was coordinate program. mechanism states reaction for 9.0 transition reaction search D.01 the and The 09W and intermediates, func- phases Gaussian level. products, these gas reactants, the and between the using solution differences of the performed tion and in APFD were mechanism and similarities states reaction M062X, the transition the M052X, B3LYP, and of the Studies and analyzed, set determined. were basis were results 6-31G(d) tionals intermediates, calculated the products, using The reactants, out of series functionals. carried a were of states analysis transition vibrational and and and phenomena optimization geometry study, experimental this In of explanation of theoretical law Details a different processes. the Computational provide new of with of findings effects consistent development are our the the for which revealed 1,3-dipolar Thus, guidance mechanism, the we cycloaddition as APFD, summary, reaction. 1,3-dipolar and used In organic the was M062X, on M052X, methods theoretically. B3LYP, substituents guiding determined functionals, chloroxime multiple density was by different mechanism synthesized four cycloaddition product gas-phase Using cycloaddition and system. 1,3-dipolar liquid- was the the the study study, on this substituents combined this different calculations of In of chemical purpose quantum effects explained. the by The were mechanism, compounds mechanisms studies. chloroxime cycloaddition reaction kinetic In of and 1,3-dipolar substitution reported. thermodynamic the of substituted rarely with of effect is on mechanism the reactions synthesized research cycloaddition such analyze be current of 1,3-dipolar to can the analysis the products theoretical of of details because natural view However, future. unclear and remains research. the method. structures compounds pesticide rapid in novel chloroxime and in therapy with simple direction drug compounds a important effective heterocyclic by an of sites, remains compound, development affinity reasonably, 1,3-dipolar compounds and the and the oxime in scientifically using of more by role properties Therefore, modified vital be and a can synthesis play indolone the studies, will these this Through and studied. new well of been development also activities. the antitumor and in anti-diabetic, anti-Parkinson, especially chemists, pharmaceutical activities, by substances. considered neurotoxic drugs. these effect been therapeutic neuroprotective of always good effects a has the A exhibited alkaloids, phidianidine as counteracted that such and showed substances, vitro results neurotoxic The in with glucose. simultaneously oxidized it neuroprotective and introducing in peroxide, by resulting cells stress, SH-SY5Y oxidative on related and these polymerization Specifically, protein effects. disease. amyloid Alzheimer’s ethylthioisoamide. prevent of of treatment can to treatment the drugs have the tuberculosis in and potential for pulmonary great experiments, showed reagents vivo of derivatives in 1,2,4-oxadiazole useful resistance indirect be the through activity, overcome to improved shown effectively found have were They analysis, tuberculosis. activity study pulmonary antitumor relationship certain relationship structure-activity a structure-activity by show designed a and antagonists Moreover, effective particularly mice. pathway. are in signaling compounds these Hedgehog that abnormal treatment confirmed the 1.9 with for and compounds tumors 2.6 urea showed piperazine of of 10500078 4-(3-(quinoline-2-yl)-1,2,4-oxadiazole-5-yl) values of DCP IC50 series and compound with a 10500071 the tubulin developed DCP of against Compounds group activity aryl activity. good the compound particularly on of fragment pharmacophore PhNH decisive 4-position the The is inhibitors. tubulin powerful as derivatives 20 17 hdaiiehsbe yteie n sdt vlaetenuortcieeet fcompounds of effects neuroprotective the evaluate to used and synthesized been has Phidianidine 26 nadto,te124oaizl eiaie,BM14,BM18,adBM10,wihwere which BDM41906, and BDM31381, BDM31343, derivatives, 1,2,4-oxadiazole the addition, In uha niatra,at-ueclss nixdn,athsaie niHV anti-inflammatory, anti-HIV, antihistamine, antioxidant, anti-tuberculosis, antibacterial, as such 23-25 nooedrvtvshv odbooia oeta eas fisvrosbiological various its of because potential biological good a have derivatives Indolone o clrbnoie n opud ihbt electrophilic both with compounds and -chlorobenzoxime, 2 27 tpeet eea fteebooia ciiishave activities biological these of several present, At 21-22 μ nooe stemi kltnof skeleton main the as Indolone, ,respectively. M, 30 ofiuainoptimiza- Configuration 18-19 nadto,afew a addition, In β 16 53,hydrogen 25-35, 28 ualae al. et Muraglia naddition, In 29 Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. r lovlneeetos hti,teeetosi h rnirobtl,i oeua ecin During reaction. there molecular atom, a in single orbitals, a frontier of the interaction in electron electrons valence the the is, to that electrons, similar valence theory, also orbital are frontier to According theory. orbital Frontier 2. Scheme various using calculations theory 1. functional Scheme density performed we Supporting substituents, see different characterization, main functionals. of The our and effect published 46–96%. methods has and of synthetic group nism yields specific research with our (for synthesized 1). addition, results were In Information related compounds 2. and with- target Scheme conditions 36 methods in reaction of shown synthetic mild is total relatively mechanism A under reaction reaction catalyst. proposed one-step metal 1,2,4-oxadiazolindolone a any polyheterocyclic in novel using yield 1, out Scheme high in in shown obtained route were synthetic compounds the in ( indicated chloroxime As substituted used terials. initially we the study, in this In trends and compounds Discussion substituted and different Results of energy reactions (zero-point The stationary data the thermodynamic ( obtained. relevant of energies were the activation energies energy) and single-point free level, the reflect Gibbs MP2/cc-pVTZ Finally, truly the the and products. can out at state the the carried calculated transition and were also and the reactants We points whether level, the determine analysis. M062X/6-31G(d) between to vibration the coordinates relationship by reaction at the The determined intrinsic analyzed level. the be B3LYP/6-31G(d) of is can the analysis frequency state at (IRC) vibration transition molecules the and the of intermediate and orbitals reaction searched frontier the is view state to transition 5.0 GaussView used we And rpsdrato ehns ftesnhtcroute. synthetic the of mechanism reaction Proposed compounds. 1,2,4-oxadiazolindolone heterocyclic of Synthesis 31 odel n ytmtclysuytedtiso h ,-ioa yladto mecha- cycloaddition 1,3-dipolar the of details the study systematically and deeply To Δ E a uigterato eecmae n analyzed. and compared were reaction the during ) 3 1a – o n stn( isatin and ) 2a – e opud sterwma- raw the as compounds ) Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. nraeteLM nrylvlo h ecat a togreeto-ihrwn ffc hnC and Cl than the effect reduce electron-withdrawing to stronger a used OCH has were groups F electron-donating Br reactant. the and the hand, of Cl with other level consistent the F, energy On is groups, 1,3-dipole LUMO which reactant. A the electron-withdrawing level, the increase the energy of dienophile. level LUMO Among the energy lower of LUMO a results. level has calculated energy group LUMO the electron-withdrawing the an reduces with group substituted electron-withdrawing an reactions, nteodrBr order the in hnteclrxm opudcnan usiue hnlgop h UOeeg ee nrae in increases level energy LUMO the group, phenyl substituted Br a with order consistent S1). contains the table is compound levels which and chloroxime energy table1 reaction, the LUMO see the When the data, of experimental that Ph progress (For indicates the order results to S2.1-S2.4 formation experimental the Table conducive to the the in more and conducive are 1 increase to more Tables compounds is compounds leads in phenyl-substituted compound substituted data compounds chloroxime the the two the isatin, of of for the substituted Analysis level the between energy reaction. of interaction LUMO the lower HOMO The a and reaction, acceptor, LUMO-controlled donor. electron electron the a the as of as acts acts which LUMO chloroxime, which 1, Tables substituted conditions in the above seen the be of can of 1,3- As both the wherein reaction. by controlled those provided < LUMO-HOMO (3) HOMO called the and the collectively by reaction, are provided with HOMO-controlled occur LUMO those the called (2) with collectively those reaction, are (1) LUMO-controlled dipole types: called three collectively into are divided be 1,3-dipole can reactions cycloaddition Dipolar 1,3 of (HOMOs) orbitals molecular information. occupied supporting of S2.1-S2.4 1. Table Table and 1 1 -CH Tables orbital -OCH, in molecular shown -F, unoccupied are -H, lowest with The substituted isatin intermediates. these between (LUMO difference intermediates energy of those orbital are frontier cyclization in involved orbitals frontier precedence. take will reactant orbital leave frontier the bonding, LUMO σ od hc eue h nryo h ytm eas h ,-ioepoie h UOfra for LUMO the provides 1,3-dipole the Because system. the of energy the reduces which bond, 1 -ihs cuidmlclrobtl2(HOMO 2 orbital molecular occupied )-highest 2 o -r-.35 0235-.05 0.32223 0.30998 -0.00259 -0.24335 -0.03354 -0.01513 -0.23110 -0.04608 n-Pr Thiophene 1o’ 1n’ 1m’ 1l’ 1k’ 1j’ 1i’ 1h’ e ht-.41 0252-.11 0.30460 -0.01219 -0.22572 -0.04314 PhEt 1g’ 1f’ 1e’ 1d’ 1c’ a .78 0005// 0.31181 -0.01732 / -0.23293 -0.03095 -0.04827 0.07888 LUMO HOMO LUMO Ph H 1b’ 1a’ 2a’ R Reactant nrylvldffrne ewe h oetuocpe oeua rias(UO)adhighest and (LUMOs) orbitals molecular unoccupied lowest the between differences level Energy -HUMO < 1a Cl > ofr intermediate form to 1 Cl < hrfr,13dplrccodiinrqie ymtymthn ewe h LUMO the between matching symmetry requires cycloaddition 1,3-dipolar therefore, ; F p o m p o m p p o m p > -BrC -ClC -ClC -FC -FC -OCH -CH -CH -ClC -FC -CH < F H 6 6 > 3 3 6 6 6 3 H H 6 C C 6 H H H C 3 H < H 4 4 H 6 6 C 4 4 4 6 4 H H 4 H 6 OCH > 4 4 H 4 4 OCH 3 0092-.34 00870.31530 0.31801 -0.02867 -0.23642 -0.02808 -0.05962 -0.23913 -0.05903 0003-.46 00980.32150 -0.02948 -0.24262 -0.06043 0092-.36 00870.31652 -0.02837 -0.23764 -0.05932 0048-.34 00330.31536 -0.02393 -0.23648 -0.05488 0076-.41 00610.31899 -0.02611 -0.24011 -0.05706 0094-.36 00890.31251 -0.01809 -0.23363 -0.04904 0050-.20 00450.30695 0.30846 -0.01425 -0.22807 -0.01563 -0.04520 -0.22958 -0.04658 0049-.32 00340.30916 -0.01374 -0.23028 -0.04469 0042-.27 00370.30566 -0.01327 -0.22678 -0.04422 < 1a’ 3 CH 1a’ > 3 r-radclrxm opud ihdffrn substituents different with compounds chloroxime and -Br or , hl h tmleaves atom H the while , CH 3 – < 1o’ 3 t hl h ereo iclyo h ecindecreases reaction the of difficulty of degree the while Et, > 32 and uig13dplrccodiin h n latoms Cl and H the cycloaddition, 1,3-dipolar During t codn otegnrllwo rai pericyclic organic of law general the to According Et. 4 2a’ 2 n LUMO and ) < . thiophene 1a’ 1 -HOMO and 2 < 2a -HOMO 2a’ -r hrfr,teLMsof LUMOs the Therefore, n-Pr. ofr intermediate form to 2 hrfr,w eemndthe determined we Therefore, . 1 LUMO nrydffrne between differences energy 2 -HOMO 3 CH , 1 1 2a’ 3 -HOMO n Et and , The , 2 Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. rmfote ria hoydsusdi eto ..Frclrxm opud otiigasubstituted a containing compounds derived chloroxime conclusion is For the group and alkyl 3.1. the data section hand, experimental in other the with discussed the group, consistent On theory phenyl is orbital reaction. which the frontier progress, for from reaction favorable to most the conducive is not group phenyl the substituents, of on effect The minor calculated (ΔΓ). a the ενεργψ triethylamine, has φρεε of only ability solvent Γιββς of electron-withdrawing the levels induced as energy the triethylamine HOMO to of and owing LUMO However, use for with difference the phase. the consistent level that gas completely calculate energy proves the is the to This effect Specifically, substituent solvent reaction. phase. the the the gas that shows as the data triethylamine in the that with of Analysis PCM between information. used difference supporting we energy economical level, orbital more B3LYP/6-31G(d) is frontier B3LYP the Therefore, compounds. at consistent. these Finally, completely of energies calculation are as orbital batch functionals long frontier for as four the twice efficient of the about and calculations using the are the APFD system from M062X using and obtained and this consumption, B3LYP conclusions M052X for are time the using summary, similar of times In are B3LYP. computing terms determine that using the In to that functionals However, impossible the M062X. system. is and compound, and this M052X same it level for and the comparison, energy calculations for for LUMO parameters value for higher calculation reference suitable the same no more in the is is reflected using the there functional mainly calculated in Because which is using values differences level. calculated This The those energy few different. however, HOMO a functional; are error. lower B3LYP are functionals experimental the M062X using there of calculated and details). although range those M052X for to conclusions, the similar 2 above within are Information the functional is Supporting APFD with which (see agreement value, functionals numerical intermediates good APFD relative in of and are levels M062X, results energy M052X, The HOMO and set and basis symmetry LUMO and 6-31G(d) the hindrance steric calculated as we such Subsequently, factors, other on orbitals. level, depends between the energy also difference of difficulty level HOMO matching of energy higher the degree a addition, the have In reaction, group actual results. a calculated above such the HOMO with with LUMO the agreement substituted increases Br good compounds group in order electron-donating Isatin is an the which dienes. reactions, in of pericyclic HOMO increase organic level the of energy compounds that law indicates general substituted data the different theoretical to the According the of reaction. Analysis of alkyl HOMO. the levels the the to provides of energy conducive isatin length not system, the When reaction is ortho increasing this However, which order position. In level, the reaction. para level, energy the in or to energy LUMO increases ortho conducive the LUMO level more the increases lower energy is at chain a LUMO substituent substitution ortho the to an with group, leads having compared alkyl position is, an reaction, meta is the the substituent to at the is conducive substitution more latter halogen, overlap is the a can which combined, is orbitals substituent are two the abilities the When Consequently, electron-withdrawing substituent. However, F induced being radius. F. the and because of orbital by ring ability donor exhibited 2p benzene electron-withdrawing electron still similar the induced conjugate a to the weakens the have conjugated but is C when conjugation F and strengthens of F which electron better, period, orbital 2p same the the 1,3-dipole, in the in However, Br. h 02,M6X n PDfntoaswr loue ocluaethe calculate to used also were functionals APFD and reaction. M062X, organic M052X, of law The relevant the with agrees basically which Cl Δ > a eue opeittedffiut res fterato.Aogtepey,tipee n alkyl and thiophene, phenyl, the Among reaction. the of ease or difficulty the predict to used be can G Δ r oevr h ffc fa rh usiun ssrne hntoeo eaadpr substituents, para and meta of those than stronger is substituent ortho an of effect the Moreover, Br. fec ecinwscluae tteBLP63Gd ee,a hw nTbe2 h magnitude The 2. Table in shown as level, B3LYP/6-31G(d) the at calculated was reaction each of G 1 n HOMO and Δ n ec,dffiut,o h ecin erae nteodrEt order the in decreases reaction, the of difficulty, hence, and G 2 lorflcstedge fdffiut fterato oacranetn.Hwvr nthe in However, extent. certain a to reaction the of difficulty of degree the reflects also 2a’ r lgtylower. slightly are 1a’ and 2a’ 5 n h eut r hw nTbeS.-28of S2.5-S2.8 Table in shown are results the and , 1a’ ntesletpaei aial ls ota in that to close basically is phase solvent the in Δ < fte3 ecin (see reactions 36 the of G F < 1a’ > < OCH H meta and > 3 2a’ OCH < < H aa that para, sn the using 3 < > CH F > 3 . Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. ovn,adterslsaesoni uprigifrain31 The 3. Scheme states. 3.1. transition triethylamine. information and in mechanism supporting spontaneously Reaction in occur reactions shown the are that indicating results negative, the and solvent, The less takes functional APFD The < state. substituted gaseous For similar standard reaction. yield the and consuming in time occur the although can time, reactions computing the The that details). indicating for 3 Information Supporting h ffc ssrnetwe h usiun si h rh oiin o reactant For reaction. position. the to ortho conducive the more in is halides is other substituent or the Br, when Cl, F, strongest OCH with is substitution effect is, The that lower, is reaction the ossetwt h eea a fogncreaction. 2. organic Table of law general the the with analysis, consistent above the on group to electron-donating According an group, electron-withdrawing an contains thiophene Δ 3 auswr locluae tteBLP63Gd ee sn C ihtityaiea the as triethylamine with PCM using level B3LYP/6-31G(d) the at calculated also were values G rohreeto-oaiggop smr odcv oterato.I a ecnlddta if that concluded be can It reaction. the to conducive more is groups electron-donating other or Δ fteratosudrgspaecondition. gas-phase under reactions the of G ,-ioa yladto of cycloaddition 1,3-Dipolar < 1f+2b 1b+2b 1a+2b 1o+2a 1n+2a 1m+2a 1l+2a 1k+2a 1j+2a 1i+2a 1h+2a 1g+2a 1f+2a 1e+2a 1d+2a 1c+2a 1b+2a 1a+2a Product Reaction -r o hooiecmonscnann aoe-usiue hnlgop the group, phenyl halogen-substituted a containing compounds chloroxime For n-Pr. 3r 3q 3p 3o 3n 3m 3l 3k 3j 3i 3h 3g 3f 3e 3d 3c 3b 3a 1a ecat,the reactants, Δ euaiyo ahrato ssal 02 n 02 acltosare calculations M062X and M052X small. is reaction each of regularity G Δ -1.20 -0.91 0.35 1.51 0.14 0.50 -0.53 0.59 0.54 -2.52 0.45 0.67 -0.83 0.68 -2.13 0.55 -1.17 0.60 Δ austa r aial ossetwt h eea a forganic of law general the with consistent basically are that values G Δ (kcal G auscluae sn 3Y,M5X n 02 r basically are M062X and M052X, B3LYP, using calculated values G α- Δ hooezloieadisatin. and chlorobenzaldoxime Δ n ec,dffiut,o h ecinicessi h re Ph order the in increases reaction the of difficulty, hence, and G · ausotie sn hs he ucinl r negative, are functionals three these using obtained values G mol -1 ecinProduct Reaction ) 6 j2 4j 4i 1j+2e 4h 1g+2e 4g 1d+2e 4f 1b+2e 4e 1a+2e 4d 1j+2d 4c 1i+2d 4b 1h+2d 4a 1g+2d 3z 1d+2d 3y 1b+2d 3x 1a+2d 3w 1i+2c 3v 1g+2c 3u 1d+2c 3t 1b+2c 3s 1a+2c 1g+2b 2a smr odcv otereaction. the to conducive more is Δ auso h ecin are reactions the of values G 0.63 0.70 -2.26 -0.43 0.50 0.58 -2.56 0.38 0.70 -2.18 -0.48 0.64 -3.70 -0.48 -3.12 -2.16 -0.53 0.47 Δ (kcal G 2a · mol usiuinwith substitution , -1 ) Δ of G 1a Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. eeec,teeeg ee iga feeetr ecin1wsdrvdadi hw nFgr 2. Figure in shown is and derived was 1 reaction elementary on of point diagram saddle level first-order from energy a leads the has is TS1 reference, whole it reaction. a that the as confirmed of molecule which The surface the calculation, energy and IRC potential by increases, the traced atom was O TS1 the state on Transition 122.42 that to from while 1.283 increases decreases, angle from charge. atom net bond shortened departure N no C(12)–N(13)–O(14) gradually The the and The is hybridization on formed. high. charge bond sp is relatively The C(12)–N(13) to bond, is leading The double polarity bond, C–N charge. double bond partial Because negative C–N C–Cl the atom. the the O carrying attack hydroxyl 1.161 atom, atom atom The the Cl Cl N on orbital. the the the empty charge of to an on the provides adjacent electrons in atom is increase pair H an lone bond the in while double leaves resulting electron, C(12)–N(13) it atom triethylamine, pair to the H lone to hydroxyl connected a migrates the group provides hydroxyl base, atom atom the organic H weak N of a triethylamine atom solvent, H The triethylamine the . the making by electrons, activation pair Through lone acidic. its to in owing effect Cl(16)–C(12)–N(13)–O(14) withdrawing angle dihedral The 1. Figure 1. termediate, compound chloroxime First, is reaction liquid-phase 1. the in reaction point Elementary stationary 4. each Information of structure Supporting optimized in the provided of coordinates Cartesian mechanism. product The reaction end and liquid-phase TS3, the and of reactants TS2, Study of TS1, geometries states transition The med2, conditions. and med1, liquid-phase and gas- under reaction The Δ n h (3–(4 odfo .4 o1.241 to 1.349 from bond N(13)–O(14) the and A ˚ E a o hsse is step this for emtiso h ttoaypit nteatvto of activation the in points stationary the of Geometries 1a’ 1a hog rniinsaeT1 h emtyo ahsainr on ssoni Figure in shown is point stationary each of geometry The TS1. state transition through , + 2a - 3a Δ E hw nShm ,wstkna neape piiainwscridout carried was Optimization example. an as taken was 3, Scheme in shown , 1a a1 21kcal 22.1 = satvtdi h rsneo rehlmn ofr h irl xd in- oxide nitrile the form to triethylamine of presence the in activated is · mol -1 sn h nryo h rdc,[ product, the of energy the Using . 1a 7 scpaa.N1)hsasrn nue electron- induced strong a has N(13) coplanar. is .Teitreit 1,3-dipole, intermediate The A. ˚ 1a to 1a 1a’ 1a ointermediate to hc sterato intermediate. reaction the is which , 3a and eeobtained. were 2a intermediates , 1a’ 1a’ +Et 1a’ ytriethylamine. by 3 Hl,a the as NHCl], hc a a has which , ° 1a’ o180.00 to , 2a’ 1a ° . , Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. h emtyo ahsainr on ssoni iue4. Figure in shown is point stationary each of geometry The intermediate, dipole intermediates the between occurs addition Nucleophilic 2. reaction Elementary 3. Figure in This shown triethylamine. is base, point organic weak stationary each the of of amide geometry atom the N The on the state. atom to transition 3. H a bonds Figure the without and groups, spontaneously easily carbonyl more occurs N(4)– the leaves process The of It character. effect acidic. electron-withdrawing more bond strong is double the partial of a Because formed. has 1.236 1.358 N(4)–C(5) to to thus, 1.213 1.380 106.46 bond; from from shortened 1.379 increases double is to length C–N bond 1.404 bond and C(3) from C(3)–O(11) bond The shortened single is N(4). C–N bond on charge N(4)–C(5) the the in while increase an to ( leading isatin of H(12) Simultaneously, 1. 2. Figure ° h eaiecag nN4 nrae hnintermediate when increases N(4) on charge negative The . nrni ecincodnt IC uv fT1adeeg ee iga feeetr reaction elementary of diagram level energy and TS1 of curve (IRC) coordinate reaction Intrinsic emtiso h ttoaypit ntefraino no intermediate anion of formation the in points stationary the of Geometries 1a’ edn otefraino nemdaemd hog rniinsaeTS2. state transition through med1 intermediate of formation the to leading , 2a ,wihi once oN4,lae ntepeec ftriethylamine, of presence the in leaves N(4), to connected is which ), ,wieteC3–()C5 odagecagsfo 112.08 from changes angle bond C(3)–N(4)–C(5) the while A, ˚ 1a’ 8 and 2a’ .Telte odlnt sbtenta fa of that between is length bond latter The A. ˚ lcrnrc (8 of N(28) Electron-rich . 2a’ hc a e eaiecag,is charge, negative net a has which , 2a’ 2a’ rmiai ( isatin from tak ()of C(6) attacks 2a ° A, ˚ to ). Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. iue5. Figure 5. Figure in shown as overlap, effective of an to LUMO leading the match, reaction, TS2. this state During transition through generated is med1 Intermediate 4. Figure emtiso h ttoaypit ntencepii diino intermediates of addition nucleophilic the in points stationary the of Geometries vrapn oetuocpe oeua ria of orbital molecular unoccupied lowest Overlapping 1a’ n OOof HOMO and 9 2a’ r ls oec te n hi symmetries their and other each to close are 1a’ n ihs cuidmlclrorbital molecular occupied highest and 1a’ and 2a’ . Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. .Teeeto-ihO1)ao fmd- ste rtntdi ouint omproduct and form directly, to Carbonyl solution the in on protonated atom then med1- is C intermediate med1-1 form the of to attacks 7. TS3’, atom group Figure state, O(14) nitroso transition electron-rich five-membered the The the of 1. through occur cyclized atom can is O med1 2, electron-rich intermediate reaction The elementary by 1: Path formed was pathways. which two med1, following the intermediate through of reaction intramolecular The 3. reaction Elementary 2. 6. Figure 6. Figure in shown poor. is more relatively and the yields is obtained combining not and LQA product was by of does accuracy With 2 that obtained algorithm. highest it while curve HPC the because intermediate, the IRC has errors, is with the GS2 algorithm the such shows GS2 of in avoid HPC 6 accuracy easily time, can The converge The Figure shortest algorithms size. not products. the does GS2 step and takes steps reactants correction and LQA of accurate of LQA number size, problem of the step and the use and generated time, involve the number is longest However, IRC step the when algorithm. takes same that HPC HPC concluded the place, is structures, with second it intermediate state comparison, the and By takes transition reactant calculated. same accurate were reaction. steps more the the of obtain for of size to and surface adopted number energy were the potential GS2, and the and in LQA point HPC, saddle including first-order a is The TS2 that proved calculation IRC 117.76 of angle bond 2.050 O(29) is distance C(16)–N(28) 147.96 the is which angle at TS2 state transition through of C(6) of ring benzene The of 2a’ Δ E . 1a’ a o hsse is step this for nrni ecincodnt IC uv fT2adeeg ee iga feeetr reaction elementary of diagram level energy and TS2 of curve (IRC) coordinate reaction Intrinsic n (8 of N(28) and ° ial,teC1)N2)snl odfrswt odlnt f1.432 of length bond a with forms bond single C(16)–N(28) the Finally, . 1a’ Δ oae,adteC1)N2)O2)bn nl erae rdal rm180.00 from gradually decreases angle bond C(16)–N(28)–O(29) the and rotates, 2a’ E ° . a2 r ls oec te,wihfclttsterbnig h ecinproceeds reaction The bonding. their facilitates which other, each to close are .6kcal 9.76 = 3a · sterfrne h nrylvldarmo lmnayreaction elementary of diagram level energy the reference, the as mol -1 o h R nlsso hspoes ieetalgorithms, different process, this of analysis IRC the For . 10 calcall ewr sesz ,mxon 200) = maxpoint 5, = (stepsize keyword n h (6–(8–(9 bond C(16)–N(28)–O(29) the and A ˚ n C(16)–N(28)– and A ˚ 3a ssonin shown as , ° . Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. iue8. Figure H that these hypothesized under was unstable it is and med1-1 ring. C(8)–O(14) ring that the occur, five-membered proves 8-membered optimized, the cannot which is unstable of 1 ring, med1-1 very five-membered path intermediate a stable of Therefore, and a structure broken conditions. form the is cannot after away and time, bond far breaks same energy. become C(8)–N(7) in the bond O(14) the point At and bonded, highest C(8) formed. the not as is reaching are that without system shows increases O(14) continuously scan and during system The C(8) qst3 curve the respectively. of or energy When 9, energy qst2, and the and changes ts, other, 8 structural the each Figures The either from in using flexibly. shown found scanned are not was scan was length the process bond this C(8)–O(14) of The state method. transition H the the tested, were that configurations assumed we 1, path For 3a 7. Figure . emtiso h ttoaypit nteitaoeua ecino nemdaemd oform to med1 intermediate of reaction intramolecular the in points stationary the of Geometries emtiso h ttoaypit nteuasse cyclization. unassisted the in points stationary the of Geometries + nslto sntivle ntecciainpoes lhuhvarious Although process. cyclization the in involved not is solution in 11 + atcptsi h formation the in participates Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. ()O1)bn eghi 1.378 is 113.29 length is bond angle C(7)–O(14) bond N(13)–C(16)–N(28) the carbonyl to migrates 113.11 125.87 O(19) of to 1.316 1.346 angle to bound to bond increases atom increases length H length bond The C(7)–O(14) bond other. the C(7)–O(14) each the approach and O(29) transition O(14), and a C(7) without proceeds, spontaneously reaction occurs 124.88 is process angle this bond 2.940 theory, N(13)–C(16)–N(28) of In the med2, optimization. In geometry state. after stable be H to the reaction, the During 10. Figure the of geometries the and reasonable, is path this 10. Figure that in show shown are analysis reaction and the Product calculation in points atom. The and stationary O med2 carbonyl into TS3. the converted is to state, med1 migrates intermediate atom after H occurs the migration hydrogen Intramolecular protonation. H The 2: Path 9. Figure ° n h ofiuainleeg otne odces,rsligi h omto of formation the in resulting decrease, to continues energy configurational the and ) n h abnlC7–(4 odsosdul odcaatr(odlnt f1.221 of length (bond character bond double shows bond C(7)–O(14) carbonyl the and A), ˚ lxbesa fteC8–(4 bond. C(8)–O(14) the of scan Flexible emtiso h ttoaypit nH in points stationary the of Geometries + nslto atcptsi h ylzto rcs n tak lcrnrc (9,laigto leading O(29), electron-rich attacks and process cyclization the in participates solution in ° stemlcl otne ortt,teC8–()O2)bn nl erae to decreases angle bond C(8)–C(7)–O(29) the rotate, to continues molecule the As . + nslto irtst (9 ofr nemdaemd,wihwsconfirmed was which med2, intermediate form to O(29) to migrates solution in A. ˚ ° ,adC7 n (9 om odwt C(8)–C(7)–O(29) a with bond a forms O(29) and C(7) and A, ˚ h ()O2)bn eghi 1.431 is length bond C(7)–O(29) the , 12 + asse ylzto ognrt product generate to cyclization -assisted 3a’ ° .A h ecincosstasto tt TS3, state transition crosses reaction the As A. ˚ sfre hog h v-ebrdtransition five-membered the through formed is ()adO2)aentbne bn distance (bond bonded not are O(29) and C(7) , ,adtecarbonyl the and A, ˚ 3a’ 3a’ ) sthe As A). ˚ In . . 3a’ , Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. iue12. Figure product, final the 12. obtain Figure to in optimized shown 1 are further of points was length stationary and step the energy a of of lowest with the H(30) steps has 360 that in product seen scanned be flexibly can was C(8)–C(7)–O(14)–H(30) it structure, the From 3. 11. Figure in point saddle first-order a is it 11. that Figure The in proved reaction. which the calculation, of product IRC surface by energy potential traced the was TS3 state Transition 3a sterfrne h nrylvldarmo lmnayrato a acltdadi shown is and calculated was 3 reaction elementary of diagram level energy the reference, the as nrni ecincodnt IC uv fT3adeeg ee iga feeetr reaction elementary of diagram level energy and TS3 of curve (IRC) coordinate reaction Intrinsic emtiso h ttoaypit fe piiaino the of optimization after points stationary the of Geometries Δ 3a’ E 13 a oae.A hw nFgr 3 h ierlangle dihedral the 13, Figure in shown As rotated. o hspoesis process this for 3a’ Δ E structure. a3 ° ofiuain3a Configuration . 69 kcal 26.92 = 3a h geometries The . · mol -1 0 With . fthe of Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. o lmnayratos13 h a-hs ecinflostesm ecinptsa h liquid-phase 14. the Figure as in paths shown as reaction similar, same basically TS1 the states follows transition reaction as gas-phase the Intermediates Therefore, from reaction. 1–3, differences reaction. reactions and the elementary similarities in the For involved and analyzed. are discussed, were themselves is condition condition molecules reaction This solution-phase gas-phase solvent the processes. the the on the under reaction effects studied, mechanism different different have we reaction the likely solvation the system in and and the molecules strength, rates solvent For ionic reaction polarity, are different rate. constant, there are dielectric that the there is because reaction, reactions is same liquid-phase the and For gas- the latter. between difference biggest mechanism. The reaction gas-phase the of Study 13. Figure lxbesa fteC8–()O1)H3)dihedral. C(8)–C(7)–O(14)–H(30) the of scan Flexible 1a’ a,TS2 gas, gas, 2a’ a,adTS3 and gas, a,med1 gas, a,admed2 and gas, a.Teotmzdsrcue ftesainr onsare points stationary the of structures optimized The gas. 14 a,wr omddrn h ecin swell as reaction, the during formed were gas, Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. neeto-oaigo lcrnwtdaiggop iue 5ah hw h R uvsfrtedifferent the for out. curves IRC carried the was shows tracing dienophile 15(a–h) Figures IRC of reactants. and group. path substituted electron-withdrawing optimized, reaction or were the electron-donating products an that shows and reactants calculation the The of hand, configurations other molecular the reactant On on respectively. elementary substituents, substituent of Therefore, the 2) changing Reactants reaction substituent. controlled, (elementary a LUMO reactions by substituents. is The different affected reaction with greatly the reactants is selecting Because by that investigated reaction further was intermolecular 2 an reaction is intermediates TS2 between state reaction the removal hand, The to other states. med2 transition intermediate three of and cyclization reactions elementary three 3 are H reaction there of Elementary process, reaction whole the For 2 reaction Elementary the of Comparison 1 reaction Elementary phase Gas solvent as triethylamine with phase Liquid Condition triethylamine no is Δ there 1, reaction elementary in However, 3. other Table the phase. On gas the the the solvent. 3, the in from triethylamine and and H solvent, those inferred 2 polar the than reactions the on be elementary higher effect by can for attractive slightly affected It reactant comparison, an less comprehensive has the molecules. triethylamine is a environment, solvent, 3, to the system gas-phase triethylamine reaction of the elementary a the that collision in in In hand, effective 3.1 out section the carried resistance. in hinders is without discussion which reaction directly solvated, the collide are When can molecules 13. molecules Table reactant in the the shown reaction, are elementary two-step environments the For phase formed. H be cannot 3, intermediate reaction elementary In 14. Figure Ε α + (κςαλ·μολ n Cl and ciaineege ( energies Activation 1a emtiso nemdae n rniinsae neeetr ecin – ntegsphase. gas the in 1–3 reactions elementary in states transition and intermediates of Geometries - , rmreactant from 1b Δ E -1 , a ) o omn intermediates forming for 1f Δ E , 1g a fdffrn reactions. different of 779426.4 26.9 9.4 9.8 27.7 22.1 + , 1a Δ 1j osaeas eddt omtefiemmee ig tews,astable a otherwise, ring; five-membered the form to needed also are ions E hog rniinsaeT1i are u ntityaieslet The solvent. triethylamine in out carried is TS1 state transition through and , a 3a fec ecinse ntelqi n a phases. gas and liquid the in step reaction each of ) hog rniinsaeT3i nitaoeua ecin nthe On reaction. intramolecular an is TS3 state transition through 1m 1a oti hnlgopwt ,CH H, with group phenyl a contain , 1n 1a’ 1b 1a’ stipeesbtttdand substituted thiophene is , and 15 and 1f 2a’ , 2a’ 1g rmreactants from 1a ofr nemdaemd hog transition through med1 intermediate form to , 1j osntcag hte h usiun is substituent the whether change not does , 1m Δ , E 1n Δ 1a a E and , ausi h ovn hs are phase solvent the in values and a + ausi h a-adliquid- and gas- the in values 1o osi ouin According solution. in ions 2a 3 1o saklsbtttd The substituted. alkyl is 1a OCH , epciey shigher. is respectively, , with a rae effect. greater a has 3 ,C,adBr and Cl, F, , 2a eestudied. were Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. tutr ftefie on ntelqi hs ecincnb eni h tahetspotinformation. ( support coordinates attachment the Cartesian in the seen And be can Notes reaction levels. phase different orbital liquid the PDF) at the levels, molecular i.e., in different type, phase unoccupied point at (file gas fixed reactants lowest the the the the of of in structure (HOMOs) between reaction orbital difference molecular each energy occupied of highest the the and steps, (LUMOs) experimental specific charge. of The free available are files following future. The the long-term in a kind have this to Information of expected Supporting drugs is effective process study more reaction This of The design process. higher CONTENT reaction the product. ASSOCIATED with the for the curve on ideas of effect IRC useful structure minor providing an the a by produced has significance to HPC only Using closer solvent were the compared. the discussed. curve comparing that were and by the disadvantages IRC Finally, calculated of and the advantages calculated. were ends was the producing two phases and in the confirmed, gas GS2 was and and states accuracy, and mecha- liquid corresponding transition HPC, the reaction and the LQA, of reactions the in an accuracy of elementary and the TS3, with main this determined, method, and three substituted In IRC was TS2, The the is system reaction. TS1, level. isatin the this B3LYP/6-31G(d) states, to When to the transition beneficial at functional also B3LYP reaction. discussed is was the the which nism the of facilitate increases, reduce applicability thus level can the energy and group study, more HOMO phenyl reactant is the the chloroxime the group, on in of substituent electron-donating group substituted electron-withdrawing level phenyl of an a energy showed HOMO of and because LUMO results and presence reaction geometries The the the compounds the Furthermore, chloroxime to products. optimize reaction. conducive substituted 36 LUMO-controlled to and of the used intermediates, LUMO in were 5 isatin the reactants, functionals between 5 APFD matching of symmetry and frequencies reaction. M062X, vibrational one-step synthe- the M052X, we a B3LYP, determine where by and cycloaddition compounds 1,3-dipolar set 1,2,4-oxadiazolindolone on work basis polyheterocyclic previous novel our 36 of advantage sized takes study this conclusion, In Conclusions CH with 4. Substitution Table weaker. electron- is induced higher donor, the reaction. a electron because the the to reactants conjugate to to lead Br-substituted a groups conducive and is electron-donating Cl- more which other the F, are of of Br, those effect and than withdrawing a higher Cl, benzene. of slightly of that F, the is that than as lower reactant as larger such they is good groups, because orbital as 3p electron-withdrawing reaction not a is benzene, of thiophene substituted radius of For the effect hybridized because are conjugation worse ring the slightly Consequently, benzene is the orbital. on orbitals sp 2p atoms of the C overlap The in The reaction. orbitals electrons. the 2p for favorable provide more to is system ring conjugated a reactant for 14, Table Δ in seen be can As 15. Figure E a .. ereo icly o lmnayrato nrae nteodrPh order the in increases 2 reaction elementary for difficulty, of degree i.e., , ciaineege ( energies Activation nrni ecincodnt IC uvsfrtedffrn usiue reactants. substituted different the for curves (IRC) coordinate reaction Intrinsic Δ Substituent E a (kcal . · Δ mol 2 E Δ oe hl h tmi hohn scnuae ihte3 orbital 3p the with conjugated is thiophene in atom S the while mode, -1 E a . 031. . . . 0211.0 10.2 8.9 8.8 9.8 10.6 10.3 9.8 ) o ieetsbtttdcompounds. substituted different for ) a mn h usiue ecat,the reactants, substituted the Among . 1a usiue ihpey,tipee n ly rus h required the groups, alkyl and thiophene, phenyl, with substituted Δ E a ausfrtegs n iudpaeratos twsproven was it reactions, liquid-phase and gas- the for values Δ E 16 a hti,a lcrndntn ru sntconducive not is group electron-donating an is, that , Δ < E thiophene a o h F-substituted the for )o h optimal the of A) ˚ 31 < h 6-31G(d) The 3 -r Thus, n-Pr. OCH , 3 Δ or , G Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. .Gai-ioi,J;Oat,I;Ctvea . eeo . eio . xeietladComputational and Experimental P., Merino, Nitrones. and T.; 2,3-Dihydrothiazoles Chem Tejero, Pure Org Enantiomerically J C.; between Eur Cycloaddition Cativiela, 1,3-Dipolar I.; the on Osante, 1,3-Dipolar- Studies through J.; Heterohelicenes Gracia-Vitoria, to Pieters, Approach 2. G.; Sydnone-Based Muller, M.; D., Johnson, Audisio, P.; N.; Thuery, S.; K. Cycloadditions. Gabillet, Houk, L.; F.; Plougastel, Taran, A.; G.; P. Champagne, E.; Yen-Pon, and 1. 21465025 Nos. Yunnan for of University (Grant Center Yunnan References Computing China of Performance Center of Technology High Information Foundation the support. as and technical Science well resources providing as Natural computing work, providing National this for of University the support thank financial for to 81860623) like would We interest. Acknowledgment financial competing no declare authors The .Rn . u . i . ytei fnvldispiro[indoline-3,2’-pyrrolidine-3’,10”- novel of Synthesis X., Li, X.; reaction. Hu, cycloaddition 1,3-dipolar Compounds Heterocyclic D.; by of derivatives Ren, thiazolo[3’,2’:1,2]pyrimido[5,4-g]indolizine] 3. .Bre .D;Shebr .L,Apann taeyfrdvriyoine synthesis. diversity-oriented for strategy planning A L., S. Schreiber, Engl D.; M. Burke, 7. multicompo- one-pot Diversity-oriented Y., Zhou, S.-W.; Xu, reaction. X.-L.; cycloaddition Liu, 1,3-dipolar a X.; via Letters Tetrahedron selected 3,3’-pyrrolidinyl-spirooxindoles Zuo, chromanone-based of S.; of reactions synthesis Chen, cycloaddition nent J.; 3-Dipolar Yue, 1, E., 5. study. Adei, computational R.; Model A cleavage: Graph Tia, thermolytic Mol E.; follow-up J Opoku, and H.; 7-isopropylidenenorbornadiene with A. 1,3-dipoles Adams, G.; Arhin, 4. .Ay,P;Jsp,R;Gn . ai,B,Epoignwceia pc yseecnrle diversity- stereocontrolled by space chemical new Exploring B., Rakic, Z.; Gan, R.; Discovery. synthesis. Joseph, Drug oriented P.; in Arya, Synthesis 9. Organic Diversity-Oriented and Target-Oriented S., 2000, Diversity- Schreiber, the for 8. Strategies R., D. Spring, F.; H. Sore, A.; T. King, J.; Macrocycles. T. of Osberger, Synthesis T.; Oriented K. Mortensen, 6. 3 ua,D;Ptl . iaarsnn . atdr .G;Ry . einadsnhsso 3,5- of synthesis and Design A., Ray, G.; S. Dastidar, Linked L.; 1,2,4-Oxadiazol Vijayakrishnan, phosphodiesterase4b2. 810-818. of G.; of (5), Activity inhibitors Patel, potent Anticancer as D.; and disubstituted-1,2,4-oxadiazoles Kumar, Synthesis B., 13. Ram, Giofre, S.; L.; Satyaveni, Veltri, Derivatives. evaluation. M.; D.; Benzimidazole biological Iannazzo, Srinivas, and L.; synthesis Giuseppe, 12. tamoxifen: B.; of Paola, analogues A.; as Chem Campisi, 1,2,4-Oxadiazole-5-ones Biomol L.; R., Legnani, Romeo, A.; S.; M. 1,2,4-Oxadiazole-derived Chiacchio, F.-X., bridge. Chen, 11. methylene G.; Fan, a H.; by Yin, reduced J.; sensitivity Song, 2019, with S.; Wang, compounds G.; energetic Wang, C.; polynitro Wang, T.; Lu, 10. 2004, 287 43 3) 13330-13333. (34), 40,1964-1969. 5460), ( 43 2019, 1,46-58. (1), mCe Soc Chem Am J 2019, hmBiol Chem 2019, 2019, 17 2019 1) 4892-4905. (19), usa ora fGnrlChemistry General of Journal Russian 60 92 2019, 2) 4426-4435. (27), 2005, 2,137-141. (2), 267-279. , 2019, 55 hmRev Chem 12 3,275-279. (3), 141 2,163-180. (2), 4,1435-1440. (4), 2019, 17 119 1) 10288-10317. (17), 2019, 88 1) 2653-2657. (12), hmBo rgDes Drug Biol Chem e ora fChemistry of Journal New ne hmItEd Int Chem Angew Chemistry 2012, Science Org 79 Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. 6 hn,C;L,Z;Su . i . hn,B,Snhsso sxzldnsb ,-ioa yladto and cycloaddition 1,3-dipolar by isoxazolidines of Synthesis B., Zhang, T.; Li, J.; Shu, bioactivity. Z.; their Li, C.; Cheng, 26. L. Arnold, E.; DiMilo, investiga- A.; the disorders. for Alsafran, . neurodegenerative properties J.; and improved E. psychiatric with Dickson, blocker of channel D.; tion Kv7.2/7.3 C. anthrone-based Weaver, An between L.; C., O. Dockendorff, Interactions Vivas-Rodriguez, A.; o., D.; J. F. Porter, Nepveu, 25. Nallet; Jean-Pierre Albumin. Kim; Serum enantiose- Sothea Human 3341-3351 for and Ibrahim; catalysts Derivatives Hany alkaloid Indolone-N-oxide cinchona Antimalarial Ibrahim; of Nehal polyesters chiral nitroalkenes. 24. of to anthrone Synthesis of Synthesis S., W., addition Itsuno, Y. Michael T.; Guo, lective Y.; B. H. Kumpuga, Zhang, W.; 23. Xiao, Z.; Z. multifunctional Wang, as X.; derivatives agents. 1,2,4-oxadiazoles J. indole-based neuroprotective Gong, marine-derived L.; novel of Zhang, evaluation Y.; biological Fu, and S.; 1,2,4-oxadiazole C. new Jiang, of 22. synthesis 1,2,4oxadiazoles. the of for Q. methodologies process synthetic for Ito, Li, Research the on Sciences biomarkers S.; review to C.; short Iwamoto, amyloid-beta Modifications Fowler, the Y.; S., plasma and V.; analogues Subbiah, Arahata, performance Periyasmay; Dore, K.; High Senthil J.; Ishii, K., 21. K.; Doecke, Yanagisawa, Ishii, T.; L.; K.; Kato, C. Matsuzaki, disease. Masters, L.; Alzheimer’s T.; Tomita, V. K.; Tanaka, C.; Villemagne, Rowe, K.; N.; R.; H.; Ethionamide Kaneko, Martins, S. N., A.; Piveteau, X.; Willand, pharmacokinetic Soror, inhibitors. Nakamura, solve R.; F.; R.; EthR to A. 1,2,4-oxadiazole Wintjens, design Leroux, 20. Baulard, potent drug A.; B.; of N.; structure-based Wohlkonig, Deprez, series and Blondiaux, P.; a V.; replacement in Brodin, bioisosteric B.; Villeret, issues C.; Combining J.; Villemagne, Locht, 2. Siepmann, K.; N.; boosters. H. P.; C.; Lecat-Guillet, Jeon, M. Locht, T.; M.; Flament, B.; Christophe, V.; Desroses, Deprez, Mathys, M.; G.; C.; Flipo, Lippens, P.; 19. ligands. England, synthetic and V.; Mycobacterium natural from mimicking Villeret, EthR Wintjens, change repressor A.; acid B.; 40 transcriptional Wohlkonig, amino the C.; Dirie, Z.; of single activation Lens, by Giuliano, Structural F.; tuberculosis N.; R., Frenois, Lecat-Guillet, A. M.; P., Baulard, S.; H.; N.; Fonsi, Jones, Hoos, Willand, S. E.; C.; A.; Willery, Soror, N.; Steinkuhler, Bresciani, R.; Blondiaux, M.; X.; G.; Rowley, Carette, C.; Dessole, 18. Torrisi, an- D.; C.; smoothened Branca, M. potent Palumbi, tagonists. M.; highly E.; J. as Monteagudo, N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides Ontoria, L.; 5-amino- diaryl E.; Bufi, of Llauger Muraglia, Identification 3-(2-fluorophenyl)-5-(4-methoxyphenyl)amino- E., of Hamel, case 17. L.; special T. Nguyen, the M.; Krasavin, inhibitors: 1,2,4-oxadiazole. V.; tubulin A. as Sosnov, M., A.; 1,2,4-oxadiazoles Amini, A. A.; Gakh, Shafiee, 16. M.; triaryl-1,2,4-oxadiazole. H. of Kandelousi, activity An- M.; anticancer A., Norouzi, and Research K. A.; study, Werbovetz, Amirhamzeh, docking M.; L.; molecular Synthesis, Salimi, S. P.; Croft, Miralinaghi, K.; 15. DeLuca-Fradley, M.; M. Salem, 3-aryl-5-thiocyanatomethyl-1,2,4-oxadiazoles. J.; 2815-2824. of Capers, activity M.; tikinetoplastid D. Cottrell, 14. 7,3018-3030. (7), 2013, iogMdCe Lett Chem Med Bioorg iogMdCe Lett Chem Med Bioorg 22 rnir fCeityi China in Chemistry of Frontiers 2019, 9,4253-4262. (9), Nature iogMdCe Lett Chem Med Bioorg 7 2,87-104. (2), 2018, 2011, 554 79) 249-254. (7691), 2013, 21 1) 5283-5288. (18), 23 2015, 2006, 5,1262-1268. (5), iognc&MdcnlCeityLetters Chemistry Medicinal & Bioorganic 18 ora fCatalysis of Journal 25 1 2,216-220. (2), 4,427-433. (4), e Chem Med J Biomacromolecules iogMdChem Med Bioorg 2018, 2012, nentoa ora fLife of Journal International 361 55 uli cd Res Acids Nucleic 1,68-83. (1), 398-406. , eiia Chemistry Medicinal 2004, 2010, 2019, 12 11 126681 2012, (11), (12), Posted on Authorea 29 May 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159078914.44654675 — This a preprint and has not been peer reviewed. Data may be preliminary. 2 uu,K;Ynzw,T;Ngt,C;Sig,H,MlclrObtlTer fOinaini Aromatic, in Orientation of Theory Orbital Molecules. Molecular Conjugated H., 1442. Shingu, Other C.; and Nagata, 1,2,4-Oxadiazole[4,5-a]indolone Tautomeric-Heteroaromatic, T.; Yonezawa, J., of K.; Lin, Fukui, Y.; Synthesis Jin, 32. Facile N.; Neamati, Oxide: N.; Muangsin, Nitrile K.; An, with Derivatives. Y.; Cycloaddition S. Zhao, Lactam U.; Zhe Luesakul, Dependent G. M.; K. Bloino, Jiang, J. Scuseria, 31. Izmaylov, GE AF Schlegel, HB Hratchian, Trucks, HP GW Frisch, Li, MJ 01, X. G. 3- A. Cheeseman, Revision JR 09, of Robb, Gaussian MA In F., Synthesis Clemente, Pesticides M.; Oxime Frisch, Stereoselective Carbamoyl 30. and N-Methylcarbamate Lene, Of Degradation Raie R., Water. Yost, Chlorinated M.; Kirby; Trehy, C.; Miles, (-)-Pancracine. Rajinikanth; 29. of Synthesis Lingampally; Formal a V.; 556-559 in (3), profile S. Application antipsychotic the and Pansare, on Aryloctahydroindoles modifications bridge linking 28. of derivatives. Effect isoindolillone G., and phthalimide Rigdon, some D.; of Minick, M.; Norman, 27. C Omega ACS ultnO niomna otmnto n Toxicology and Contamination Environmental Of Bulletin 2017, clai .Brn,B enci APtrsn .Nktui .Caricato, M. Nakatsuji, H. Petersson, GA Mennucci, B. Barone, V. Scalmani, 2 7,3123-3134. (7), ora fMdcnlChemistry Medicinal Of Journal 19 h ora fCeia Physics Chemical of Journal The . 1988, rai Letters Organic 1996, 41 1954, 6,838-843. (6), 39 22 1,149-157. (1), 8,1433- (8), 2010, 12