WA MALI MA LTA MARIAUS 20180002309A1 DEL CHIA TANA LATIH ( 19 ) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018 /0002309 A1 Haim et al. ( 43 ) Pub . Date : Jan . 4 , 2018

(54 ) PROCESSES FOR THE PREPARATION OF A CO7D 235 / 02 (2006 . 01) DIARYLTHIOHYDANTOIN COMPOUND C07D 213 /84 ( 2006 .01 ) ( 52 ) U . S. CI. (71 ) Applicant: Aragon Pharmaceuticals , Inc. , San CPC .. . C07D 401/ 04 ( 2013 .01 ) ; C07D 235 / 02 Diego , CA (US ) ( 2013 .01 ) ; CO7D 233 / 86 (2013 . 01 ) ; C07D 213 / 84 ( 2013 .01 ) ; B01J 31/ 24 ( 2013 .01 ) ; (72 ) Inventors : Cyril Ben Haim , Beerse (BE ) ; Andras CO7B 43/ 06 (2013 .01 ) ; BOIJ 31 / 26 (2013 .01 ) ; Horvath , Turnhout (BE ) ; Johan Erwin CO7D 213 /61 ( 2013 . 01) ??????? Edmond , Beerse (BE ) ; Jennifer Albaneze - Walker, Mol (BE ) (57 ) ABSTRACT ( 21 ) Appl . No. : 15 / 537, 859 Disclosed are processes and intermediates for the prepara tion of compound ( X ), which is currently being investigated (22 ) PCT Filed : Dec . 17, 2015 for the treatment of prostate cancer. ( 86 ) PCT No .: PCT/ US2015 / 066345 $ 371 ( C ) ( 1 ) , (X ) ( 2 ) Date : Jun . 19 , 2017 F NC N CONHMe PuuPublication Classification S (51 ) Int. Cl. CO7D 401/ 04 ( 2006 . 01 ) F2C CO7D 233 /86 ( 2006 .01 ) C07D 213 /61 ( 2006 .01 ) B01J 31 /24 ( 2006 .01 ) w C07B 43 / 06 ( 2006 . 01 ) B01J 31/ 26 (2006 .01 ) US 2018 /0002309 A1 Jan . 4 , 2018

PROCESSES FOR THE PREPARATION OF A [0006 ] reacting compound (V ) with cyclobutanone in the DIARYLTHIOHYDANTOIN COMPOUND presence of sodium cyanide; in a solvent such as acetic acid , or a solvent system comprised , consisting , or consisting CROSS -REFERENCE TO RELATED essentially of an alcoholic solvent and a protic acid ; at a APPLICATIONS temperature of about 0° C . to about 20° C .; to yield the corresponding compound ( VI) ; [0001 ] This application claims priority to U . S . Provisional Patent Application No . 62 /094 ,425 , filed Dec . 19 , 2014 , which is hereby incorporated by reference in its entirety . ( 16 ) STATEMENT REGARDING FEDERALLY F SPONSORED RESEARCH OR DEVELOPMENT NC . N [0002 ] The research and development of the invention + described below was not federally sponsored . C F NH, NON FIELD OF THE INVENTION IVIV 0003 ] The present invention is directed to the preparation 210 of compound ( X ) and intermediates in its synthesis . More NC N specifically , the present invention is directed to processes for the preparation of compound ( X ), disclosed in U . S . Pat. No . 8 ,445 , 507 , issued on May 21 , 2013 , which is hereby incor F3C porated by reference in its entirety . BACKGROUND OF THE INVENTION gad [0004 ) Compound ( X ) of the present invention is currently being investigated for use in the treatment of prostate cancer. The present invention describes processes and intermediates [0007 ] reacting compound (IV ) and compound (VI ) in the for the preparation of such compound . presence of a thiocarbonylating agent; in an organic solvent ; at a temperature of about 0° C . to about 100° C .; to yield the SUMMARY OF THE INVENTION corresponding compound ( VII) ; [ 0005 ] The present invention is directed to a process for the preparation of compound ( X ) ( 1x )

- NC N F NC N CONHMe F3C

F C ' N VII WidtF 0 NC NHMe Comprising , consisting of, and / or consisting essentially of F3C ( la ) F Diction F

[0008 ] converting compound (VII ) to compound ( X ) , dis HON cussed in further detail below . [0009 ] In one embodiment, compound (VII ) is converted ?? to compound ( X ) via its corresponding carboxylic acid ( 1c ) , as shown in scheme ( 1c ), by US 2018 /0002309 A1 Jan . 4 , 2018

( 1c ) ( le ) NCN , NC N

= payoF3C sayoF3C VII VII F F NC , N , NC N CO (OC1 - talkyl ) 1 CO2H NN Fzc ??

[ 0010 ) ( i ) reacting compound (VII ) with an organomag [0014 ] ( i ) reacting compound (VII ) with an organomag nesium halide ; in the presence or absence of a lithium halide ; nesium halide ; in the presence or absence of a lithium halide ; followed by the addition of carbon dioxide gas ; in an aprotic in an aprotic organic solvent; at a temperature of about – 50° organic solvent; at a temperature of about 0° C . ; to yield the C . to about room temperature ; followed by the addition of an corresponding carboxylic acid compound ( 1c ); or, Ci- galkyl chloroformate or C - galkyl cyanoformate ; to yield [ 0011 ] ( ii ) reacting compound (VII ) under a carbon mon the corresponding ester of formula ( le ); or oxide atmosphere ; in the presence of a palladium catalyst ; in [ 0015 ] ( ii ) reacting compound (VII ) under suitable the presence of one or more phosphorus ligands ; in the alkoxycarbonylation conditions ; under a carbon mon presence of an organic base ; in a the presence of water ; in oxide atmosphere ; in the presence of a palladium an organic solvent; at a temperature of about 0° C . to about catalyst ; in the presence of one or more phosphorus ligands ; in the presence of a base ; in a C - alcoholic 100° C .; to yield the corresponding compound ( 1c ); then , solvent; at a temperature of about room temperature to about 100° C . ; to yield the corresponding compound of (1d ) formula ( le ) ; then F NCN . _ C02H S ( 11)

F C NC N CO (OC1 - 6alkyl )

. F C FO

NC . ???S NHMe Te 0

FC NC N NHMe

F C

[ 0012 ] reacting compound ( 1c) with a coupling agent; in an aprotic or protic solvent; at about room temperature ; X followed by the addition of methylamine; to yield the corresponding compound (X ). [0016 ] treating a compound of formula ( le ) with methyl [0013 ] In another embodiment, compound ( VII ) is con amine; in a protic or aprotic solvent; at a temperature of verted to compound ( X ) via its corresponding C1- 6alkyl ester about 0° C . to about 60° C . ; to yield the corresponding (le ), as shown in scheme ( le ), by compound ( X ). US 2018 /0002309 A1 Jan . 4 , 2018

[0017 ] In another embodiment, compound ( VII ) is con [0027 ] The term " oxo ” or " oxido ” refers to the group verted directly to compound ( X ), as shown in scheme (1g ), GO ) . oby en manera moderne a con [0028 ] Whenever the term “ alkyl ” or “ aryl” or either of their prefix roots appear in a name of a substituent ( e. g ., arylalkyl, alkylamino ) the name is to be interpreted as including those limitations given above for " alkyl ” and (1g ) “ aryl. ” Designated numbers of carbon atoms ( e . g . , C . - C . ) refer independently to the number of carbon atoms in an alkyl moiety , an aryl moiety , or in the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl and alkoxy substituents , the designated number of carbon atoms includes all of the independent members Fzc included within a given range specified . For example C1- 6 quo alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub - combinations thereof ( e . g . , C1- 2 , C1- 3 , C1- 4 , C1- 5 , C2- 6 , C3- 6 , C4- 6 , C5- 6 , C2- 5 , etc . ) . VII [0029 ] In general, under standard nomenclature rules used FO throughout this disclosure , the terminal portion of the des ignated side chain is described first followed by the adjacent NCN , S functionality toward the point of attachment. Thus , for NHMe example , a “ C , - C . alkylcarbonyl” sub stituent refers to a group of the formula : F C

C - C1- C6 alkyl .

m

[ 0018 ]. ( i ) reacting compound ( VII) in the presence of (0030 ) The term " room temperature ” or “ ambient tem molybdenum hexacarbonyl; optionally in the presence of perature ” , as used herein refers to a temperature in the range one or more reagents such as norbornadiene, tetrabutylam of from about 18° C . to about 22° C . monium bromide , or a base selected from triethylamine or [0031 ] Abbreviations used in the instant specification , DABCO ; in an organic solvent ; followed by the addition of particularly the schemes and examples, are as follows: methylamine; at a temperature of about 60° C . to about 140° Abbreviations C .; to yield the corresponding compound ( X ) ; or, [ 0032 ] aq aqueous [ 0019 ] ( ii ) reacting compound (VII ) under suitable amin [0033 ] BA [ 1, 1' -biphenyl ] -2 - amine ocarbonylation conditions ; under a atmo [0034 ] Boc tert - butoxycarbonyl sphere ; in the presence of a palladium catalyst; in the [0035 ] CDI 1 , 1 ' - carbonyldiimidazole presence of one ormore phosphorus ligands; in the presence [0036 ] CPME cyclopentyl methylether of a base ; in the presence of methylamine ; in an organic [0037 ] Cy cyclohexyl solvent; at a temperature of about room temperature to about [0038 ] DABCO 1 , 4 - diazabicyclo [ 2 . 2 . 2 ] octane 100° C .; to yield the corresponding compound (X ). 100391 DCM dichloromethane DETAILED DESCRIPTION OF THE [0040 ] DIEA or DIPEA diisopropylethylamine INVENTION [0041 ] DMA dimethylacetamide [ 0020 ] The term “ alkyl” whether used alone or as part of (0042 ] DMF dimethylformamide a substituent group , refers to straight and branched carbon [0043 ] DMSO methyl sulfoxide chains having 1 to 8 carbon atoms. Therefore , designated [ 0044 ] dppf 1 , 1 '- bis ( diphenylphosphino ) ferrocine numbers of carbon atoms ( e .g ., C1-8 ) refer independently to [0045 ] h hour( s ) the number of carbon atoms in an alkylmoiety or to the alkyl 100461 HC1 hydrochloric acid portion of a larger alkyl -containing substituent. In substitu [0047 ] HPLC high performance liquid chromatography ent groups with multiple alkyl groups such as, (C1 - 6alkyl ) [0048 ] Me methyl zamino - , the C1- alkyl groups of the dialkylamino may be [0049 ] MeCN acetonitrile the same or different . [0050 ] MeOH methyl alcohol [ 0021] The term “ alkoxy” refers to an O - alkyl group , 10051] mg milligram wherein the term “ alkyl” is as defined above . [ 0052 ] MTBE methyl tert- butylether [ 0022 ] The term " cycloalkyl” refers to a saturated or 10053 ] NMP N -methyl - 2 -pyrrolidone partially saturated, monocyclic hydrocarbon ring of 3 to 8 [ 0054 ] PdCl ( dppf ) CH2Cl2 1 , 1 '- bis ( diphenylphosphino ) carbon atoms. Examples of such rings include cyclopropyl, ferrocene -palladium (II ) dichloride dichloromethane com cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. plex ) [ 0023] The term “ aryl ” refers to an unsaturated , aromatic [0055 ] P ( o - tol) z tri (o - tolyl) monocyclic or bicyclic ring of 6 to 10 carbon members . [0056 ] rt room temperature Examples of aryl rings include phenyl and naphthalenyl. [00571 THF tetrahydrofuran [ 0024 ] The term “ halogen ” , “ halide" , or " halo ” refers to [0058 ] 2 -MeTHF 2 -methyl tetrahydrofuran fluorine , , bromine and iodine atoms. [0025 ] The term " carboxy ” refers to the group CEO) General Schemes OH . [0059 ] The overall scheme for the present invention is [ 0026 ] The term “ formyl” refers to the group CEO ) H . illustrated in Scheme A , shown below . US 2018 / 0002309A1 Jan . 4 , 2018

CONHME

valkyl " = VII= CO2H - )0C1 0 ( C ?

SchemeA NC 1cF 1e NO NH

NC, C F3C Fac C - NC NC F3C NO,

Br, Fac- ????????? VII -NO, ??

HO F3C H2N NC F3C US 2018 /0002309 A1 Jan . 4 , 2018

[0060 ] In Scheme A , a compound ( V ) may be reacted with [0073 ] It has been found that a variety of palladium cyclobutanone and at least one molar equivalent of sodium catalysts and phosphorus ligands are suitable for this trans cyanide ; in a solvent such as acetic acid , or in a solvent formation . In an embodiment, the palladium catalyst is system comprised , consisting , or consisting essentially of at either a pre - formed palladium catalyst or a palladium - ligand least one molar equivalent of an acid such as acetic acid or catalyst complex that is formed in situ . When the palladium hydrochloric acid and a C , alcoholic solvent such as metha catalyst is a pre - formed palladium catalyst , it is selected nol, ethanol, propanol , or butanol; at a temperature of about from CAT1 to CATS , shown in Table 1 , and may be used for 0° C . to about 20° C . ; to yield the corresponding compound the above -described preparation of compound (1c ). (VI ) . 10061] In one embodiment, the solvent is acetic acid . TABLE 1 [0062 ] In another embodiment, the solvent system is 90 % acetic acid and 10 % ethanol. Pre - formed Palladium Catalysts [0063 ] Compound ( IV ) may be reacted with a compound Catalyst of formula (VI ) in the presence of a thiocarbonylating agent No . Catalyst Name Structure selected from 1- (2 -oxopyridine - 1 -carbothioyl ) pyridin - 2 CAT1 Pd (OMS ) (BA ) one , 1 , 1' - thiocarbonyl diimidazole , phenylthionochlorofor ( P (tBuz - 4- N , N mate , beta -naphthyl thionochloroformate , 1 , 1 '- thiocarbonyl dimethylaniline ) bis (pyridin - 2 ( 1H )- one ), 0 , 0 -di ( pyridin - 2 - yl) tBu carbonothioate , 1 , 1' - thiocarbonylbis (1H - benzotriazole ), or ; in an organic solvent such as THF, 2 -methyl tBu THF, acetonitrile , DMA , toluene , DMF, NMP, DMSO , or the like ; at a temperature of about 0° C . to about 100° C . ; to O= CEO H H yield the corresponding compound ( VII ) . [0064 ] In one embodiment , the thiocarbonylating agent is 1 - ( 2 -oxopyridine - 1 - carbothioyl) pyridin - 2 -one . CAT2 Pd (OMS ) ( BA ) [ 0065 ] In another embodiment, the organic solvent is (P (tBuz - neopentyl ) DMA . tBu Conversion to Compound (X ) Via Carboxylic Acid ( 10 ) P - - - - Pd . / N [0066 ] ( i) Compound (VII ) may be converted to com tBu pound (X ) via its corresponding carboxylic acid , compound ? ? ? (1c ), by reacting compound ( VII ) with an organomagnesium s= halide selected from C , alkylmagnesium halide or Cs- - cy O= cloalkylmagnesium halide; in the presence or absence of a CH ; lithium halide such as lithium chloride, lithium bromide , or lithium iodide ; followed by the addition of carbon dioxide CAT3 Pd( P (tBuz ) 2 gas ; in an aprotic organic solvent selected from THF , 2 -MeTHF , MTBE , CPME, or toluene ; at a temperature of about 0° C . ; to yield the corresponding carboxylic acid P ------Pd compound ( 1c ). [ 0067 ] More particularly , the C1- galkylmagnesium halide is a C1- galkylmagnesium chloride or C1- galkylmagnesium bromide , and the C3- cycloalkylmagnesium halide is a Cs- cycloalkylmagnesium chloride or C5- 7cycloalkylmag nesium bromide . [0068 ] In one embodiment, the C1- galkylmagnesium CAT4 [ Pd (OAC ) halide is selected from isopropylmagnesium chloride, sec ( P ( 0 - Tol) 312 butylmagnesium chloride , n - pentylmagnesium chloride , hexylmagnesium chloride , ethylmagnesium chloride , ethyl magnesium bromide , n - butylmagnesium chloride , or isopro pylmagnesium chloride . [0069 ] In a further embodiment, the C1- galkylmagnesium halide is n - pentylmagnesium chloride ; and the aprotic organic solvent is THF . [0070 ] In a further embodiment, a lithium halide is absent. [0071 ] In another embodiment, the C5- cycloalkylmagne sium halide is cyclohexylmagnesium chloride. - Pd [0072 ] ( ii ) Alternatively , compound (VII ) may be reacted under a carbon monoxide atmosphere , in the presence of a palladium catalyst ; in the presence of one or more phospho rus ligands ; in the presence of water ; in a solvent such as methanol, ethanol, or the like; at a temperature of about 0° C . to about 100° C . ; to yield the corresponding compound ( 1c ) . US 2018 /0002309 A1 Jan . 4 , 2018

TABLE 1- continued TABLE 2 - continued Pre - formed Palladium Catalysts Phosphorus Ligands Catalyst Ligand No . StructureStructure No . Catalyst Name Structure L3 CAT5 [PdC12 ( L3 ) ] = PC12 ( dppf)

Fe A

-

Fe

L4

MPPh [0074 ] In another embodiment, one or more phosphorus ligands selected from L1 to L17 , shown in Table 2 , may be used in combination with either a pre - formed palladium PPh2 catalyst ( Table 1) or a palladium metal compound ( Table 3 ), for the preparation of compound ( 1c ).

TABLE 2 L5 Phosphorus Ligands Ligand No. Structure L1

L6 QuoFe ambao L2

L7

VITICH3 Fe H M

US 2018 /0002309 A1 Jan . 4 , 2018

TABLE 2 - continued TABLE 2 - continued Phosphorus Ligands Phosphorus Ligands Ligand No . Structure Ligand No . Structure L8 L14

19

L15

L10

— L16 F - B - F —

PA +

L11

L17

L12

[0075 ] In another embodiment, a palladium metal com pound selected from M1 to M2, shown in Table 3 may be used . L13 TABLE 3 Palladium Metal Compounds Metal No. Metal Cpd Name Structure M1 palladium acetate

Pd 0 US 2018 /0002309 A1 Jan . 4 , 2018

TABLE 3 - continued catalyst ; in the presence of one or more phosphorus ligands ; with a base such as DIPEA , K2CO3 , K3PO4, or Cy2NMe; in Palladium Metal Compounds a C1- 4alcoholic solvent selected from methanol, ethanol, , n - butyl alcohol , or t -butyl alcohol; to Metal No . Metal Cpd Name Structure yield the corresponding compound of formula ( le ) . M2 [Pd (OMS ) ( BA )] 2 [0087 ] It has been found that a variety of palladium BA) , catalysts and phosphorus ligands are suitable for this trans 1 CH? formation . In an embodiment, the palladium catalyst is either a pre -formed palladium catalyst or a palladium - ligand catalyst complex that is formed in situ . When the palladium catalyst is a pre - formed palladium catalyst, it is selected from CAT1 to CATS , shown in Table 1 ( above ), and may be NH2 used for the preparation of a compound of formula (le ). CH3 [0088 ]. In another embodiment, one or more phosphorus ligands selected from L1 to L17 , shown in Table 2 (above ) , may be used in combination with either a pre - formed palladium catalyst ( Table 1 ) or a palladium metal compound [ 0076 ] In an embodiment, the palladium catalyst is com ( Table 3 ) , for the preparation of a compound of formula ( le ) . prised , consisting , or consisting essentially of the phospho 100891. In another embodiment, a palladium metal com rus ligand dppf (L1 , Table 2 ) and the palladium metal pound selected from M1 or M2 ( Table 3 , above ) may be compound palladium acetate (M1 , Table 3 ) . used , in combination with one or more phosphorus ligands [ 0077 ] Compound ( lc ) may then be treated with a cou selected from L1 to L17 from Table 2 , for the above pling agent such as CDI; in an aprotic or protic solvent such described alkoxycarbonylation reaction . as THF, toluene, or the like ; at about room temperature ; [0090 ] Table 4 describes certain reaction conditions (E1 to followed by the addition of methylamine; to yield the E8 ) for the conversion of compound (VII ) to methyl ester corresponding compound ( X ) . ( le - 1 ) , wherein Cl- galkyl of a compound of formula ( 1e) is [0078 ] In one embodiment, methylamine is added as a methyl. solution in a protic or aprotic solvent . In a further embodi ment, methylamine is added as a THF solution . [0079 ] In another embodiment, methylamine is added in F its gaseous state . NCN [0080 ] In yet another embodiment, methylamine is added as its methyl ammonium salt . 4 mol % cat, CO ( 5 bar ) , F C Base , MeOH , 60° C ., 3 h Conversion to Compound ( X ) Via Ester (le ) [0081 ] ( i) Compound (VII ) may also be converted to compound (X ) via its corresponding C1- alkyl ester (le ), by VII reacting compound (VII ) with an organomagnesium halide F selected from a C alkylmagnesium halide or a C5- cy NO CO2Me cloalkylmagnesium halide ; in the presence or absence of a S lithium halide such as lithium chloride , lithium bromide , or lithium iodide; in an aprotic organic solvent selected from FC THF, 2 -MeTHF , toluene , or the like ; at a temperature of about - 50° C . to about 22° C . ; followed by the addition of a C - alkyl chloroformate or C1- galkyl cyanoformate ; to yield the corresponding ester of formula ( le ) . le - 1 [0082 ] More particularly , the C1-galkylmagnesium halide is a C , alkylmagnesium chloride or C , alkylmagnesium bromide, and the C5- 7cycloalkylmagnesium halide is a C5 - 7 cycloalkylmagnesium chloride or C5- 7cycloalkylmagnesium TABLE 4 bromide . Conditions for Alkoxycarbonylation of [0083 ] In one embodiment, the C1- galkylmagnesium Compound ( VII) to Methyl Ester ( le - 1 ) halide is selected from isopropylmagnesium chloride , sec butylmagnesium chloride , cyclohexylmagnesium chloride , Metal/ Cat . Ligand Base Conv . ( % ) Yield ( % ) n -pentylmagnesium chloride , hexylmagnesium chloride , E1 Pd (P (tBuz ) 2 DIPEA 100 . 0 82 . 1 ethylmagnesium chloride , ethylmagnesium bromide , n -bu E2 [ Pd (OMS ) BA ) ] 2 L10 Cy2NMe 99 . 0 72 . 5 E3 PdCl2dppf Cy NMe 98 . 8 81. 7 tylmagnesium chloride, or isopropylmagnesium chloride. E4 PdCl dppf DIPEA 98 . 7 84 . 8 [0084 ] In another embodiment, the Cl- galkylmagnesium I [Pd (OMS ) BA )] 2 L17 Cy2NMe 98 .4 83. 8 halide is n -pentylmagnesium chloride and the aprotic 1a [Pd (OMS ) BA )] 2 L13 Cy2NMe 92 . 0 72 .8 organic solvent is THF or 2 -MeTHF . E7 Pd (OAC )2 L10 Cy2NMe 84 . 0 75 .4 0085 ] In a further embodiment, a lithium halide is absent. E8 Pd (OAC ) 2 L16 Cy2NMe 78 . 8 73 . 0 [0086 ] ( ii ) Alternatively , compound (VII ) may be reacted under suitable alkoxycarbonylation conditions, under a car [0091 ] In an embodiment, the process for the conversion bon monoxide atmosphere ; in the presence of a palladium of compound (VII ) to a compound of formula ( le ) is in the US 2018 /0002309 A1 Jan . 4 , 2018 10 presence of the palladium catalyst Pd ( P (tBuz ) 2 (CAT3 , Table [0105 ] In another embodiment, a palladium metal com 1 ), and 1 . 2 equivalents of DIPEA . pound selected from M1 or M2 ( Table 3 , above ) may be [ 0092 ] In another embodiment, the palladium catalyst is used , in combination with one or more phosphorus ligands comprised , consisting , consisting essentially of the phos selected from L1 to L17 ( Table 2 ), for the above- described phorus ligand L10 ( Table 2 ) and the palladium metal com aminocarbonylation reaction . pound [ Pd (OMS ) (BA ) ] , (M2 , Table 3 ) . In another embodi [0106 ] Table 5 describes certain reaction conditions (GI to ment, the organic base is Cy ,NMe . G7) for the conversion of compound (VII ) to Compound [ 0093] In another embodiment, the palladium catalyst is ( X ). comprised , consisting , or consisting essentially of of the phosphorus ligand dppf (L1 , Table 2 ) and the palladium metal compound palladium acetate (M1 , Table 3 ) . In another embodiment, the organic base is Cy2NMe. NC . N I 4 mol % cat, CO (5 bar) , [ 0094 ] In a further embodiment, the C1- alcoholic solvent Base , NH2Me (5 eq . ) , is methanol. 3C THF 60° C ., 1 h [0095 ] A compound of formula ( le ) may be treated with N methylamine ; in a protic or aprotic solvent such as THF , DMF, DMA , ethanol, or a mixture thereof; at a temperature VII of about 0° C . to about 60° C .; to yield the corresponding F compound ( X ) . [0096 ] In an embodiment ,methylamine is added as a THF NC CONHMe solution . = [ 0097 ] In another embodiment, methylamine is added as a solution in MeOH . F C [ 0098 ] In another embodiment, methylamine is added in its gaseous state. Direct Conversion of Compound (VII ) to Compound ( X ) X [0099 ] (i ) Compound (VII ) may be converted directly to compound ( X ) by reacting compound ( VII ) in the presence ofmolybdenum hexacarbonyl; optionally in the presence of TABLE 5 one or more reagents such as norbornadiene , tetrabutylam Conditions for Aminocarbonylation monium bromide , or a base selected from triethylamine or of Compound (VII ) to Compound ( X ) DABCO ; in an organic solvent selected from diglyme , dioxane, butyronitrile , propionitrile , or the like ; followed by Metal/ Cat . Precursor Ligand Base Conv. [ % ] Yield the addition of methylamine ; at a temperature of from about G1 Pd ( P ( tBuz) 2 DIPEA 100 95 G2 Pd (OAC ) 2 L10 Cy2NMe 100 93. 9 60° C . to about 140° C .; to yield the corresponding com G3 Pd (OAC ) 2 L16 Cy2NMe 100 93 . 1 pound ( X ) . ?? [ Pd (OMS ) BA )] 2 L10 Cy2NMe 100 91. 8 [ 0100 ] In one embodiment, the reagents norbornadiene , G5 [ Pd ( OMs ) BA )] L16 Cy NMe 100 88 . 5 tetrabutylammonium bromide, and DABCO are present. G6 Pd (OAC ) 2 L16 K3PO4 100 83 . 7 [ 0101 ] In another embodiment, the organic solvent is G7 Pd (OAC ) 2 L17 Cy2NME 95 . 1 83, 5 butyronitrile or diglyme. [0102 ] ( ii ) Alternatively , compound (VII ) may be reacted [0107 ] In one embodiment , the palladium catalyst is Pd ( P under suitable aminocarbonylation conditions ; under a car (tBuz )2 (CAT3 , Table 1) , and the organic base is 1 .2 equiva bon monoxide atmosphere ; in the presence of a palladium lents of DIPEA . catalyst ; in the presence of one or more phosphorus ligands; [0108 ] In another embodiment, the palladium catalyst is in the presence of a base selected from DIPEA , K2CO3, comprised , consisting or consisting essentially of the phos K PO4, Cy, NMe, or excess methylamine ; in the presence of phorus ligand L10 ( Table 2 ) and the palladium metal com methylamine ; at a temperature of from about room tempera pound Pd (OAC )2 (M1 , Table 3 ) . In a further embodiment , the ture to about 100° C .; to yield the corresponding compound base is Cy2NMe. ( X ) . [0109 ] In one embodiment, methylamine is added as a [0103 ] It has been found that a variety of palladium solution in a protic or aprotic solvent. catalysts and phosphorus ligands are suitable for this trans [0110 ] In another embodiment, methylamine is added as a formation . In an embodiment, the palladium catalyst is THF solution . either a pre - formed palladium catalyst or a palladium - ligand [0111 ] In another embodiment, methylamine is added in catalyst complex that is formed in situ . When the palladium its gaseous state . catalyst is a pre - formed palladium catalyst, it is selected [0112 ] In another embodiment, methylamine is added as a from CAT1 to CATS , shown in Table 1 ( above) , and may be solution in methanol. used for the preparation of compound (X ). [0113 ] In yet another embodiment, methylamine is added [0104 ] In another embodiment, one or more phosphorus as its methyl ammonium hydrochloride salt . ligands selected from L1 to L17 , shown in Table 2 ( above ) , [0114 ] In another embodiment, the organic solvent is THF . may be used in combination with either a pre -formed [0115 ] One skilled in the art will further recognize that the palladium catalyst ( Table 1 ) or a palladium metal compound reaction or process step ( s ) as herein described (or claimed ) ( Table 3 ) , for the preparation of compound ( X ) . are allowed to proceed for a sufficient period of time, at a US 2018 /0002309 A1 Jan . 4 , 2018 11

suitable temperature or range of temperatures , until the Step A . Preparation of Compound II . reaction is complete , as determined by any method known to one skilled in the art , for example , chromatography ( e . g . [0119 ] HPLC , TLC , etc . ). In this context a “ completed reaction or process step ” means that the reaction mixture contains a decreased amount of the starting material ( s ) / reagent( s ) and BrN an increased amount of the desired product( s ), as compared to the amounts of each present at the beginning of the reaction . F C V NO , SPECIFIC EXAMPLES 10120 ] A vessel was charged with 19 g of compound ( 1 ) , [0116 ] The following Examples are set forth to aid in the 5 g of triethylamine hydrobromide, 49 g of xylenes and 67 understanding of the invention , and are not intended and g DMF. A solution of 26 g of phosphorous oxybromide in 16 should not be construed to limit in any way the invention set 0910gof xylene was dosed into the reaction mixture . The reaction forth in the claims which follow thereafter . mixture was heated to 100° C . for 3 h . The mixture was then [ 0117 ] In the Examples that follow , some synthesis prod cooled to 70° C . To this mixture was added 75 g of a solution ucts are listed as having been isolated as a residue . It will be of NaOH ( 10M ) . After phase separation at room tempera understood by one of ordinary skill in the art that the term ture, the organic layer was washed with a 84 g of an aqueous “ residue ” does not limit the physical state in which the solution of NaOH ( 10M ) followed by 84 g of an aqueous product was isolated and may include, for example , a solid , solution of NaCl (25 % ) . The organic phase was carried an oil , a foam , a gum , a syrup , and the like . forward into the next step without further purification . Isolation by crystallization from heptane was performed for Example 1 characterization purposes of compound ( II ) . ' H NMR ( 300 [0118 ] MHz, CDC1z ) 8 9 .36 , 8 .75 .

HOHO Br NC F3C 2. NO2 - 02V NO2 -F3C NO2 NC F NC F NH2

FC

H N NC NH VI VII F 8 - 20NC - CO2H S

FO3

VIII F NCN NC N CO2Me NCN CONHMe Fzc F3C F3C

VII US 2018 /0002309 A1 Jan . 4 , 2018

Step B . Preparation of Compound ( III ) . [0128 ] To a reactor containing compound ( VI) (25 g ) and compound ( IV ) ( 14 g ) was added 1 - ( 2 - oxopyridine - 1 - car [0121 ] bothioyl) pyridin - 2 - one (18 g ) and toluene (316 mL ) . The reaction mixture was stirred and heated to 100° C . for 20 h . A solvent switch from toluene to DMA ( 8 L /kg final com NC position ) was performed , then EtOH ( 400 mL ) was added . The mixture was then heated to 70° C . before addition of HC1 ( 2 M , 160 mL ) . After stirring for 2 h , the reaction was cooled down to 0° C . The precipitate was collected by F3C V NO2 filtration , rinsed with EtOH / H , O ( 100 mL, 1 : 1 ), and dried to give compound (VII ) (24 g , 63 % ). ' H NMR (300 MHz, 10122 ] To the previous solution of compound ( II ) in CDC1z ) 0 9 .09 ( d , J = 2 . 1 Hz, 1H ) , 8 . 35 ( d , J = 2 . 1 Hz, 1H ) , xylenes was added 8 . 7 g of sodium cyanide and 6 . 8 g of 8 . 01 ( dd , J = 8 . 3 , 6 . 8 Hz, 1H ) , 7 .07 (dd , J = 7 . 9 , 2 . 3 Hz, 1H ) , copper ( I) iodide and 45 g of butyronitrile . The mixture was 6 . 94 ( dd , JJ = 8 . 0 , 2 .0 Hz, 1H ) , 2 . 72 ( m , 2H ) , 2 . 58 ( m , 2H ) , heated to 120° C . for 20 h . The reaction mixture was cooled , 2 . 30 ( m , 1H ) , 1 . 74 ( m , 1H ) . washed twice with an aqueous solution of sodium carbonate ( 10 % ) . The organic phase was carried forward into the next Step E . Preparation of Compound (VIII ). step . Isolation was performed for characterization purposes of compound ( III ) . ' H NMR (300 MHz, DMSO - do) 8 149. 3 , [0129 ] 145 . 4 , 133 . 9 , 131 . 9 , 130 . 1 , 119 . 5 , 114 . 0 . VIII Step C . Preparation of Compound (IV ) . F VIII [0123 ] Preparation of Modified Catalyst Slurry . NC CO2H 10124 ] In a 20 mL beaker glass 0 . 156 g ( 0 . 129 mL , 50 S w / w ) of H PO , was added to a slurry of 1 .00 g 5 % Pt/ C catalyst F101 R / W ( from Evonik AG , contains - 60 % water ) F C and 4 .0 mL of deionized water. After 15 minutes while stirring with a magnetic stirring bar , 58 mg of NH VOZ was added and the slurry was again stirred for 15 minutes . [0125 ] Hydrogenation . 10126 ] A 100 mL autoclave was charged with a solution of [0130 ] A reactor was charged with a solution of 5 g of 10 .0 g of compound ( III ) (46 .1 mmol) in 26 .7 mL of xylenes compound (VII ) in 50 mL of anhydrous THF and stirring and 13 . 3 mL of butyronitrile . To this solution , the modified begun . The reaction solution was cooled to an internal catalyst slurry was added with the aid of 2 mL of deionized temperature of 0° C . A solution of n -pentylmagnesium water . The autoclave was closed , then inertized by pressur chloride ( 1 eq ) was added slowly to maintain a reaction izing 3 times with nitrogen to 10 bar and 3 times hydrogen temperature of 0° C . After 30 min , carbon dioxide gas was to 10 bar . The reactor pressure was set to 5 . 0 bar hydrogen , added into the stirred reaction mixture . Upon consumption stirring was started (hollow shaft turbine stirrer, 1200 rpm ) of the starting material, the reaction mixture was added to a and the mixture heated up to 70° C . within 50 min . As soon solution of aqueous acetic acid ( 10 % ) to yield compound as 70° C . was reached , the hydrogen uptake ceased . After stirring for another 40 min , the heating was stopped and the (VIII ) ( 75 % ). " H NMR ( 300 MHz, CDCI, ) 9 . 11 ( d , 1H ) , autoclave was allowed to cooling . The slurry was filtered 8 .37 ( d , 1H ) , 8 .20 ( m , 1H ) , 7 . 25 ( m , 2H ) , 5 . 30 ( s , 1H ) , 2 .75 through a fiberglass filter and washed in portions using 40 ( m , 2H ) , 2 .61 ( m , 2H ) , 2 . 31 ( m , 1H ) , 1 .74 ( m , 1H ) . mL of xylenes at 20 - 23° C . Compound ( IV ) was crystallized Step F . Preparation of Compound (IX ) . from the solution upon distillation of the butyronitrile sol vent. ' H NMR ( 300 MHz, DMSO - da ) 8 8 . 20 ( d , J = 2 . 4 Hz, (0131 ] 1H ) , 7 .31 (d , J = 2 .6 Hz , 1H ), 7 .04 ( s , NH ) . Step D . Preparation of Compound (VII ).

[0127 ] NC - CO2Me

VII F F3C NC S F2C [ 0132 ] Method A . A pressure reactor was charged with Compound ( VII ) ( 1 g ) , palladium acetate ( 10 mol % ) , dppf ???? (10 mol???? % ), and diisopropylamine ( 1 eq ) and methanol (10 mL ) . The reaction was placed under carbon monoxide ( 4 bar) and heated for 4 h at 60° C . The reaction was allowed US 2018 /0002309 A1 Jan . 4 , 2018 13 to cool to ambient temperature , diluted with dichlorometh Example 2 ane ( 5 mL ), then washed with a 3 % cysteine aqueous solution . The organic layer was separated , concentrated , and ([0139 ] ] dried to yield compound (IX ) (85 % ). ' H NMR (300 ated MHz, and , CDC1z ) 9 . 10 ( d , J= 1 . 9 Hz, 1H ), 8 .36 ( d , J= 1. 9 Hz , 1H ), 8 .20 ( m , 1H ) , 7 .20 ( m , 2H ) , 4 .00 ( s , 3H ) , 2 .75 ( m , 2H ) , 2 .58 ( m , 2H ), 2 .30 ( m , 1H ) , 1 .76 ( m , 1H ) ; 13C NMR (CDC12 , NC . NS HMOD ) 8 179. 6 , 174 . 2 , 163 . 3 , 159. 2 , 153 . 4 (ArH ) , 140 . 9 , 135 . 5 (ArH ), 132. 9 ( ArH ) , 128 . 9 , 126 .5 (ArH ), 118 . 9 ( ArH ) , 114 . 2 , 67. 7 , 52 .6 , 31. 1 , 13. 4 . F3C [0133 ] Method B . [0134 ] A reactor was charged with 2 . 5 g of compound ( VII) in 25 mL 2 -methyl - THF. The mixture was stirred under Argon at - 15° C . A solution of n - pentylmagnesium S chloride in THF ( 2M , 2 .4 mL ) was dosed over 1 h . After 15 NC CONHCH, min of stirring , ( 1. 1 eq , 0 .40 mL ) was added dropwise and the temperature was then allowed to warm to 15º C . The reaction was quenched with a solution F3C of 10 % ACOH in water ( 20 mL ) . After phase separation , the organic layer was washed with water and then concentrated to yield compound ( IX ) in 77 % yield . [0135 ] Method C . [0140 ] Method A . [ 0136 ] A reactor was charged with 2 g of compound ( VII ) [0141 ] In a 10 mL test tube, compound (VII ) ( 0 . 3 g , 0 . 55 in 20 mL of THF . The mixture was stirred under Argon at mmol ), molybdenum hexacarbonyl (0 .145 g , 0 . 55 mmol) , 50° C . A solution of isopropylmagnesium chloride lithium norbornadiene (0 .05 g , 0 .545 mmol) , tetrabutylammonium chloride complex in THF ( 1 . 3M , 3 . 4 mL ) was dosed over 10 bromide (0 . 177 g , 0 . 55 mmol) and DABCO (0 .185 g , 1. 65 min . After 5 min of stirring , methyl cyanoformate ( 1 .25 eq , mmol) were charged under nitrogen , followed by 3 mL of 0 . 37 mL ) was added dropwise and the temperature was then diglyme. The mixture was heated with stirring under a allow to warm to 15º C . The reaction was quenched with a nitrogen atmosphere to 140° C . Methylamine hydrochloride solution of 10 % ACOH in water ( 20 mL ) . After the phase ( 0 . 05 g , 0 .61 mmol ) was added , and the mixture was stirred separation , the organic layer was washed with water and at 140° C . for 1 h to yield compound ( X ) ( 13 % ) . then concentrated to yield compound (IX ) in 75 % yield . [0142 ] Method B . [0143 ] In a 10 mL test tube , compound (VII ) ( 0 . 3 g , 0 . 55 Step G . Preparation of Compound ( X ) . mmol) , molybdenum hexacarbonyl ( 0 . 145 g , 0 . 55 mmol) , norbornadiene ( 0 .05 g , 0 .545 mmol ) , tetrabutylammonium [0137 ] bromide ( 0 . 177 g , 0 . 55 mmol) and DABCO ( 0 . 185 g , 1. 65 mmol) were charged under nitrogen , followed by 3 mL of butyronitrile . The mixture was heated with stirring under a nitrogen atmosphere to 140° C . Methylamine hydrochloride F ( 0 . 05 g , 0 .61 mmol) was added in 3 portions over 30 min , NC, N CONHMe and the mixture was stirred at 118° C . for 1 h to yield compound ( X ) (43 % ) . [0144 ] Method C . [0145 ] A 30 mg ( 0 .059 mmol) portion of Pd ( t- BuzP ) 2 was Fzc placed in a 10 mL Schlenk flask , which was subsequently set under an inert atmosphere ( Argon ). Then 3 mL of degassed THF was added and the solution stirred for 5 min at ambient temperature . In a second 20 mL Schlenk flask , 0 . 8 g of compound (VII ) ( 1 .464 mmol) was inertized and 4. 3 mL [0138 ] A reactor was charged with compound ( IX ) ( 0 . 3 g ) degassed THF, 3 . 7 mL ( 7 .32 mmol, 2M in THF ) N -methyl and a solution of methylamine in ethanol ( 10 eq ) and stirring amine , and 0 .37 mL dicyclohexylmethylamine (1 . 75 mmol) begun . The reaction was stirred at ambient temperature . were added . Both the substrate solution and the catalyst Upon consumption of compound ( IX ) , the reaction was solution were transferred via cannula into the 50 mL auto concentrated , re - dissolved in toluene, and washed with clave , which was previously set under an inert atmosphere aqueous HCI ( 2M ) until all base was neutralized . The of Argon . The reactor was sealed and purged with Argon , toluene phase was then concentrated to give compound ( X ) and finally the Argon was replaced by 5 bar CO ( three purge ( 80 % ) . H NMR ( 300 MHz, DMSO ) S 9 . 22 ( d , J = 1 . 9 Hz , cycles) . The reaction was stirred and heated to 60° C . for 2 1H ) , 8 . 76 ( d , J = 1 . 9 Hz , 1H ) , 8 . 50 ( d , J = 4 . 5 Hz, 1H ) , 7 .84 ( t, h . J = 2x8 . 0 Hz, 1H ) , 7 .48 ( dd , J = 10 . 5 , 1 . 8 Hz, 1H ) , 7 .39 ( dd , [0146 ] While the foregoing specification teaches the prin J = 8 . 2 , 1. 8 Hz, 1H ), 4 . 00 (s , 3H ), 2 . 75 ( m , 2H ) , 2 . 58 ( m , 2H ), ciples of the present invention , with examples provided for 2 . 30 ( m , 1H ) , 1 . 76 ( m , 1H ) . the purpose of illustration , it will be understood that the US 2018 /0002309 A1 Jan . 4 , 2018 14 Jan. 4, 2018 practice of the invention encompasses all of the usual solvent; at a temperature of about 0° C . to about 100° variations , adaptations and /or modifications as come within C . ; to yield the corresponding compound (VII ) ; the scope of the following claims and their equivalents . What is claimed is : 1. A process for the preparation of compound (X ) ( 1x )

NC

F NC N CONHMe F3C

' N F3C VII

NC . NHMe comprising F C

( 1a) F

converting compound (VII ) to compound ( X ) . HN NC 2 . The process of claim 1 , wherein step ( 1a ) further comprises - & VI reacting compound (V ) with cyclobutanone in the (1a ) presence of sodium cyanide ; in acetic acid , or a F solvent system comprised of an alcoholic solvent and a protic acid ; at a temperature of about 0° C . to about 20° C .; to yield the corresponding compound ( VI) ; H2N NC À (1b ) VI NC N reacting compound ( V ) with cyclobutanone in the pres F3C NH ence of at least one molar equivalent of sodium cya IV nide ; in acetic acid , or a solvent system comprised of at F least one molar equivalent of acetic acid or hydrochlo ric acid and a C1- falcoholic solvent selected from the group consisting of methanol, ethanol, propanol, and butanol; at a temperature of about 0° C . to about 20° C .; to yield the corresponding compound (VI ) . NC NH 3 . The process of claim 2 wherein the solvent system is VI acetic acid . F 4 . The process of claim 2 wherein the solvent system is NC 90 % acetic acid and 10 % ethanol. S 5 . The process of claim 1 , wherein step ( 1b ) further comprises F3C (1b ) NC

VII Fzc V NH2 reacting compound ( IV ) and compound (VI ) in the IV restingpresence compang of a thiocarbonylating( 19 and compama agent ; in odan organic in the US 2018 /0002309 A1 Jan . 4 , 2018

- continued followed by the addition of carbon dioxide gas ; in an aprotic organic solvent; at a temperature of about 0° C .; to yield the corresponding carboxylic acid compound ( 1c ) . 9 . The process of claim 8 , comprising reacting compound (VII ) with an organomagnesium halide selected from the NC IZ group consisting of a Cj- galkylmagnesium halide and a VIVI Cs- - cycloalkylmagnesium halide ; in the presence or absence F of a lithium halide selected from the group consisting of lithium chloride, lithium bromide , and lithium iodide ; fol NC . lowed by the addition of carbon dioxide gas ; in an aprotic S organic solvent selected from the group consisting of THF, 2 -MeTHF , MTBE , CPME , and toluene ; at a temperature of F C about 0° C . ; to yield the corresponding carboxylic acid compound ( 1c ). 10 . The process of claim 9 wherein the C1- galkylmagne sium halide is a C1- galkylmagnesium chloride or C1- galky VII Imagnesium bromide . 11 . The process of claim 10 wherein the Cl- galkylmag nesium halide is selected from the group consisting of reacting compound ( IV ) and compound (VI ) in the pres isopropylmagnesium chloride , sec - butylmagnesium chlo ence of a thiocarbonylating agent selected from the ride , n -pentylmagnesium chloride , hexylmagnesium chlo group consisting of 1 - ( 2 -oxopyridine - 1 - carbothioyl) ride , ethylmagnesium chloride , ethylmagnesium bromide , pyridin - 2 - one , 1 , 1 ' - thiocarbonyl diimidazole , phenyl n -butylmagnesium chloride , and isopropylmagnesium chlo thionochloroformate , beta- naphthyl thionochlorofor ride. mate , 1 , 1 ' -thiocarbonylbis ( pyridin - 2 ( 1H ) -one ) , 0 , 0 - di 12. The process of claim 11 further comprising reacting (pyridin - 2 -yl ) carbonothioate , 1 , 1' - thiocarbonylbis ( 1H compound (VII ) with n -pentylmagnesium chloride; in the benzotriazole ) , and thiophosgene ; in an organic solvent absence of a lithium halide ; followed by the addition of selected from the group consisting of THF, 2 -methyl carbon dioxide gas; in THF ; at a temperature of about 0° C . ; THF , acetonitrile , DMA , toluene, DMF, NMP, and to yield the corresponding carboxylic acid compound (1c ). DMSO ; at a temperature of about 0° C . to about 100° 13. The process of claim 9 wherein the C5- cycloalkyl C .; to yield the corresponding compound (VII ). magnesium halide is a C5- cycloalkylmagnesium chloride or 6 . The process of claim 5 wherein the thiocarbonylating C5- 7cycloalkylmagnesium bromide. agent is 1 -( 2 -oxopyridine - 1 -carbothioyl ) pyridin - 2 -one . 14 . The process of claim 13 wherein the C5- 7cycloalky 7. The process of claim 6 wherein the organic solvent is Imagnesium halide is cyclohexylmagnesium chloride. DMA. 15 . The process of claim 1 , wherein step ( 1x ) further 8 . The process of claim 1 , wherein step ( 1x ) further comprises the conversion of compound (VII ) to compound comprises the conversion of compound (VII ) to compound ( X ) via carboxylic acid (1c ), by ( X ) via carboxylic acid (1c ) , by ( 1c ) (1c ) NC NC N F3C FC

VII Soud Syd-T) - NC N CO2H NC N CO2H S

FC F C

sq yd1c 3yo reacting compound ( VII ) under a carbon monoxide atmo reacting compound ( VII ) with an organomagnesium sphere ; in the presence of a palladium catalyst ; in the halide; in the presence or absence of a lithium halide ; presence of one or more phosphorus ligands; with an US 2018 /0002309 A1 Jan . 4 , 2018 16

organic base ; in a the presence of water , in an organic -continued solvent; at a temperature of about 0° C . to about 100° C . ; to yield the corresponding compound ( 1c ) . 16 . The process of claim 15 wherein the palladium catalyst is comprised of a phosphorus ligand that is dppf and NC CO (OC1 - 6alkyl) a palladium metal compound that is palladium acetate . : 17 . The process of claim 1 wherein step (1x ) further comprises the conversion of compound ( 1c ) to compound FC ( X ) via carboxylic acid ( 1c ), by

( 10 )

NC N - CO2H reacting compound (VII ) with an organomagnesium halide ; in the presence or absence of a lithium halide ; in an aprotic organic solvent; at a temperature of about - 50° C . to about room temperature ; followed by the addition of an Cl- galkyl chloroformate or Cl- galkyl Dayed cyanoformate ; to yield the corresponding ester of for mula ( le ). 23. The process of claim 22 , wherein step ( 1e) further NCVN S NHMe comprises reacting compound ( VII) with an organomagne sium halide selected from the group consisting of a C1- galky Imagnesium halide and a C5- cycloalkylmagnesium halide ; in the presence or absence of a lithium halide selected from the group consisting of lithium chloride , lithium bromide , and lithium iodide ; in an aprotic organic solvent selected X from THF , 2 -MeTHF , or toluene; at a temperature of about reacting compound (1c ) with a coupling agent; in an - 50° C . to about 22° C .; followed by the addition of an aprotic or protic solvent ; at about room temperature ; C1- talkyl chloroformate or Cl- galkyl cyanoformate ; to yield followed by the addition of methylamine ; to yield the the corresponding ester of formula ( le ). corresponding compound ( X ). 24 . The process of claim 23 wherein the C1- galkylmag 18 . The process of claim 17, further comprising reacting nesium halide is a C1- galkylmagnesium chloride or compound ( 1c ) with a coupling agent that is CDI; wherein C1- galkylmagnesium bromide. the aprotic or protic solvent is THF or toluene ; at about room temperature ; followed by the addition of methylamine ; to 25 . The process of claim 24 wherein the C1- galkylmag yield the corresponding compound ( X ) . nesium halide is selected from the group consisting of 19 . The process of claim 18 wherein methylamine is isopropylmagnesium chloride, sec -butylmagnesium chlo added as a THF solution . ride, cyclohexylmagnesium chloride , n -pentylmagnesium 20 . The process of claim 18 wherein methylamine is chloride, hexylmagnesium chloride , ethylmagnesium chlo added in its gaseous state . ride, ethylmagnesium bromide , n -butylmagnesium chloride , 21 . The process of claim 18 wherein methylamine is and isopropylmagnesium chloride . added as its methyl ammonium salt . 26 . The process of claim 25 further comprising reacting 22 . The process of claim 1 , wherein step ( 1x ) further compound (VII ) in the presence of n -pentylmagnesium comprises the conversion of compound (VII ) to compound chloride ; in the absence of a lithium halide ; in an aprotic ( X ) via an ester of formula ( le ), by organic that is THF or 2 -MeTHF ; at a temperature of about - 50° C . to about 22° C . ; followed by the addition of an C1- alkyl chloroformate or Cl- talkyl cyanoformate ; to yield ( le ) the corresponding ester of formula (le ) . NC 27 . The process of claim 23 wherein the C3- cycloalky Imagnesium halide is a C5- cycloalkylmagnesium chloride or C5- 7cycloalkylmagnesium bromide. F3C 28 . The process of claim 27 wherein the C3- -cycloalky Imagnesium halide is cyclohexylmagnesium chloride. 29 . The process of claim 1, wherein step (1x ) further VII comprises the conversion of compound (VII ) to compound ( X ) via an ester of formula ( le ) , by US 2018 /0002309 A1 Jan . 4 , 2018 US2018 / 0002309 A1 17in Jan. 4, 2018 35 . The process of claim 1 , wherein step ( 1x ) further (le ) comprises the conversion of the ester of formula ( le ) to F compound ( X ), by NC N

NC , N , CO (OC1 - talkyl) Duo F C HoVII Duo NC , N le CO (OC1 - talkyl ) F

= NC . NHMe F C = F C w reacting compound (VII ) under a carbon monoxide atmo sphere ; in the presence of a palladium catalyst ; in the presence of one or more phosphorus ligands; with a treating an ester of formula (le ) with methylamine; in a base ; in a C . calcoholic solvent; at a temperature of protic or aprotic solvent; at a temperature of about 0° C . about room temperature to about 100° C . ; to yield the to about 60° C . ; to yield the corresponding compound corresponding ester of formula ( le ). ( X ) . 30 . The process of claim 29 , wherein step (le ) further 36 . The process of claim 35 wherein the protic or aprotic comprises reacting compound (VII ) under a carbon monox solvent is selected from the group consisting of THF, DMF, ide atmosphere; in the presence of a palladium catalyst; in DMA, and ethanol, or a mixture thereof. the presence of one or more phosphorus ligands; in the 37 . The process of claim 36 wherein the methylamine is presence of a base selected from the group consisting of added as a THF solution . DIPEA , K2CO3, K3PO4, and Cy2NMe; in a Cj- alcoholic 38 . The process of claim 36 wherein the methylamine is solvent selected from the group consisting of methanol, added as a MeOH solution . ethanol, isopropyl alcohol, n - butyl alcohol, and t- butyl alco 39 . The process of claim 36 wherein the methylamine is hol; at a temperature of about room temperature to about added in its gaseous state . 100° C .; to yield the corresponding ester of formula ( le ) . 40 . The process of claim 1 wherein step ( 1x ) further 31 . The process of claim 30 wherein the palladium comprises the conversion of compound (VII ) directly to catalyst is Pd ( P (tBux ) , and the base is 1 . 2 equivalents of compound ( X ), by DIPEA . 32 . The process of claim 30 , wherein the palladium catalyst is comprised of a phosphorus ligand , L10 , and a ( 1g ) palladium metal compound that is [Pd (OMS ) ( BA ) ]2 ; in the I presence of Cy2NMe. NC N

F C F - -WB - F .

VII

NC N NHMe L10

33 . The process of claim 30 wherein the palladium F C catalyst is comprised of a phosphorus ligand , dppf, and a palladium metal compound that is palladium acetate ; in the presence of DIPEA . 34 . The process of claim 28 wherein the Cj- alcoholic solvent is methanol. US 2018 /0002309 A1 Jan . 4 , 2018

reacting compound (VII ) in the presence of molybdenum presence of one or more phosphorus ligands ; in the hexacarbonyl; optionally in the presence of one or more presence of a base; in the presence of methylamine; in reagents selected from the group consisting of norbor an organic solvent; at a temperature of about room nadiene, tetrabutylammonium bromide, and a base temperature to about 100° C . ; to yield the correspond selected from triethylamine or DABCO ; in an organic ing compound ( X ) . solvent selected from the group consisting of diglyme, 44. The process as in claim 43 wherein step ( 1g ) further dioxane , butyronitrile , and propionitrile ; followed by comprises reacting compound ( VII ) under a carbon monox the addition of methylamine ; at a temperature of about ide atmosphere; in the presence of a palladium catalyst; in 60° C . to about 140° C . ; to yield the corresponding the presence of one or more phosphorus ligands; in the compound ( X ) . presence of a base selected from the group consisting of 41. The process as in claim 40 wherein norbornadiene , DIPEA , K2CO3, K3PO4, Cy2NMe, and excess methylamine ; tetrabutylammonium bromide, and DABCO are present. in the presence of methylamine ; in an organic solvent; at a 42 . The process as in claim 41 wherein the organic solvent temperature of about room temperature to about 100° C . ; to is butyronitrile or diglyme. yield the corresponding compound ( X ) . 43 . The process as in claim 1, wherein step (1x ) further 45 . The process as in claim 44 wherein the palladium comprises the conversion of compound (VII ) directly to catalyst is Pd (P ( tBuz ) , and the base is DIPEA . compound ( X ), by 46 . The process as in claim 44 wherein the palladium catalyst is comprised of the phosphorus ligand , L10 , and the palladium metal compound Pd (OAC ) 2 ; in the presence of F (1g ) Cy2NMe. NC T F - B - F .

LET 7-

PH

VII FO L10 NC , zN , S NHMe 47 . The process as in claim 44 wherein methylamine is F3C NN added as a THF solution . 48 . The process as in claim 44 wherein methylamine is added as a MeOH solution . 49 . The process as in claim 44 wherein methylamine is added in its gaseous state . 50 . The process as in claim 44 wherein methylamine is reacting compound (VII ) under a carbon monoxide atmo added as its methyl ammonium hydrochloride salt . sphere ; in the presence of a palladium catalyst ; in the * * * * *