Stereoselective synthesis of TYK2 inhibitors and intermediates

Abstract

Disclosed herein are methods of the stereoselective synthesis of TYK2 inhibitors and synthetic intermediates useful in the preparation thereof, said TYK2 inhibitors being useful for the treatment of diseases and disorders.

Description

WSGR Docket No. 59318-727.601STEREOSELECTIVE SYNTHESIS OF TYK2 INHIBITORS AND INTERMEDIATES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 777,201 filed on March 25, 2025, which is incorporated herein by reference in its entirety.SUMMARY OF THE DISCLOSURE

[0002] Described herein are stereoselective methods of making the TYK2 inhibitor Formula 11 [(5)-6-(cyclopropanecarboxamido)-N-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5-c][l,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide]:

[0003] Described herein are stereoselective methods of making synthetic intermediates of Formula A: / N-NFormula A.

[0004] Described herein are stereoselective methods of making synthetic intermediates of Formula B:WSGR Docket No. 59318-727.601

[0005] Described herein are stereoselective methods of making synthetic intermediates of Formula C:Formula C.

[0006] Described herein are stereoselective methods of making synthetic intermediates of Formula D:Formula D.

[0007] Described herein are stereoselective methods of making synthetic intermediates of Formula E: / N-N / L / Y( NX XFormula E.

[0008] Described herein are stereoselective methods of making synthetic intermediates of Formula F:Formula F.WSGR Docket No. 59318-727.601

[0009] Described herein are stereoselective methods of making synthetic intermediates of Formula G:Formula G.

[0010] Described herein are stereoselective methods of making synthetic intermediates of Formula H:ZFormula H.

[0011] In some embodiments, X is Cl.

[0012] In some embodiments, Y is F.

[0013] In some embodiments, Z is Br.

[0014] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.INCORPORATION BY REFERENCE

[0015] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.DETAILED DESCRIPTION OF THE DISCLOSURE

[0016] The present invention relates to stereoselective synthesis of compounds that bind to the pseudokinase domain (JH2) of the non-receptor tyrosine-protein kinase 2 (TYK2). Formula 11 of the present disclosure may inhibit certain cytokine signaling, for example IL-12, IL-23, andWSGR Docket No. 59318-727.601IFNa signaling. Additional aspects of the invention include synthetic intermediates, reaction mixtures, and processes useful in the synthesis of the compounds.

[0017] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g. IFN-a, IFN-P, IFN-K, IFN-6, IFN-s, IFN-T, IFN-CO, and IFN- (also known as limitin), and interleukins (e.g. IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). The activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT3, STAT4, and STAT6.

[0018] In one aspect, described herein is a process for the stereoselective preparation of Formula A: / N-NFormula A;wherein X is a second suitable leaving group;comprising:(1) contacting a compound of Formula B:Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable acid and a suitable solvent to provide a reaction mixture; and(2) contacting the reaction mixture of step (1) with a suitable base;to provide a compound of Formula A.WSGR Docket No. 59318-727.601

[0019] In some embodiments, the suitable acid in step (1) is hydrogen chloride or trifluoroacetic acid.

[0020] In some embodiments, the suitable acid in step (1) is hydrogen chloride.

[0021] In some embodiments, the suitable acid in step (1) is hydrogen chloride in dioxane.

[0022] In some embodiments, the suitable acid in step (1) is about 4 N hydrogen chloride in dioxane.

[0023] In some embodiments, the suitable solvent in step (1) is 1,4-dioxane, isopropanol, cyclopentyl methyl ether, or a mixture thereof.

[0024] In some embodiments, the suitable solvent in step (1) is 1,4-dioxane

[0025] In some embodiments, the suitable base in step (2) is triethylamine or diisopropylethylamine.

[0026] In some embodiments, the suitable base in step (2) is diisopropylethylamine.

[0027] In some embodiments, the reaction mixture of step (1) is concentrated under reduced pressure prior to contact with the suitable base in step (2).

[0028] In some embodiments, the process further comprises contacting the concentrated reaction mixture of step (1) with a second suitable solvent.

[0029] In some embodiments, the second suitable solvent is 1,4-dioxane.

[0030] In some embodiments, the compound of Formula B:Q^-O / Ki MNFormula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;is prepared by a process comprising:(3) contacting a compound of Formula D:S'°NFormula D;wherein X is a second suitable leaving group; andWSGR Docket No. 59318-727.601Y is a first suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (4) contacting the reaction mixture of step (3) with a suitable methylating agent; to provide a compound of Formula B.

[0031] In some embodiments, the suitable reducing agent in step (3) is L-Selectride, N-Selectride, K-Selectride, lithium triethylborohydride, diisobutyl aluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, or potassium borohydride.

[0032] In some embodiments, the suitable reducing agent in step (3) is L-Selectride.

[0033] In some embodiments, the suitable reducing agent in step (3) is a solution of L-Selectride in tetrahydrofuran, 2-methyl tetrahydrofuran, or a mixture thereof.

[0034] In some embodiments, the suitable reducing agent in step (3) is a solution of L-Selectride in tetrahydrofuran.

[0035] In some embodiments, the suitable methylating agent in step (4) is methyl iodide, methyl bromide, methyl mesylate, or dimethyl sulfate.

[0036] In some embodiments, the suitable methylating agent in step (4) is methyl iodide.

[0037] In some embodiments, the suitable solvent in step (3) is 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

[0038] In some embodiments, the suitable solvent in step (3) is 2-methyl tetrahydrofuran, tetrahydrofuran, or a mixture thereof.

[0039] In some embodiments, the compound of Formula B:Q-S-0 / Ni N-NFormula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;is prepared by a process comprising:WSGR Docket No. 59318-727.601(5) contacting a compound of Formula C:Formula C;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable methylating agent, a suitable base, and a suitable solvent to provide a compound of Formula B.

[0040] In some embodiments, the suitable methylating agent in step (5) is methyl iodide, methyl bromide, methyl mesylate, or dimethyl sulfate.

[0041] In some embodiments, the suitable methylating agent in step (5) is methyl iodide.

[0042] In some embodiments, the suitable base in step (5) is sodium hydride, potassium carbonate, or sodium carbonate.

[0043] In some embodiments, the suitable base in step (5) is sodium hydride.

[0044] In some embodiments, the suitable solvent in step (5) is 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, DMF, or a mixture thereof.

[0045] In some embodiments, the suitable solvent in step (5) is tetrahydrofuran, DMF, or a mixture thereof.

[0046] In some embodiments, the compound of Formula C:Formula C;wherein X is a second suitable leaving group; andY is a first suitable leaving group;is prepared by a process comprising:WSGR Docket No. 59318-727.601(6) contacting a compound of Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable reducing agent and a suitable solventto provide a compound of Formula C.

[0047] In some embodiments, the suitable reducing agent in step (6) is L-Selectride, N-Selectride, K-Selectride, lithium triethylborohydride, diisobutyl aluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride.

[0048] In some embodiments, the suitable reducing agent in step (6) is L-Selectride.

[0049] In some embodiments, the suitable solvent in step (6) is 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

[0050] In some embodiments, the suitable solvent in step (6) is 2-methyl tetrahydrofuran.

[0051] In some embodiments, the compound of Formula D:Q^-0 / KI MFormula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;is prepared by a process comprising:(7) contacting a compound of Formula E:N-NX1N JL XFormula E;wherein X is a second suitable leaving group; andWSGR Docket No. 59318-727.601Y is a first suitable leaving group;with (7?)-tert-butylsulfinamide and a suitable solventto provide a compound of Formula D.

[0052] In some embodiments, the process further comprises contacting the compound of Formula E with a suitable desiccant.

[0053] In some embodiments, the process of step (7) further comprises contacting the compound of Formula E with a suitable desiccant.

[0054] In some embodiments, the suitable desiccant in step (7) is titanium(IV) isopropoxide.

[0055] In some embodiments, the suitable solvent in step (7) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

[0056] In some embodiments, the suitable solvent in step (7) is tetrahydrofuran.

[0057] In some aspects, described herein is a process for the stereoselective preparation of Formula A:Formula A;wherein X is a second suitable leaving group;comprising:(1) contacting a compound of Formula B:Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable acid and a suitable solvent to provide a reaction mixture; and(2) contacting the reaction mixture of step (1) with a suitable base to provide a compound of formula A;wherein the compound of Formula B is prepared by a process comprising:WSGR Docket No. 59318-727.601(3) contacting a compound of Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (4) contacting the reaction mixture of step (3) with a suitable methylating agent to provide a compound of Formula B;wherein the compound of Formula D is prepared by a process comprising:(7) contacting a compound of Formula E:N-l / Formula E;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with (7 )-tert-butylsulfinamide and a suitable solventto provide a compound of Formula D.

[0058] In some embodiments, the compound of Formula E is prepared by a process comprising:(8) contacting a compound of Formula 2:OFormula 2;WSGR Docket No. 59318-727.601with a compound of Formula 3:[M]Formula 3;wherein [M] is a suitable metal or metalloid group;X is a second suitable leaving group; andY is a first suitable leaving group;and a first suitable palladium catalyst, a first suitable ligand, and a suitable solvent to provide a compound of Formula E.

[0059] In some embodiments, the suitable metal or metalloid group in step (8) is an organoboron or organotin reagent.

[0060] In some embodiments, the suitable metal or metalloid group in step (8) is a boronic acid, boronic ester, or trifluoroborate.

[0061] In some embodiments, the suitable metal or metalloid group in step (8) is -B(OH)2.

[0062] In some embodiments, the first suitable palladium catalyst in step (8) is Pd2(dba)s.

[0063] In some embodiments, the first suitable ligand in step (8) is tri -tert-butyl phosphine or a salt thereof.

[0064] In some embodiments, the first suitable ligand in step (8) is [(7-Bu)3PH]BF4.

[0065] In some embodiments, the suitable solvent in step (8) is tetrahydrofuran, water, or a mixture thereof.

[0066] In some embodiments, the suitable solvent in step (8) is about a 10:1 mixture of tetrahydrofuran and water.

[0067] In some embodiments, step (8) further comprises contacting the compound of Formula 2 and compound of Formula 3 with a suitable base.

[0068] In some embodiments, the suitable base in step (8) is potassium fluoride or cesium fluoride.

[0069] In some embodiments, the compound of Formula 2 is prepared by a process comprising:(9) contacting a compound of Formula 1:NIFormula 1;WSGR Docket No. 59318-727.601with a suitable metal-halogen exchange reagent and a suitable solvent to provide a reaction mixture; and(10) contacting the reaction mixture of step (9) with / ' / / ' -dim ethyl acetamide;to provide a compound of Formula 2.

[0070] In some embodiments, the suitable metal-halogen exchange reagent in step (9) is an organolithium reagent or a Grignard reagent.

[0071] In some embodiments, the suitable metal-halogen exchange reagent in step (9) is n-butyllithium, n-hexyllithium, or isopropyl magnesium chloride.

[0072] In some embodiments, the suitable metal-halogen exchange reagent in step (9) is n-butyllithium.

[0073] In some embodiments, the suitable metal-halogen exchange reagent in step (9) is a solution of n-butyl lithium in hexanes.

[0074] In some embodiments, the suitable solvent in step (9) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, pentane, hexanes, or a mixture thereof.

[0075] In some embodiments, the suitable solvent in step (9) is tetrahydrofuran, hexanes, or a mixture thereof.

[0076] In some embodiments, the compound of Formula B:Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;is prepared by a process comprising:(11) contacting a compound of Formula F:Formula F;wherein Z is a third suitable leaving group;WSGR Docket No. 59318-727.601with a compound of Formula 3:[M]fYkN^XFormula 3;wherein [M] is a suitable metal or metalloid group;X is a second suitable leaving group; andY is a first suitable leaving group;and a second suitable palladium catalyst, a second suitable ligand, and a suitable solvent to provide a compound of Formula B.

[0077] In some embodiments, the suitable metal or metalloid group in step (11) is an organoboron or organotin reagent.

[0078] In some embodiments, the suitable metal or metalloid group in step (11) is a boronic acid, boronic ester, or trifluoroborate.

[0079] In some embodiments, the suitable metal or metalloid group in step (11) is -B(OH)2.

[0080] In some embodiments, the second suitable palladium catalyst in step (11) is Pd2(dba)s.

[0081] In some embodiments, the second suitable ligand in step (11) is tri- / c / 7-butyl phosphine or a salt thereof.

[0082] In some embodiments, the second suitable ligand in step (11) is [( / -Bu)3PH]BF4.

[0083] In some embodiments, the suitable solvent in step (11) is tetrahydrofuran, water, or a mixture thereof.

[0084] In some embodiments, the suitable solvent in step (11) is a 10:1 mixture of tetrahydrofuran and water.

[0085] In some embodiments, step (11) further comprises contacting the compound of Formula 2 with a suitable base.

[0086] In some embodiments, the suitable base in step (11) is potassium fluoride or cesium fluoride.

[0087] In some embodiments, the suitable base in step (11) is potassium fluoride.

[0088] In some embodiments, the compound of Formula F:Formula F;wherein Z is a third suitable leaving group;WSGR Docket No. 59318-727.601is prepared by a process comprising:(12) contacting a compound of Formula G:Formula G;wherein Z is a third suitable leaving group; andwith a suitable methylating agent, a suitable base, and a suitable solvent to provide a compound of Formula F.

[0089] In some embodiments, the suitable methylating agent in step (12) is methyl iodide, methyl bromide, methyl mesylate, or dimethyl sulfate.

[0090] In some embodiments, the suitable methylating agent in step (12) is methyl iodide.

[0091] In some embodiments, the suitable base in step (12) is sodium hydride, potassium carbonate, or sodium carbonate.

[0092] In some embodiments, the suitable base in step (12) is sodium hydride.

[0093] In some embodiments, the suitable solvent in step (12) is 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, DMF, or a mixture thereof.

[0094] In some embodiments, the suitable solvent in step (12) is tetrahydrofuran, DMF, or a mixture thereof.

[0095] In some embodiments, the compound of Formula G:Formula G;wherein Z is a third suitable leaving group;is prepared by a process comprising:(13) contacting a compound of Formula H:Formula H;wherein Z is a third suitable leaving group;with a suitable reducing agent and a suitable solvent;WSGR Docket No. 59318-727.601to provide a compound of Formula G.

[0096] In some embodiments, the compound of Formula F:Formula F;wherein Z is a third suitable leaving group;is prepared by a process comprising:(14) contacting a compound of Formula H:Formula H;wherein Z is a third suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (15) contacting the reaction mixture of step (14) with a suitable methylating agent; to provide a compound of Formula F.

[0097] In some embodiments, the suitable reducing agent in step (13) is L-Selectride, N-Selectride, K-Selectride, lithium triethylborohydride, diisobutyl aluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride.

[0098] In some embodiments, the suitable solvent in step (13) is tetrahydrofuran.

[0099] In some embodiments, the suitable reducing agent in step (13) is L-Selectride.

[0100] In some embodiments, the suitable solvent in step (13) is 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

[0101] In some embodiments, the suitable solvent in step (13) is tetrahydrofuran.

[0102] In some embodiments, the compound of Formula F:ZFormula F;wherein Z is a third suitable leaving group;is prepared by a process comprising:WSGR Docket No. 59318-727.601(14) contacting a compound of Formula H:ZFormula H;wherein Z is a third suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (15) contacting the reaction mixture of step (14) with a suitable methylating agent; to provide a compound of Formula F.

[0103] In some embodiments, the suitable reducing agent in step (14) is L-Selectride, N-Selectride, K-Selectride, lithium triethylborohydride, diisobutyl aluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride.

[0104] In some embodiments, the suitable reducing agent in step (14) is L-Selectride.

[0105] In some embodiments, the suitable methylating agent in step (15) is methyl iodide, methyl bromide, methyl mesylate, or dimethyl sulfate.

[0106] In some embodiments, the suitable methylating agent in step (15) is methyl iodide.

[0107] In some embodiments, the suitable solvent in step (14) is 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

[0108] In some embodiments, the suitable solvent in step (14) is tetrahydrofuran.

[0109] In some embodiments, the compound of Formula H:Formula H;wherein Z is a third suitable leaving group;is prepared by a process comprising:(16) contacting a compound of Formula I:ZFormula I;wherein Z is a third suitable leaving group;with ( / )-tert-butylsulfinamide and a suitable solvent;WSGR Docket No. 59318-727.601to provide a compound of Formula H.

[0110] In some embodiments, step (16) further comprises contacting the compound of Formula I with a suitable desiccant.[OHl] In some embodiments, the suitable desiccant in step (16) is titanium(IV) isopropoxide.

[0112] In some embodiments, the suitable solvent in step (16) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

[0113] In some embodiments, the suitable solvent in step (16) is tetrahydrofuran.

[0114] In some embodiments, the compound of Formula I:N-N?ZFormula I;wherein Z is a third suitable leaving group;is prepared by a process comprising:(17) contacting a compound of Formula J:N-l / ZFormula J;wherein Z is a third suitable leaving group;with a suitable metal-halogen exchange reagent and a suitable solvent to provide a reaction mixture; and(18) contacting the reaction mixture of step (17) with / ' / / ' -dim ethyl acetamide;to provide a compound of Formula I.

[0115] In some embodiments, the suitable metal-halogen exchange reagent in step (17) is an organolithium reagent or a Grignard reagent.

[0116] In some embodiments, the suitable metal-halogen exchange reagent in step (17) is n-butyllithium, n-hexyllithium, or isopropyl magnesium chloride.

[0117] In some embodiments, the suitable metal-halogen exchange reagent in step (17) is n-butyllithium.

[0118] In some embodiments, the suitable metal-halogen exchange reagent in step (17) is a solution of n-butyl lithium in hexanes.

[0119] In some embodiments, the suitable solvent in step (17) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, pentane, hexanes, or a mixture thereof.WSGR Docket No. 59318-727.601

[0120] In some embodiments, the suitable solvent in step (17) is tetrahydrofuran, hexanes, or a mixture thereof.

[0121] In some embodiments, the process further comprises:(19) contacting a compound of Formula A with:RC(O)NH2, wherein R is an unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group, a third suitable palladium catalyst, a third suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 8: / N-NROFormula 8wherein R is an unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group.

[0122] In some embodiments, the third suitable palladium catalyst in step (19) is Pd2(dba)s.

[0123] In some embodiments, the third suitable ligand in step (19) is Xantphos or Josiphos (SL-J009-1).

[0124] In some embodiments, the third suitable ligand in step (19) is Josiphos (SL-J009-1).

[0125] In some embodiments, the third suitable ligand in step (19) is Xantphos.

[0126] In some embodiments, the suitable base in step (19) is CS2CO3.

[0127] In some embodiments, the suitable solvent in step (19) is toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, or a mixture thereof.

[0128] In some embodiments, the suitable solvent in step (19) is toluene, 1,4-di oxane, or a mixture thereof.

[0129] In some embodiments, the suitable solvent in step (19) is toluene.

[0130] In some embodiments, R is cyclopropyl.

[0131] In some embodiments, R is Zc / V-butoxy.

[0132] In some embodiments, the process further comprises:WSGR Docket No. 59318-727.601(20) contacting a compound of Formula 8 with a suitable base and a suitable solvent to provide a compound of Formula 9: / N-NFormula 9.

[0133] In some embodiments, the suitable base in step (20) is lithium hydroxide or sodium hydroxide.

[0134] In some embodiments, the suitable base in step (20) is lithium hydroxide monohydrate.

[0135] In some embodiments, the suitable solvent in step (20) is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methanol, water, or a mixture thereof.

[0136] In some embodiments, the suitable solvent in step (20) is tetrahydrofuran, water, or a mixture thereof.

[0137] In some embodiments, the process further comprises:(21) contacting a compound of Formula 8 with a suitable acid and a suitable solvent to provide a compound of Formula 9: / N-NIts; I1 )H2N NFormula 9. / N-NS^ JZ^NTTSJ | / N. 1I ]HN^N

[0138] In some embodiments, the compound of Formula 8 is: '^ ''0 0

[0139] In some embodiments, the suitable acid in step (21) is hydrogen chloride or trifluoroacetic acid.

[0140] In some embodiments, the suitable acid in step (21) is hydrogen chloride.

[0141] In some embodiments, the suitable solvent in step (21) is toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methanol, water, or a mixture thereof.

[0142] In some embodiments, the process further comprises:WSGR Docket No. 59318-727.601O ClD’C'NHM 1N<- JL.(22) contacting a compound of Formula 9with N Cl ,asuitable base, and a suitable solvent to provide a compound of Formula 10:

[0143] In some embodiments, the suitable base in step (22) is sodium hydride or LiHMDS.

[0144] In some embodiments, the suitable base in step (22) is LiHMDS.

[0145] In some embodiments, the suitable base in step (22) is a solution of LiHMDS in tetrahydrofuran.

[0146] In some embodiments, the suitable solvent in step (22) is 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, DMF, or a mixture thereof.

[0147] In some embodiments, the suitable solvent in step (22) is 2-methyl tetrahydrofuran, tetrahydrofuran, or a mixture thereof.

[0148] In some embodiments, the process further comprises:(23) contacting a compound of Formula 10 with cyclopropanecarboxamide, a fourth suitable palladium catalyst, a fourth suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 11:

[0149] In some embodiments, the fourth suitable palladium catalyst in step (23) Pd2(dba)s.

[0150] In some embodiments, the fourth suitable ligand in step (23) is Xantphos.

[0151] In some embodiments, the suitable base in step (23) is CS2CO3.WSGR Docket No. 59318-727.601

[0152] In some embodiments, the suitable solvent in step (23) is 1,4-di oxane, water, or a combination thereof.

[0153] In some embodiments, the suitable solvent in step (23) is about a 7.5:1 mixture of 1,4-di oxane and water.

[0154] In some aspects, described herein is a process for the stereoselective preparation of Formula 11:comprising:(23) contacting a compound of Formula 10:Formula 10;with cyclopropanecarboxamide, a fourth suitable palladium catalyst, a fourth suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 11; wherein the compound of Formula 10 is prepared by a process comprising:(22) contacting a compound of Formula 9: / N-NFormula 9;WSGR Docket No. 59318-727.601O ClHN<- JLwith N Cl , a suitable base, and a suitable solvent to provide a compound of Formula 10;wherein the compound of Formula 9 is prepared by a process comprising:(20) contacting a compound of Formula 8;N-N / NTrsj |ZN. AHN 1 N ]Formula 8wherein R is an unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted Ci-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group; witha suitable base and a suitable solvent to provide a compound of Formula 9; wherein the compound of Formula 8 is prepared by a process comprising:(19) contacting a compound of Formula A: / N-NFormula A;wherein X is a second suitable leaving group;with:RC(O)NH2, wherein R is an unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group,a third suitable palladium catalyst, a third suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 8;wherein the compound of Formula A is prepared by a process comprising:(1) contacting a compound of Formula B:WSGR Docket No. 59318-727.601Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable acid and a suitable solvent to provide a reaction mixture; and(2) contacting the reaction mixture of step (1) with a suitable base to provide a compound of formula A;wherein the compound of Formula B is prepared by a process comprising:(3) contacting a compound of Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (4) contacting the reaction mixture of step (3) with a suitable methylating agent to provide a compound of Formula B;wherein the compound of Formula D is prepared by a process comprising:(7) contacting a compound of Formula E:Formula E;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with (7?)-tert-butylsulfinamide and a suitable solventto provide a compound of Formula D;WSGR Docket No. 59318-727.601wherein the compound of Formula E is prepared by a process comprising:(8) contacting a compound of Formula 2:OFormula 2;with a compound of Formula 3:[M]Formula 3;wherein [M] is a suitable metal or metalloid group;X is a second suitable leaving group; andY is a first suitable leaving group;and a first suitable palladium catalyst, a first suitable ligand, and a suitable solvent to provide a compound of Formula E;wherein the compound of Formula 2 is prepared by a process comprising:(9) contacting a compound of Formula 1:Formula 1;with a suitable metal-halogen exchange reagent and a suitable solvent to provide a reaction mixture; and(10) contacting the reaction mixture of step (9) with / ' / / ' -dim ethyl acetamide; to provide a compound of Formula 2.WSGR Docket No. 59318-727.601

[0155] In some aspects, described herein is a process for the stereoselective preparation of Formula 11:comprising:(23) contacting a compound of Formula 10:Formula 10;with cyclopropanecarboxamide, a fourth suitable palladium catalyst, a fourth suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 11; wherein the compound of Formula 10 is prepared by a process comprising:(22) contacting a compound of Formula 9: / N-NFormula 9;O ClHwith 'N Cl ,asuitable base, and a suitable solvent to provide a compound of Formula 10;wherein the compound of Formula 9 is prepared by a process comprising:(21) contacting a compound of Formula 8;WSGR Docket No. 59318-727.601N-NHN NROFormula 8wherein R is an unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted Ci-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group; witha suitable acid and a suitable solvent to provide a compound of Formula 9; wherein the compound of Formula 8 is prepared by a process comprising:(19) contacting a compound of Formula A:N-NZ^NRs;N.Formula A;wherein X is a second suitable leaving group;with:RC(O)NH2, wherein R is an unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group,a third suitable palladium catalyst, a third suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 8;wherein the compound of Formula A is prepared by a process comprising:(1) contacting a compound of Formula B:Q^O / r N-NNFormula B;WSGR Docket No. 59318-727.601wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable acid and a suitable solvent to provide a reaction mixture; and(2) contacting the reaction mixture of step (1) with a suitable base to provide a compound of formula A;wherein the compound of Formula B is prepared by a process comprising:(3) contacting a compound of Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (4) contacting the reaction mixture of step (3) with a suitable methylating agent to provide a compound of Formula B;wherein the compound of Formula D is prepared by a process comprising:(7) contacting a compound of Formula E:Formula E;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with (7?)-tert-butylsulfinamide and a suitable solventto provide a compound of Formula D;wherein the compound of Formula E is prepared by a process comprising:(8) contacting a compound of Formula 2:O— BrN, ,NNWSGR Docket No. 59318-727.601Formula 2;with a compound of Formula 3:[M]Formula 3;wherein [M] is a suitable metal or metalloid group;X is a second suitable leaving group; andY is a first suitable leaving group;and a first suitable palladium catalyst, a first suitable ligand, and a suitable solvent to provide a compound of Formula E;wherein the compound of Formula 2 is prepared by a process comprising:(9) contacting a compound of Formula 1:NIFormula 1;with a suitable metal-halogen exchange reagent and a suitable solvent to provide a reaction mixture; and(10) contacting the reaction mixture of step (9) with / ' / / ' -dim ethyl acetamide; to provide a compound of Formula 2.

[0156] In some embodiments, the compound of Formula 11:contains less than 100 ppm of palladium.

[0157] In some embodiments,X is a second leaving group which is a halogen or sulfonate leaving group; and Y is a first leaving group which is a halogen or sulfonate leaving group.WSGR Docket No. 59318-727.601

[0158] In some embodiments, X is a sulfonate leaving group, wherein the sulfonate group is -OS(=O)2RZ, wherein Rzis Cnio alkyl, Cnio fluoroalkyl, or C3-10 carbocycle optionally substituted with 1-5 groups selected from C1-6 alkyl and fluoro.

[0159] In some embodiments,X is a sulfonate leaving group selected from mesylate (-OMs, methanesulfonate), esylate (-OEs, ethanesulfonate), tosylate (-OTs, para-toluenesulfonate), tritiate (-OTf, trifluoromethanesulfonate), besylate (-OBs, benzenesulfonate), nonaflate (-ONf, perfluorobutanesulfonate), or the like.

[0160] In some embodiments, Y is a sulfonate leaving group, wherein the sulfonate group is -OS(=O)2RZ, wherein Rzis Ci-10 alkyl, Ci-10 fluoroalkyl, or C3-10 carbocycle optionally substituted with 1-5 groups selected from C1-6 alkyl and fluoro.

[0161] In some embodiments,Y is a sulfonate leaving group selected from mesylate (-OMs, methanesulfonate), esylate (-OEs, ethanesulfonate), tosylate (-OTs, para-toluenesulfonate), tritiate (-OTf, trifluoromethanesulfonate), besylate (-OBs, benzenesulfonate), nonaflate (-ONf, perfluorobutanesulfonate), or the like.

[0162] In some embodiments,X is a second leaving group which is a halogen; andY is a first leaving group which is a halogen or sulfonate leaving group.

[0163] In some embodiments,X is F; andY is a first leaving group which is a halogen or sulfonate leaving group.

[0164] In some embodiments,X is a second leaving group which is a halogen; andY is a first leaving group which is a halogen.

[0165] In some embodiments,X is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; andY is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.

[0166] In some embodiments,X is a second leaving group selected from the group consisting of Cl, Br, and I; and Y is F.

[0167] In some embodiments,X is a second leaving group selected from the group consisting of Cl and Br; andWSGR Docket No. 59318-727.601Y is F.

[0168] In some embodiments,X is a second leaving group selected from the group consisting of F, Cl, Br, and I; and Y is a first leaving group selected from the group consisting of F, Cl, Br, and I.

[0169] In some embodiments,X is a Cl; andY is F.

[0170] In some embodiments,Z is a third leaving group which is a halogen.

[0171] In some embodiments,Z is a third leaving group selected from the group consisting of Cl, Br, and I.

[0172] In some embodiments,Z is a third leaving group selected from the group consisting of Br, and I.

[0173] In some embodiments,Z is Br.

[0174] In some embodiments, the compound of Formula A has an enantiopurity of greater than 90% enantiomeric excess (ee).

[0175] In some embodiments, the compound of Formula A has an enantiopurity of greater than 95% enantiomeric excess (ee).

[0176] In some embodiments, the compound of Formula A has an enantiopurity of greater than 98% enantiomeric excess (ee).

[0177] In some embodiments, the compound of Formula A has an enantiopurity of greater than 99% enantiomeric excess (ee).

[0178] In some embodiments, the compound of Formula 11 has an enantiopurity of greater than 90% enantiomeric excess (ee).

[0179] In some embodiments, the compound of Formula 11 has an enantiopurity of greater than 95% enantiomeric excess (ee).

[0180] In some embodiments, the compound of Formula 11 has an enantiopurity of greater than 98% enantiomeric excess (ee).

[0181] In some embodiments, the compound of Formula 11 has an enantiopurity of greater than 99% enantiomeric excess (ee).WSGR Docket No. 59318-727.601

[0182] In some aspects, described herein is a compound selected from:

[0183] In some aspects, described herein is a compound selected from

[0184] In some aspects, described herein is a compound selected fromsalt thereof.

[0185] In some aspects, described herein is a compound selected fromsalt thereof.WSGR Docket No. 59318-727.601

[0186] In some aspects, described herein is a compound selected fromor a salt thereof.

[0187] In some aspects, described herein is a compound selected fromor a salt thereof.

[0188] In some aspects, described herein is a compound selected fromor a salt thereof.

[0189] In some aspects, described herein is a compound selected fromI , or a salt thereof.

[0190] In some aspects, described herein is a compound selected fromor a salt thereof, wherein X is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; and Y is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.WSGR Docket No. 59318-727.601N-NZ

[0191] In some aspects, described herein is a compound selected fromN Xor asalt thereof, wherein X is a second leaving group selected from the group consisting of Cl, Br, and I; and Y is F.N-N

[0192] In some aspects, described herein is a compound selected from, or a salt thereof, wherein X is Cl; and Y is F.

[0193] In some aspects, described herein is a compound selected fromor a salt thereof, wherein X is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; and Y is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.S

[0194] In some aspects, described herein is a compound selected fromor a salt thereof, wherein X is a second leaving group selected from the group consisting of Cl, Br, and I; and Y is F.WSGR Docket No. 59318-727.601

[0195] In some aspects, described herein is a compound selected fromor a salt thereof, wherein X is Cl; and Y is F.

[0196] In some aspects, described herein is a compound selected froma salt thereof, wherein X is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; and Y is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.

[0197] In some aspects, described herein is a compound selected froma salt thereof, wherein X is a second leaving group selected from the group consisting of Cl, Br, and I; and Y is F.

[0198] In some aspects, described herein is a compound selected fromor a salt thereof, wherein X is Cl; and Y is F.WSGR Docket No. 59318-727.601

[0199] In some aspects, described herein is a compound selected fromor a salt thereof, wherein X is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; and Y is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.

[0200] In some aspects, described herein is a compound selected froma salt thereof, wherein X is a second leaving group selected from the group consisting of Cl, Br, and I; and Y is F.

[0201] In some aspects, described herein is a compound selected froma salt thereof, wherein X is Cl; and Y is F.

[0202] In some embodiments, X is a second leaving group selected from the group consisting of Cl, Br, and I; and Y is a first leaving group selected from the group consisting of F.

[0203] In some embodiments, X is selected from the group consisting of F, Cl, Br, and I and Y is selected from the group consisting of F, Cl, Br, and I.

[0204] In some embodiments, X is Cl and Y is F.WSGR Docket No. 59318-727.601Nx,NN

[0205] In some aspects, described herein is a compound selected fromI , or a salt thereof, wherein Z is a third leaving group selected from the group consisting of Cl, Br, I, OTf, OTs, and OMs.N "OZN

[0206] In some aspects, described herein is a compound selected fromI , or a salt thereof, wherein Z is a third leaving group selected from the group consisting of Cl, Br, and I.N O ZNx,NN

[0207] In some aspects, described herein is a compound selected fromI , or a salt thereof, wherein Z is Br.HN "O ZN. ,N N

[0208] In some aspects, described herein is a compound selected fromI , or a salt thereof, wherein Z is a third leaving group selected from the group consisting of Cl, Br, I, OTf, OTs, and OMs.WSGR Docket No. 59318-727.601HN "O zN. ,N N

[0209] In some aspects, described herein is a compound selected fromI , or a salt thereof, wherein Z is a third leaving group selected from the group consisting of Cl, Br, and I.HN "O

[0210] In some aspects, described herein is a compound selected fromI , or a salt thereof, wherein Z is Br.\ zSxN O

[0211] In some aspects, described herein is a compound selected fromI , or a salt thereof, wherein Z is a third leaving group selected from the group consisting of Cl, Br, I, OTf, OTs, and OMs.\N O

[0212] In some aspects, described herein is a compound selected fromI , or a salt thereof, wherein Z is a third leaving group selected from the group consisting of Cl, Br, and I.\ zSxN O

[0213] In some aspects, described herein is a compound selected fromI , or a salt thereof, wherein Z is Br.WSGR Docket No. 59318-727.601

[0214] In some aspects, described herein is a reaction mixture comprising Formula B:N ,Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;a suitable acid; anda suitable solvent.

[0215] In some embodiments, Z is selected from the group consisting of Cl, Br, and I.

[0216] In some embodiments, Z is Br.

[0217] In some embodiments, the suitable acid is hydrogen chloride.

[0218] In some embodiments, the suitable solvent is 1,4-di oxane.

[0219] In some aspects, described herein is a reaction mixture comprising Formula D:Q-^O / N-NNUZNFormula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;a suitable reducing agent; anda suitable solvent.

[0220] In some embodiments, the suitable reducing agent is L-Selectride, N-Selectride, K-Selectride, lithium triethylborohydride, diisobutyl aluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, or potassium borohydride.

[0221] In some embodiments, the suitable reducing agent is L-Selectride.

[0222] In some embodiments, the suitable solvent is 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

[0223] In some embodiments, the suitable solvent is 2-methyl tetrahydrofuran.

[0224] In some aspects, described herein is a reaction mixture comprising Formula E:WSGR Docket No. 59318-727.601N-NZ°yLN( 1N XFormula E;wherein X is a second suitable leaving group; andY is a first suitable leaving group;(7 )-tert-butylsulfinamide; anda suitable solvent.

[0225] In some embodiments, the reaction mixture further comprises a suitable desiccant.

[0226] In some embodiments, the suitable desiccant is titanium(IV) isopropoxide.

[0227] In some embodiments, the suitable solvent is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

[0228] In some embodiments, the suitable solvent is tetrahydrofuran.

[0229] In some embodiments,X is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; andY is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.

[0230] In some embodiments,X is a second leaving group selected from the group consisting of F, Cl, Br, and I; and Y is a first leaving group selected from the group consisting of F, Cl, Br, and I.

[0231] In some embodiments,X is Cl; andY is a first leaving group selected from the group consisting of F, Cl, Br, and I.

[0232] In some embodiments,X is a second leaving group selected from the group consisting of Cl, Br, and I; and Y is F.

[0233] In some embodiments,X is a Cl; andY is F.Certain Terminology

[0234] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such asWSGR Docket No. 59318-727.601“include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0235] As used herein, Ci-Cxincludes C1-C2, C1-C3 . . . Ci-Cx. By way of example only, a group designated as "Ci-Ce" indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, Ao-propyl, / / -butyl, iso-butyl, ec-butyl, and / -butyl.

[0236] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a Ci-Cioalkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a Ci-Ce alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0237] An “alkylene” group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a Ci-Ce alkylene. In other embodiments, an alkylene is a Ci-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-.

[0238] An “alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0239] The term “alkylamine” refers to the -N(alkyl)xHygroup, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

[0240] An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl. In some embodiments, a hydroxyalkyl is a Ci-C4hydroxy alkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, and the like.

[0241] An “aminoalkyl” refers to an alkyl in which one hydrogen atom is replaced by an amino. In some embodiments, aminoalkyl is a Ci-C4aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like.WSGR Docket No. 59318-727.601

[0242] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR.2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Nonlimiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0243] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C=C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C=CH, -OCCH3 -OCCH2CH3, -CH2OCH.

[0244] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. -NH-, -N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ceheteroalkyl.

[0245] The term “aromatic” refers to a planar ring having a delocalized 71-electron system containing 4n+271 electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0246] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.

[0247] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a Ce-Cioaryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0248] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. InWSGR Docket No. 59318-727.601some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[l.l.l]pentyl. In some embodiments, a cycloalkyl is a C3-Cecycloalkyl. In some embodiments, a cycloalkyl is a C3-C4cycloalkyl.

[0249] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0250] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a Ci-Cefluoroalkyl.

[0251] The term "heterocycle" or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindoline-1, 3-dionyl, 3,4-dihydroisoquinolin-l(2H)-onyl, 3,4-dihydroquinolin-2(lH)-onyl, isoindoline-1, 3-dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or TV-attached whereWSGR Docket No. 59318-727.601such is possible. For instance, a group derived from pyrrole includes both pyrrol-l-yl (TV-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both TV-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=0) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0252] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls.Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a Ci-Cgheteroaryl. In some embodiments, monocyclic heteroaryl is a Ci-Csheteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a Ce-Cgheteroaryl.

[0253] A “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2, 5-dithionyl, pyrrolidine-2, 5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-Cioheterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-Cioheterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring. In some embodiments, a heterocycloalkyl containsWSGR Docket No. 59318-727.6010-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0254] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moi eties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0255] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0256] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(Ci-C4alkyl), -C(=O)NH2, -C(=O)NH(Ci-C4alkyl), -C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(Ci-C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi-C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).

[0257] In some embodiments, each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more Rsgroups independently selected from the group consisting of deuterium, halogen, Ci-Ce alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR18, -CO2R18, -C(=O)N(R18)2, -N(R18)2, -NR18C(=O)R19, -SR18, -S(=O)R19, -SO2R19, or -SO2N(R18)2; each R18is independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-Ce cycloalkyl, C2-Ce heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R18groups are taken together with the N atom to which they are attached to form a N-containing heterocycle; each R19is independently selected from Ci-Ce alkyl, Ci-Ce fluoroalkyl, Ci-Ce heteroalkyl, C3-Ce cycloalkyl, C2-C6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.WSGR Docket No. 59318-727.601

[0258] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0259] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0260] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an antagonist. In some embodiments, a modulator is an inhibitor.

[0261] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0262] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0263] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0264] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect ofWSGR Docket No. 59318-727.601therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0265] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g. a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g. a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[0266] The terms “article of manufacture” and “kit” are used as synonyms.

[0267] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0268] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development or progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a secondary condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.

[0269] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.WSGR Docket No. 59318-727.601

[0270] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary up to 10% of the stated number or numerical range.

[0271] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0272] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below:

[0273] As used herein, Ci-Cxincludes C1-C2, C1-C3 . . . Ci-Cx. By way of example only, a group designated as “C1-C4” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, Ao-propyl, / / -butyl, isobutyl, ec-butyl, and / -butyl.WSGR Docket No. 59318-727.601Synthetic Route I-A:Procedure Procedure (9)+(10) (7) Br Br Wstep-1Step-3 N, „N - * NFormula 1 Formula 2Step-4 Procedure (3)+(4)Formula DFormula A Formula 8 Formula 9Procedure (22) Step-9Formula 10 Formula 11WSGR Docket No. 59318-727.601Synthetic Route I-B:Procedure Procedure (9)+(10) (7) Step-1 Step-3Formula 1 Formula 2Procedure Procedure (6) (5) Step-4' Step-5'Formula BFormula DFormula 10 Formula 11WSGR Docket No. 59318-727.601Synthetic Route II-A:Procedure Procedure7_z(17)+(18) (16)Step-1A Step-2AN. ,N - - NFormula J Formula IProcedure Procedure(13) (12) Procedure (11) Step-3A Step-4A Step-5AFormula H Formula FProcedure ProcedureklzProcedure (1)+(2) Step-6Formula B Formula A Formula 8Formula 9 Formula 10WSGR Docket No. 59318-727.601Synthetic Route II-B:Procedure Procedure(17)+(18) (16)Step-2AFormula J Formula IProcedure (11) Step-3A ' Step-5A Procedure (14)+(15)Formula HProcedurek / ProcedureFormula B Formula A Formula 8Formula 9 Formula 10 Synthesis

[0274] Compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC are employed.WSGR Docket No. 59318-727.601

[0275] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.

[0276] In the reactions described, it may be necessary to protect reactive functional groups, for example hydroxy or amino groups, where these are desired in the final product, in order to avoid their unwanted participation in reactions. A detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.Synthesis of Formula A from Formula BFormula B Formula A

[0277] Disclosed herein are methods for the synthesis of compounds of Formula A.

[0278] As disclosed herein, a compound of Formula A is prepared from a compound of Formula B by:(1) contacting a compound of Formula B:Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable acid and a suitable solvent to provide a reaction mixture; and(2) contacting the reaction mixture of step (1) with a suitable base;to provide a compound of Formula A.WSGR Docket No. 59318-727.601

[0279] In some embodiments, X is a second leaving group which is a halogen or sulfonate leaving group. In some embodiments, Y is a first leaving group which is a halogen or sulfonate leaving group. In some embodiments, X is a second leaving group which is a halogen; and Y is a first leaving group which is a halogen. In some embodiments, X is Cl; and Y is F.

[0280] In some embodiments the suitable acid in step (1) is hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, acetic acid, nitric acid, trifluoroacetic acid, citric acid, phosphoric acid, methane sulfonic acid, p-toluene sulfonic acid, or a combination thereof. In some embodiments, the suitable acid in step (1) is hydrogen chloride or trifluoroacetic acid. In some embodiments, the suitable acid in step (1) is trifluoroacetic acid. In some embodiments, the suitable acid in step (1) is hydrogen chloride. In some embodiments, the suitable acid in step (1) is anhydrous hydrogen chloride. In some embodiments, the suitable acid in step (1) is hydrogen chloride in an alcohol solvent. In some embodiments, the suitable acid in step (1) is hydrogen chloride in methanol. In some embodiments, the suitable acid in step (1) is hydrogen chloride in an ethereal solvent. In some embodiments, the suitable acid in step (1) is hydrogen chloride in diethyl ether. In some embodiments, the suitable acid in step (1) is hydrogen chloride in dioxane. In some embodiments the hydrogen chloride in dioxane is about 1.0 N to about 5.0 N. In some embodiments the hydrogen chloride in dioxane is about 4.0 N.

[0281] In some embodiments, the suitable solvent in step (1) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable solvent is methanol. In some embodiments, the suitable solvent is isopropanol. In some embodiments, the suitable solvent is diethyl ether. In some embodiments, the suitable solvent is 1,4-di oxane.

[0282] In some embodiments, there is a molar excess of the suitable acid in step (1) with respect to the compound of Formula B. In some embodiments, at least 1.0, 2.0, 5.0, 10.0, 15.0, 20.0, or 50.0 molar equivalents of the suitable acid in step (1) with respect to the compound of Formula B are used. In some embodiments, from about 1.0 to about 20.0 molar equivalents of the suitable acid in step (1) with respect to the compound of Formula B are used. In some embodiments, from about 2.0 to about 10.0 molar equivalents of the suitable acid in step (1) with respect to the compound of Formula B are used. In some embodiments, from about 2.0 to about 5.0 molar equivalents of the suitable acid in step (1) with respect to the compound of Formula B are used. In some embodiments, the concentration of the suitable acid in step (1) in the suitable solvent is about 0.5 N to about 8.0 N. In some embodiments, the concentration of the suitable acid in step (1) in the suitable solvent is about 3.0 N to about 5.0 N. In someWSGR Docket No. 59318-727.601embodiments, the concentration of the suitable acid in step (1) in the suitable solvent is about 4.0 N.

[0283] In some embodiments, the reaction mixture of step (1) is concentrated under reduced pressure prior to contact with the suitable base in step (2).

[0284] In some embodiments, the reaction mixture of step (1) is concentrated under reduced pressure and subsequently dissolved in dioxane and re-concentrated (azeotroped) one or more times prior to contact with the suitable base in step (2).

[0285] In some embodiments, step (1) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (1) further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about -20° Celsius to about 100° Celsius. In some embodiments, the suitable temperature is about 0° Celsius to about 90° Celsius. In some embodiments, the suitable temperature is about 0° Celsius to about 50° Celsius. In some embodiments, the suitable temperature is about 0° Celsius to about 40° Celsius. In some embodiments, the suitable temperature is about 20° Celsius to about 40° Celsius. In some embodiments, the suitable temperature is 25±10° Celsius. In some embodiments, the suitable temperature is 25±5° Celsius. In some embodiments, the suitable quantity of time is about 30 minutes to about 72 hours. In some embodiments, the suitable quantity of time is about 2 hours to about 48 hours. In some embodiments, the suitable quantity of time is about 4 hours to about 24 hours. In some embodiments, the suitable quantity of time is about 8 hours to about 24 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.

[0286] In some embodiments, the process further comprises contacting the concentrated reaction mixture of step (1) with a second suitable solvent.

[0287] In some embodiments, the suitable solvent in step (2) is the same as the suitable solvent in step (1). In some embodiments, the suitable solvent in step (2) is different from the suitable solvent in step (1).

[0288] In some embodiments, the suitable solvent in step (2) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable solvent in step (2) is methanol. In some embodiments, the suitable solvent in step (2) is isopropanol. In some embodiments, the suitable solvent in step (2) is diethyl ether. In some embodiments, the suitable solvent in step (2) is 1,4-di oxane.WSGR Docket No. 59318-727.601

[0289] In some embodiments, the suitable base in step (2) is an amine, hydroxide, alkoxide, or carbonate base. In some embodiments, the suitable base in step (2) is a carbonate base. In some embodiments, the suitable base in step (2) is an amine base. In some embodiments, the suitable base in step (2) is triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium 2-methylbutan-2-olate, sodium trimethylsilanolate, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, l,8-diazabicyclo[5.4.0]undec-7-ene, DABCO, lithium diisopropyl ami de, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide or a combination thereof. In some embodiments, the suitable base in step (2) is triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, sodium 2-methylbutan-2-olate, sodium trimethyl silanolate, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium phosphate, l,8-diazabicyclo[5.4.0]undec-7-ene, DABCO, or a combination thereof. In some embodiments, the suitable base in step (2) is triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, l,8-diazabicyclo[5.4.0]undec-7-ene, DABCO, or a combination thereof. In some embodiments, the suitable base in step (2) is triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, DABCO, or a combination thereof. In some embodiments, the suitable base in step (2) is triethylamine or diisopropylethylamine. In some embodiments, the suitable base in step (2) is diisopropylethylamine.

[0290] In some embodiments, there is a molar excess of the suitable base in step (2) with respect to the compound of Formula B. In some embodiments, at least 1.0, 2.0, 5.0, 10.0, 15.0, 20.0, or 50.0 molar equivalents of the suitable base in step (2) with respect to the compound of Formula B are used. In some embodiments, from about 1.0 to about 10.0 molar equivalents of the suitable base in step (2) with respect to the compound of Formula B are used. In some embodiments, from about 2.0 to about 8.0 molar equivalents of the suitable base in step (2) with respect to the compound of Formula B are used. In some embodiments, from about 4.0 to about 6.0 molar equivalents of the suitable base in step (2) with respect to the compound of Formula B are used. In some embodiments, about 5.0 molar equivalents of the suitable base in step (2) with respect to the compound of Formula B are used.WSGR Docket No. 59318-727.601

[0291] In some embodiments, step (2) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (2) further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about 0° Celsius to about 150° Celsius. In some embodiments, the suitable temperature is about 20° Celsius to about 101° Celsius. In some embodiments, the suitable temperature is about 40° Celsius to about 101° Celsius. In some embodiments, the suitable temperature is about 60° Celsius to about 101° Celsius. In some embodiments, the suitable temperature is about 80° Celsius to about 101° Celsius. In some embodiments, the suitable temperature is 90±20° Celsius. In some embodiments, the suitable temperature is 90±10° Celsius. In some embodiments, the suitable temperature is 90±5° Celsius. In some embodiments, the suitable quantity of time is about 10 minutes to about 48 hours. In some embodiments, the suitable quantity of time is about 30 minutes to about 24 hours. In some embodiments, the suitable quantity of time is about 30 minutes to about 12 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 6 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 4 hours. In some embodiments, the suitable quantity of time is about 2 hours to about 3 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.Synthesis of Formula B from Formula DProcedure(3)+(4)Formula D Formula B

[0292] Disclosed herein are methods for the synthesis of compounds of Formula B.

[0293] As disclosed herein, a compound of Formula B is prepared from a compound of Formula D by:(3) contacting a compound of Formula D:Formula D;WSGR Docket No. 59318-727.601wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (4) contacting the reaction mixture of step (3) with a suitable methylating agent;to provide a compound of Formula B.

[0294] In some embodiments, X is a second leaving group which is a halogen or sulfonate leaving group. In some embodiments, Y is a first leaving group which is a halogen or sulfonate leaving group. In some embodiments, X is a second leaving group which is a halogen; and Y is a first leaving group which is a halogen. In some embodiments, X is Cl; and Y is F.

[0295] In some embodiments the suitable reducing agent in step (3) is a hydride reducing agent. In some embodiments, the suitable reducing agent in step (3) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, BH3, BFF'THF, BFF'DMS, sodium cyanoborohydride, zirconocene chloride hydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (3) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, lithium borohydride, sodium borohydride, potassium borohydride, diisobutylaluminum hydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (3) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (3) is lithium tri-sec-butylborohydride, lithium triethylborohydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (3) is lithium tri-sec-butylborohydride.

[0296] In some embodiments the suitable reducing agent in step (3) is an alcohol. In some embodiments, the suitable reducing agent in step (3) is isopropanol. In some embodiments, the alcohol serves as a reducing agent in the presence of a transfer hydrogenation catalyst.

[0297] In some embodiments, the suitable reducing agent in step (3) is dissolved in a suitable solvent. In some embodiments, the suitable reducing agent in step (3) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In someWSGR Docket No. 59318-727.601embodiments, the suitable reducing agent in step (3) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable reducing agent in step (3) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a combination thereof. In some embodiments, the suitable reducing agent in step (3) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable reducing agent in step (3) is dissolved in tetrahydrofuran. In some embodiments, the suitable reducing agent in step (3) is dissolved in 2-methyl tetrahydrofuran.

[0298] In some embodiments, at least 0.25, 1.0, 2.0, or 5.0 molar equivalents of the suitable reducing agent in step (3) with respect to the compound of Formula D are used. In some embodiments, from about 1.0 to about 2.0 molar equivalents of the suitable reducing agent in step (3) with respect to the compound of Formula D are used. In some embodiments, from about 1.4 to about 1.8 molar equivalents of the suitable reducing agent in step (3) with respect to the compound of Formula D are used. In some embodiments, the concentration of the suitable reducing agent in step (3) in the suitable solvent is about 0.25 N to about 4.0 N. In some embodiments, the concentration of the suitable reducing agent in step (3) in the suitable solvent is about 0.5 N to about 2.0 N. In some embodiments, the concentration of the suitable reducing agent in step (3) in the suitable solvent is about 1.0 N. In some embodiments, the concentration of the suitable reducing agent in step (3) in tetrahydrofuran, 2-methyl tetrahydrofuran, or a mixture thereof, is about 1.0 N.

[0299] In some embodiments, the suitable solvent in step (3) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable solvent in step (3) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable solvent in step (3) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a combination thereof. In some embodiments, the suitable solvent in step (3) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent in step (3) is tetrahydrofuran. In some embodiments, the suitable solvent in step (3) is 2-methyl tetrahydrofuran.WSGR Docket No. 59318-727.601

[0300] In some embodiments, the suitable methylating agent in step (4) is selected from methyl iodide, methyl bromide, methyl mesylate, methyl tritiate, or dimethyl sulfate. In some embodiments, the suitable methylating agent in step (4) is selected from methyl iodide, methyl bromide, or dimethyl sulfate. In some embodiments, the suitable methylating agent in step (4) is selected from methyl iodide or methyl bromide. In some embodiments, the suitable methylating agent in step (4) is methyl iodide.

[0301] In some embodiments, there is a molar excess of the suitable methylating agent in step (4) with respect to the compound of Formula D. In some embodiments, at least 1.0, 2.0, 5.0, 10.0, 15.0, or 20.0 molar equivalents of the suitable methylating agent in step (4) with respect to the compound of Formula D are used. In some embodiments, from about 1.0 to about 5.0 molar equivalents of the suitable methylating agent in step (4) with respect to the compound of Formula D are used. In some embodiments, from about 1.0 to about 3.0 molar equivalents of the suitable methylating agent in step (4) with respect to the compound of Formula D are used. In some embodiments, from about 1.0 to about 2.0 molar equivalents of the suitable methylating agent in step (4) with respect to the compound of Formula D are used. In some embodiments, from about 1.4 to about 1.8 molar equivalents of the suitable methylating agent in step (4) with respect to the compound of Formula D are used. In some embodiments, about 1.6 molar equivalents of the suitable methylating agent in step (4) with respect to the compound of Formula D are used.

[0302] In some embodiments, step (3) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (3) further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about -30° Celsius to about 30° Celsius. In some embodiments, the suitable temperature is about -20° Celsius to about 20° Celsius. In some embodiments, the suitable temperature is about -15° Celsius to about 15° Celsius. In some embodiments, the suitable temperature is about -10° Celsius to about 10° Celsius. In some embodiments, the suitable temperature is 0±20° Celsius. In some embodiments, the suitable temperature is 0±10° Celsius. In some embodiments, the suitable temperature is 0±5° Celsius. In some embodiments, the suitable quantity of time is about 10 minutes to about 24 hours. In some embodiments, the suitable quantity of time is about 30 minutes to about 12 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 4 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 3 hours. In some embodiments, the suitable quantity of time is about 2 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.WSGR Docket No. 59318-727.601

[0303] In some embodiments, step (4) further comprises maintaining the reaction mixture at a first suitable temperature for a first suitable time followed by maintaining the reaction at a second suitable temperature for a second suitable time. In some embodiments, the first suitable temperature is about -30° Celsius to about 30° Celsius. In some embodiments, the first suitable temperature is about -20° Celsius to about 20° Celsius. In some embodiments, the first suitable temperature is about -10° Celsius to about 10° Celsius. In some embodiments, the first suitable temperature is about -10° Celsius to about 5° Celsius. In some embodiments, the first suitable quantity of time is about 10 minutes to about 8 hours. In some embodiments, the first suitable quantity of time is about 30 minutes to about 4 hours. In some embodiments, the first suitable quantity of time is about 1 hour to about 3 hours. In some embodiments, the first suitable quantity of time is about 2 hours. In some embodiments, the second suitable temperature is about 0° Celsius to about 60° Celsius. In some embodiments, the second suitable temperature is about 10° Celsius to about 50° Celsius. In some embodiments, the second suitable temperature is about 10° Celsius to about 40° Celsius. In some embodiments, the second suitable temperature is about 15° Celsius to about 30° Celsius. In some embodiments, the second suitable quantity of time is about 2 hours to about 72 hours. In some embodiments, the second suitable quantity of time is about 8 hours to about 48 hours. In some embodiments, the second suitable quantity of time is about 12 hours to about 24 hours. In some embodiments, the second suitable quantity of time is about 16 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.

[0304] In some embodiments, the reaction mixture of step (4) is quenched with sodium hydroxide. In some embodiments, the reaction mixture of step (4) is treated with hydrogen peroxide. In some embodiments, the reaction mixture of step (4) is treated with sodium thiosulfate.Synthesis of Formula D from Formula EFormula E Formula D

[0305] Disclosed herein are methods for the synthesis of compounds of Formula D.WSGR Docket No. 59318-727.601

[0306] As disclosed herein, a compound of Formula D is prepared from a compound of Formula E by:(7) contacting a compound of Formula E:N-NZ( IN XFormula E;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with (A)-tert-butylsulfinamide and a suitable solvent to provide a compound of Formula D

[0307] In some embodiments, X is a second leaving group which is a halogen or sulfonate leaving group. In some embodiments, Y is a first leaving group which is a halogen or sulfonate leaving group. In some embodiments, X is a second leaving group which is a halogen; and Y is a first leaving group which is a halogen. In some embodiments, X is Cl; and Y is F.

[0308] In some embodiments, at least 1.0, 2.0, or 5.0 molar equivalents of (A)-tert-butylsulfinamide in step (7) with respect to the compound of Formula E are used. In some embodiments, from about 1.0 to about 2.0 molar equivalents of (A)-tert-butylsulfinamide in step (7) with respect to the compound of Formula E are used. In some embodiments, from about 1.0 to about 1.5 molar equivalents of (A)-tert-butylsulfinamide in step (7) with respect to the compound of Formula E are used. In some embodiments, from about 1.1 to about 1.3 molar equivalents of (A)-tert-butylsulfinamide in step (7) with respect to the compound of Formula E are used. In some embodiments, about 1.2 molar equivalents of (A)-tert-butylsulfinamide in step (7) with respect to the compound of Formula E are used.

[0309] In some embodiments, the suitable solvent in step (7) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, di chloromethane, heptane, hexane, pentane, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (7) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, glyme, diglyme, tri ethylene glycol dimethyl ether,di chloromethane, heptane, hexane, pentane, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (7) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, glyme, diglyme, tri ethylene glycol dimethyl ether, heptane, hexane, pentane, toluene, or a combination thereof. In some embodiments, the suitable solventWSGR Docket No. 59318-727.601in step (7) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, glyme, diglyme, triethylene glycol dimethyl ether, or a combination thereof. In some embodiments, the suitable solvent in step (7) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, or a combination thereof. In some embodiments, the suitable solvent in step (7) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent in step (7) is tetrahydrofuran.

[0310] In some embodiments, the process of step (7) further comprises contacting the compound of Formula E with a suitable desiccant. In some embodiments, the suitable desiccant is selected from titanium(IV) isopropoxide, titanium(IV) ethoxide, titanium(IV) butoxide, TiCl(OiPr)3, titanium (IV) chloride, zirconium (IV) tert-butoxide, triisopropyl borate, or a combination thereof. In some embodiments, the suitable desiccant is selected from titanium(IV) isopropoxide, titanium(IV) ethoxide, titanium(IV) butoxide, titanium (IV) chloride, or a combination thereof. In some embodiments, the suitable desiccant is selected from titanium(IV) isopropoxide, titanium(IV) ethoxide, titanium(IV) butoxide, or a combination thereof. In some embodiments, the suitable desiccant is selected from titanium(IV) isopropoxide, titanium(IV) ethoxide, or a combination thereof. In some embodiments, the suitable desiccant is selected from titanium(IV) isopropoxide.

[0311] In some embodiments, at least 1.0, 2.0, 5.0, 10.0, 15.0, or 20.0 molar equivalents of the suitable desiccant in step (7) with respect to the compound of Formula E are used. In some embodiments, from about 1.0 to about 10.0 molar equivalents of the suitable desiccant in step (7) with respect to the compound of Formula E are used. In some embodiments, from about 2.0 to about 8.0 molar equivalents of the suitable desiccant in step (7) with respect to the compound of Formula E are used. In some embodiments, from about 3.0 to about 5.0 molar equivalents of the suitable desiccant in step (7) with respect to the compound of Formula E are used. In some embodiments, about 4.0 molar equivalents of the suitable desiccant in step (7) with respect to the compound of Formula E are used.

[0312] In some embodiments, step (7) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (7) further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about 25° Celsius to about 150° Celsius. In some embodiments, the suitable temperature is about 30° Celsius to about 110° Celsius. In some embodiments, the suitable temperature is about 40° Celsius to about 100° Celsius. In some embodiments, the suitable temperature is about 60° Celsius to about 90° Celsius. In some embodiments, the suitable temperature is about 70° Celsius to about 80° Celsius. In some embodiments, the suitable temperature is 75±20° Celsius. In some embodiments, the suitable temperature isWSGR Docket No. 59318-727.60175±10° Celsius. In some embodiments, the suitable temperature is 75±5° Celsius. In some embodiments, the suitable quantity of time is about 6 hours to about 1 week. In some embodiments, the suitable quantity of time is about 12 hours to about 96 hours. In some embodiments, the suitable quantity of time is about 18 hours to about 72 hours. In some embodiments, the suitable quantity of time is about 24 hours to about 72 hours. In some embodiments, the suitable quantity of time is about 36 hours to about 60 hours. In some embodiments, the suitable quantity of time is about 48 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.Synthesis of Formula E from Formula 2 and Formula 3N-N7Formula 2 Formula 3 Formula E

[0313] As disclosed herein, a compound of Formula E is prepared from a compound of Formula 2 by:(8) contacting a compound of Formula 2:OFormula 2;with a compound of Formula 3:[M]Formula 3;wherein [M] is a suitable metal or metalloid group;X is a second suitable leaving group; andY is a first suitable leaving group;and a first suitable palladium catalyst, a first suitable ligand, and a suitable solvent to provide a compound of Formula E.

[0314] In some embodiments, X is a second leaving group which is a halogen or sulfonate leaving group. In some embodiments, Y is a first leaving group which is a halogen or sulfonateWSGR Docket No. 59318-727.601leaving group. In some embodiments, X is a second leaving group which is a halogen; and Y is a first leaving group which is a halogen. In some embodiments, X is Cl; and Y is F.

[0315] In some embodiments, the suitable metal or metalloid group in step (8) is an organoboron or organotin reagent. In some embodiments, the suitable metal or metalloid group in step (8) is a boronic acid, boronic ester, boronate salt, or trifluoroborate. In some embodiments, the suitable metal or metalloid group in step (8) is a boronic acid, boronic ester, or trifluoroborate. In some embodiments, the suitable metal or metalloid group in step (8) isselected from:O0, or . In some embodiments, the suitable metal or metalloid group in step (8) is -BF3K or -B(OH)2. In some embodiments, the suitable metal or metalloid group in step (8) is -B(OH)2.

[0316] In some embodiments the first suitable palladium catalyst in step (8) is Pd(PPhs)4, Pd(dba)2or Pd2(dba)3. In some embodiments the first suitable palladium catalyst in step (8) is Pd(dba)2or Pd2(dba)3. In some embodiments the first suitable palladium catalyst in step (8) is Pd2(dba)3.

[0317] In some embodiments, the first suitable ligand in step (8) is a phosphine, N-heterocyclic carbene, or a salt thereof. In some embodiments, the first suitable ligand in step (8) is a phosphine or a salt thereof. In some embodiments, the first suitable ligand in step (8) is a trialkyl phosphine or a salt thereof. In some embodiments, the first suitable ligand in step (8) is a tri -tert-butyl phosphine, tri-adamantyl phosphine, di(l-adamantyl)-n-butylphosphine, di(l-adamantyl)-benzylphosphine, or a salt thereof. In some embodiments, the first suitable ligand in step (8) is tri-tert-butyl phosphine or a salt thereof. In some embodiments, the first suitable ligand in step (8) is [( / -Bu)3PH]BF4.

[0318] In some embodiments, the palladium catalyst and ligand are pre-complexed prior to addition to the reaction mixture.

[0319] In some embodiments, the suitable solvent in step (8) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol,WSGR Docket No. 59318-727.601DMF, DMSO, DMA, NMP, dichloromethane, acetonitrile, heptane, hexane, pentane, toluene, xylene, or a combination thereof. In some embodiments, the suitable solvent in step (8) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2, 2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, toluene, xylene, or a combination thereof. In some embodiments, the suitable solvent in step (8) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-dioxane, glyme, diglyme, triethylene glycol dimethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, toluene, xylene, or a combination thereof. In some embodiments, the suitable solvent in step (8) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-dioxane, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, or a combination thereof. In some embodiments, the suitable solvent in step (8) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, water, methanol, ethanol, isopropanol, or a combination thereof. In some embodiments, the suitable solvent in step (8) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, water, or a combination thereof. In some embodiments, the suitable solvent in step (8) is tetrahydrofuran, water, or a combination thereof. In some embodiments, the suitable solvent in step (8) is a mixture of tetrahydrofuran and water in a ratio of about 1 : 1 to about 100: 1. In some embodiments, the suitable solvent in step (8) is a mixture of tetrahydrofuran and water in a ratio of about 2:1 to about 25:1. In some embodiments, the suitable solvent in step (8) is a mixture of tetrahydrofuran and water in a ratio of about 10:1.

[0320] In some embodiments, step (8) further comprises contacting the compound of Formula 2 and compound of Formula 3 with a suitable base. In some embodiments, the suitable base is a fluoride salt, a carbonate base, an alkoxide base, a hydroxide base, or an amine. In some embodiments, the suitable base is a fluoride salt. In some embodiments, the suitable base is sodium fluoride, potassium fluoride, or cesium fluoride. In some embodiments, the suitable base is potassium fluoride or cesium fluoride. In some embodiments, the suitable base is potassium fluoride.

[0321] In some embodiments, step (8) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (8) further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about 30° Celsius to about 100° Celsius. In some embodiments, the suitable temperature is about 40° Celsius to about 80° Celsius. In some embodiments, the suitable temperature is about 50° Celsius to about 60° Celsius. In some embodiments, the suitable quantity of time is about 30 minutes to about 12 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 6 hours. In some embodiments, the suitableWSGR Docket No. 59318-727.601quantity of time is about 2 hours to about 3 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.Synthesis of Formula 2 from Formula 1OBr. Br Procedureo) +(io)N„ ,N - NFormula 1 Formula 2

[0322] Disclosed herein are methods for the synthesis of compounds of Formula 2.

[0323] As disclosed herein, a compound of Formula 2 is prepared from a compound of Formula 1 by:(9) contacting a compound of Formula 1:Formula 1;with a suitable metal-halogen exchange reagent and a suitable solvent to provide a reaction mixture; and(10) contacting the reaction mixture of step (9) with N, 7V-di methyl acetamide; to provide a compound of Formula 2.

[0324] In some embodiments, the suitable metal-halogen exchange reagent in step (9) is an organolithium reagent or a Grignard reagent. In some embodiments, the suitable metal-halogen exchange reagent in step (9) is an organolithium reagent. In some embodiments, the suitable metal-halogen exchange reagent in step (9) is a Grignard reagent. In some embodiments, the suitable metal-halogen exchange reagent in step (9) is methyllithium, ethyllithium, isopropyllithium, n-propyllithium n-butyllithium, pentyllithium, n-hexyllithium, tertbutyllithium, phenyllithium, phenyl magnesium chloride, phenyl magnesium bromide, methyl magnesium chloride, methyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, iPrBu2MgLi, or BusMgLi. In some embodiments, the suitable metal-halogen exchange reagent in step (9) is n-butyllithium, n-hexyllithium, tert-butyllithium, methyl magnesium chloride, methyl magnesium bromide, isopropyl magnesium chloride, or isopropyl magnesium bromide. In some embodiments, the suitable metal-halogen exchange reagent in step (9) is n-butyllithium, n-hexyllithium, tert-butyllithium, isopropyl magnesium chloride, or isopropyl magnesium bromide. In some embodiments, the suitable metal-halogen exchangeWSGR Docket No. 59318-727.601reagent in step (9) is n-butyllithium, n-hexyllithium, or isopropyl magnesium chloride. In some embodiments, the suitable metal-halogen exchange reagent in step (9) is n-butyllithium, n-hexyllithium, isopropyl magnesium chloride, or isopropyl magnesium bromide. In some embodiments, the suitable metal-halogen exchange reagent in step (9) is n-butyllithium or n-hexyllithium. In some embodiments, the suitable metal-halogen exchange reagent in step (9) is n-butyllithium. In some embodiments, the suitable metal-halogen exchange reagent in step (9) is a solution of n-butyllithium in hexanes.

[0325] In some embodiments, the suitable solvent in step (9) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, pentane, hexanes, or a mixture thereof. In some embodiments, the suitable solvent in step (9) is tetrahydrofuran, hexanes, or a mixture thereof.Synthesis of Formula C from Formula DFormula D Formula C

[0326] Disclosed herein are methods for the synthesis of compounds of Formula C.

[0327] As disclosed herein, a compound of Formula C is prepared from a compound of Formula D by:(6) contacting a compound of Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable reducing agent and a suitable solventto provide a compound of Formula C.

[0328] In some embodiments, X is a second leaving group which is a halogen or sulfonate leaving group. In some embodiments, Y is a first leaving group which is a halogen or sulfonateWSGR Docket No. 59318-727.601leaving group. In some embodiments, X is a second leaving group which is a halogen; and Y is a first leaving group which is a halogen. In some embodiments, X is Cl; and Y is F.

[0329] In some embodiments the suitable reducing agent in step (6) is a hydride reducing agent. In some embodiments, the suitable reducing agent in step (6) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, BH3, BHs'THF, BHs'DMS, sodium cyanoborohydride, zirconocene chloride hydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (6) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, lithium borohydride, sodium borohydride, potassium borohydride, diisobutylaluminum hydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (6) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (6) is lithium tri-sec-butylborohydride, lithium triethylborohydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (6) is lithium tri-sec-butylborohydride.

[0330] In some embodiments the suitable reducing agent in step (6) is an alcohol. In some embodiments, the suitable reducing agent in step (6) is isopropanol. In some embodiments, the alcohol serves as a reducing agent in the presence of a transfer hydrogenation catalyst.

[0331] In some embodiments, the suitable reducing agent in step (6) is dissolved in a suitable solvent. In some embodiments, the suitable reducing agent in step (6) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable reducing agent in step (6) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable reducing agent in step (6) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a combination thereof. In some embodiments, the suitable reducing agent in step (6) is dissolved in a suitable solvent selected fromWSGR Docket No. 59318-727.601tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable reducing agent in step (6) is dissolved in tetrahydrofuran. In some embodiments, the suitable reducing agent in step (6) is dissolved in 2-methyl tetrahydrofuran.

[0332] In some embodiments, at least 0.25, 1.0, 2.0, or 5.0 molar equivalents of the suitable reducing agent in step (6) with respect to the compound of Formula D are used. In some embodiments, from about 1.0 to about 2.0 molar equivalents of the suitable reducing agent in step (6) with respect to the compound of Formula D are used. In some embodiments, from about 1.4 to about 1.8 molar equivalents of the suitable reducing agent in step (6) with respect to the compound of Formula D are used. In some embodiments, the concentration of the suitable reducing agent in step (6) in the suitable solvent is about 0.25 N to about 4.0 N. In some embodiments, the concentration of the suitable reducing agent in step (6) in the suitable solvent is about 0.5 N to about 2.0 N. In some embodiments, the concentration of the suitable reducing agent in step (6) in the suitable solvent is about 1.0 N. In some embodiments, the concentration of the suitable reducing agent in step (6) in tetrahydrofuran, 2-methyl tetrahydrofuran, or a mixture thereof, is about 1.0 N.

[0333] In some embodiments, the suitable solvent in step (6) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable solvent in step (6) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable solvent in step (6) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a combination thereof. In some embodiments, the suitable solvent in step (6) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent in step (6) is tetrahydrofuran. In some embodiments, the suitable solvent in step (6) is 2-methyl tetrahydrofuran.WSGR Docket No. 59318-727.601Synthesis of Formula B from Formula CFormula C Formula B

[0334] Disclosed herein are methods for the synthesis of compounds of Formula B.

[0335] As disclosed herein, a compound of Formula B is prepared from a compound of Formula C by:(5) contacting a compound of Formula C:Formula C;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable methylating agent, a suitable base, and a suitable solvent to provide a compound of Formula B.

[0336] In some embodiments, X is a second leaving group which is a halogen or sulfonate leaving group. In some embodiments, Y is a first leaving group which is a halogen or sulfonate leaving group. In some embodiments, X is a second leaving group which is a halogen; and Y is a first leaving group which is a halogen. In some embodiments, X is Cl; and Y is F.

[0337] In some embodiments, the suitable methylating agent in step (5) is selected from methyl iodide, methyl bromide, methyl mesylate, methyl tritiate, or dimethyl sulfate. In some embodiments, the suitable methylating agent in step (5) is methyl iodide, methyl bromide, methyl mesylate, or dimethyl sulfate. In some embodiments, the suitable methylating agent in step (5) is selected from methyl iodide, methyl bromide, or dimethyl sulfate. In some embodiments, the suitable methylating agent in step (5) is selected from methyl iodide or methyl bromide. In some embodiments, the suitable methylating agent in step (5) is methyl iodide.

[0338] In some embodiments, there is a molar excess of the suitable methylating agent in step (5) with respect to the compound of Formula C. In some embodiments, at least 1.0, 2.0, 5.0,WSGR Docket No. 59318-727.60110.0, 15.0, or 20.0 molar equivalents of the suitable methylating agent in step (5) with respect to the compound of Formula C are used. In some embodiments, from about 1.0 to about 5.0 molar equivalents of the suitable methylating agent in step (5) with respect to the compound of Formula C are used. In some embodiments, from about 1.0 to about 3.0 molar equivalents of the suitable methylating agent in step (5) with respect to the compound of Formula C are used. In some embodiments, from about 1.0 to about 2.0 molar equivalents of the suitable methylating agent in step (5) with respect to the compound of Formula C are used. In some embodiments, from about 1.4 to about 1.8 molar equivalents of the suitable methylating agent in step (5) with respect to the compound of Formula C are used. In some embodiments, about 1.6 molar equivalents of the suitable methylating agent in step (5) with respect to the compound of Formula C are used.

[0339] In some embodiments, the suitable base in step (5) is an amine, hydroxide, alkoxide, carbonate, amide, or hydride base. In some embodiments, the suitable base in step (5) is tri ethylamine, diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, DABCO, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium 2-methylbutan-2-olate, sodium trimethylsilanolate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (5) is a carbonate, amide, or hydride base. In some embodiments, the suitable base in step (5) is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (5) is an amide or hydride base. In some embodiments, the suitable base in step (5) is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (5) is an amide base. In some embodiments, the suitable base in step (5) is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or a combination thereof. In some embodiments, the suitable base in step (5) is a hydride base. In some embodiments, the suitable base in step (5) is lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (5) is sodium hydride. In some embodiments, the suitable base in step (5) isWSGR Docket No. 59318-727.601sodium hydride, potassium carbonate, or sodium carbonate. In some embodiments, the suitable base in step (5) is sodium hydride.

[0340] In some embodiments, the suitable solvent in step (5) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, DMF, DMSO, DMA, NMP, di chloromethane, acetonitrile, or a combination thereof. In some embodiments, the suitable solvent in step (5) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, DMF, DMSO, DMA, NMP, di chloromethane, acetonitrile, or a combination thereof. In some embodiments, the suitable solvent in step (5) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable solvent in step (5) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable solvent in step (5) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, DMF, or a combination thereof. In some embodiments, the suitable solvent in step (5) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, or a combination thereof. In some embodiments, the suitable solvent in step (5) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent in step (5) is tetrahydrofuran. In some embodiments, the suitable solvent in step (5) is 2-methyl tetrahydrofuran. In some embodiments, the suitable solvent in step (5) is tetrahydrofuran, DMF, or a mixture thereof.Synthesis of Formula B from Formula F and Formula 3Formula F Formula 3 Formula B

[0341] Disclosed herein are methods for the synthesis of compounds of Formula B.

[0342] As disclosed herein, a compound of Formula B is prepared from a compound of Formula F by:WSGR Docket No. 59318-727.601(11) contacting a compound of Formula F:Formula F;wherein Z is a third suitable leaving group;with a compound of Formula 3:[M]Formula 3;wherein [M] is a suitable metal or metalloid group;X is a second suitable leaving group; andY is a first suitable leaving group;and a second suitable palladium catalyst, a second suitable ligand, and a suitable solvent to provide a compound of Formula B.

[0343] In some embodiments, X is a second leaving group which is a halogen or sulfonate leaving group. In some embodiments, Y is a first leaving group which is a halogen or sulfonate leaving group. In some embodiments, X is a second leaving group which is a halogen; and Y is a first leaving group which is a halogen. In some embodiments, X is Cl; and Y is F.

[0344] In some embodiments, Z is a third leaving group which is a halogen. In some embodiments, Z is a third leaving group selected from the group consisting of Cl, Br, and I. In some embodiments, Z is a third leaving group selected from the group consisting of Br, and I. In some embodiments, Z is Br.

[0345] In some embodiments, the suitable metal or metalloid group in step (11) is an organoboron or organotin reagent. In some embodiments, the suitable metal or metalloid group in step (11) is a boronic acid, boronic ester, boronate salt, or trifluoroborate. In some embodiments, the suitable metal or metalloid group in step (11) is a boronic acid, boronic ester, or trifluorob orate. In some embodiments, the suitable metal or metalloid group in step (11) isOHselected from:WSGR Docket No. 59318-727.601oJ \O YBF3’K0•, or . In some embodiments, the suitable metal or metalloid group in step (11) is -BF3K or -B(0H)2. In some embodiments, the suitable metal or metalloid group in step (11) is -B(OH)2.

[0346] In some embodiments the second suitable palladium catalyst in step (11) is Pd(PPhs)4, Pd(dba)2, or Pd2(dba)3. In some embodiments the second suitable palladium catalyst in step (11) is Pd(dba)2or Pd2(dba)3. In some embodiments the second suitable palladium catalyst in step (11) is Pd2(dba)3.

[0347] In some embodiments, the second suitable ligand in step (11) is a phosphine, N-heterocyclic carbene, or a salt thereof. In some embodiments, the second suitable ligand in step (11) is a phosphine or a salt thereof. In some embodiments, the second suitable ligand in step (11) is a trialkyl phosphine or a salt thereof. In some embodiments, the second suitable ligand in step (11) is a tri- / c / 7-butyl phosphine, tri-adamantyl phosphine, di(l-adamantyl)-n-butylphosphine, di(l-adamantyl)-benzylphosphine, or a salt thereof. In some embodiments, the second suitable ligand in step (11) is tri -tert-butyl phosphine or a salt thereof. In some embodiments, the second suitable ligand in step (11) is [( / -Bu)3PH]BF4.

[0348] In some embodiments, the palladium catalyst and ligand are pre-complexed prior to addition to the reaction mixture.

[0349] In some embodiments, the suitable solvent in step (11) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, DMSO, DMA, NMP, di chloromethane, acetonitrile, heptane, hexane, pentane, toluene, xylene, or a combination thereof. In some embodiments, the suitable solvent in step (11) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, toluene, xylene, or a combination thereof. In some embodiments, the suitable solvent in step (11) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, glyme, diglyme, triethylene glycol dimethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, toluene, xylene, or a combination thereof. In some embodiments, the suitable solvent in step (11) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, or aWSGR Docket No. 59318-727.601combination thereof. In some embodiments, the suitable solvent in step (11) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, water, methanol, ethanol, isopropanol, or a combination thereof. In some embodiments, the suitable solvent in step (11) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, water, or a combination thereof. In some embodiments, the suitable solvent in step (11) is tetrahydrofuran, water, or a combination thereof. In some embodiments, the suitable solvent in step (11) is a mixture of tetrahydrofuran and water in a ratio of about 1 : 1 to about 100: 1. In some embodiments, the suitable solvent in step (11) is a mixture of tetrahydrofuran and water in a ratio of about 2: 1 to about 25 : 1. In some embodiments, the suitable solvent in step (11) is a mixture of tetrahydrofuran and water in a ratio of about 10:1.

[0350] In some embodiments, step (11) further comprises contacting the compound of Formula F and the compound of Formula 3 with a suitable base. In some embodiments, the suitable base is a fluoride salt, a carbonate base, an alkoxide base, a hydroxide base, or an amine. In some embodiments, the suitable base is a fluoride salt. In some embodiments, the suitable base is sodium fluoride, potassium fluoride, or cesium fluoride. In some embodiments, the suitable base is potassium fluoride or cesium fluoride. In some embodiments, the suitable base is cesium fluoride. In some embodiments, the suitable base is potassium fluoride.

[0351] In some embodiments, step (11) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (11) further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about 20° Celsius to about 100° Celsius. In some embodiments, the suitable temperature is about 30° Celsius to about 80° Celsius. In some embodiments, the suitable temperature is about 40° Celsius to about 60° Celsius. In some embodiments, the suitable temperature is about 45° Celsius to about 50° Celsius. In some embodiments, the suitable quantity of time is about 1 hour to about 24 hours. In some embodiments, the suitable quantity of time is about 2 hours to about 24 hours. In some embodiments, the suitable quantity of time is about 4 hours to about 12 hours. In some embodiments, the suitable quantity of time is about 7 hours to about 8 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.WSGR Docket No. 59318-727.601Synthesis of Formula F from Formula GProcedure(12)Formula G Formula F

[0352] Disclosed herein are methods for the synthesis of compounds of Formula F.

[0353] As disclosed herein, a compound of Formula F is prepared from a compound of Formula Gby:(12) contacting a compound of Formula G:Formula G;wherein Z is a third suitable leaving group; andwith a suitable methylating agent, a suitable base, and a suitable solvent to provide a compound of Formula F.

[0354] In some embodiments, Z is a third leaving group which is a halogen. In some embodiments, Z is a third leaving group selected from the group consisting of Cl, Br, and I. In some embodiments, Z is a third leaving group selected from the group consisting of Br, and I. In some embodiments, Z is Br.

[0355] In some embodiments, the suitable methylating agent in step (12) is selected from methyl iodide, methyl bromide, methyl mesylate, methyl tritiate, or dimethyl sulfate. In some embodiments, the suitable methylating agent in step (12) is methyl iodide, methyl bromide, methyl mesylate, or dimethyl sulfate. In some embodiments, the suitable methylating agent in step (12) is selected from methyl iodide, methyl bromide, or dimethyl sulfate. In some embodiments, the suitable methylating agent in step (12) is selected from methyl iodide or methyl bromide. In some embodiments, the suitable methylating agent in step (12) is methyl iodide.

[0356] In some embodiments, there is a molar excess of the suitable methylating agent in step (12) with respect to the compound of Formula G. In some embodiments, at least 1.0, 2.0, 5.0, 10.0, 15.0, or 20.0 molar equivalents of the suitable methylating agent in step (12) with respect to the compound of Formula G are used. In some embodiments, from about 1.0 to about 5.0 molar equivalents of the suitable methylating agent in step (12) with respect to the compound ofWSGR Docket No. 59318-727.601Formula G are used. In some embodiments, from about 1.0 to about 3.0 molar equivalents of the suitable methylating agent in step (12) with respect to the compound of Formula G are used. In some embodiments, from about 1.0 to about 2.0 molar equivalents of the suitable methylating agent in step (12) with respect to the compound of Formula G are used. In some embodiments, from about 1.3 to about 1.7 molar equivalents of the suitable methylating agent in step (12) with respect to the compound of Formula G are used. In some embodiments, about 1.5 molar equivalents of the suitable methylating agent in step (12) with respect to the compound of Formula G are used.

[0357] In some embodiments, the suitable base in step (12) is an amine, hydroxide, alkoxide, carbonate, amide, or hydride base. In some embodiments, the suitable base in step (12) is tri ethylamine, diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, DABCO, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium 2-methylbutan-2-olate, sodium trimethylsilanolate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (12) is a carbonate, amide, or hydride base. In some embodiments, the suitable base in step (12) is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (12) is an amide or hydride base. In some embodiments, the suitable base in step (12) is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (12) is an amide base. In some embodiments, the suitable base in step (12) is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or a combination thereof. In some embodiments, the suitable base in step (12) is a hydride base. In some embodiments, the suitable base in step (12) is lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (12) is sodium hydride. In some embodiments, the suitable base in step (12) is sodium hydride, potassium carbonate, or sodium carbonate. In some embodiments, the suitable base in step (12) is sodium hydride.WSGR Docket No. 59318-727.601

[0358] In some embodiments, the suitable solvent in step (12) is selected from tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, tri ethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, DMF, DMSO, DMA, NMP, dichloromethane, acetonitrile, or a combination thereof. In some embodiments, the suitable solvent in step (12) is selected from tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-di oxane, DMF, DMSO, DMA, NMP, dichloromethane, acetonitrile, or a combination thereof. In some embodiments, the suitable solvent in step (12) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable solvent in step (12) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable solvent in step (12) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, DMF, or a combination thereof. In some embodiments, the suitable solvent in step (12) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, or a combination thereof. In some embodiments, the suitable solvent in step (12) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent in step (12) is tetrahydrofuran. In some embodiments, the suitable solvent in step (12) is 2-methyl tetrahydrofuran. In some embodiments, the suitable solvent in step (12) is tetrahydrofuran, DMF, or a mixture thereof. In some embodiments, the suitable solvent in step (12) is DMF.Synthesis of Formula G from Formula HProcedureFormula H Formula G

[0359] Disclosed herein are methods for the synthesis of compounds of Formula G.

[0360] As disclosed herein, a compound of Formula G is prepared from a compound of Formula H by:(13) contacting a compound of Formula H:WSGR Docket No. 59318-727.601Formula H;wherein Z is a third suitable leaving group;with a suitable reducing agent and a suitable solvent;to provide a compound of Formula G.

[0361] In some embodiments, Z is a third leaving group which is a halogen. In some embodiments, Z is a third leaving group selected from the group consisting of Cl, Br, and I. In some embodiments, Z is a third leaving group selected from the group consisting of Br, and I. In some embodiments, Z is Br.

[0362] In some embodiments the suitable reducing agent in step (13) is a hydride reducing agent. In some embodiments, the suitable reducing agent in step (13) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, BH3, BFF'THF, BFF'DMS, sodium cyanoborohydride, zirconocene chloride hydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (13) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, lithium borohydride, sodium borohydride, potassium borohydride, diisobutylaluminum hydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (13) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (13) is lithium tri-sec-butylborohydride, lithium triethylborohydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (13) is lithium tri-sec-butylborohydride.

[0363] In some embodiments the suitable reducing agent in step (13) is an alcohol. In some embodiments, the suitable reducing agent in step (13) is isopropanol. In some embodiments, the alcohol serves as a reducing agent in the presence of a transfer hydrogenation catalyst.

[0364] In some embodiments, the suitable reducing agent in step (13) is dissolved in a suitable solvent. In some embodiments, the suitable reducing agent in step (13) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methylWSGR Docket No. 59318-727.601tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable reducing agent in step (13) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable reducing agent in step (13) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a combination thereof. In some embodiments, the suitable reducing agent in step (13) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable reducing agent in step (13) is dissolved in tetrahydrofuran. In some embodiments, the suitable reducing agent in step (13) is dissolved in 2-methyl tetrahydrofuran.

[0365] In some embodiments, at least 0.25, 1.0, 2.0, or 5.0 molar equivalents of the suitable reducing agent in step (13) with respect to the compound of Formula H are used. In some embodiments, from about 1.0 to about 2.0 molar equivalents of the suitable reducing agent in step (13) with respect to the compound of Formula H are used. In some embodiments, from about 1.4 to about 1.8 molar equivalents of the suitable reducing agent in step (13) with respect to the compound of Formula H are used. In some embodiments, from about 1.4 to about 1.6 molar equivalents of the suitable reducing agent in step (13) with respect to the compound of Formula H are used. In some embodiments, the concentration of the suitable reducing agent in step (13) in the suitable solvent is about 0.25 N to about 4.0 N. In some embodiments, the concentration of the suitable reducing agent in step (13) in the suitable solvent is about 0.5 N to about 2.0 N. In some embodiments, the concentration of the suitable reducing agent in step (13) in the suitable solvent is about 1.0 N. In some embodiments, the concentration of the suitable reducing agent in step (13) in tetrahydrofuran, 2-methyl tetrahydrofuran, or a mixture thereof, is about 1.0 N.

[0366] In some embodiments, the suitable solvent in step (13) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable solvent in step (13) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. InWSGR Docket No. 59318-727.601some embodiments, the suitable solvent in step (13) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a combination thereof. In some embodiments, the suitable solvent in step (13) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent in step (13) is 2-methyl tetrahydrofuran. In some embodiments, the suitable solvent in step (13) is tetrahydrofuran.Synthesis of Formula F from Formula HProcedure (14)+(15)Formula H

[0367] Disclosed herein are methods for the synthesis of compounds of Formula F.

[0368] As disclosed herein, a compound of Formula F is prepared from a compound of Formula H by:(14) contacting a compound of Formula H:Q-^O / Nl MZFormula H;wherein Z is a third suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (15) contacting the reaction mixture of step (14) with a suitable methylating agent;to provide a compound of Formula F.

[0369] In some embodiments, Z is a third leaving group which is a halogen. In some embodiments, Z is a third leaving group selected from the group consisting of Cl, Br, and I. In some embodiments, Z is a third leaving group selected from the group consisting of Br, and I. In some embodiments, Z is Br.

[0370] In some embodiments the suitable reducing agent in step (14) is a hydride reducing agent. In some embodiments, the suitable reducing agent in step (14) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, lithium borohydride, sodium borohydride, potassium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, BH3, BHs'THF, BHs'DMS, sodium cyanoborohydride,WSGR Docket No. 59318-727.601zirconocene chloride hydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (14) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, lithium borohydride, sodium borohydride, potassium borohydride, diisobutylaluminum hydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (14) is lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (14) is lithium tri-sec-butylborohydride, lithium triethylborohydride, or a combination thereof. In some embodiments, the suitable reducing agent in step (14) is lithium tri-sec-butylborohydride.

[0371] In some embodiments the suitable reducing agent in step (14) is an alcohol. In some embodiments, the suitable reducing agent in step (14) is isopropanol. In some embodiments, the alcohol serves as a reducing agent in the presence of a transfer hydrogenation catalyst.

[0372] In some embodiments, the suitable reducing agent in step (14) is dissolved in a suitable solvent. In some embodiments, the suitable reducing agent in step (14) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable reducing agent in step (14) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable reducing agent in step (14) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a combination thereof. In some embodiments, the suitable reducing agent in step (14) is dissolved in a suitable solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable reducing agent in step (14) is dissolved in tetrahydrofuran. In some embodiments, the suitable reducing agent in step (14) is dissolved in 2-methyl tetrahydrofuran.

[0373] In some embodiments, at least 0.25, 1.0, 2.0, or 5.0 molar equivalents of the suitable reducing agent in step (14) with respect to the compound of Formula H are used. In some embodiments, from about 1.0 to about 2.0 molar equivalents of the suitable reducing agent in step (14) with respect to the compound of Formula H are used. In some embodiments, from about 1.4 to about 1.6 molar equivalents of the suitable reducing agent in step (14) with respectWSGR Docket No. 59318-727.601to the compound of Formula H are used. In some embodiments, the concentration of the suitable reducing agent in step (14) in the suitable solvent is about 0.25 N to about 4.0 N. In some embodiments, the concentration of the suitable reducing agent in step (14) in the suitable solvent is about 0.5 N to about 2.0 N. In some embodiments, the concentration of the suitable reducing agent in step (14) in the suitable solvent is about 1.0 N. In some embodiments, the concentration of the suitable reducing agent in step (14) in tetrahydrofuran, 2-methyl tetrahydrofuran, or a mixture thereof, is about 1.0 N.

[0374] In some embodiments, the suitable solvent in step (14) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2, 2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, or a combination thereof. In some embodiments, the suitable solvent in step (14) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable solvent in step (14) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a combination thereof. In some embodiments, the suitable solvent in step (14) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent in step (14) is tetrahydrofuran. In some embodiments, the suitable solvent in step (14) is 2-methyl tetrahydrofuran.

[0375] In some embodiments, the suitable methylating agent in step (15) is selected from methyl iodide, methyl bromide, methyl mesylate, methyl tritiate, or dimethyl sulfate. In some embodiments, the suitable methylating agent in step (15) is selected from methyl iodide, methyl bromide, or dimethyl sulfate. In some embodiments, the suitable methylating agent in step (15) is selected from methyl iodide or methyl bromide. In some embodiments, the suitable methylating agent in step (15) is methyl iodide.

[0376] In some embodiments, there is a molar excess of the suitable methylating agent in step (15) with respect to the compound of Formula H. In some embodiments, at least 1.0, 2.0, 5.0, 10.0, 15.0, or 20.0 molar equivalents of the suitable methylating agent in step (15) with respect to the compound of Formula H are used. In some embodiments, from about 1.0 to about 5.0 molar equivalents of the suitable methylating agent in step (15) with respect to the compound of Formula H are used. In some embodiments, from about 1.0 to about 3.0 molar equivalents of the suitable methylating agent in step (15) with respect to the compound of Formula H are used. In some embodiments, from about 1.0 to about 2.0 molar equivalents of the suitable methylating agent in step (15) with respect to the compound of Formula H are used. In some embodiments,WSGR Docket No. 59318-727.601from about 1.3 to about 1.8 molar equivalents of the suitable methylating agent in step (15) with respect to the compound of Formula H are used. In some embodiments, about 1.5 molar equivalents of the suitable methylating agent in step (15) with respect to the compound of Formula H are used.

[0377] In some embodiments, step (14) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (14) further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about -30° Celsius to about 30° Celsius. In some embodiments, the suitable temperature is about -20° Celsius to about 20° Celsius. In some embodiments, the suitable temperature is about -15° Celsius to about 15° Celsius. In some embodiments, the suitable temperature is about -10° Celsius to about 10° Celsius. In some embodiments, the suitable temperature is 0±20° Celsius. In some embodiments, the suitable temperature is 0±10° Celsius. In some embodiments, the suitable temperature is 0±5° Celsius. In some embodiments, the suitable quantity of time is about 10 minutes to about 12 hours. In some embodiments, the suitable quantity of time is about 30 minutes to about 6 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 4 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 3 hours. In some embodiments, the suitable quantity of time is about 2 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.

[0378] In some embodiments, step (15) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (15) further comprises maintaining the reaction mixture at a suitable temperature for a suitable time. In some embodiments, the suitable temperature is about -30° Celsius to about 30° Celsius. In some embodiments, the suitable temperature is about -20° Celsius to about 20° Celsius. In some embodiments, the suitable temperature is about -10° Celsius to about 10° Celsius. In some embodiments, the suitable temperature is about -10° Celsius to about 5° Celsius. In some embodiments, the suitable quantity of time is about 10 minutes to about 8 hours. In some embodiments, the suitable quantity of time is about 30 minutes to about 4 hours. In some embodiments, the suitable quantity of time is about 1 hour to about 3 hours. In some embodiments, the suitable quantity of time is about 2 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.

[0379] In some embodiments, the reaction mixture of step (15) is quenched with sodium hydroxide. In some embodiments, the reaction mixture of step (15) is treated with hydrogenWSGR Docket No. 59318-727.601peroxide. In some embodiments, the reaction mixture of step (15) is treated with sodium thiosulfate.Synthesis of Formula H from Formula IProcedure(16)Formula I Formula H

[0380] Disclosed herein are methods for the synthesis of compounds of Formula H.

[0381] As disclosed herein, a compound of Formula H is prepared from a compound of Formula I by:(16) contacting a compound of Formula I:ZFormula I;wherein Z is a third suitable leaving group;with (A)-tert-butylsulfinamide and a suitable solvent;to provide a compound of Formula H.

[0382] In some embodiments, Z is a third leaving group which is a halogen. In some embodiments, Z is a third leaving group selected from the group consisting of Cl, Br, and I. In some embodiments, Z is a third leaving group selected from the group consisting of Br, and I. In some embodiments, Z is Br.

[0383] In some embodiments, at least 1.0, 2.0, or 5.0 molar equivalents of (A)-tert-butylsulfinamide in step (16) with respect to the compound of Formula I are used. In some embodiments, from about 1.0 to about 2.0 molar equivalents of (A)-tert-butylsulfmamide in step (16) with respect to the compound of Formula I are used. In some embodiments, from about 1.0 to about 1.5 molar equivalents of (A)-tert-butylsulfinamide in step (16) with respect to the compound of Formula I are used. In some embodiments, from about 1.1 to about 1.3 molar equivalents of (A)-tert-butylsulfinamide in step (16) with respect to the compound of Formula I are used. In some embodiments, about 1.2 molar equivalents of (A)-tert-butylsulfmamide in step (16) with respect to the compound of Formula I are used.

[0384] In some embodiments, the suitable solvent in step (16) is selected from tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, tri ethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethylWSGR Docket No. 59318-727.601tetrahydrofuran, diethyl ether, dichloromethane, heptane, hexane, pentane, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (16) is selected from tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-di oxane, glyme, diglyme, tri ethylene glycol dimethyl ether, dichloromethane, heptane, hexane, pentane, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (16) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, glyme, diglyme, tri ethylene glycol dimethyl ether, heptane, hexane, pentane, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (16) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, glyme, diglyme, triethylene glycol dimethyl ether, or a combination thereof. In some embodiments, the suitable solvent in step (16) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, or a combination thereof. In some embodiments, the suitable solvent in step (16) is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, or a combination thereof. In some embodiments, the suitable solvent in step (16) is tetrahydrofuran.

[0385] In some embodiments, the process of step (16) further comprises contacting the compound of Formula I with a suitable desiccant. In some embodiments, the suitable desiccant is selected from titanium(IV) isopropoxide, titanium(IV) ethoxide, titanium(IV) butoxide, TiCl(OiPr)3, titanium (IV) chloride, zirconium (IV) tert-butoxide, triisopropyl borate, or a combination thereof. In some embodiments, the suitable desiccant is selected from titanium(IV) isopropoxide, titanium(IV) ethoxide, titanium(IV) butoxide, titanium (IV) chloride, or a combination thereof. In some embodiments, the suitable desiccant is selected from titanium(IV) isopropoxide, titanium(IV) ethoxide, titanium(IV) butoxide, or a combination thereof. In some embodiments, the suitable desiccant is selected from titanium(IV) isopropoxide, titanium(IV) ethoxide, or a combination thereof. In some embodiments, the suitable desiccant is selected from titanium(IV) isopropoxide.

[0386] In some embodiments, at least 1.0, 2.0, 5.0, 10.0, 15.0, or 20.0 molar equivalents of the suitable desiccant in step (16) with respect to the compound of Formula I are used. In some embodiments, from about 1.0 to about 10.0 molar equivalents of the suitable desiccant in step (16) with respect to the compound of Formula I are used. In some embodiments, from about 2.0 to about 8.0 molar equivalents of the suitable desiccant in step (16) with respect to the compound of Formula I are used. In some embodiments, from about 3.0 to about 5.0 molar equivalents of the suitable desiccant in step (16) with respect to the compound of Formula I are used. In some embodiments, about 4.0 molar equivalents of the suitable desiccant in step (16) with respect to the compound of Formula I are used.

[0387] In some embodiments, step (16) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (16) further comprises maintaining theWSGR Docket No. 59318-727.601reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about 25° Celsius to about 150° Celsius. In some embodiments, the suitable temperature is about 30° Celsius to about 110° Celsius. In some embodiments, the suitable temperature is about 40° Celsius to about 100° Celsius. In some embodiments, the suitable temperature is about 60° Celsius to about 90° Celsius. In some embodiments, the suitable temperature is about 70° Celsius to about 80° Celsius. In some embodiments, the suitable temperature is 75±20° Celsius. In some embodiments, the suitable temperature is 75±10° Celsius. In some embodiments, the suitable temperature is 75±5° Celsius. In some embodiments, the suitable quantity of time is about 6 hours to about 1 week. In some embodiments, the suitable quantity of time is about 12 hours to about 96 hours. In some embodiments, the suitable quantity of time is about 18 hours to about 72 hours. In some embodiments, the suitable quantity of time is about 24 hours to about 72 hours. In some embodiments, the suitable quantity of time is about 36 hours to about 60 hours. In some embodiments, the suitable quantity of time is about 48 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.Synthesis of Formula I from Formula J. Procedure / N-N (17)+(18) N-NZ- N - - yZ ZFormula J Formula I

[0388] Disclosed herein are methods for the synthesis of compounds of Formula I.

[0389] As disclosed herein, a compound of Formula I is prepared from a compound of Formula J by:(17) contacting a compound of Formula J:N-NZZFormula J;wherein Z is a third suitable leaving group;with a suitable metal-halogen exchange reagent and a suitable solvent to provide a reaction mixture; and(18) contacting the reaction mixture of step (17) with N, 7V-di methyl acetamide; to provide a compound of Formula I.WSGR Docket No. 59318-727.601

[0390] In some embodiments, Z is a third leaving group which is a halogen. In some embodiments, Z is a third leaving group selected from the group consisting of Cl, Br, and I. In some embodiments, Z is a third leaving group selected from the group consisting of Br, and I. In some embodiments, Z is Br.

[0391] In some embodiments, the suitable metal-halogen exchange reagent in step (17) is an organolithium reagent or a Grignard reagent. In some embodiments, the suitable metal-halogen exchange reagent in step (17) is an organolithium reagent. In some embodiments, the suitable metal-halogen exchange reagent in step (17) is a Grignard reagent. In some embodiments, the suitable metal-halogen exchange reagent in step (17) is methyllithium, ethyllithium, isopropyllithium, n-propyllithium n-butyllithium, pentyllithium, n-hexyllithium, tertbutyllithium, phenyllithium, phenyl magnesium chloride, phenyl magnesium bromide, methyl magnesium chloride, methyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, iPrBu2MgLi, or BusMgLi. In some embodiments, the suitable metal-halogen exchange reagent in step (17) is n-butyllithium, n-hexyllithium, tert-butyllithium, methyl magnesium chloride, methyl magnesium bromide, isopropyl magnesium chloride, or isopropyl magnesium bromide. In some embodiments, the suitable metal-halogen exchange reagent in step (17) is n-butyllithium, n-hexyllithium, tert-butyllithium, isopropyl magnesium chloride, or isopropyl magnesium bromide. In some embodiments, the suitable metal-halogen exchange reagent in step (17) is n-butyllithium, n-hexyllithium, or isopropyl magnesium chloride. In some embodiments, the suitable metal-halogen exchange reagent in step (17) is n-butyllithium, n-hexyllithium, isopropyl magnesium chloride, or isopropyl magnesium bromide. In some embodiments, the suitable metal-halogen exchange reagent in step (17) is n-butyllithium or n-hexyllithium. In some embodiments, the suitable metal-halogen exchange reagent in step (17) is n-butyllithium. In some embodiments, the suitable metal-halogen exchange reagent in step (17) is a solution of n-butyllithium in hexanes.

[0392] In some embodiments, the suitable solvent in step (17) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, pentane, hexanes, or a mixture thereof. In some embodiments, the suitable solvent in step (17) is tetrahydrofuran, hexanes, or a mixture thereof.WSGR Docket No. 59318-727.601Synthesis of Formula 8 from Formula A / / N-NK OFormula A Formula 8

[0393] Disclosed herein are methods for the synthesis of compounds of Formula 8.

[0394] As disclosed herein, a compound of Formula 8 is prepared from a compound of Formula A by:(19) contacting a compound of Formula A with:RC(O)NH2, wherein R is an unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group,a third suitable palladium catalyst, a third suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 8: / N-NNhsj |I ]HN NRXDFormula 8wherein R is an unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group.

[0395] In some embodiments, X is a second leaving group which is a halogen or sulfonate leaving group. In some embodiments, X is a second leaving group which is a halogen. In some embodiments, X is Cl.

[0396] In some embodiments the third suitable palladium catalyst in step (19) is Pd(OAc)2, [Pd(allyl)Cl]2, Pd(PPhs)4, Pd(dba)2 or Pd2(dba)s. In some embodiments the third suitable palladium catalyst in step (19) is Pd(dba)2 or Pd2(dba)s. In some embodiments, the third suitableWSGR Docket No. 59318-727.601palladium catalyst in step (19) is Pd(0Ac)2. In some embodiments the third suitable palladium catalyst in step (19) is Pd2(dba)3.

[0397] In some embodiments, the third suitable ligand in step (19) is a phosphine, N-heterocyclic carbene, or a salt thereof. In some embodiments, the third suitable ligand in step (19) is a phosphine or a salt thereof. In some embodiments, the third suitable ligand in step (19) is a trialkyl monophosphine, an or / Ao-biaryl phosphine (Buchwald phosphine), a bisphosphine, or a salt thereof. In some embodiments, the third suitable ligand in step (19) an ortAo-biaryl phosphine (Buchwald phosphine), a bisphosphine, or a salt thereof. In some embodiments, the third suitable ligand in step (19) is Xantphos, X-Phos, S-Phos, tert-butyl X-Phos, BINAP, DPPF, DCPF, Josiphos (SL-J009-1), or the like. In some embodiments, the third suitable ligand in step (19) is Xantphos, X-Phos, S-Phos, tert-butyl X-Phos, BINAP, DPPF, or Josiphos (SL-J009-1). In some embodiments, the third suitable ligand in step (19) is Xantphos, BINAP, DPPF, DCPF, or Josiphos (SL-J009-1). In some embodiments, the third suitable ligand in step (19) is Xantphos or Josiphos (SL-J009-1). In some embodiments, the third suitable ligand in step (19) is Josiphos (SL-J009-1). In some embodiments, the third suitable ligand in step (19) is Xantphos.

[0398] In some embodiments, the third suitable ligand in step (19) is a tri-tertebutyl phosphine, tri-adamantyl phosphine, di(l-adamantyl)-n-butylphosphine, di(l-adamantyl)-benzylphosphine, or a salt thereof. In some embodiments, the third suitable ligand in step (19) is tri-tertebutyl phosphine or a salt thereof. In some embodiments, the third suitable ligand in step (19) is [(CBu)3PH]BF4.

[0399] In some embodiments, the palladium catalyst and ligand are pre-complexed prior to addition to the reaction mixture.

[0400] In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, DMSO, DMA, NMP, di chloromethane, dichloroethane, acetonitrile, heptane, hexane, pentane, toluene, xylene, benzene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, toluene, xylene, benzene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is 1,4-dioxane, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, DMF, DMSO, DMA, NMP, dichloromethane, dichloroethane, acetonitrile, heptane, hexane, pentane, toluene, xylene, or a combination thereof. In someWSGR Docket No. 59318-727.601embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, DMF, DMA, NMP, di chloromethane, dichloroethane, acetonitrile, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-dioxane, DMF, DMA, NMP, dichloromethane, dichloroethane, acetonitrile, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, toluene or a combination thereof. In some embodiments, the suitable solvent in step (19) is 1,4-dioxane, toluene or a combination thereof. In some embodiments, the suitable solvent in step (19) is toluene, benzene, xylene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is toluene.

[0401] In some embodiments, the suitable base in step (19) is a carbonate base, an alkoxide base, a hydroxide base, amidine, or an amine. In some embodiments, the suitable base in step (19) is a carbonate base, an alkoxide base, a hydroxide base, or an amine. In some embodiments, the suitable base in step (19) is a carbonate base, an alkoxide base, a hydroxide base, or an amidine. In some embodiments, the suitable base in step (19) is a carbonate base, an alkoxide base, or a hydroxide base. In some embodiments, the suitable base in step (19) is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tripotassium phosphate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, l,5-Diazabicyclo[4.3.0]non-5-ene, DABCO, or a combination thereof. In some embodiments, the suitable base in step (19) is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the suitable base in step (19) is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, sodium tert-butoxide, potassium tert-butoxide, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-Diazabicyclo[4.3.0]non-5-ene, or a combination thereof. In some embodiments, the suitable base in step (19) is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the suitable base in step (19) isWSGR Docket No. 59318-727.601sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof. In some embodiments, the suitable base in step (19) is sodium carbonate, potassium carbonate, cesium carbonate, l,8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof. In some embodiments, the suitable base in step (19) is potassium carbonate, l,8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof. In some embodiments, the suitable base in step (19) is cesium carbonate.

[0402] In some embodiments, step (19) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (19) further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about 30° Celsius to about 180° Celsius. In some embodiments, the suitable temperature is about 50° Celsius to about 150° Celsius. In some embodiments, the suitable temperature is about 80° Celsius to about 130° Celsius. In some embodiments, the suitable temperature is about 90° Celsius to about 120° Celsius. In some embodiments, the suitable temperature is about 100° Celsius to about 120° Celsius. In some embodiments, the suitable quantity of time is about 2 hours to about 48 hours. In some embodiments, the suitable quantity of time is about 8 hours to about 36 hours. In some embodiments, the suitable quantity of time is about 12 hours to about 24 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.

[0403] In some embodiments, R is an unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group. In some embodiments, R is an unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group. In some embodiments, R is an unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted carbocycle, or unsubstituted or substituted C1-C10 alkoxy group. In some embodiments, R is an unsubstituted or substituted C1-C10 alkyl, or unsubstituted or substituted carbocycle. In some embodiments, R is an unsubstituted or substituted C1-C10 alkyl. In some embodiments, R is an unsubstituted or substituted carbocycle. In some embodiments, R is an unsubstituted or substituted C1-C10 alkoxy group. In some embodiments, R is cyclopropyl.OV / ^NH2In some embodiments, R is / c / V-butoxy. In some embodiments, RC(O)NH2 isv. Insome embodiments, RC(O)NH2 is0 NH2 .WSGR Docket No. 59318-727.601Synthesis of Formula 9 from Formula 8 / N-NProcedure(20)Formula 8 Formula 9

[0404] Disclosed herein are methods for the synthesis of compounds of Formula 9.

[0405] As disclosed herein, a compound of Formula 9 is prepared from a compound of Formula 8 by:(20) contacting a compound of Formula 8 with a suitable base and a suitable solvent to provide a compound of Formula 9: / N-NFormula 9.

[0406] In some embodiments, the suitable base in step (20) is lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof. In some embodiments, the suitable base in step (20) is lithium hydroxide, sodium hydroxide, potassium hydroxide, or a combination thereof. In some embodiments, the suitable base in step (20) is lithium hydroxide. In some embodiments, the suitable base in step (20) is lithium hydroxide monohydrate.

[0407] In some embodiments, the suitable solvent in step (20) is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methanol, ethanol, isopropanol, water, DMF, Acetonitrile, DMSO, toluene, or a mixture thereof. In some embodiments, the suitable solvent in step (20) is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methanol, ethanol, isopropanol, water, or a mixture thereof. In some embodiments, the suitable solvent in step (20) is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methanol, water, or a mixture thereof. In some embodiments, the suitable solvent in step (20) is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, water, or a mixture thereof. In some embodiments, the suitable solvent in step (20) is tetrahydrofuran, 1,4-di oxane, water, or a mixture thereof. In some embodiments, the suitable solvent in step (20) is tetrahydrofuran, water, or a mixture thereof.WSGR Docket No. 59318-727.601

[0408] In some embodiments, step (20) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (20) further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about 30° Celsius to about 120° Celsius. In some embodiments, the suitable temperature is about 50° Celsius to about 100° Celsius. In some embodiments, the suitable temperature is about 60° Celsius to about 100° Celsius. In some embodiments, the suitable temperature is about 60° Celsius to about 80° Celsius. In some embodiments, the suitable quantity of time is about 2 hours to about 48 hours. In some embodiments, the suitable quantity of time is about 4 hours to about 24 hours. In some embodiments, the suitable quantity of time is about 6 hours to about 12 hours. In some embodiments, the residence time of the reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.Alternative Synthesis of Formula 9 from Formula 8Formula 8 Formula 9

[0409] Disclosed herein are methods for the synthesis of compounds of Formula 9.

[0410] As disclosed herein, a compound of Formula 9 is prepared from a compound of Formula 8 by:(21) contacting a compound of Formula 8 with a suitable acid and a suitable solvent to provide a compound of Formula 9: / Formula 9.

[0411] In some embodiments, the compound of Formula 8 is:WSGR Docket No. 59318-727.601

[0412] In some embodiments, the suitable acid in step (21) is hydrogen chloride or trifluoroacetic acid. In some embodiments, the suitable acid in step (21) is hydrogen chloride.

[0413] In some embodiments, the suitable solvent in step (21) is toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methanol, water, or a mixture thereof. In some embodiments, the suitable solvent in step (21) is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, water, or a mixture thereof. In some embodiments, the suitable solvent in step (21) is tetrahydrofuran, water, or a mixture thereof.Alternative One-Pot Synthesis of Formula 9 from Formula AProcedure Procedure (19) (21)Formula A Formula 8 Formula 9

[0414] Disclosed herein are methods for the synthesis of compounds of Formula 9.

[0415] As disclosed herein, a compound of Formula 9 is prepared from a compound of Formula A by:(19) contacting a compound of Formula A with:RC(O)NH2, wherein R is an unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted Ci-Cio heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted Ci-Cio alkoxy group,a third suitable palladium catalyst, a third suitable ligand, a suitable base, and a suitable solvent to provide a reaction mixture,(21) contacting the reaction mixture of step (19) with a suitable acid and a suitable solvent to provide a compound of Formula 9: / N-NFormula 9.

[0416] In some embodiments, R is Zc / V-butoxy.WSGR Docket No. 59318-727.601

[0417] In some embodiments, X is a second leaving group which is a halogen or sulfonate leaving group. In some embodiments, X is a second leaving group which is a halogen. In some embodiments, X is Cl.

[0418] In some embodiments the third suitable palladium catalyst in step (19) is Pd(OAc)2, [Pd(allyl)Cl]2, Pd(PPhs)4, Pd(dba)2 or Pd2(dba)3. In some embodiments the third suitable palladium catalyst in step (19) is Pd(dba)2 or Pd2(dba)3. In some embodiments, the third suitable palladium catalyst in step (19) is Pd(OAc)2. In some embodiments the third suitable palladium catalyst in step (19) is Pd2(dba)3.

[0419] In some embodiments, the third suitable ligand in step (19) is a phosphine, N-heterocyclic carbene, or a salt thereof. In some embodiments, the third suitable ligand in step (19) is a phosphine or a salt thereof. In some embodiments, the third suitable ligand in step (19) is a trialkyl monophosphine, an or / Ao-biaryl phosphine (Buchwald phosphine), a bisphosphine, or a salt thereof. In some embodiments, the third suitable ligand in step (19) an ortAo-biaryl phosphine (Buchwald phosphine), a bisphosphine, or a salt thereof. In some embodiments, the third suitable ligand in step (19) is Xantphos, X-Phos, S-Phos, tert-butyl X-Phos, BINAP, DPPF, DCPF, Josiphos (SL-J009-1), or the like. In some embodiments, the third suitable ligand in step (19) is Xantphos, X-Phos, S-Phos, tert-butyl X-Phos, BINAP, DPPF, or Josiphos (SL-J009-1). In some embodiments, the third suitable ligand in step (19) is Xantphos, BINAP, DPPF, DCPF, or Josiphos (SL-J009-1). In some embodiments, the third suitable ligand in step (19) is Xantphos or Josiphos (SL-J009-1). In some embodiments, the third suitable ligand in step (19) is Josiphos (SL-J009-1). In some embodiments, the third suitable ligand in step (19) is Xantphos.

[0420] In some embodiments, the third suitable ligand in step (19) is a tri-tertebutyl phosphine, tri-adamantyl phosphine, di(l-adamantyl)-n-butylphosphine, di(l-adamantyl)-benzylphosphine, or a salt thereof. In some embodiments, the third suitable ligand in step (19) is tri-tertebutyl phosphine or a salt thereof. In some embodiments, the third suitable ligand in step (19) is [(CBu)3PH]BF4.

[0421] In some embodiments, the palladium catalyst and ligand are pre-complexed prior to addition to the reaction mixture.

[0422] In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, DMSO, DMA, NMP, di chloromethane, dichloroethane, acetonitrile, heptane, hexane, pentane, toluene, xylene, benzene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, toluene, xylene,WSGR Docket No. 59318-727.601benzene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is 1,4-dioxane, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, DMF, DMSO, DMA, NMP, dichloromethane, dichloroethane, acetonitrile, heptane, hexane, pentane, toluene, xylene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2, 2, 5, 5 -tetramethyl tetrahydrofuran, diethyl ether, DMF, DMA, NMP, di chloromethane, dichloroethane, acetonitrile, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-dioxane, DMF, DMA, NMP, dichloromethane, dichloroethane, acetonitrile, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, or a combination thereof. In some embodiments, the suitable solvent in step (19) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, toluene or a combination thereof. In some embodiments, the suitable solvent in step (19) is 1,4-dioxane, toluene or a combination thereof. In some embodiments, the suitable solvent in step (19) is toluene, benzene, xylene, or a combination thereof. In some embodiments, the suitable solvent in step (19) is toluene.

[0423] In some embodiments, the suitable base in step (19) is a carbonate base, an alkoxide base, a hydroxide base, amidine, or an amine. In some embodiments, the suitable base in step (19) is a carbonate base, an alkoxide base, a hydroxide base, or an amine. In some embodiments, the suitable base in step (19) is a carbonate base, an alkoxide base, a hydroxide base, or an amidine. In some embodiments, the suitable base in step (19) is a carbonate base, an alkoxide base, or a hydroxide base. In some embodiments, the suitable base in step (19) is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tripotassium phosphate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, l,5-Diazabicyclo[4.3.0]non-5-ene, DABCO, or a combination thereof. In some embodiments, the suitable base in step (19) is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the suitable base in step (19) is sodium carbonate,WSGR Docket No. 59318-727.601potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, sodium tert-butoxide, potassium tert-butoxide, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-Diazabicyclo[4.3.0]non-5-ene, or a combination thereof. In some embodiments, the suitable base in step (19) is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the suitable base in step (19) is sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof. In some embodiments, the suitable base in step (19) is sodium carbonate, potassium carbonate, cesium carbonate, l,8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof. In some embodiments, the suitable base in step (19) is potassium carbonate, l,8-diazabicyclo[5.4.0]undec-7-ene, or a combination thereof. In some embodiments, the suitable base in step (19) is cesium carbonate.

[0424] In some embodiments, the suitable acid in step (21) is hydrogen chloride or trifluoroacetic acid. In some embodiments, the suitable acid in step (21) is hydrogen chloride.

[0425] In some embodiments, the suitable solvent in step (21) is toluene, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-di oxane, methanol, water, or a mixture thereof. In some embodiments, the suitable solvent in step (21) is tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methanol, water, or a mixture thereof. In some embodiments, the suitable solvent in step (21) is toluene, 1,4-dioxane, water, or a mixture thereof. In some embodiments, the suitable solvent in step (21) is toluene.Synthesis of Formula 10 from Formula 9Formula 10

[0426] Disclosed herein are methods for the synthesis of compounds of Formula 10.

[0427] As disclosed herein, a compound of Formula 10 is prepared from a compound of Formula 9 by:O Cl-' Y(22) contacting a compound of Formula 9withN C|, a suitable base, and a suitable solvent to provide a compound of Formula 10:WSGR Docket No. 59318-727.601"'■sYN;NAl.CIFormula 10.

[0428] In some embodiments, the suitable base in step (22) is an amine, hydroxide, alkoxide, carbonate, amide, or hydride base. In some embodiments, the suitable base in step (22) is tri ethylamine, diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, DABCO, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, sodium 2-methylbutan-2-olate, sodium trimethylsilanolate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (22) is an amide or hydride base. In some embodiments, the suitable base in step (22) is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (22) is an amide base. In some embodiments, the suitable base in step (22) is lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, or a combination thereof. In some embodiments, the suitable base in step (22) is a hydride base. In some embodiments, the suitable base in step (22) is lithium hydride, sodium hydride, potassium hydride, or a combination thereof. In some embodiments, the suitable base in step (22) is sodium hydride. In some embodiments, the suitable base in step (22) is lithium bis(trimethylsilyl)amide.

[0429] In some embodiments, the suitable base in step (22) is sodium hydride or LiHMDS. In some embodiments, the suitable base in step (22) is LiHMDS. In some embodiments, the suitable base in step (22) is a solution of LiHMDS in tetrahydrofuran.

[0430] In some embodiments, the suitable solvent in step (22) is 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, DMF, or a mixture thereof. In some embodiments, the suitable solvent in step (22) is 2-methyl tetrahydrofuran, tetrahydrofuran, or a mixture thereof.Synthesis of Formula 11 from Formula 10WSGR Docket No. 59318-727.601D3c.Formula 10

[0431] Disclosed herein are methods for the synthesis of compounds of Formula 11.

[0432] As disclosed herein, a compound of Formula 11 is prepared from a compound of Formula 10 by:(23) contacting a compound of Formula 10 with cyclopropanecarboxamide, a fourth suitable palladium catalyst, a fourth suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 11:

[0433] In some embodiments the fourth suitable palladium catalyst in step (23) is Pd(OAc)2, [Pd(allyl)Cl]2, Pd(PPhs)4, Pd(dba)2 or Pd2(dba)s. In some embodiments the fourth suitable palladium catalyst in step (23) is Pd(dba)2 or Pd2(dba)s. In some embodiments, the fourth suitable palladium catalyst in step (23) is Pd(OAc)2. In some embodiments the fourth suitable palladium catalyst in step (23) is Pd2(dba)s.

[0434] In some embodiments, the fourth suitable ligand in step (23) is a phosphine, N-heterocyclic carbene, or a salt thereof. In some embodiments, the fourth suitable ligand in step (23) is a phosphine or a salt thereof. In some embodiments, the fourth suitable ligand in step (23) is a trialkyl monophosphine, an or / Ao-biaryl phosphine (Buchwald phosphine), a bisphosphine, or a salt thereof. In some embodiments, the fourth suitable ligand in step (23) an or / Ao-biaryl phosphine (Buchwald phosphine), a bisphosphine, or a salt thereof. In some embodiments, the fourth suitable ligand in step (23) is Xantphos, X-Phos, S-Phos, tert-butyl X-Phos, BINAP, DPPF, DCPF, Josiphos (SL-J009-1), or the like. In some embodiments, the fourth suitableWSGR Docket No. 59318-727.601ligand in step (23) is Xantphos, X-Phos, S-Phos, tert-butyl X-Phos, BINAP, DPPF, DCPF, or Josiphos (SL-J009-1). In some embodiments, the fourth suitable ligand in step (23) is Xantphos, BINAP, or DPPF. In some embodiments, the fourth suitable ligand in step (23) is Xantphos.

[0435] In some embodiments, the fourth suitable ligand in step (23) is a tri-tert-butyl phosphine, tri-adamantyl phosphine, di(l-adamantyl)-n-butylphosphine, di(l-adamantyl)-benzylphosphine, or a salt thereof. In some embodiments, the fourth suitable ligand in step (23) is tri-tert-butyl phosphine or a salt thereof. In some embodiments, the fourth suitable ligand in step (23) is [(teBu)3PH]BF4.

[0436] In some embodiments, the palladium catalyst and ligand are pre-complexed prior to addition to the reaction mixture.

[0437] In some embodiments, the suitable solvent in step (23) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, 2-butoxyethanol, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isoamyl alcohol, DMF, DMSO, DMA, NMP, di chloromethane, dichloroethane, acetonitrile, heptane, hexane, pentane, toluene, xylene, benzene, or a combination thereof. In some embodiments, the suitable solvent in step (23) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, toluene, xylene, benzene, or a combination thereof. In some embodiments, the suitable solvent in step (23) is 1,4-dioxane, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (23) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, DMF, DMSO, DMA, NMP, dichloromethane,di chloroethane, acetonitrile, heptane, hexane, pentane, toluene, xylene, or a combination thereof. In some embodiments, the suitable solvent in step (23) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water, DMF, DMA, NMP, dichloromethane, di chloroethane, acetonitrile, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (23) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, water, DMF, DMA, NMP, di chloromethane, di chloroethane, acetonitrile, toluene, or a combination thereof. In some embodiments, the suitable solvent in step (23) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, methyl tert-butyl ether, cyclopentyl methyl ether, glyme, diglyme, triethylene glycol dimethyl ether, 2,2,5,5-tetramethyl tetrahydrofuran, diethyl ether, water or a combination thereof. In some embodiments, the suitable solvent in step (23) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, toluene, water, or a combination thereof. In some embodiments, the suitable solvent in step (23) is 1,4-WSGR Docket No. 59318-727.601dioxane, toluene, water, or a combination thereof. In some embodiments, the suitable solvent in step (23) is 1,4-dioxane, tetrahydrofuran, 2-m ethyl tetrahydrofuran, toluene, benzene, xylene, water, or a combination thereof. In some embodiments, the suitable solvent in step (23) is 1,4-dioxane, water, or a combination thereof. In some embodiments, the suitable solvent in step (23) is mixture of about 1:1 to about 100:1 1,4-dioxane and water. In some embodiments, the suitable solvent in step (23) is mixture of about 2: 1 to about 20: 1 1,4-dioxane and water. In some embodiments, the suitable solvent in step (23) is mixture of about 5:1 to about 10:1 1,4-dioxane and water. In some embodiments, the suitable solvent in step (23) is mixture of about 7.5:1 1,4-dioxane and water.

[0438] In some embodiments, the suitable base in step (23) is a carbonate base, an alkoxide base, a hydroxide base, or an amine. In some embodiments, the suitable base in step (23) is a carbonate base, an alkoxide base, or a hydroxide base. In some embodiments, the suitable base in step (23) is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tripotassium phosphate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the suitable base in step (23) is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the suitable base in step (23) is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, tripotassium phosphate, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the suitable base in step (23) is sodium carbonate, potassium carbonate, cesium carbonate, or a combination thereof. In some embodiments, the suitable base in step (23) is cesium carbonate.

[0439] In some embodiments, step (23) further comprises maintaining the reaction mixture at a suitable temperature. In some embodiments, step (23) further comprises maintaining the reaction mixture at a suitable temperature for a suitable quantity of time. In some embodiments, the suitable temperature is about 30° Celsius to about 180° Celsius. In some embodiments, the suitable temperature is about 50° Celsius to about 150° Celsius. In some embodiments, the suitable temperature is about 80° Celsius to about 130° Celsius. In some embodiments, the suitable temperature is about 90° Celsius to about 120° Celsius. In some embodiments, the suitable temperature is about 90° Celsius to about 110° Celsius. In some embodiments, the suitable quantity of time is about 2 hours to about 48 hours. In some embodiments, the suitable quantity of time is about 8 hours to about 36 hours. In some embodiments, the suitable quantity of time is about 12 hours to about 24 hours. In some embodiments, the residence time of theWSGR Docket No. 59318-727.601reaction mixture in the one or more flow reactors is configured to be approximately equal to the suitable quantity of time.Heavy Metal Scavenging

[0440] Due to the fact that some of the synthetic methods described above utilize a transition metal catalyst, purification steps can be performed to reduce the amount of palladium in the product(s). Purification steps to reduce the amount of palladium in a product are conducted so that active pharmaceutical ingredients meet palladium specification guidelines. (“Guideline on the Specification Limits for Residues of Metal Catalysts” European Medicines Agency Preauthorisation Evaluation of Medicines for Human Use, London, January 2007, Doc. Ref.CPMP / SWP / QWP / 4446 / 00 corr.). In some embodiments, purification steps to reduce the amount of palladium in a product includes, but is not limited to, treatment with solid trimercaptotriazine (TMT), polystyrene-bound TMT, mercapto-porous polystyrene-bound TMT, polystyrene-bound ethylenediamine, activated carbon, glass bead sponges, Smopex™, silica bound scavengers, thiol -derivatized silica gel, N-acetylcysteine, n-BusP, crystallization, extraction, L-cysteine, n-BusP / lactic acid (Garrett et al., Adv. Synth. Catal. 2004, 346, 889-900). In some embodiments, activated carbon includes but is not limited to DARCO® KB-G, DARCO® KB-WJ. In one aspect silica bound scavengers include but are not limited tosilica gel. In some embodiments, the purification steps to reduce the amount of palladium include the use of activated carbon, derivatized silica gel (e.g., thiol derivatized silica gel), or combinations thereof.

[0441] In some embodiments, Compound 11, or salt thereof, is further treated with a metal scavenger to remove residual palladium. In some embodiments, the metal scavenger comprises SiC>2, charcoal, aqueous solution of L-cysteine, a Silicycle metal scavenger, Si -thiol, SiliaBond DMT, SiliaBond Cysteine, SiliaMetS Thiol (SH), or 3 -mercaptopropyl ethyl sulfide silica. In some embodiments, the scavenger loading (w / w) is about 1:3, about 1 :2, or about 1:1. In someWSGR Docket No. 59318-727.601embodiments, the scavenger loading (w / w) is about 10 % w / w to about 100% w / w. In some embodiments, the scavenger loading (w / w) is about 20 % w / w to about 60% w / w. In some embodiments, the scavenger loading (w / w) is about 30 % w / w. In some embodiments, the scavenger loading (w / w) is about 50 % w / w. In some embodiments, the metal scavenger is 3-mercaptopropyl ethyl sulfide silica. In some embodiments, the metal scavenger is L-cysteine. In some embodiments, the metal scavenger comprises Silicycle, SiliaMetS Thiol (SH) metal scavenger.

[0442] In some of these embodiments, palladium levels are reduced to about 200 ppm or less. In some of these embodiments, palladium levels are reduced to about 100 ppm or less. In some of these embodiments, palladium levels are reduced to about 50 ppm or less. In some of these embodiments, palladium levels are reduced to about 20 ppm or less. In some of these embodiments, palladium levels are reduced to about 10 ppm or less. In some of these embodiments, palladium levels are reduced sufficiently to be undetectable.

[0443] In some embodiments, the presence of residual heavy metal (e.g. palladium) impurities is determined by utilizing methods known in the art. In some embodiments, the presence of residual heavy metal (e.g. palladium) impurities is determined by the use of inductively coupled plasma mass spectrometry (ICP-MS). In some embodiments, the presence of residual heavy metal (e.g. palladium) impurities is determined by the use of techniques described in U.S.Pharmacopeia General Chapter <231> Heavy Metals.Additional Considerations

[0444] As described herein, Xantphos (4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, CAS No. 161265-03-8) has the structure depicted below:PhxPh Ph PhWSGR Docket No. 59318-727.601

[0445] As described herein, Josiphos (SL-J009-1) may refer to either enantiomer, or mixture thereof, of [(R)-l-[(SP)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine, CAS No. 158923-11-6) having the structure depicted below:

[0446] As described herein, DCPF refers to l,l'-Bis(dicyclohexylphosphino)ferrocene, CAS No. 146960-90-9.

[0447] As described herein, DPPF refers to l,l'-Ferrocenediyl-bis(diphenylphosphine), CAS No. 12150-46-8.

[0448] As described herein, X-Phos refers to 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, CAS No. 564483-18-7.

[0449] As described herein, Zc / V-butyl-X-Phos refers to 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl, CAS No. 564483-19-8.

[0450] As described herein, S-Phos refers to 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl, CAS No. 657408-07-6.

[0451] As described herein, Pd2(dba)s refers to tris(dibenzylideneacetone)dipalladium(0).

[0452] As described herein, L-Selectride refers to lithium tri-sec-butylborohydride.

[0453] As described herein, N-Selectride refers to sodium tri-sec-butylborohydride.

[0454] As described herein, K-Selectride refers to potassium tri-sec-butylborohydride.

[0455] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0456] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich:Wiley-VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so areWSGR Docket No. 59318-727.601useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0457] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with an acid. In some embodiments, the compound disclosed herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, l-hydroxy-2-naphthoic acid; 2, 2-di chloroacetic acid; 2-hydroxy ethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane- 1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-l,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid ( ); and undecylenic acid.

[0458] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound disclosed herein with a base. In some embodiments, the compound disclosed herein is acidic and is reacted with a base. In such situations, an acidic proton of the compound disclosed herein is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, di cyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like. In some embodiments, theWSGR Docket No. 59318-727.601compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-m ethylglucamine salt or ammonium salt.

[0459] In some embodiments, a TYK2 inhibitor (e.g., Compound 11) made according to the methods disclosed herein are further processed to provide pharmaceutically-acceptable salts of said TYK2 inhibitor. As used herein, “pharmaceutically acceptable salt” includes pharmaceutically acceptable co-crystalline materials comprising a compound of the present disclosure (e.g., Compound 11).

[0460] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0461] Therapeutic agents that are administrable to mammals, such as humans, must be prepared by following regulatory guidelines. Such government regulated guidelines are referred to as Good Manufacturing Practice (GMP). GMP guidelines outline acceptable contamination levels of active therapeutic agents, such as, for example, the amount of residual solvent in the final product. Preferred solvents are those that are suitable for use in GMP facilities and consistent with industrial safety concerns. Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), “Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005).

[0462] Solvents are categorized into three classes. Class 1 solvents are toxic and are to be avoided. Class 2 solvents are solvents to be limited in use during the manufacture of the therapeutic agent. Class 3 solvents are solvents with low toxic potential and of lower risk to human health. Data for Class 3 solvents indicate that they are less toxic in acute or short-term studies and negative in genotoxicity studies.

[0463] Class 1 solvents, which are to be avoided, include: benzene; carbon tetrachloride; 1,2-di chloroethane; 1,1 -di chloroethene; and 1,1,1 -tri chloroethane.

[0464] Examples of Class 2 solvents are: acetonitrile, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxy ethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-di oxane, 2-ethoxy ethanol, ethyleneglycol, formamide, hexane, methanol, 2-methoxyethanol, methylbutyl ketone, methylcyclohexane, N-WSGR Docket No. 59318-727.601methylpyrrolidine, nitromethane, pyridine, sulfolane, tetralin, toluene, 1,1, 2 -tri chloroethene and xylene.

[0465] Class 3 solvents, which possess low toxicity, include: acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, / c / V-butylmethyl ether (MTBE), cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl- 1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-m ethyl- 1 -propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate, and tetrahydrofuran.

[0466] Residual solvents in active pharmaceutical ingredients (APIs) originate from the manufacture of API. In some cases, the solvents are not completely removed by practical manufacturing techniques. Appropriate selection of the solvent for the synthesis of APIs may enhance the yield, or determine characteristics such as crystal form, purity, and solubility.Therefore, the solvent is a critical parameter in the synthetic process.

[0467] In some embodiments, compositions comprising Compound 11 or a pharmaceutically acceptable salt thereof comprise an organic solvent(s). In some embodiments, compositions comprising Compound 11 or a pharmaceutically acceptable salt thereof include a residual amount of an organic solvent(s). In some embodiments, compositions comprising Compound 11 or a pharmaceutically acceptable salt thereof comprise a residual amount of a Class 3 solvent. In some embodiments, the Class 3 solvent is selected from the group consisting of acetic acid, acetone, anisole, 1 -butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, cumene, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3 -methyl- 1 -butanol, methylethyl ketone, methylisobutyl ketone, 2-methyl-l -propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran. In some embodiments, the Class 3 solvent is selected from ethyl acetate, isopropyl acetate, tertebutylmethylether, heptane, isopropanol, and ethanol.

[0468] In some embodiments, the compositions comprising Compound 11 or a pharmaceutically acceptable salt thereof include a detectable amount of an organic solvent. In some embodiments, the organic solvent is a Class 3 solvent.

[0469] In other embodiments are compositions comprising Compound 11 or a pharmaceutically acceptable salt thereof wherein the composition comprises a detectable amount of solvent that is less than about 1%, wherein the solvent is selected from acetone, 1,2-dimethoxyethane, acetonitrile, ethyl acetate, tetrahydrofuran, methanol, ethanol, heptane, and 2-propanol. In a further embodiment are compositions comprising Compound 11 or a pharmaceutically acceptable salt thereof wherein the composition comprises a detectable amount of solvent which is less than about 5000 ppm. In yet a further embodiment are compositionsWSGR Docket No. 59318-727.601comprising Compound 11 or a pharmaceutically acceptable salt thereof, wherein the detectable amount of solvent is less than about 5000 ppm, less than about 4000 ppm, less than about 3000 ppm, less than about 2000 ppm, less than about 1000 ppm, less than about 500 ppm, or less than about 100 ppm.

[0470] In another embodiment, the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0471] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,18O,170,35S,18F,36C1,123I,124I,125I,1311,32P and33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or altered metabolic pathways to reduce undesirable metabolites or reduced dosage requirements.

[0472] In some embodiments, one or more hydrogen atoms on Compound 11 are replaced with deuterium. In some embodiments, substitution with deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.EXAMPLES

[0473] The following examples are included for illustrative purposes only and are not intended to limit the scope of the disclosure.List of Abbreviations

[0474] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:S.no Abbreviation Full form1 RM Reaction mass2 °C Degree Celsius3 V Volume4 min. Minutes5 eq. Equivalent6 h HourWSGR Docket No. 59318-727.601S.no Abbreviation Full form7 g Gram8 kg Kilogram9 L Liter10 Temp. Temperature11 w.r.t. With respect to12 RBF Round bottom flask13 NMT Not more than14 NLT Not less than15 HPLC High performance liquid chromatography16 NMR Nuclear magnetic resonance spectroscopy17 IPA Propan-2-ol (isopropanol)18 MTBE Methyltert-butyl ether19 DIPEA Di-isopropyl ethyl amine20 mL Milliliter21 comp Compound22 ATD Air tray drying23 VTD Vacuum tray dryingI. Chemical Synthesis

[0475] Unless otherwise noted, solvents were used as received from commercial suppliers. All commercially available chemical reagents were used as received without further purification unless otherwise noted. Proton NMR data was recorded on 400 MHz, Bruker Avance II. 400 NMR spectrometer equipped with a 5mm Dual and BBFO probe. Mass Spectroscopic data was recorded using a Waters Acquity UPLC instrument, Column: Acquity BEH C182.1 X 50 mm, 1.7 pm. HPLC data recorded on Waters Alliance 2609 Instrument.Example 1: Synthesis of R07 [Formula A (X = Cl)]; (S)-6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5-c][l,7]naphthyridine.WSGR Docket No. 59318-727.601o N-N (R)-t-butyl Br, Br sulfinamide, n-BuLi, DMA i2' h Ti(Oi-Pr)4N, ,N F N THF, -78 °C, 1-2 h N HO THF B Step i Cl Step iii HOR01 R02 Cl R03Step ii i) 4 M HCI / 1 ,4-dioxane 0 °C-rt, 16 h N-N ii) DIPEA, 1,4-dioxane 85 °C, 5 h Step v Cl R06 R07 Step I: Synthesis of l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one (R02)0 Br Br — Br n-BuLi, DMA N, ,N - Nx,N N THF, -78 °C, 1-2 h NI I Step iR01 R02

[0476] The synthesis of compound R02 from R01 is described in WO 2022175747 Al.

[0477] Procedure: To a solution of 4,5-dibromo-2-methyl-2J / -l,2,3-triazole (R01) (5.0 kg, 20.76 mol) in tetrahydrofuran (50 L, 10 v) at -78 °C was added / / -butyl lithium (9.12 L, 22.84 mol, 1.1 eq., 2.5 M in / / -hexane) under nitrogen atmosphere. The mixture was stirred at the same temperature for 15 - 20 min. N, A-di methyl acetamide (1.92 L, 20.76 mol, 1.0 eq.) was added to the above mixture while maintaining temperature of the mixture below - 75 °C. The reaction mass was stirred at the same temperature (-78 °C to -75 °C) for 30 min. Completion of reaction was confirmed by TLC (20% ethyl acetate / heptane).

[0478] Work up: After the completion of the reaction as confirmed by TLC, RM was quenched with 5% NH4CI solution (10.0 L, 2.0 v) at -78 °C, followed by addition of water (50 L, 10 v). The mixture was then brought to RT and further diluted ethyl acetate (100 L, 20 v).The mixture was stirred for 20 min at RT. Layers were separated. The aqueous layer was extracted with ethyl acetate (50 L, 10 v). All the organic layers were combined and washed with 15 % brine solution (50 L,10 v). Finally, the organic layer was dried over sodium sulphate, filtered and distilled under reduced pressure at 40 °C to obtain crude material as off white solid.

[0479] Purification: The obtained crude material was slurred in MTBE (25 L, 5 v) and cooled to 0 °C to 5 °C. The mixture was stirred at 0 °C - 5 °C for 30 min. and filtered on a -Ill-WSGR Docket No. 59318-727.601Buchner funnel to obtain the desired material as off-white solid. The solids were washed with ice cold MTBE (5.0 L, 1 v). Finally, the material was dried under reduced pressure.TheoreticalProduct Practical yield (kg) yield (kg)1 -(5-bromo-2-methyl-2JT- 1 ,2,3 -triazol-4-yl)ethan- 1 -one 3.704.23(R02) (87.3%)

[0480] Details of Batches:Mass yield LCMSS.No R01 (kg) R02 (kg)(%) Purity (%)1 1 0.7 82.65 99.862 5 4.1 96.81 99.763 10 7.6 89.73 99.434 12 9.3 91.5 97.83

[0481] A total of 313.0 kg of R01 was converted to 235.0 kg of R02. An average yield varying in range of 80 - 90 % was obtained.

[0482] Analytical Data:'H NMR (400 MHz, DMSO-d6) 84.24 (s, 3H), 2.52 (s, 3H).MS (ESI+): m / z calcd for [CsH7BrN3O]+ ([M+H]+), 203.98; (not ionized)

[0483] Other Optimization Experiments:ReactionS.No Current condition Optimization work required condition / / -butyl lithium (1.1 eq), Replacement of / / -butyl lithium with / / -hexyl 1 ReagentsDMA (1.0 eq) lithium2 Solvent THF (lOv) NAExploration of higher temp, and its effects on 3 Temperature -78 °C to -70 °Coutput4 Quenching Sat.aq.NH4C! Solution -20 °C to -10 °CEthyl acetate / water5 Work up Extraction in MTBE \CPME workupReplacement of diethyl ether with CPME or 6 Purification Diethyl etherMTBEInput Output Yield PurityS.NO Condition Remarks (g) (g) (%) (%)SM (1.0 eq), / / -hexyllithium (1.2eq), DMA 'H NMR 1 10 6.7 78.91 97.99(1.1 eq), THF (lOv) , - complies 78° C to -70° CSM (1.0 eq), / / -butyl 'H NMR 2 10 6.8 80.37 98.05lithium (1.2eq), DMA compliesWSGR Docket No. 59318-727.601Input Output Yield PurityS.NO Condition Remarks (g) (g) (%) (%)(1.1 eq), THF (lOv) , - (MTBE used 78° C to -70° C for purification) 'H NMR SM (1.0 eq), / / -butylcomplies lithium (1.2eq), DMA3 10 6.0 70.67 91.25 (Heptane used (1.1 eq), THF (lOv), - for70° C to -60° Cpurification) 'H NMR SM (1.0 eq), / / -butylcomplies lithium (1.2eq), DMA4 100 64 75.56 98.48 (MTBE used (1.1 eq), THF (lOv), - for78° C to -70° Cpurification) 'H NMR SM (1.0 eq), / / -butylcomplies lithium (1.2eq), DMA5 500 350 82.66 97.98 (MTBE used (1.1 eq), THF (lOv), - for78° C to -70° Cpurification)

[0484] Entry 1 : / / -hexyl lithium was found to equipotent to / / -butyl lithium for the conversion (Note: Hexyl lithium is twice the price of n-BuLi)Entry 2: Use of / / -butyl lithium at -78 °C to -70 °C resulted in good conversion (~80 %).Entry 3 : Addition of reagents ( / / -butyl lithium & DMA) at -70 °C to -60 °C resulted in lesser yield. Entry 4: 100 g batch using entry 2 reaction conditions.Purification solvent diethyl ether replaced with MTBE.CPP: Temperature (-78 °C to -70 °C), CQA: KF of THF and DMF (NMT 0.1%)Step II: Synthesis of l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-l,2,3-triazol-4-yl)ethanone (R03)Pd2(dba)3, [(t-Bu)3PH]BF4,KF, THF, H2OStep iiR02 R03

[0485] The synthesis of compound R03 from R02 is described in WO 2023227946 Al.

[0486] Procedure: To a solution of l-(5-bromo-2-methyl-2J / -l,2,3-triazol-4-yl)ethan-l-one (R02) (5.0 kg, 24.51 mol, 1.0 eq) in tetrahydrofuran (50.0 L, 10 v) was added (2-chloro-3-fhioro-4-pyridyl)boranediol (5.16 kg, 29.43 mol, 1.2 eq.), potassium fluoride (2.85 kg, 49.05 mol, 2.0 eq.), tri-tert-butylphosphonium tetrafluoroborate (0.53 kg, 1.83 mol, 0.075 eq.), andWSGR Docket No. 59318-727.601water (5.0 L, 1 v). The mixture was stirred at RT and purged with nitrogen for 30 min. and then to it was added Pd2(dba)s (1.12 kg, 1.22 mol, 0.05 eq.). The RM was purged with nitrogen through the mixture for another 30 minutes. The reaction mass was then stirred at 50 - 60 °C for 2 - 3 h. Completion of reaction was confirmed by TLC (50% ethyl acetate / hexanes).

[0487] Work up: After completion of the reaction, the reaction mass was brought to RT and filtered through a bed of celite. The bed of celite was washed with ethyl acetate (25 L, 5 v) to ensure complete removal of material. Ethyl acetate (75 L, 15 v) / water work (100 L, 20 v) up was done. The organic layer was separated and then washed with 10 % brine solution (100 L, 20 v). Finally, the organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material as dark brown viscous oil.

[0488] Purification: The obtained crude material was adsorbed on silica (100- 200 mesh) and the pad filtered using 60 - 120 mesh silica in 0 - 50 % ethyl acetate / heptane. Appropriate fractions were collected and the solvent was distilled off to obtain pure material as an off white solid.

[0489] Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 88.38 (d, J= 4.8 Hz, 1H), 7.66 (t, J= 4.8 Hz, 1H), 4.35 (s, 3H), 2.57 (s, 3H).MS (ESI+): m / z calcd for [CioH9ClFN40]+([M+H]+), 255.04; found, 255.15.Theoretica Practical Product M.wt.1 yield (kg) yield (kg) l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2JT- 4.57254.65 6.24l,2,3-triazol-4-yl) ethanone (R03) (73.23 %)

[0490] All temperatures mentioned are internal; All the volumes and equivalents mentioned are with respect to starting material; The reaction proceeds well using the above conditions.

[0491] Details of Batches:Purity byMass yieldS.No R02 (kg) R03 (kg) LCMS(%)(%)1 1.00 0.89 71.31 99.312 5.00 4.57 73.23 98.983-36 6.00 5.18-5.89 69.17-78.65 91.19-99.5

[0492] A total of 211.0 kg of R02 was converted to 188.0 kg of R03. An average yield varying in range of 69 - 75 % was obtained. LCMS analysis provided the qualitative results. Some impurities were present which were related to catalyst byproduct. The LCMS purity wasWSGR Docket No. 59318-727.601greater than 90% and had no impact on the next reaction. Therefore, the next step was conducted without any further purification.Step III: Synthesis of (R, Z)-N-( 1 -(5-(2-chloro-3-fluoropy ridin-4-yl )-2-methyl-2 / / - 1,2,3-triazol-4-yl)ethylidene)-2-methylpropane-2-sulfinamide (R04)(R)-t-butylsulfinamide, Ti(Oi-Pr)4, THF, 75 °C, 48 hStep HiR03

[0493] Procedure: (J1783-1540953)

[0494] To a solution of l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2J / -l,2,3-triazol-4-yl)ethan-l-one (R03) (5.0 kg, 19.63 mol, 1.0 eq) in tetrahydrofuran (25 L, 5 v) was added (R)-(+)- / c / 7-Butylsulfinamide (2.85 kg, 23.56 mol, 1.2 eq) and titanium isopropoxide (23.82 L, 78.52 mol, 4 eq.). The reaction mass was stirred at 75 °C for 48 h. Completion of the reaction was confirmed by TLC. (50% ethyl acetate in hexanes)

[0495] Work up: After the completion of reaction as confirmed by TLC. The reaction mass was brought to RT and further diluted with 10 % methanol / DCM (50 L, 10 v) followed by water (50 L, 10 v) (During the addition of water solid precipitation was observed). The mixture was stirred at RT for 15 min. and then filtered through a bed of celite. The bed of celite was washed with 10% methanol / DCM (50 L, 10 v). Check the TLC of filtrate to ensure complete removal of material. (# If material is not completely removed then take the solids in reactor and stir the solid in a mixture of 10 % methanol / DCM for 30 min. and fdter under reduced pressure over Nutsche to ensure complete isolation of desired material). Filtrate was taken in separatory funnel. The organic layer was washed with water (100 L, 20 v) to ensure complete precipitation of titanium salts. Finally, all the organic layer was once again passed through bed of celite. The filtrate was concentrated under reduced pressure to obtain crude material as a dark colored solid.

[0496] Purification: Crude material was dissolved in MTBE (15.0 L, 3v) and cooled to -10 °C. The mixture was stirred at the same temperature for 30 min. and filtered under reduced pressure to obtain desired off white solid.

[0497] Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 88.37 (d, J= 4.8 Hz, 1H), 7.63 (t, J= 4.8 Hz, 1H), 4.33 (s, 3H), 2.74 (s, 3H), 0.82 (s, 9H).MS (ESI+): m / z calcd for [Ci4Hi8ClFN5OS]+([M+H]+), 358.09; found, 358.12

[0498] Results:WSGR Docket No. 59318-727.601Theoretical Practical Product M.wt.yield (kg) yield (kg) (R, Z)-A-(l-(5-(2-chloro-3-fluoropyridin-4-yl)-2- 4.2 methyl-2J / -l,2,3-triazol-4-yl)ethylidene)-2- 357.83 7.02(59.7%)methylpropane-2-sulfmamide (R04)

[0499] Note: All temperatures mentioned are internal; All the volumes and equivalents mentioned are with respect to starting material; The reaction proceeds well using the above conditions.

[0500] Details of Batches:R03 Mass yield LCMS PurityS.No R04 (kg)(kg) (%) (%)1-3 6 4.5-4.7 53.37-55.75 94.53-97.474-14 12 9.5-10.5 56.34-62.27 91.59-99.29

[0501] A total of 169.0 kg of R03 was converted to 142.0 kg of R04. An average yield varying in range of 55 - 60 % was obtained. LCMS analysis provided the qualitative results therefore the variability in purity profile was observed. In order to get exact purity profile HPLC method development needs to be done which provides quantative results. Since the LCMS purity was greater than 90 % and had no impact on next reaction; therefore we proceeded to next step without any further purification. Lower yield was attributed to loss of the material to the MLR during purification process.

[0502] Note: The product can be purified by crystallization from MTBE at -10 °C.Step IV: Synthesis of ( / ?)- \-((.S)-l-(5-(2-chloro-3-nuoropyridin-4-yl)-2-methyl-2 / / -1.2.3-triazol-4-yl)ethyl)-7V,2-dimethylpropane-2-sulfinamide (R06)i) L-Selectride (1.6 eq); 2 Me-THF (10v),-10 °C - 0 °C, 1-2 h ii) Mel (1.6 eq);-10 °C - 0 °C, 1-2 h, 20 °C, 16 hStep ivR06

[0503] Procedure:WSGR Docket No. 59318-727.601

[0504] To a solution of (5, Z)-A-(l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2J / -l,2,3-triazol-4-yl)ethylidene)-2-methyl propane-2-sulfmamide (R04) (3.5 kg, 9.78 mol, 1.0 eq.) in 2-methyl tetrahydrofuran (35.0 L,10.0 v) was added Z-selectride (15.63 L, 15.64 mol, 1.6 eq., IM in THF) at -5 °C ± 5 °C. The reaction mass was stirred at 0 °C for 2 h. Formation of R05 was confirmed by TLC (30% ethyl acetate / heptane, 60% ethyl acetate / heptane)? N-NHN\JLN( X

[0505] After the formation of R05 (NCl , (j?)-N-((5)-l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-l,2,3-triazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide), methyl iodide (0.97 L, 15.64 mol, 1.6 eq) was added to the reaction mass at - 5 °C - 0 °C (exothermicity of 4 °C - 5 °C observed). The reaction mass was stirred at 0 - 5 °C temperature for 2 h. The temperature of the reaction mass was raised to 20 °C and the mixture stirred for 16 h at 20 °C. Completion of reaction was confirmed by TLC (60% ethyl acetate / heptane).

[0506] Work up: After the completion of reaction as confirmed by TLC, the RM was quenched with 2ANaOH solution (7.0 L, 2 v) at 0 ° - 5 °C. Then 30 % hydrogen peroxide (7.0 L, 2 v) was added to quench the side product of Z-selectride at 0 ° - 20 °C (Change in color of reaction mass observed, red dark color RM observed). The mixture was stirred at 25 °C - 30 °C for Ih to ensure complete quenching of the reaction mass. Ethyl acetate (52.5 L, 15 v) and water (52.5 L, 15 v) work up was done under stirring. The organic layer was separated and washed with 10 % brine solution (35.0 L, 10 v) under stirring. The organic layer was then washed with 2N NaOH solution (7.0 L, 2 v) under stirring for 15 - 20 min. (Change in color of reaction mass observed, light color reaction mass observed). The organic layer was washed with 5.0 % sodium thiosulphate solution (17.5 L, 5 v). The mixture was stirred for 15 min. (Change in the color of reaction mass observed, light color reaction mass observed). Finally, the separated organic layer was washed with water (35.0 L, 10 v) and 10 % brine (35.0 L, 10 v). The aqueous layer was checked for peroxide content using peroxide test strip. The organic layer was dried over sodium sulphate, filtered and cone, under reduced pressure to obtain the desired crude product as a brown oil. Submit the sample forXH NMR and LCMS analysis.

[0507] Purification: The obtained crude material (- 3.56 kg) was forwarded to the next step as such without any further purification.

[0508] Results:Theoretical Practical Product M.wt.yield (kg) yield (kg)WSGR Docket No. 59318-727.6013.56 (A)-A-((5)-l-(5-(2-chloro-3-fluoropyridin-4-yl)-2- (Crude) methyl -27 / - 1 ,2,3 -triazol-4-yl)ethyl)-7V,2- 373.88dimethylpropane-2-sulfmamide (R06) 97.35 %

[0509] All temperatures mentioned are internal. All the volumes and equivalents mentioned are with respect to starting material. The reaction proceeds well using the above conditions. Crude carried to the next step as such.

[0510] Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 68.39 (d, J= 4.8 Hz, 1H), 7.71 (t, J= 4.8 Hz, 1H), 4.80 (q, J = 6.8 Hz, 1H), 4.27 (s, 3H), 2.21 (s, 3H), 1.52 (d, J= 6.8 Hz, 3H), 0.87 (s, 9H).MS (ESL): m / z calcd for [CI5H22C1FN5OS]+([M+H]+), 374.12; found, 374.205

[0511] Details of Batches:Mass yield Purity (%)S.No R04 (kg) R06 (kg)(%) by LCMS1 0.50 0.52 97.89 83.592-40 3.50 3.51-3.60 95.98-98.44 53.45-89.96

[0512] LCMS analysis provides the qualitative results and it is not quantified. Therefore, purity data varied from batch to batch. A total of 140.0 kg of R04 was converted to 142.0 kg of R06. An average crude yield varying in range of 95 - 99 % was obtained. The main reason for variability in the yields is attributed to the methods of analysis. LCMS method of analysis provides the qualitative results, not the quantitative results. HPLC analysis method needs to be developed. Apart from it one impurity i.e. des methyl R07 was also formed. These two factors were mainly responsible for lower LCMS purity in this step.

[0513] Other Optimization Experiments:S.N Inpu Outpu Yield Purity Temp.Condition Remarks0 t (g) t (g) (%) (%) (°C)9.0 -10 °C- 01 10.0 86.5 63.68 HNMR(crude) Comp. 3 °C complies(1.0 eq.),50.0 -10 °C- 02 50.0 100.0 74.31 L- ’HNMR(crude) °Cselectride complies365.0 -10 °C- 03 360.0 101.0 76.81 (L5 ’HNMR(crude) eq.),THF °C complies(10.0 Reaction did58.11 %vol.), Mel not go to(pdt) + -10 °C- 04 5.0 - - (1.5 eq.) completion34.16 % °Cdue to impure(R05)R04WSGR Docket No. 59318-727.601Reaction did13.65 %- not go to(pdt) + -10 °C - 05 5.0 - completion78.32 % °Cdue to impure(R05)R04- 10 °C85.89%4.0 (comp- R04,6 5.0 - (pdt) + 2.23 - 10 °C(crude) charcoal% (R05)treated)- 40 °C81.61%4.0 (comp- R04,7 5.0 - (pdt) + 9.46 - 40 °C(crude) charcoal% (R05)treated)Step V: Synthesis of (5)-6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]ti'iazolo[4,5-c][l,7]naphthyridine (R07)i)4 M HCI / 1 ,4-dioxane20 °C-30 °C, 10-16 hii) DIPEA, 1,4-dioxane90 °C, 2-3 hStep vR07

[0514] Procedure: To a solution of (A)-A-((5)-l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2J / -l,2,3-triazol-4-yl)ethyl)-A,2-dimethylpropane-2-sulfinamide (R06) (7.1 kg, 18.99 mol, 1.0 eq) in dioxane (17.75 L, 2.5 v) was added 4 AHC1 in dioxane (17.75 L, 2.5 v) at 20 -30 °C. The reaction was stirred at RT for 10 - 16 h. Hydrolysis of the sulfmamide group was confirmed by LCMS (SM (R06) <1.0%). After hydrolysis the reaction mass was concentrated under reduced pressure to obtain hydrolyzed material. This material was azeotrope (To obtained crude 27 L of dioxane was added and distilled under reduced pressure. This process was repeated thrice) with dioxane (27 L X 3) to get rid of trapped HC1 residue. After azeotrope, the hydrolyzed material was dissolved in dioxane. DIPEA (16.53 L, 94.95 mol., 5.0 eq) was added at 20 °C - 30 °C. The reaction mass was heated at 90 °C for 2 - 3 h. Completion of reaction was confirmed by LCMS (SM (hydrolysed material) <1.0%).

[0515] Work up: After completion of reaction, the RM was brought to RT. Ethyl acetate (71 L x 2, 2 x 10 v) / water work up (71 L, 10 v) was done. The separated organic layer was washed with 10 % brine solution (71 L, 10 v). The organic layers were combined and dried over sodium sulphate. Finally, the organic layer was filtered and concentrated under reduced pressure to obtain crude material as a brown solid.WSGR Docket No. 59318-727.601

[0516] Purification: The obtained crude material was slurred in IPA (14.2 L, 2.0 v) and the mixture was then heated at 70 °C for 30 min. to form a clear solution. Mixture was then cooled to 25 °C and stirred at 25 °C for 30 minutes (solid formation observed). Obtained solids were filtered under reduced pressure to obtain desired material as an off white solid.

[0517] Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 88.16 (d, J= 4.8 Hz, 1H), 7.63 (d, J= 4.8 Hz, 1H), 4.64 (q, J = 6.8 Hz, 1H), 4.24 (s, 3H), 2.74 (s, 3H), 1.13 (d, J= 6.8 Hz, 3H).MS (ESI+): m / z calcd for [CHHI3C1N5]+([M+H]+), 250.09; found, 250.12

[0518] Results:M.W Theoretical Practical Productt. yield (kg) yield (kg)(S)-6-chloro-2,4,5-trimethyl-4,5-dihydro-2H- 249.7 3.204.75[ 1 ,2,3 ]triazolo[4,5 -c] [ 1 ,7]naphthyridine (R07) 0 (67.39 %)All temperatures mentioned are internal. All the volumes and equivalents mentioned are with respect to starting material. The reaction proceeds well using the above conditions

[0519] A total of 142.0 kg of R06 was converted to 65.0 kg of R07. An average yield varying in range of 67 - 70 % was obtained. Product was lost to MLR during purification process.Attempts were made to isolate the second crop. All the actions to recover the material from MLR turned to be futile.WSGR Docket No. 59318-727.601Example 2: Synthesis of Formula 11 [(5)-6-(cyclopropanecarboxamido)-7V-(methyl-d3)-4-((2.4.5-triinethyl-4.5-dihydro-2 / / -| 1.2.3 ]triazolo[4,5-c][l,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide] from R07.R11Step I: Synthesis of ( S)- \-(2.4.5-triinethyl-4.5-dihydro-2 / / -| 1.2.3|triazolo|4.5-c][l,7]naphthyridin-6-yl) cyclopropanecarboxamide (R08)R07

[0520] The synthesis of compound R08 from R07 is described in WO 2022175747 Al.

[0521] Procedure: To a solution of (5)-6-chloro-2,4,5-trimethyl-4,5-dihydro-2JT-[l,2,3]triazolo[4,5-c][l,7]naphthyridine (2.4 kg, 9.61 mol., 1.0 eq.) in toluene (24 L, 10 v) was added cyclopropanecarboxamide (1.63 kg, 19.22 mol., 2.0 eq.), cesium carbonate (6.26 kg, 19.22 mol., 2.0 eq), xantphos (0.56 kg, 0.961 mol., 0.1 eq.). Mixture was purged with nitrogen for 15 - 20 min. and then to it was added Pd2(dba)s (0.88 kg, 0.961 mol., 0.1 eq.). Reaction mass was again purged with nitrogen for 10 min. and then heated at 110 °C for 16 h - 20 h.Completion of reaction was confirmed by TLC (neat ethyl acetate).

[0522] Work up: After completion reaction, RM was brought to RT. Reaction mass was filtered through bed of celite. Bed of celite was washed with ethyl acetate (24 L, lOv) to ensure complete removal of the compound. Filtrate was further diluted with ethyl acetate (12 L,5 v) andWSGR Docket No. 59318-727.601given water washing (24 L,10 v) was done. Organic layer was washed with 10% brine (24 L,10v). Organic layer was then dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material.

[0523] Purification: Obtained crude material was column chromatographed using 60 -120 mesh silica in 0 - 50 % ethylacetate / heptane. Pure fractions pooled and distilled under reduced pressure to obtain pure material.

[0524] Analytical Data:

[0525] 1H NMR (400 MHz, DMSO-t / 6) 89.84 (s, 1H), 8.01 (d, J= 4.8 Hz, 1H), 7.40 (d, J = 4.8 Hz, 1H), 4.60 (q, J= 7.2 Hz, 1H), 4.25 (s, 3H), 2.74 (s, 3H), 2.03 (quint, J= 6.4 Hz, 1H), 1.15 (d, J= 6.8 Hz, 3H), 0.885-0.855 (m, 4H).

[0526] MS (ESI+): m / z calcd for [Ci5Hi9N6O]+([M+H]+), 299.16; found, 299.37

[0527] Results:Theoretica Practical Product M.wt.1 yield (kg) yield (kg) (5)-7V-(2,4,5-trimethyl-4,5-dihydro-2Z7- 2.55 [ 1 ,2,3 ]triazolo[4,5 -c] [ 1 ,7]naphthyridin-6- 298.35 2.87(85%)yl)cyclopropanecarboxamide

[0528] All temperatures mentioned are internal. All the volume and equivalents mentioned are with respect to starting material. The reaction proceeds well using the above conditions.

[0529] Details of Batches:Comp- Comp- YieldEntry R07 R08 Hl NMR(%)(kg) (kg)1 0.50 0.49 complies 82.022.45- 2-3 2.40 complies 85.45-88.942.55Step II: Synthesis of (N)-2.4, 5-triniethyl-4.5-dihydro-2 / / -| 1.2,3]triazolo[4, 5-c] [l,7]naphthyridin-6-amine (R09)N-N / N-Naq. LiOH.H2O, THF70 °C, 16 h Step iiR08 R09WSGR Docket No. 59318-727.601

[0530] The synthesis of compound R09 from R08 is described in WO 2022175747 Al.

[0531] Procedure: To a solution of (5)-A-(2,4,5-trimethyl-4,5-dihydro-2JT-[l,2,3]triazolo[4,5-c][l,7]naphthyridin-6-yl) cyclopropane carboxamide (2.4 kg, 8.04 mol., 1.0 eq.) in THF (15.98 L, 6.66 v) was added solution of LiOH hO (1.68 kg, 40.22 mol., 5.0 eq) dissolved in water (7.99 L, 3.33v). Reaction mixture was heated at 75 °C for 7 - 8 h.Completion of reaction was confirmed by TLC (50% acetone / heptane) andXH NMR.

[0532] Work up: After completion reaction, RM was brought to RT. 10 % methanol / DCM (36 L,15 v), water work up (24 L,10 v) was done. Organic layer was washed with water until the pH of aqueous layer was found to be neutral. All the aqueous layers were combined and extracted with 10 % methanol / DCM (24 L,10 v). Finally, all the organic layers were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material.

[0533] Purification: Obtained crude material was pad filtered using 60 - 120 mesh silica in 0 - 10 % methanol / DCM. Appropriate fractions were collected and distilled off to obtain pure material.

[0534] Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 87.79 (d, J= 5.2 Hz, 1H), 6.82 (d, J= 5.2 Hz, 1H), 5.82 (s, 2H), 4.33 (q, J= 6.8 Hz, 1H), 4.19 (s, 3H), 2.42 (s, 3H), 1.10 (d, J= 6.8 Hz, 3H).MS (ESI+): m / z calcd for [CiiHi5N6]+([M+H]+), 231.14; found, 231.22

[0535] Results:Theoretical Practical Product M.wt.yield (kg) yield (kg) (5)-2,4,5-trimethyl-4,5-dihydro-2J / -[l,2,3]triazolo [4,5- 230.27 1.85 1.50 c] [ 1 ,7]naphthyridin-6-amine

[0536] All temperatures mentioned are internal. All the volume and equivalents mentioned are with respect to starting material. The reaction proceeds well using the above conditions.

[0537] Details of Batches:Comp- Comp- C.HPLC% HPLC Yield Entry 08 09(AUC) Purity NMR (%)(kg) (kg)1 0.48 0.27 97.50 95.29 complies 72.97 2 2.40 1.50 97.78 91.42 complies81.08WSGR Docket No. 59318-727.601Other Optimization Experiments:Reaction CurrentS.No Optimization work required condition condition1 Reagents LiOH (5.0 eq) Screening of base equivalence THF / Water (2:1,2 Solvent Lower of solvent volumes lOv)3 Temperature 70 °C - 75 °C NAEthyl acetate / 4 Work up NAwater work upColumn Elimination of column chromatography 5 Purificationchromatography and establish chiral purification conditionChiralInput Output Yield Purity HPLCS.No Condition Remarks(g) (g) (%) (%) Purity(%)0.6 98.521 1.0 78 91.61 Base Screening (crude) +1.4830 % Aim of the NaOH (2v), reaction is avoid Methanol column66(lOv), 70 purification and 21.0 (over 99.022 6.1 94.14 °C, 8h make(crude) 2 +0.98corresponding steps)HC1 salt and purify it by acid base methodLiOH Acid base (5.0eq), methodology THF applied for3 50.0 30.5 79.03 93.41 - (6.6v), purification,Water results were not (3.3v), 70 consistent w.r.t°C, 8h purity and qualityStep I+II: Multi-kilogram-scale synthesis of ( S)-2.4.5-triinethyl-4.5-dihydro-2 / / - [l,2,3]triazolo[4,5-c] [l,7]naphthyridin-6-amine (R09) / N-N aq. LiOH.H2O, THF 70 °C, 16 h Step / / R07 R09WSGR Docket No. 59318-727.601Procedure:

[0538] Buchwald-Hartwig coupling followed by hydrolysis. Compound R07 is coupled with cyclopropanecarboxamide in the presence of Xantphos, powder cesium carbonate, and tris (dibenzylideneacetone)di palladium(O) catalyst in toluene media at reflux temperature (104-109 °C) to yield Compound R08 mass complex (in-situ). The reaction mass is diluted with ethyl acetate and filtered to remove palladium salts. The filtrate is washed with water and the organic solvent distilled under vacuum at 50-55 °C. Compound R08 is further reacted with aqueous lithium hydroxide solution in THF solvent at 63-68 °C. After completion of the reaction the organic layer is washed with demineralized water and 25% brine solution. The organic layer is distilled and the product is isolated as the oxalate salt in acetonitrile solvent. Compound R09 oxalate salt is further treated with aqueous sodium hydroxide in 2-Methyl THF solvent and washed with water and the layers separated. The organic layer is distilled to dryness and the residual reaction mass is then mixed with MTBE followed by heptane followed by filtration and drying.Details of Batches:S. No. Batch Input Batch output Yield (%) 1-2 19 Kg 14.52 Kg-13.35 Kg 83.07 %-76.40% 3 21 Kg 16.76 Kg 86.74%Step III: Synthesis of CS’)-6-chIoro-X-( ni el Iiy l-ds )-4-( (2.4..5-1 rim et Iiy 1-4,5-d iliy d ro-2 / / -[l,2,3]triazolo[4,5-c] [1,7] naphthyridin-6-yl)amino)pyridazine-3-carboxamide (RIO)R09R10

[0539] The synthesis of compound R10 from R09 is described in WO 2022175747 Al.

[0540] Procedure:1. To a stirred solution of (5)-4,8-dimethyl-7-methyl-3,4,5,8,l 1-pentaazatricyclo[7.4.0.02,6]trideca-l(9),2,5, 10,12-pentaen-10-ylamine (1 kg, 4.34 mol) in 2-methyltetrahydrofuran (8 L) at 25 °C was charged A-(2H3)methyl-4,6-dichloro-3-pyridazinecarboxamide (1.36 kg, 1.5 eq., 6.51 mol) under nitrogen atmosphere in one lotWSGR Docket No. 59318-727.601(Observation: tan color suspension observed) , stirred the reaction mixture for another 10 min for uniform mixing.2. Reaction mixture was then cooled to 10 °C and then to it was added lithium bis(trimethylsilyl)azanide (15 L, 5 eq., 21.7 mol) at 10 °C - 20 °C over a period of 2.5 h. (Observation: During the addition of LiHMDS at one point reaction mixture will become thick, during this time RPM should be on the higher side, when 90% of LiHMDS is added into the reaction mixture it will turn into clear solution)3. After complete addition of LiHMDS, reaction mass stirred at 10 °C - 20 °C for Ih.4. Completion of reaction was confirmed by TLC (neat ethyl acetate) and HPLC.

[0541] Workup1. After the completion of reaction as confirmed by TLC and HPLC, reaction mixture was reversed quenched into ice-cooled water (25 L, 25v).2. After quenching mixture was stirred at RT for 30 - 45 min. Aqueous layer was extracted with 10% methanol / DCM (20 L x 2, 20v x 2).3. Combined organic layers were washed with 10% brine solution (10L, lOv),organic layer separated and distilled under reduced pressure to tan color solid as crude (1.5 kg)

[0542] Purification:1. Obtained crude material was slurred in methanol (4.5 L, 3v w.r.t crude) and stirred for 30 min. at 25 °C.2. Filtered the solid suspension on Buchner funnel, suction dried.3. Wet cake was washed with methanol until the color of the filtrate turned into colorless.4. After methanol washing, suction dried the cake.5. Unload the material from Buchner funnel and dried in ATD at 60 °C for 3.0 h to afford compound R10 as off white solid.

[0543] Analytical Data:IH NMR (400 MHz, DMSO-t / 6) 8 12.44 (s, IH), 9.42 (s, IH), 9.27 (s, IH), 8.27 (d, J= 5.2 Hz, IH), 7.36 (d, J= 5.2 Hz, IH), 4.58 (q, J= 6.8 Hz, IH), 4.25 (s, 3H), 2.56 (s, 3H), 1.15 (d, J = 7.2 Hz, 3H).MS (ESL): m / z calcd for [CnHieDsC O] ([M+H]+), 403.16; found, 403.31

[0544] Results:Theoretical Practical Product M.wt.yield (kg) yield (kg) (5)-6-chloro-A-(methyl-d3)-4-((2,4,5-trimethyl-4,5- 1.20 dihydro-27 / -[ 1 ,2,3 ]triazolo[4, 5-c] [ 1 ,7]naphthyridin-6- 402.86 1.75(68%)yl)amino)pyridazine-3-carboxamideWSGR Docket No. 59318-727.601

[0545] All temperatures mentioned are internal. All the volume and equivalents mentioned are with respect to starting material. The reaction proceeds well using the above conditions.

[0546] Details of Batches:Comp- Comp- HPLCC. HPLC *H Yield Entry 09 10 Purity(% AUC) NMR (%)(kg) (kg) (%)1 0.26 0.26 99.89 99.00 complies 57.261.10- 99.21- 2-4 1.00 99.18 complies 62.89- 1.20 99.8268.59Other Optimization Experiments:

[0547] Procedure with sodium hydride: To a solution of sodium hydride (26.0 g, 0.65 mol, 5.0 eq.) in DMF (300 mL, lOv) at 0 °C was added a mixture of A-(2H3)methyl-4,6-dichloro-3-pyridazinecarboxamide (81.7 g, 0.39 mol, 3.0 eq.) and (5)-2,4,5-trimethyl-4,5-dihydro-2JT-[l,2,3]triazolo[4,5-c][l,7]naphthyridin-6-amine (30.0 g, 0.13 mol, 1.0 eq.) dissolved in DMF (150 mL, 5v) at 0 °C - 5 °C over a period of 1.5 h. After complete addition reaction was stirred at 25 °C for 15 - 30 min. Completion of reaction was confirmed by TLC.ReactionS.No Current condition Optimization work required conditionExploration of reagents such as1 Reagents Int-A (3.0eq), NaH (5.0 eq) LiHMDS, K’OBu, etc or proceed with Li-Sat of int-A.Exploration of workable volumes to 2 Solvent DMF (15v)increase batch size0 °C - 25 °C (exothermic at3 Temperature Exotherm of reaction is to be studied 25 °C)Quenching with sat. Quenching volumes and temperature to 4 Work upaq. solution of NH4CI be screenedRe-purification method to be developed 5 Purification No column chromatographyto improve chiral puritiesConditionInput LiHMDS Output Yield Purity *HS.NO 2-Me(g) Int-A (eq.) (IM in THE)THF (v) (g) (%) (%) NMR(eq.)1 1.0 1.1 7.0 10 0.70 40.2 99.57 complies 2 1.0 1.3 7.0 10 0.85 48.8 97.50 complies 3 1.0 1.5 7.0 10 1.00 57.4 99.75 compliesWSGR Docket No. 59318-727.6014 1.0 2.0 7.0 10 1.00 57.4 99.71 complies 5 1.0 3.0 7.0 10 0.90 51.7 99.88 complies 6 1.0 1.5 5.0 10 0.87 50.0 93.80 complies 7 1.0 1.5 9.0 10 0.89 51.1 98.25 complies 8 5.0 1.5 7.0 10 5.10 58.3 99.04 complies 5.0 (1.4 M in9 10.0 1.5 10 11.5 65.7 98.78 complies THF)5.0 (1.4 M in10 10.0 1.5 10 10.0 57.17 94.53 compliesTHF)Step III: Multi-kilogram-scale synthesis of (5)-6-chloro-7V-(methyl-d3)-4-((2,4,5-trimethyl- 4.5-dihydro-2 / / -| l,2,3]triazolo[4,5-c][l,7] naphthyridin-6-yl)amino)pyridazine-3-carboxamide (RIO).R09R10Procedure: Compound R09 reacts with Compound R12 in 2-methyl THF in the presence of lithium bis (trimethyl silyl) amide (1.4 M solution in THF) to afford crude Compound RIO which is then slurried in methanol to obtained pure Compound RIO as an off white solid.Details of Batches:S. No. Batch Input Batch output Yield (%)1-2 13.30 Kg-13.66 Kg 16.28 Kg-15.88 Kg 69.99 % - 66.47 % 3 15.03 Kg 18.34 Kg 69.78 %WSGR Docket No. 59318-727.601Step IV: Synthesis of (5)-6-(cyclopropanecarboxamido)-7V-(methyl-d3)-4-((2,4,5-trimethyl- 4.5-dihydro-2 / / -| 1.2.3 ]triazolo[4,5-c][l,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide (Rll)

[0548] Compound Rll is described in WO 2022175747 Al.

[0549] Procedure: To a solution of (5)-6-chloro-A-(methyl-d3)-4-((2,4,5-trimethyl-4,5-dihydro-2J / -[l,2,3]triazolo[4,5-c][l,7] naphtha yridin-6-yl)amino)pyridazine-3-carboxamide (2.0 kg, 4.96 mol., 1.0 eq.) in dioxane (50 L, 25 v) was added cyclopropanecarboxamide (1.06 kg, 12.45 mol., 2.5 eq.), cesium carbonate (4.05 kg, 12.43 mol., 2.5 eq), xantphos (0.288 kg, 0.498 mol., 0.1 eq.), water (6..68 L, 3.34v). Mixture was purged with nitrogen for 15 - 20 min. and then to it was added Pd2(dba)s (0.46 kg, 0.502 mol., 0.1 eq.). Reaction mass was again purged with nitrogen for 10 min. and then heated at 110 °C for 16 h - 20 h. Completion of reaction was confirmed by TLC (neat ethyl acetate).

[0550] Work up: After completion reaction, RM was brought to RT. Reaction mass was filtered through bed of celite. Bed of celite was washed with 10% methanol / DCM (30 L, 15v) to ensure complete removal of the compound. Filtrate was charged into separating funnel and washed with water (20 L,10v). Organic layer separated and was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material.

[0551] Purification: Obtained crude material was column chromatographed using 100 - 200 mesh silica in 0 - 5 % methanol / DCM. Pure compound eluted. Pure fractions pooled and distilled under reduced pressure to obtain Rll with 85% purity, having residual cyclopropane carboxamide and Pd 2(dba)s related impurities.

[0552] Purification in Ethyl acetate: Column purified Rll (2.0 kg) was taken in Ethyl acetate (10 L, 5.0v) and stirred at 65°C, for 4.0 Hr. (Observation bright yellow color solid suspension). Cooled the RM to 25°C and filtered. Cake washed with ethyl acetate (5.0 L, 2.5v). Suction dried. Material unloaded and dried in VTD at 50°C for 6 Hr to afford Pure Rll with NLT 98% purity by HPLC and Chiral HPLC.WSGR Docket No. 59318-727.601

[0553] Palladium scavenging: Material obtained after Ethyl acetate purification was subjected for palladium scavenging. 2.6 Kg of Rll was dissolved in 10 % MeOH / DCM (78 L, 30 v). SiliaMetS Thiol (780 g, 30 % wt. / wt.) was added and mixture was stirred at RT for 16h. Mixture was then filtered through the bed of celite. The bed of celite was washed repeatedly with 10 % MeOH / DCM to ensure complete removal of desired material. Finally, filtrate was passed through 0.2-micron filtration cartridge, Micron filtered filtrate distilled off under reduced pressure at 40°C to obtain desired material. Obtained pure Rll was dried in VTD at 80 °C for 48 Hr to remove residual DCM, MeOH and EtOAc.

[0554] In a smaller-scale syntheses of Compound R11 (conducted with 300 g of Compound R10), material obtained after column chromatography was subjected to palladium scavenging. Material was dissolved in 10 % MeOH / DCM (30 v). SiliaMetS Thiol (SH) (30 % wt. / wt.) was added and mixture was stirred at RT for 16h. Mixture was then filtered through the bed of celite. The bed of celite was washed repeatedly with 10 % MeOH / DCM to ensure complete removal of desired material. Finally, filtrate was distilled off under reduced pressure to obtain desired material. Palladium content analysis (ICP-MS) revealed the presence of 7.85 ppm palladium in isolated material.Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 8 12.25 (s, 1H), 11.30 (s, 1H), 9.84 (s, 1H), 9.16 (s, 1H), 8.15 (d, J= 5.2 Hz, 1H), 7.27 (d, J= 5.2 Hz, 1H), 4.56 (q, J= 7.2 Hz, 1H), 4.24 (s, 3H), 2.54 (s, 3H), 2.12 (quint, = 6.4 Hz, 1H), 1.15 (d, J= 6.8 Hz, 3H), 0.885-0.855 (m, 4H).MS (ESI+): m / z calcd for [C2iH22D3Nio02]+([M+H]+), 452.23; found, 452.24

[0555] Results:Theoretica Practical Product M.Wt.1 yield (kg) yield (kg) (5)-6-(cyclopropane carboxamido)-A-(methyl-d3)-4- ((2,4,5-trimethyl-4,5-dihydro-2J / -[l,2,3] triazolo[4,5- 451.51 3.8 2.3 (60%) c][l,7] naphthyridin-6-yl)amino) pyridazine-3-carb oxami deWSGR Docket No. 59318-727.601Step IV: Multi-kilogram-scale synthesis of (3)-6-(cyclopropanecarboxamido)-7V-(methyl-d3)-4-((2.4.5-trimethyl-4.5-dihydro-2 / / -| 1 ,2,3 ]triazolo[4,5-c][l,7]naphthyridin-6-yl)amino)pyridazine-3-carboxamide (R11)Procedure: Compound RIO reacts with cyclopropanecarboxamide, cesium carbonate, Xantphos, water, and tris(dibenzylideneacetone)dipalladium(0) catalyst in the presence of 1,4-di oxane to afford crude Compound Rll. The crude Compound Rll wet material was treated with silica gel and ethyl acetate solvent leaching and palladium scavenging was accomplished in 10% Methanol :DCM using SiliaMetS Thiol (SH) to afford Compound Rll crude wet material followed by further purification with 10 % methanol : DCM to get Pure compound Rll as off white to yellow colored solid powder.Details of Batches:S. No. Batch Input Batch output Yield (%) 1-3 14 Kg 8.77 kg - 9.29 kg 55.93 % - 65.21%Example 3: Synthesis of 4,6-dichloro-7V-(methyl-d3)pyridazine-3-carboxamide (R12)Int-A R12

[0556] Compound R12 is described in WO2022175746 Al.

[0557] Procedure: To stirred solution of lithium 4,6-dichloropyridazine-3-carboxylate (Int-A) (2.0 kg, 5.02 mmol ) in THF(20 L) at 25°C, was added DIPEA ( 8.78 L, 50.27 mol) Stirred for 10 min. Cool the RM to 10-20°C and charged TsP(50%in EtOAc, 9.62 L, 32.16 mol) over a period of 1.5 Hr. After addition stir the RM at 10-20°C for 1.0 Hr Add Methyl-t / 3-amineWSGR Docket No. 59318-727.601hydrochloride (0.70 Kg, 10.05 mol.) into the RM and maintained RM at same temperature for 2.0 Hr. Progress of reaction monitored by TLC (50% ethyl acetate / heptane).

[0558] Workup: After completion of reaction RM quench with ice cold water (20L, lOv) and extracted in EtOAc (3x10 L); combined organic extracts were washed with brine (10L, 5v), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. Crude was purified in DCM (3.0 V, 6.0 L)

[0559] Results:Theoretical Practical Product M.Wt.Yield (kg) Yield (kg)4,6-dichloro-N-(methyl-d3)pyridazine-3-carboxamide 208 2.1 1.45

[0560] All temperatures mentioned are internal. All the volume and equivalents mentioned are with respect to starting material. The reaction proceeds well using the above conditions

[0561] Other Optimization Experiments:ReactionS.No Current condition Optimization work required conditionCyclopropane carboxamide (2.5 eq),1 Reagents Pd2(dba)s (0.1 eq), Xantphos (0.1 eq), NACs2CO3(3.0 eq),2 Solvent Dioxane / water (lOv : lv)) Exploration of different solvents 3 Temperature 105 °C - 110 °C NA4 Work up Ethyl acetate / water work up NA Elimination of column chromatography and purification 5 Purification Column chromatographycondition to improve chiral purities Palladium6 Yes SiliaMetS loading to be screenedscavengingCondition TimeInput Remarks S.NO Cyclopropane Cesium(g) Pd2(dba)3Xantphoscarboxamide carbonate (h)1 0.5 1.5 3 0.1 0.1 242 0.5 2 3 0.1 0.1 24 • All the reaction went well 3 0.5 2.5 3 0.1 0.1 24 on small scale (0.5 g). 4 0.5 1.5 2 0.1 0.1 24 • However, when reaction 5 0.5 1.5 2.5 0.1 0.1 24 was performed on 5.0 g 6 0.5 1.5 2 0.05 0.1 24 scale reaction did not went 7 0.5 1.5 2 0.075 0.1 24 to completion (Entry-10) 8 0.5 1.5 2 0.5 0.05 24 • Therefore, reaction on 5.0 9 0.5 1.5 2 0.5 0.075 24 g scale was performed using entry-11. This10 5.0 1.5 2 0.5 0.05 24WSGR Docket No. 59318-727.60111 5.0 2 2 0.1 0.1 24 reaction went to completion.• Entry -11 conditions were 12 20.0 2 2 0.1 0.1 24 considered final and reaction was performed on20.0 g scale (entry-12).Example 4: Alternate synthesis of (S)-6-chloro-2,4,5-trimethyl-4,5-dihydro-2H- [1 ,2,3] triazolo [4,5-c] [l,7]naphthyridine (R07)(R)-t-butyl Br Br sulfinamide, n-BuLi, DMA Ti(Oi-Pr)4L-Selectride N, ,N - - N THF, -78 °C, 1-2 h THF THF IStep i Step ii Step iiiR01 R02 N03Pd2(dba)3, Mel, [(t-Bu)3PH]BF4, NaH CsF, THF, 50 °C, 16 h Step ivN05Step I: Synthesis of l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one (R01)On-BuLi, DMATHF, -78 °C, 1-2 hStep iR01 R02

[0562] The synthesis of compound R02 from R01 is described in WO 2022175747 Al.

[0563] Procedure: To a solution of 4,5-dibromo-2-methyl-2J / -l,2,3-triazole (100.0 g, 0.41 mol) in tetrahydrofuran (1.0 L, lOv) at -78 °C was added w-butyllithium (200.0 mL, 0.49 mol, 1.2 eq., 2.5 M in n-Hexane) under nitrogen atmosphere . Mixture was stirred at sametemperature for 15 - 20 min. / ' / / ' / -dim ethyl acetamide (42 mL, 0.45 mol, 1.0 eq.) was added to the above mixture while maintaining temperature of the mixture below - 70 °C. Reaction mass was stirred at same temperature (-78 °C to -70 °C) for 30 min. Completion of reaction was confirmed by TLC (20% ethyl acetate / heptane).WSGR Docket No. 59318-727.601

[0564] Work up: After the completion of reaction as confirmed by TLC. RM was quenched with 5% NH4CI solution (200 mL, 2v) at -78 °C, followed by added water (1 L, lOv). Mixture was then brought to RT and further diluted ethyl acetate (2 L, 20v). Mixture was stirred for 20 min at RT. Layers were separated. Aqueous layer was extracted with ethyl acetate (IL, lOv). All the organic layers were combined and washed with 15% brine solution (lL,10v). Finally, organic layer was dried over sodium sulphate, filtered and distilled under reduced pressure at 40 °C to obtain crude material.

[0565] Purification: Obtained crude material was slurred in MTBE (5v) and cooled to 0 °C -5 °C. Mixture was stirred at same temperature for 30 min. and filtered over Buchner funnel to obtain desired material as white solid. Obtained solids were washed with ice cold MTBE (Iv). Finally, material was dried under reduced pressure.

[0566] Analytical Data:'H NMR (400 MHz, DMSO-d6) 84.24 (s, 3H), 2.52 (s, 3H).MS (ESI+): m / z calcd for [CsH7BrN3O]+ ([M+H]+), 203.98; (not ionized)

[0567] Results:Theoretica Practical % Product MWt.1 yield (g) yield (g) Yield l-(5-bromo-2-methyl-2J / -l,2,3-triazol-4- 204.03 84.6 64.0 75.56yl)ethan-l-oneStep II: Synthesis of (S,Z)-N-(l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)ethylidene)-2-methylpropane-2-sulfinamide (N03)(R)-t-butylsulfinamide, Ti(Oi-Pr)4, THF, 67 °C, 24 hStep iiR02 N03

[0568] Procedure: To a solution of l-(5-bromo-2-methyl-2J / -l,2,3-triazol-4-yl)-l-ethanone (360 g, 1.76 mol, 1.0 eq) in tetrahydrofuran (1.8 L, 5 v) under nitrogen atmosphere was added (A)-(+)-tert-Butylsulfinamide (256 g, 2.11 mol, 1.2 eq) and titanium isopropoxide (2.14 L, 7.05 mol, 4 eq.) mol). Reaction mass was stirred at 75 °C for 48 h. Completion of reaction was confirmed by TLC (30% ethyl acetate / hexanes) and LCMS.

[0569] Work up: After the completion of reaction as confirmed by TLC. Reaction mass was brought to RT and further diluted with 10% methanol / DCM (3.6 L, 10 v) followed by water (3.6 L, 10 v) (During the addition of water solid precipitation was observed). Mixture wasWSGR Docket No. 59318-727.601stirred at RT for 15 min. and then filtered through bed of celite. Bed of celite was washed with 10% methanol / DCM (3.6 L, 10 v). Check the TLC of filtrate to ensure complete removal of material. (# If material is not completely removed then take the solids in reactor and stirred the solid in the mixture of 10% methanol / DCM for 30 min. and fdtered under reduced pressure over Nutsche to ensure complete isolation of desired material). Filtrate was taken in separatory funnel.

[0570] Organic layer was washed with water to ensure complete precipitation of titanium salts. Finally, all the organic layer was once again passed through bed of celite. Filtrate was concentrated under reduced pressure to obtain crude material.

[0571] Purification: Crude material was dissolved in MTBE (3v) and cooled to -10°C. Mixture was stirred at same temperature for 30 minutes. Observed solids were filtered under reduced pressure to obtain desired compound.

[0572] Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 84.23 (s, 3H), 2.68 (s, 3H), 1.25 (s, 9H).MS (ESI+): m / z calcd for [C9Hi6BrN4OS]+([M+H]+), 307.02; found, 307.02

[0573] Results:Theoretical Practical % Product MWt.yield (g) yield (g) Yield (5,Z)-7V-(1 -(5-bromo-2-m ethyl -2 / 7- 1,2,3- triazol-4-yl) ethylidene)-2-methylpropane- 307.21 542 460 84.872-sulfinamide

[0574] The reaction proceeds well using the above conditions. Obtained material used as such without any purification in next step.Step III: Synthesis of (S)-N-((R)-l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)ethyl)-2- methylpropane-2-sulfinamide (N04)N O HN OBr L-SelectrideBrTHFN,XNN Step iiiN03 N04

[0575] Procedure: To a solution of (5,Z)-7V-(l-(5-bromo-2-methyl-2J / -l,2,3-triazol-4-yl) ethylidene)-2-methylpropane-2-sulfinamide (25 g, 0.08 mol, 1.0 eq.) in tetrahydrofuran (250 mL,10 v) was added Z-selectride (122 mL, 0.12 mol, 1.5 eq., IM in THF) at - 5 °C ± 5 °C. Reaction mass was stirred at 0 °C for 1 - 2 h. Completion of reaction was confirmed by TLC.WSGR Docket No. 59318-727.601

[0576] TLC sampling: 0.1 mL of RM was quenched with ice cold water (1 mL) and diluted with ethyl acetate (2 mL). The organic layer was spotted on TLC along with starting material (30% ethyl acetate / heptane, 80% ethyl acetate / heptane).

[0577] Work up:1. After the completion of reaction as confirmed by TLC, RM was quenched with 2N NaOH solution (2 v) at 0 ° - 5 °C.2. Then 30 % hydrogen peroxide (2 v) was added to quench the side product of L - selectride at 0 ° - 20 °C (Change in color of reaction mass observed, red dark color RM observed).3. Stir the mixture at 25 °C - 30 °C for 1 h to ensure complete quenching of the reaction mass.4. Ethyl acetate (15 v) and water (15 v) work up was done under stirring.5. Organic layer was separated and washed with 10 % brine solution (5 v) under stirring. 6. Organic layer was washed with 2N NaOH solution (2 v) on stirring for 15 - 20 min. (Change in color of reaction mass observed, light color reaction mass observed).7. Organic layer was washed with 5 % sodium thiosulphate solution (5 v). Mixture was stirred for 15 min. (Change in the color of reaction mass observed, light color reaction mass observed).8. Finally, organic layer was washed with water (5 v) and 10 % brine (5 v). Aqueous layer was checked for peroxide content using peroxide test strip.9. Organic layer was dried over sodium sulphate and cone, under reduced pressure to obtain desired crude product.10. Submit the sample for1H NMR and LCMS analysis.

[0578] Purification: Obtained crude material was forwarded to next as such without any further purification.

[0579] Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 85.42 (s, 1H), 4.49 (q, J = 6.4 Hz, 1H), 4.12 (s, 3H), 1.55 (d, J = 6.4 Hz, 3H), 1.09 (s, 9H).MS (ESI+): m / z ealed for [C9Hi8BrN4OS]+([M+H]+), 309.04; found 309.07

[0580] Results:Theoretical PracticalProduct MWt. % Yield yield (g) yield (g)(5)-A-((A)-l-(5-bromo-2-methyl-2JT- l,2,3-triazol-4-yl)ethyl)-2- 309.23 25.16 20.13 80.0methylpropane-2-sulfmamideWSGR Docket No. 59318-727.601Step IV: Synthesis of (S)-N-((R)-l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)ethyl)-N,2-dimethylpropane-2-sulfinamide (N05)S X sHN" " "O N" " "OMel, NaHN N DMF, 0 °C, 2 h N NN' VI Step iv IN04 N05

[0581] Procedure: DMF (2625 mL, 5 v) was taken in RBF and to it was added sodium hydride (170 g, 4.24 mol, 2.5 eq.) under nitrogen atmosphere. Mixture was cooled to 0 °C. A solution of (S)-N-((R)- 1 -(5-bromo-2-methyl-2Z7- 1 ,2,3 -triazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (525 g, 1.69 mol, 1.0 eq.) in DMF (2625 mL, 5 v) was added to the mixture at 0 °C. Mixture was stirred at 0 °C for 5 -10 min. and then to it was added at methyl iodide (159 mL, 2.54 mol, 1.5eq). Reaction mass was stirred at 0 °C for 2 - 3 h. Completion of reaction was confirmed by TLC (neat ethyl acetate).

[0582] Work up: After reaction completion, RM was quenched by reverse quenching in ice cold water. Ethyl acetate / water work up was done. Organic layer was washed with sat. NFLCl to break the emulsion. Organic layer (15 L) was then washed with 15% brine solution (5 L X 3). Finally, organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain desired material. Obtained material was pure enough to proceed for next step without any further purification.

[0583] Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 84.52 (q, J= 6.4 Hz, 1H), 4.14 (s, 3H), 2.36 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H), 1.10 (s, 9H).MS (ESI+): m / z calcd for [CioH2oBrN4OS]+([M+H]+), 323.05; found, 325.10

[0584] Results:Theoretical Practical Product MWt. % Yield yield (g) yield (g)(S)-N-((R)~ 1 -(5 -bromo-2-methyl-2Z7- 1,2,3- triazol-4-yl)ethyl)-A,2-dimethylpropane-2- 323.2 548.8 510.0 80.3sulfinamideWSGR Docket No. 59318-727.601Step V: Synthesis of (S)-N-((R)-l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2H-l,2,3-triazol-4-yl)ethyl)-N,2-dimethylpropane-2-sulfinamide (R06)Step vN05 R06

[0585] Procedure: To a solution of [(A)-l-(5-bromo-2-methyl-2J / -l,2,3-triazol-4-yl)ethyl]-A-methyl(tert-butylsulfinyl)amine 5 (330 g, 1.02 mol) in tetrahydrofuran (3.3 L, 10 v) was added (2-chloro-3-fluoro-4-pyridyl)boranediol (358 g, 2.0 eq., 2.04 mol), potassium fluoride (118.6 g, 2.0 eq., 2.04 mol), tri-tert-butylphosphonium tetrafluoridoborate (22.2 g, 0.075 eq., 0.07 mol), water (250 mL, 1 v). Mixture was stirred at RT and purged with nitrogen for 20 min. and then to it was added Pd2(dba)3 (70.1 g, 0.075 eq., 0.07 mol). RM was purged with nitrogen for another 10 minutes. Reaction mass was then stirred at 45 ° - 50 °C for 7 - 8 h. Completion of reaction was confirmed by TLC (neat ethyl acetate).

[0586] Work up: After completion RM was filtered through bed of celite. Bed of celite was washed with ethyl acetate (10 v). Ethyl acetate (10 v) / water (10 v) work up was done. Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material.

[0587] Purification: Obtained crude material was column chromatographed using 60 - 120 mesh silica in 0 - 50 % ethyl acetate / heptane. Appropriate fractions were collected and distilled off to obtain pure material.

[0588] Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 88.39 (d, J= 4.8 Hz, 1H), 7.71 (t, J= 4.8 Hz, 1H), 4.80 (q, J = 6.8 Hz, 1H), 4.27 (s, 3H), 2.21 (s, 3H), 1.52 (d, J= 6.8 Hz, 3H), 0.87 (s, 9H).MS (ESI+): m / z calcd for [Ci5H22ClFN5OS]+([M+H]+), 374.12; found, 374.205

[0589] Results:Theoretical Practical Product MWt. % Yield yield (g) yield (g)(5)-A-((A)-l-(5-(2-chloro-3-fluoropyridin-4- yl)-2-methyl-2J / -l,2,3-triazol-4-yl)ethyl)- 373.88 381.6 274.0 71.8N,2-dimethylpropane-2-sulfinamideWSGR Docket No. 59318-727.601Other Optimization Experiments:ReactionS.No Current condition Optimization work required conditionBoronic acid (2.5eq), KFScreening of stoichiometry of catalyst and 1 Reagents (2.5eq), Pd2(dba)3(0.075eq),reagents[(t-Bu)3PH]BF4 (0.075eq)Exploration of workable volumes to increase 2 Solvent THF (lOv), water (Iv)batch size3 Temperature 55 °C to 60 °C NA1. Filter through celite bed4 Work up 2. Ethyl acetate / water Elimination of water workup work up5 Purification Column chromatography Elimination of column chromatography Optimization of reaction condition required 6 Yield (%) 45 - 50with respect to yield.Step VI: Synthesis of (5)-6-chloro-2,4,5-trimethyl-4,5-dihydro-2H-[l,2,3]triazolo[4,5-c][l,7]naphthyridine (R07)R06 R07

[0590] Procedure: To a solution of (5)-A-((A)-l-(5-(2-chloro-3-fluoropyridin-4-yl)-2-methyl-2J / -l,2,3-triazol-4-yl)ethyl)-A,2-dimethylpropane-2-sulfinamide 6 (274 g, 0.73 mol) in dioxane (685 mL, 2.5 v) was added 4N HC1 in dioxane (685 mL, 2.5 v) at 20 - 30 °C. Reaction was stirred at RT for 10 - 16 h. Hydrolysis of the sulfmamide group was confirmed by LCMS. After hydrolysis reaction mass was concentrated under reduced pressure to obtain hydrolyzed material. This material was azeotrophed with dioxane (2L X 3) to get rid of trapped HC1 residue. After azeotroph, hydrolyzed material was dissolved in dioxane. DIPEA (1370 mL, 3.66 mol., 5.0 eq) was added at 20 ° - 30 °C. Reaction mass was heated at 90 °C for 2 - 3 h. Completion of reaction was confirmed by LCMS.

[0591] Work up: After completion of reaction, RM was brought to RT. Ethyl acetate ( 10 v X 2) / water work (10 v) up was done. Organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to obtain crude material.WSGR Docket No. 59318-727.601

[0592] Purification: Obtained crude material was dissolved in IPA (2.0v) and mixture was stirred at RT for 30 minutes (solid formation observed). Obtained solids were filtered under reduced pressure to obtain desired material.

[0593] Analytical Data:1H NMR (400 MHz, DMSO-t / 6) 88.16 (d, J= 4.8 Hz, 1H), 7.63 (d, J= 4.8 Hz, 1H), 4.61 (q, J = 6.8 Hz, 1H), 4.24 (s, 3H), 2.74 (s, 3H), 1.13 (d, J= 6.8 Hz, 3H).MS (ESI+): m / z calcd for [CHH13C1N5]+ ([M+H]+), 250.09; found, 250.12

[0594] Result:Theoretical Practical Product MWt. % Yield yield (g) yield (g)(5)-6-chloro-2,4,5-trimethyl-4,5- dihydro-2Z7-[l,2,3]triazolo[4,5- 249.7 182.9 112.0 61.23c][l,7]naphthyridineOther Optimization Experiments:ReactionS.No Current condition Optimization work required condition1. 4M HC1 / Dioxane1 Reagents (5v), Use of TFA or HC1 in IPA for hydrolysis 2. DIPEA (5.0 eq)2 Solvent Dioxane (5v) Replacement of Dioxane with IPA or CPME 3 Temperature RT, 80 °C NA4 Work up Ethyl acetate / water work up NA5 Purification Column chromatography Elimination of column chromatographyWSGR Docket No. 59318-727.601HPLCInput Output Yield PurityS.NO Purity Condition Remarks(g) (g) (%) (%)(%)1. 4NHCl indioxane(2.5v),dioxane(2.5v), RT, • 'HNMR1 274 112 61.20 98.39 99.8812h. complies 2. DIPEA (5.0eq), dioxane(5.0v), 90°C, 2-3 h1. TFA (2v),DCM (5v),RT, h.• 'HNMR2 2 0.5 37.59 98.96 99.50 2. DIPEA (5.0complies eq), dioxane(5.0v), 90°C, 2-3 h

[0595] Hydrolysis using TFA and 1,4-di oxane in HC1 was found to be equipotent.Example 5: One-pot synthesis of (S)-N-((R)-l-(5-bromo-2-methyl-2H-l,2,3-triazol-4-yl)ethyl)-N,2-dimethylpropane-2-sulfinamide (N05) from (S,Z)-N-(l-(5-bromo-2-methyl- 2H-l,2,3-triazol-4-yl)ethylidene)-2-methylpropane-2-sulfinamide (N03)i) L-Selectride, THF,0 °C, 2 h;ii) Mel, 0 °C, 2 hN03 N05

[0596] Procedure: To a solution of (5,Z)-A-(l-(5-bromo-2-methyl-2J / -l,2,3-triazol-4-yl) ethylidene)-2-methylpropane-2-sulfinamide (400 g, 1.30 mol, 1.0 eq.) in tetrahydrofuran under nitrogen atmosphere (4.0 L,10.0 v) was added Z-selectride (1.95 L, 1.95 mol, 1.5 eq., IM in THF) at -5 °C ± 5 °C. Reaction mass was stirred at 0 °C for 2h. Formation of Int-4 was confirmed by TLC (30% ethyl acetate / heptane, 60% ethyl acetate / heptane) and LCMS .

[0597] After the formation of N04, methyl iodide (121.5 mL, 1.95 mol, 1.5 eq) was added to the reaction mass at 0°-5°C. Reaction mass was stirred at same temperature for 2h. Completion of reaction was confirmed by TLC (60% ethyl acetate / heptane).WSGR Docket No. 59318-727.601

[0598] Work up:1. After the completion of reaction as confirmed by TLC, RM was quenched with 2N NaOH solution (800 mL, 2 v) at 0 °- 5 °C.2. Then 30% Hydrogen peroxide (800 mL, 2 v) was added to quench the side product of L- selectride at 0 ° -20 °C (Change in color of reaction mass observed, red dark color RM observed).3. Stir the mixture at 25 °C - 30 °C for Ih to ensure complete quenching of the reaction mass.4. Ethyl acetate (6.0 L,15 v) and water (6.0 L, 15 v) work up was done under stirring.5. Organic layer was separated and washed with 10 % brine solution (5 v) under stirring. 6. Organic layer was washed with 2N NaOH solution (800 mL, 2 v) on stirring for 15 - 20 min. (Change in color of reaction mass observed, light color reaction mass observed).7. Organic layer was washed with 5.0 % sodium thiosulphate solution (2.0 L, 5.0 v). Mixture was stirred for 15 min. (Change in the color of reaction mass observed, light color reaction mass observed).8. Finally, organic layer was washed with water (5 v) and 10 % brine (5 v). Aqueous layer was checked for peroxide content using peroxide test strip.9. Organic layer was dried over sodium sulphate, filtered and cone, under reduced pressure to obtain desired crude product.10. Submit the sample for1H NMR and LCMS analysis.

[0599] Purification: Obtained crude material was dissolved in MTBE (2 v) and cooled to -10 °C. Mixture was stirred for 10 - 15 min. and then to it was added / / -heptane (4 v) at - 10 °C. Mixture was stirred at -10 °C - 0 °C for 30 min. and the filtered under reduced pressure to obtain desired material.

[0600] Analytical Data:IH NMR (400 MHz, DMSO-t / 6) 84.55 (q, J= 6.4 Hz, IH), 4.14 (s, 3H), 2.36 (s, 3H), 1.47 (d, J = 6.4 Hz, 3H), 1.10 (s, 9H).MS (ESI+): m / z ealed for [CioH2oBrN4OS]+([M+H]+), 323.05; found, 325.10

[0601] Results:Theoretical Practical Product MWt. % Yield yield (g) yield (g)(5)-A-((A)-l-(5-bromo-2-methyl-2J / - l,2,3-triazol-4-yl)ethyl)-7V,2- 323.2 420 330 78.5dimethylpropane-2-sulfmamide

[0602] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments areWSGR Docket No. 59318-727.601provided by way of example only. It is not intended that the disclosure be limited by the specific examples provided within the specification. While the disclosure has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. Furthermore, it shall be understood that all aspects of the disclosure are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the disclosure. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

WSGR Docket No. 59318-727.601CLAIMS WHAT IS CLAIMED IS:

1. A process for the stereoselective preparation of Formula A: / N-NFormula A;wherein X is a second suitable leaving group;comprising:(1) contacting a compound of Formula B:Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable acid and a suitable solvent to provide a reaction mixture; and(2) contacting the reaction mixture of step (1) with a suitable base;to provide a compound of Formula A.

2. The process of claim 1, wherein the suitable acid in step (1) is hydrogen chloride or trifluoroacetic acid.

3. The process of claim 1 or 2, wherein the suitable acid in step (1) is hydrogen chloride.

4. The process of any one of claims 1-3, wherein the suitable acid in step (1) is hydrogen chloride in dioxane.

5. The process of any one of claims 1-4, wherein the suitable acid in step (1) is about 4 N hydrogen chloride in dioxane.

6. The process of any one of claims 1-5, wherein the suitable solvent in step (1) is 1,4- dioxane, isopropanol, cyclopentyl methyl ether, or a mixture thereof.

7. The process of any one of claims 1-6, wherein the suitable solvent in step (1) is 1,4- di oxane.WSGR Docket No. 59318-727.6018. The process of any one of claims 1-7, wherein the suitable base in step (2) is triethylamine or diisopropylethylamine.

9. The process of any one of claims 1-8, wherein the suitable base in step (2) isdii sopropy 1 ethyl amine .

10. The process of any one of claims 1-9, wherein the reaction mixture of step (1) is concentrated under reduced pressure prior to contact with the suitable base in step (2).

11. The process of claim 10, wherein the process further comprises contacting the concentrated reaction mixture of step (1) with a second suitable solvent.

12. The process of claim 11, wherein the second suitable solvent is 1,4-dioxane.

13. The process of any one of claims 1-12, wherein the compound of Formula B:Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;is prepared by a process comprising:(3) contacting a compound of Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (4) contacting the reaction mixture of step (3) with a suitable methylating agent; to provide a compound of Formula B.

14. The process of claim 13, wherein the suitable reducing agent in step (3) is L-Selectride, N-Selectride, K-Selectride, lithium triethylborohydride, diisobutyl aluminum hydride,WSGR Docket No. 59318-727.601lithium aluminum hydride, lithium borohydride, sodium borohydride, or potassium borohydride.

15. The process of claim 13 or 14, wherein the suitable reducing agent in step (3) is L- Selectride.

16. The process of any one of claims 13-15, wherein the suitable reducing agent in step (3) is a solution of L-Selectride in tetrahydrofuran or 2-methyl tetrahydrofuran.

17. The process of any one of claims 13-16, wherein the suitable methylating agent in step (4) is methyl iodide, methyl bromide, methyl mesylate, or dimethyl sulfate.

18. The process of any one of claims 13-17, wherein the suitable methylating agent in step (4) is methyl iodide.

19. The process of any one of claims 13-18, wherein the suitable solvent in step (3) is 2- methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

20. The process of any one of claims 13-19, wherein the suitable solvent in step (3) is 2- methyl tetrahydrofuran, tetrahydrofuran, or a mixture thereof.

21. The process of any one of claims 1-12, wherein the compound of Formula B: / < N-NFormula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;is prepared by a process comprising:(5) contacting a compound of Formula C:c^O / < N-NHNV^ / NFormula C;wherein X is a second suitable leaving group; andY is a first suitable leaving group;WSGR Docket No. 59318-727.601with a suitable methylating agent, a suitable base, and a suitable solvent to provide a compound of Formula B.

22. The process of claim 21, wherein the suitable methylating agent in step (5) is methyl iodide, methyl bromide, methyl mesylate, or dimethyl sulfate.

23. The process of claim 21 or 22, wherein the suitable methylating agent in step (5) is methyl iodide.

24. The process of any one of claims 21-23, wherein the suitable base in step (5) is sodium hydride, potassium carbonate, or sodium carbonate.

25. The process of any one of claims 21-24, wherein the suitable base in step (5) is sodium hydride.

26. The process of any one of claims 21-25, wherein the suitable solvent in step (5) is 2- methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, DMF, or a mixture thereof.

27. The process of any one of claims 21-26, wherein the suitable solvent in step (5) is tetrahydrofuran, DMF, or a mixture thereof.

28. The process of any one of claims 21-27, wherein the compound of Formula C:Formula C;wherein X is a second suitable leaving group; andY is a first suitable leaving group;is prepared by a process comprising:(6) contacting a compound of Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable reducing agent and a suitable solventto provide a compound of Formula C.WSGR Docket No. 59318-727.60129. The process of claim 28, wherein the suitable reducing agent in step (6) is L-Selectride, N-Selectride, K-Selectride, lithium triethylborohydride, diisobutyl aluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride.

30. The process of claim 28 or 29, wherein the suitable reducing agent in step (6) is L- Selectride.

31. The process of any one of claims 28-30, wherein the suitable solvent in step (6) is 2- methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

32. The process of any one of claims 28-31, wherein the suitable solvent in step (6) is 2- methyl tetrahydrofuran.

33. The process of any one of claims 13-20 and 28-32, wherein the compound of Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;is prepared by a process comprising:(7) contacting a compound of Formula E:Formula E;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with (7 )-tert-butylsulfinamide and a suitable solventto provide a compound of Formula D.

34. The process of claim 33, wherein the process further comprises contacting the compound of Formula E with a suitable desiccant.

35. The process of claim 34, wherein the suitable desiccant in step (7) is titanium(IV)isopropoxide.WSGR Docket No. 59318-727.60136. The process of any one of claims 33-35, wherein the suitable solvent in step (7) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

37. The process of any one of claims 33-36, wherein the suitable solvent in step (7) is tetrahydrofuran.

38. A process for the stereoselective preparation of Formula A:Formula A;wherein X is a second suitable leaving group;comprising:(1) contacting a compound of Formula B:Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable acid and a suitable solvent to provide a reaction mixture; and(2) contacting the reaction mixture of step (1) with a suitable base to provide a compound of formula A;wherein the compound of Formula B is prepared by a process comprising:(3) contacting a compound of Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;WSGR Docket No. 59318-727.601with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (4) contacting the reaction mixture of step (3) with a suitable methylating agent to provide a compound of Formula B;wherein the compound of Formula D is prepared by a process comprising:(7) contacting a compound of Formula E:N-NFormula E;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with (7 )-tert-butylsulfinamide and a suitable solventto provide a compound of Formula D.

39. The process of any one of claims 33-38, wherein the compound of Formula E is prepared by a process comprising:(8) contacting a compound of Formula 2:OFormula 2;with a compound of Formula 3:[M]Formula 3;wherein [M] is a suitable metal or metalloid group;X is a second suitable leaving group; andY is a first suitable leaving group;and a first suitable palladium catalyst, a first suitable ligand, and a suitable solvent to provide a compound of Formula E.

40. The process of claims 39, wherein the suitable metal or metalloid group in step (8) is an organoboron or organotin reagent.WSGR Docket No. 59318-727.60141. The process of claim 39 or 40, wherein the suitable metal or metalloid group in step (8) is a boronic acid, boronic ester, or trifluoroborate.

42. The process of any one of claims 39-41, wherein the suitable metal or metalloid group in step (8) is -B(OH)2.

43. The process of any one of claims 39-42, wherein the first suitable palladium catalyst in step (8) is Pd2(dba)s.

44. The process of any one of claims 39-43, wherein the first suitable ligand in step (8) is tri- / c / V-butyl phosphine or a salt thereof.

45. The process of any one of claims 39-44, wherein the first suitable ligand in step (8) is [( / - BU)3PH]BF4.

46. The process of any one of claims 39-45, wherein the suitable solvent in step (8) is tetrahydrofuran, water, or a mixture thereof.

47. The process of any one of claims 39-46, wherein the suitable solvent in step (8) is about a 10:1 mixture of tetrahydrofuran and water.

48. The process of any one of claims 39-47, wherein step (8) further comprises contacting the compound of Formula 2 and compound of Formula 3 with a suitable base.

49. The process of claim 48, wherein the suitable base in step (8) is potassium fluoride or cesium fluoride.

50. The process of claim 48 or 49, wherein the suitable base in step (8) is potassium fluoride.

51. The process of any one of claims 39-50, wherein the compound of Formula 2 is prepared by a process comprising:(9) contacting a compound of Formula 1:Br. BrN, ,NNIFormula 1;with a suitable metal-halogen exchange reagent and a suitable solvent to provide a reaction mixture; and(10) contacting the reaction mixture of step (9) with / ' / / ' -dim ethyl acetamide; to provide a compound of Formula 2.

52. The process of claim 51, wherein the suitable metal-halogen exchange reagent in step (9) is an organolithium reagent or a Grignard reagent.

53. The process of claim 51 or 52, wherein the suitable metal-halogen exchange reagent in step (9) is n-butyllithium, n-hexyllithium, or isopropyl magnesium chloride.WSGR Docket No. 59318-727.60154. The process of any one of claims 51-53, wherein the suitable metal-halogen exchange reagent in step (9) is n-butyllithium.

55. The process of any one of claims 51-54, wherein the suitable metal-halogen exchange reagent in step (9) is a solution of n-butyllithium in hexanes.

56. The process of any one of claims 51-55, wherein the suitable solvent in step (9) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-di oxane, pentane, hexanes, or a mixture thereof.

57. The process of any one of claims 51-56, wherein the suitable solvent in step (9) is tetrahydrofuran, hexanes, or a mixture thereof.

58. The process of any one of claims 1-12, wherein the compound of Formula B:Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;is prepared by a process comprising:(11) contacting a compound of Formula F:ZFormula F;wherein Z is a third suitable leaving group;with a compound of Formula 3:[M]Formula 3;wherein [M] is a suitable metal or metalloid group;X is a second suitable leaving group; andY is a first suitable leaving group;WSGR Docket No. 59318-727.601and a second suitable palladium catalyst, a second suitable ligand, and a suitable solvent to provide a compound of Formula B.

59. The process of claim 58, wherein the suitable metal or metalloid group in step (11) is an organoboron or organotin reagent.

60. The process of claim 58 or 59, wherein the suitable metal or metalloid group in step (11) is a boronic acid, boronic ester, or trifluoroborate.

61. The process of any one of claims 58-60, wherein the suitable metal or metalloid group in step (11) is -B(OH)2.

62. The process of any one of claims 58-61, wherein the second suitable palladium catalyst in step (11) is Pd2(dba)3.

63. The process of any one of claims 58-62, wherein the second suitable ligand in step (11) is tri -tert-butyl phosphine or a salt thereof.

64. The process of any one of claims 58-63, wherein the second suitable ligand in step (11) is [( / -BU)3PH]BF4.

65. The process of any one of claims 58-64, wherein the suitable solvent in step (11) is tetrahydrofuran, water, or a mixture thereof.

66. The process of any one of claims 58-65, wherein the suitable solvent in step (11) is a 10:1 mixture of tetrahydrofuran and water.

67. The process of any one of claims 58-66, wherein step (11) further comprises contacting the compound of Formula 2 with a suitable base.

68. The process of claim 67, wherein the suitable base in step (11) is potassium fluoride or cesium fluoride.

69. The process of claim 67 or 68, wherein the suitable base in step (11) is potassium fluoride.

70. The process of any one of claims 58-69, wherein the compound of Formula F:ZFormula F;wherein Z is a third suitable leaving group;is prepared by a process comprising:(12) contacting a compound of Formula G:WSGR Docket No. 59318-727.601Formula G;wherein Z is a third suitable leaving group; andwith a suitable methylating agent, a suitable base, and a suitable solvent to provide a compound of Formula F.

71. The process of claim 70, wherein the suitable methylating agent in step (12) is methyl iodide, methyl bromide, methyl mesylate, or dimethyl sulfate.

72. The process of claim 70 or 71, wherein the suitable methylating agent in step (12) is methyl iodide.

73. The process of any one of claims 70-72, wherein the suitable base in step (12) is sodium hydride, potassium carbonate, or sodium carbonate.

74. The process of any one of claims 70-73, wherein the suitable base in step (12) is sodium hydride.

75. The process of any one of claims 70-74, wherein the suitable solvent in step (12) is 2- methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, DMF, or a mixture thereof.

76. The process of any one of claims 70-75, wherein the suitable solvent in step (12) is tetrahydrofuran, DMF, or a mixture thereof.

77. The process of any one of claims 70-76, wherein the compound of Formula G:Formula G;wherein Z is a third suitable leaving group;is prepared by a process comprising:(13) contacting a compound of Formula H:Formula H;wherein Z is a third suitable leaving group;with a suitable reducing agent and a suitable solvent;WSGR Docket No. 59318-727.601to provide a compound of Formula G.

78. The process of claim 77, wherein the suitable reducing agent in step (13) is L-Selectride, N-Selectride, K-Selectride, lithium triethylborohydride, diisobutyl aluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride.

79. The process of claim 77 or 78, wherein the suitable solvent in step (13) is tetrahydrofuran.

80. The process of any one of claims 77-79, wherein the suitable reducing agent in step (13) is L-Selectride.

81. The process of any one of claims 77-80, wherein the suitable solvent in step (13) is 2- methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

82. The process of any one of claims 77-81, wherein the suitable solvent in step (13) is tetrahydrofuran.

83. The process of any one of claims 58-69, wherein the compound of Formula F:ZFormula F;wherein Z is a third suitable leaving group;is prepared by a process comprising:(14) contacting a compound of Formula H:Formula H;wherein Z is a third suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (15) contacting the reaction mixture of step (14) with a suitable methylating agent;to provide a compound of Formula F.

84. The process of claim 83, wherein the suitable reducing agent in step (14) is L-Selectride, N-Selectride, K-Selectride, lithium triethylborohydride, diisobutyl aluminum hydride,WSGR Docket No. 59318-727.601lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride.

85. The process of claim 83 or 84, wherein the suitable reducing agent in step (14) is L- Selectride.

86. The process of any one of claims 83-85, wherein the suitable methylating agent in step (15) is methyl iodide, methyl bromide, methyl mesylate, or dimethyl sulfate.

87. The process of any one of claims 83-86, wherein the suitable methylating agent in step (15) is methyl iodide.

88. The process of any one of claims 83-87, wherein the suitable solvent in step (14) is 2- methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

89. The process of any one of claims 83-88, wherein the suitable solvent in step (14) is tetrahydrofuran.

90. The process of any one of claims 83-89, wherein the compound of Formula H:Formula H;wherein Z is a third suitable leaving group;is prepared by a process comprising:(16) contacting a compound of Formula I:Formula I;wherein Z is a third suitable leaving group;with ( / ?)-tert-butylsulfinamide and a suitable solvent;to provide a compound of Formula H.

91. The process of claim 90, wherein step (16) further comprises contacting the compound of Formula I with a suitable desiccant.

92. The process of claim 91, wherein the suitable desiccant in step (16) is titanium(IV) isopropoxide.

93. The process of any one of claims 90-92, wherein the suitable solvent in step (16) is tetrahydrofuran, 2-m ethyl tetrahydrofuran, 1,4-di oxane, or a mixture thereof.WSGR Docket No. 59318-727.60194. The process of any one of claims 90-93, wherein the suitable solvent in step (16) is tetrahydrofuran.

95. The process of any one of claims 90-94, wherein the compound of Formula I:ZFormula I;wherein Z is a third suitable leaving group;is prepared by a process comprising:(17) contacting a compound of Formula J:N- / ZFormula J;wherein Z is a third suitable leaving group;with a suitable metal-halogen exchange reagent and a suitable solvent to provide a reaction mixture; and(18) contacting the reaction mixture of step (17) with / ' / / ' -dim ethyl acetamide; to provide a compound of Formula I.

96. The process of claim 95, wherein the suitable metal-halogen exchange reagent in step (17) is an organolithium reagent or a Grignard reagent.

97. The process of claim 95 or 96, wherein the suitable metal-halogen exchange reagent in step (17) is n-butyllithium, n-hexyllithium, or isopropyl magnesium chloride.

98. The process of any one of claims 95-97, wherein the suitable metal-halogen exchange reagent in step (17) is n-butyllithium.

99. The process of any one of claims 95-98, wherein the suitable metal-halogen exchange reagent in step (17) is a solution of n-butyllithium in hexanes.

100. The process of any one of claims 95-99, wherein the suitable solvent in step (17) is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, pentane, hexanes, or a mixture thereof.

101. The process of any one of claims 95-100, wherein the suitable solvent in step (17) is tetrahydrofuran, hexanes, or a mixture thereof.

102. The process of any one of claims 1-101, wherein the process further comprises:(19) contacting a compound of Formula A with:WSGR Docket No. 59318-727.601RC(0)NH2, wherein R is an unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group,a third suitable palladium catalyst, a third suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 8: / N-Nitsi Tl JHN NR^OFormula 8wherein R is an unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group.

103. The process of claim 102, wherein the third suitable palladium catalyst in step (19) is Pd2(dba)s.

104. The process of claim 102 or 103, wherein the third suitable ligand in step (19) is Xantphos.

105. The process of any one of claims 102-104, wherein the suitable base in step (19) is CS2CO3.

106. The process of any one of claims 102-105, wherein the suitable solvent in step (19) is toluene, tetrahydrofuran, 2-m ethyltetrahydrofuran, 1,4-di oxane, or a mixture thereof.

107. The process of any one of claims 102-106, wherein the suitable solvent in step (19) is toluene, 1,4-di oxane, or a mixture thereof.

108. The process of any one of claims 102-107, wherein the suitable solvent in step (19) is toluene.

109. The process of any one of claims 102-108, wherein R is cyclopropyl.

110. The process of any one of claims 102-108, wherein R is / c / 7-butoxy.

111. The process of any one of claims 102-110, wherein the process further comprises:(20) contacting a compound of Formula 8 with a suitable base and a suitable solvent to provide a compound of Formula 9:WSGR Docket No. 59318-727.601 / Formula 9.

112. The process of claim 111, wherein the suitable base in step (20) is lithium hydroxide or sodium hydroxide.

113. The process of claim 111 or 112, wherein the suitable base in step (20) is lithium hydroxide monohydrate.

114. The process of any one of claims 111-113, wherein the suitable solvent in step (20) is tetrahydrofuran, 2-m ethyltetrahydrofuran, 1,4-di oxane, methanol, water, or a mixture thereof.

115. The process of any one of claims 111-114, wherein the suitable solvent in step (20) is tetrahydrofuran, water, or a mixture thereof.

116. The process of any one of claims 102-110, wherein the process further comprises:(21) contacting a compound of Formula 8 with a suitable acid and a suitable solvent to provide a compound of Formula 9: / N-NFormula 9.

117. The process of claim 116, wherein the compound of Formula 8 is:

118. The process of claim 116 or 117, wherein the suitable acid in step (21) is hydrogen chloride or trifluoroacetic acid.

119. The process of any one of claims 116-118, wherein the suitable acid in step (21) is hydrogen chloride.WSGR Docket No. 59318-727.601120. The process of any one of claims 116-119, wherein the suitable solvent in step (21) is toluene, tetrahydrofuran, 2-m ethyltetrahydrofuran, 1,4-di oxane, methanol, water, or a mixture thereof.

121. The process of any one of claims 111-120, wherein the process further comprises:O Cl• A(22) contacting a compound of Formula 9 withNCl , a suitable base, and a suitable solvent to provide a compound of Formula 10:Formula 10.

122. The process of claim 121, wherein the suitable base in step (22) is sodium hydride or LiHMDS.

123. The process of claim 121 or 122, wherein the suitable base in step (22) is LiHMDS.

124. The process of any one of claims 121-123, wherein the suitable base in step (22) is a solution of LiHMDS in tetrahydrofuran.

125. The process of any one of claims 121-124, wherein the suitable solvent in step (22) is 2-m ethyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, DMF, or a mixture thereof.

126. The process of any one of claims 121-125, wherein the suitable solvent in step (22) is 2-methyl tetrahydrofuran, tetrahydrofuran, or a mixture thereof.

127. The process of any one of claims 121-126, wherein the process further comprises:WSGR Docket No. 59318-727.601(23) contacting a compound of Formula 10 with cyclopropanecarboxamide, a fourth suitable palladium catalyst, a fourth suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 11:

128. The process of claim 127, wherein the fourth suitable palladium catalyst in step (23) Pd2(dba)3.

129. The process of claim 127 or 128, wherein the fourth suitable ligand in step (23) is Xantphos.

130. The process of any one of claims 127-129, wherein the suitable base in step (23) is CS2CO3.

131. The process of any one of claims 127-130, wherein the suitable solvent in step (23) is 1,4-dioxane, water, or a combination thereof.

132. The process of any one of claims 127-131, wherein the suitable solvent in step (23) is about a 7.5:1 mixture of 1,4-dioxane and water.

133. A process for the stereoselective preparation of Formula 11:comprising:(23) contacting a compound of Formula 10:WSGR Docket No. 59318-727.601Formula 10;with cyclopropanecarboxamide, a fourth suitable palladium catalyst, a fourth suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 11; wherein the compound of Formula 10 is prepared by a process comprising:(22) contacting a compound of Formula 9: / N-NFormula 9;O ClD’C'NAAhiL Jkwith N Cl , a suitable base, and a suitable solvent to provide a compound of Formula 10;wherein the compound of Formula 9 is prepared by a process comprising:(20) contacting a compound of Formula 8;Formula 8wherein R is an unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted Ci-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group; witha suitable base and a suitable solvent to provide a compound of Formula 9;WSGR Docket No. 59318-727.601wherein the compound of Formula 8 is prepared by a process comprising:(19) contacting a compound of Formula A: / N-NRs;N.Formula A;wherein X is a second suitable leaving group;with:RC(0)NH2, wherein R is an unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group, a third suitable palladium catalyst, a third suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 8;wherein the compound of Formula A is prepared by a process comprising:(1) contacting a compound of Formula B:Q^O / < N-NNU .NFormula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable acid and a suitable solvent to provide a reaction mixture; and(2) contacting the reaction mixture of step (1) with a suitable base to provide a compound of formula A;wherein the compound of Formula B is prepared by a process comprising:(3) contacting a compound of Formula D:WSGR Docket No. 59318-727.601Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (4) contacting the reaction mixture of step (3) with a suitable methylating agent to provide a compound of Formula B;wherein the compound of Formula D is prepared by a process comprising:(7) contacting a compound of Formula E:Formula E;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with (7?)-tert-butylsulfinamide and a suitable solventto provide a compound of Formula D;wherein the compound of Formula E is prepared by a process comprising:(8) contacting a compound of Formula 2:OFormula 2;with a compound of Formula 3:[M]Formula 3;wherein [M] is a suitable metal or metalloid group;WSGR Docket No. 59318-727.601X is a second suitable leaving group; andY is a first suitable leaving group;and a first suitable palladium catalyst, a first suitable ligand, and a suitable solvent to provide a compound of Formula E;wherein the compound of Formula 2 is prepared by a process comprising:(9) contacting a compound of Formula 1:IFormula 1;with a suitable metal-halogen exchange reagent and a suitable solvent to provide a reaction mixture; and(10) contacting the reaction mixture of step (9) with / ' / / ' -dim ethyl acetamide; to provide a compound of Formula 2.

134. A process for the stereoselective preparation of Formula 11:comprising:(23) contacting a compound of Formula 10:Formula 10;with cyclopropanecarboxamide, a fourth suitable palladium catalyst, a fourth suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 11;WSGR Docket No. 59318-727.601wherein the compound of Formula 10 is prepared by a process comprising:(22) contacting a compound of Formula 9: / N-NFormula 9;O Cl, a suitable base, and a suitable solvent to provide a compound of Formula 10;wherein the compound of Formula 9 is prepared by a process comprising:(21) contacting a compound of Formula 8; / N-NFormula 8wherein R is an unsubstituted or substituted Ci-Cio alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted Ci-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group; witha suitable acid and a suitable solvent to provide a compound of Formula 9;wherein the compound of Formula 8 is prepared by a process comprising:(19) contacting a compound of Formula A: / N-NFormula A;wherein X is a second suitable leaving group;with:WSGR Docket No. 59318-727.601RC(0)NH2, wherein R is an unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C2-C10 alkenyl, unsubstituted or substituted C2-C10 alkynyl, unsubstituted or substituted C1-C10 heteroalkyl, unsubstituted or substituted carbocycle, unsubstituted or substituted heterocycle, or unsubstituted or substituted C1-C10 alkoxy group,a third suitable palladium catalyst, a third suitable ligand, a suitable base, and a suitable solvent to provide a compound of Formula 8;wherein the compound of Formula A is prepared by a process comprising:(1) contacting a compound of Formula B:Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable acid and a suitable solvent to provide a reaction mixture; and(2) contacting the reaction mixture of step (1) with a suitable base to provide a compound of formula A;wherein the compound of Formula B is prepared by a process comprising:(3) contacting a compound of Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with a suitable reducing agent and a suitable solvent to provide a reaction mixture; and (4) contacting the reaction mixture of step (3) with a suitable methylating agent to provide a compound of Formula B;wherein the compound of Formula D is prepared by a process comprising:WSGR Docket No. 59318-727.601(7) contacting a compound of Formula E:N-NFormula E;wherein X is a second suitable leaving group; andY is a first suitable leaving group;with (7 )-tert-butylsulfinamide and a suitable solventto provide a compound of Formula D;wherein the compound of Formula E is prepared by a process comprising:(8) contacting a compound of Formula 2:O— BrN„ ,NNFormula 2;with a compound of Formula 3:[M]^xFormula 3;wherein [M] is a suitable metal or metalloid group;X is a second suitable leaving group; andY is a first suitable leaving group;and a first suitable palladium catalyst, a first suitable ligand, and a suitable solvent to provide a compound of Formula E;wherein the compound of Formula 2 is prepared by a process comprising:(9) contacting a compound of Formula 1:Br. BrN,XNNIFormula 1;with a suitable metal-halogen exchange reagent and a suitable solvent to provide a reaction mixture; andWSGR Docket No. 59318-727.601(10) contacting the reaction mixture of step (9) with / f-di methyl acetamide; to provide a compound of Formula 2.

135. The process of any one of claims 127-134, wherein the compound of Formula 11:Formula 11contains less than 100 ppm of palladium.

136. The process of any one of claims 1-135, whereinX is a second leaving group which is a halogen or sulfonate leaving group; andY is a first leaving group which is a halogen or sulfonate leaving group.

137. The process of any one of claims 1-136, whereinX is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; andY is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.

138. The process of any one of claims 1-137, whereinX is a second leaving group selected from the group consisting of Cl, Br, and I; and Y is F.

139. The process of any one of claims 1-138, whereinX is a Cl; andY is F.

140. The process of any one of claims 58-132 and 135, whereinZ is a third leaving group which is a halogen.

141. The process of any one of claims 58-132 and 135, whereinZ is a third leaving group selected from the group consisting of Cl, Br, and I.

142. The process of any one of claims 58-132 and 135, whereinZ is a third leaving group selected from the group consisting of Br, and I.

143. The process of any one of claims 58-132 and 135, whereinZ is Br.WSGR Docket No. 59318-727.601144. The process of any one of claims 1-143, wherein the compound of Formula A has an enantiopurity of greater than 95% enantiomeric excess (ee).

145. The process of any one of claims 1-143, wherein the compound of Formula A has an enantiopurity of greater than 98% enantiomeric excess (ee).

146. The process of any one of claims 127-139, wherein the compound of Formula 11 has an enantiopurity of greater than 95% enantiomeric excess (ee).

147. The process of any one of claims 127-139, wherein the compound of Formula 11 has an enantiopurity of greater than 98% enantiomeric excess (ee).148.

150. A compound selected fromor a salt thereof.- nO-WSGR Docket No. 59318-727.601s^oN-N151. A compound selected from, or a salt thereof, wherein X is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; and Y is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.S ON-N152. A compound selected from, or a salt thereof, wherein X is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; and Y is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.S ON-NN153. A compound selected from, or a salt thereof, wherein X is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; and Y is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.

154. A compound selected from any one of claims 151-153, wherein X is selected from the group consisting of F, Cl, Br, and I and Y is selected from the group consisting of F, Cl, Br, and I.

155. A compound selected from any one of claims 151-153, wherein X is selected from the group consisting of Cl, Br, and I and Y is F.

156. A compound selected from any one of claims 151-153, wherein X is Cl and Y is F.WSGR Docket No. 59318-727.601N157. A compound selected fromI , or a salt thereof, wherein Z is a third leaving group selected from the group consisting of Cl, Br, I, OTf, OTs, and OMs.HN O158. A compound selected from' , or a salt thereof, wherein Z is a third leaving group selected from the group consisting of Cl, Br, I, OTf, OTs, and OMs.X .S.N O159. A compound selected fromI , or a salt thereof, wherein Z is a third leaving group selected from the group consisting of Cl, Br, I, OTf, OTs, and OMs.

160. A compound selected from any one of claims 157-159, wherein Z is selected from the group consisting of Cl, Br, and I.

161. A compound selected from any one of claims 157-159, wherein Z is Br.

162. A reaction mixture comprising Formula B:Formula B;wherein X is a second suitable leaving group; andY is a first suitable leaving group;a suitable acid; anda suitable solvent.WSGR Docket No. 59318-727.601163. The reaction mixture of claim 162, wherein the suitable acid is hydrogen chloride.

164. The reaction mixture of claim 162 or 163, wherein the suitable solvent is 1,4- di oxane.

165. A reaction mixture comprising Formula D:Formula D;wherein X is a second suitable leaving group; andY is a first suitable leaving group;a suitable reducing agent; anda suitable solvent.

166. The reaction mixture of claim 165 wherein the suitable reducing agent is L- Selectride, N-Selectride, K-Selectride, lithium triethylborohydride, diisobutyl aluminum hydride, lithium aluminum hydride, lithium borohydride, sodium borohydride, or potassium borohydride.

167. The reaction mixture of claim 165 or 166, wherein the suitable reducing agent is L-Selectride.

168. The reaction mixture of any one of claims 165-167, wherein the suitable solvent is 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

169. The reaction mixture of any one of claims 165-168, wherein the suitable solvent is 2-methyl tetrahydrofuran.

170. A reaction mixture comprising Formula E: / Formula E;wherein X is a second suitable leaving group; andY is a first suitable leaving group;(A)-tert-butylsulfinamide; anda suitable solvent.WSGR Docket No. 59318-727.601171. The reaction mixture of claim 170 further comprising a suitable desiccant.

172. The reaction mixture of claim 171, wherein the suitable desiccant is titanium(IV) isopropoxide.

173. The reaction mixture of any one of claims 170-172, wherein the suitable solvent is tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-di oxane, or a mixture thereof.

174. The reaction mixture of any one of claims 170-173, wherein the suitable solvent is tetrahydrofuran.

175. The reaction mixture any one of claims 162-174, whereinX is a second leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs; andY is a first leaving group selected from the group consisting of F, Cl, Br, I, OTf, OTs, and OMs.

176. The reaction mixture any one of claims 162-174, whereinX is a second leaving group selected from the group consisting of F, Cl, Br, and I; and Y is a first leaving group selected from the group consisting of F, Cl, Br, and I.

177. The reaction mixture any one of claims 159-171, whereinX is a second leaving group selected from the group consisting of Cl, Br, and I; and Y is F.

178. The reaction mixture any one of claims 162-174, whereinX is a Cl; andY is F.

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