Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:20][CH2:19]2)=[C:14]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[N:13]=1)=[O:11])[CH2:5][CH:6]1[CH2:8][CH2:7]1.O.O.[OH-].[Li+].Cl>C1COCC1>[CH:6]1([CH2:5][C@H:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][CH2:19]3)=[C:14]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:13]=2)=[O:11])[C:3]([OH:26])=[O:2])[CH2:7][CH2:8]1
Reactant: COC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](CC1CC1)C(=O)O)c1ccc(C2CC2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
(S)-3-Cyclopropyl-2-[(5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (Example 258, 42 mg, 117 μmol) was dissolved in THF (2 mL). After addition of water (0.66 mL) and lithium hydroxide monohydrate (14.8 mg, 352 μmol) the mixture was heated and stirred for 3 hours at reflux temperature. The mixture was cooled to room temperature, water (7 mL) was added and the mixture was acidified with 1 N HCl. The mixture was then extracted with ethyl acetate (14 and 7 mL), organic layers were washed with brine (10 mL), combined, dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (36 mg, quant) as white solid; LC-MS (UV peak area/ESI) 100%, 345.1814 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([C:35]([N:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)=[O:36])[CH:30]=1>CN(C=O)C>[N:37]1([C:35]([C:31]2[N:32]=[CH:33][N:34]=[C:29]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:30]=2)=[O:36])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1cc(Cl)ncn1)n1ccc2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)n1ccc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 mg (0.34 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloride and 200 μL (1.162 mmol) DIPEA were added to 100 mg (0.39 mmol) (6-chloropyrimidin-4-yl)-indol-1-yl-methanone in 30 mL DMF. The reaction mixture was stirred for 3 h at RT. The reaction mixture was evaporated down i. vac. The residue was combined with 20 mL water and stirred for 10 min. The solid was suction filtered and purified by flash chromatography. The product fractions were combined and evaporated down i. vac. The residue was triturated with diisopropylether and suction filtered. The solid was dried at 40° C. in the CAD.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([C:24]#[C:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=[CH:20][C:19]=3[C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH:8]=2)[N:3]=1>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=[CH:20][C:19]=3[C:30]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:31])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)C#Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)CCc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-(3,3-dimethylbut-1-ynyl)phenyl)(pyrrolidin-1-yl)methanone (89 mg, 0.184 mmol, see Example 44) in ethanol (10 mL) was added palladium on activated carbon (10% wt; 150 mg). The reaction mixture was evacuated and backfilled with nitrogen gas. Then the reaction mixture was evacuated and backfilled with hydrogen gas. The reaction mixture was allowed to stir for 8 h at RT. The reaction mixture was filtered through a pad of celite. The solvent was removed under reduced pressure and the remaining residue was purified by column chromatography (10% MeOH in DCM). The titled compound was obtained as a light-yellow powder. MS (ESI, pos. ion) m/z: 487 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]2[CH2:11][CH2:10][C@:9]3([OH:26])[C@H:12]4[C@H:22]([CH2:23][CH2:24][C@:7]23[CH3:8])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([OH:25])[CH2:18][CH2:19]2)[CH2:14][CH2:13]4)=[CH:2]1.O1[C@@H]2C[C@H](C3C=COC=3)[C@]3(CC[C@H]4[C@H]([C@@]123)CC[C@H]1[C@]4(C)CC[C@H](O)C1)C.N1C=CN=C1.[Si:58](Cl)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]>O.CN(C)C=O>[Si:58]([O:25][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15]([CH2:14][CH2:13][C@@H:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@:9]3([OH:26])[CH2:10][CH2:11][C@@H:6]2[C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[CH2:16]1)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Agent: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Yield: 113.7 %

Procedure:
To a solution of 10 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc. (C), 1966, 377)in 80 ml of dimethylformamide, 18 g of imidazole and 20.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure and 15 g of crude 3β-tert-butyldimethylsilyloxy-17β-(3-furyl)-5β-androstan-14β-ol were obtained. A suspension of this protected alcohol and 1.3 g of KH in 75 ml of tetrahydrofuran was heated at 70° C. for an hr; then 2.7 g of methyl iodide were added. After 30' the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 12 g of 3β-tert-butyldimethylsilyloxy-14β-methoxy-17β-(3-furyl)-5β-androstane as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[N:16]1([CH2:22][C:23]2[CH:27]=[C:26]([NH2:28])[NH:25][N:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[N:16]1([CH2:22][C:23]2[CH:27]=[C:26]([NH:28][C:13]([C:3]3[C:2]([NH2:1])=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([Br:12])[N:4]=3)=[O:15])[NH:25][N:24]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: Nc1cc(CN2CCCCC2)n[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1cc(CN2CCCCC2)n[nH]1

Procedure:
A mixture, comprising 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2)(0.349 g, 1.221 mmol), 3-(piperidin-1-ylmethyl)-1H-pyrazol-5-amine (Intermediate 8) (0.220 g, 1.221 mmol), HATU (0.464 g, 1.221 mmol) and N-methylmorpholine (0.241 ml, 2.441 mmol) in DMF (5 ml) was stirred for 30 minutes at RT. The reaction mixture was diluted with water (20 ml) and the resulting yellow precipitate was filtered under vacuum and washed with water (20 ml). The resulting residue was loaded onto a SCX-2 cartridge eluting with MeOH followed by 7M NH3 in MeOH. The methanolic ammonia fractions were concentrated in vacuo and the residue was triturated with EtOAc/iso-hexane to yield the title compound.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][C:17]#[N:18])[CH2:6]1)(=O)C.C[O-].[Na+].Cl[C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>O1CCCC1.CO.O>[CH2:13]([O:12][C:10]([N:8]1[CH2:9][C@@H:5]([S:4][C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:6][C@H:7]1[CH2:16][C:17]#[N:18])=[O:11])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CC#N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC#N
Yield: 83.8 %

Procedure:
To a solution of (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-(cyanomethyl) pyrrolidine (8.20 g) in tetrahydrofuran (40 ml) and methanol (40 ml) was added a 28% sodium methoxide in methanol solution (6.03 ml) at ice-cooling. After stirring at ice-cooling for 30 minutes, chlorotriphenylmethane (8.31 g) was added to the cold solution. After stirring at the same temperature for 2 hours, the solution was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with aqueous sodium chloride solution twice, dried over magnesium sulfate and evaporated. The residue was subjected to a column chromatography on silica gel (eluent; n-hexane:ethyl acetate=5:1) to give (2R,4S)-1-allyloxycarbonyl-2-cyanomethyl-4-(triphenylmethylthio)pyrrolidine (11.7 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][S:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[CH3:15][S:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: CSc1cccc(N)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: CSc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-(methylthio)aniline (30 μl, 0.243 mmol) similar to Example 13 and isolated as a pink oil (67 mg, 89%). 1H NMR (CDCl3): 8.77–8.74 (m, 1H), 8.44–8.41 (m, 1H), 7.81–7.75 (m, 1H), 7.46 (s, 1H), 7.34–7.28 (m, 2H), 7.23 (t, J=8.1 Hz, 1H), 7.09–7.06 (m, 1H), 7.00–6.97 (m, 1H), 6.55 (d, J=0.6 Hz, 1H), 2.44 (s, 3H), 2.43 (d, J=0.6, 3H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14].[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nn1cccc1C(=O)c1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nn1cccc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution containing 1-amino-2-(2-fluorobenzoyl)pyrrole (25.8 g, 0.126 mol) and N-(tert-butoxycarbonyl)glycine (22.4 g, 0.128 mol) in 300 ml of dichloromethane was added dicyclohexylcarbodiimide (26.4 g, 0.128 mmol) in two portions over 3 minutes. The reaction mixture was stirred at ambient temperature for 2 hours and then filtered. The filtrate was evaporated to an oil which was purified by HPLC (silica gel, 4:3 hexane-ethyl acetate) to give 37.2 g (82%) of crystals, m.p. 114°-116°.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:35])([CH2:33][CH3:34])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([O:31]C)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>O1CCCC1>[CH3:2][C:3]([CH3:35])([CH2:33][CH3:34])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([OH:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[NH:8][CH:9]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(-c3ccc(F)cn3)cc2)OC)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1c[nH]c(C(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 70 °C

Procedure:
1.5 N Hydrochloric acid (1 mL) was added to an ambient temperature solution of 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-methoxyethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide in tetrahydrofuran (1 mL). After heating in a sealed tube at 70° C. for 2 h, the reaction mixture was cooled to 0° C., quenched with 10% aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparatory plate chromatography eluting with 100% ethyl acetate afforded the title compound. (M+H) found: 382.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@H:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]#[N:25])[CH:22]=2)[CH2:17][C:16]1([CH3:27])[CH3:26].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:24]([C:21]1[CH:22]=[C:23]2[C:18]([CH2:17][C:16]([CH3:27])([CH3:26])[C@H:15]2[NH:14][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:13])=[CH:19][CH:20]=1)#[N:25]
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1N
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc(F)ccc2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of 5-fluoro-1H-indole-2-carboxylic acid (56.0 mg, 0.312 mmol), (R)-3-amino-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (39.0 mg, 0.209 mmol), BOP reagent (180 mg, 0.407 mmol), N-methylmorpholine (0.13 mL, 1.18 mmol) in DMF (0.5 mL) was stirred at 50° C. for 2 hr. The desired title product (55.6 mg, 76% yield) was isolated as a white solid by prep. HPLC. LCMS (M+H)+=348.33. 1H NMR (500 MHz, DMSO-d6) δ: 11.7 (s, 1H), 8.58 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.62 (s, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.44 (dd, J=8.8, 5.0 Hz, 1H), 7.39 (d, J=9.9 Hz, 1H), 7.28 (s, 1H), 7.04 (t, J=9.35 Hz, 1H), 5.37 (d, J=9.35 Hz, 1H), 2.87 (dd, J=22.0, 16.5 Hz, 2H), 1.21 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1)#[N:2].CCOC(C)=O.CC(O)=O>[Fe].CCOCC>[NH2:10][C:6]1[CH:7]=[C:8]([F:9])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: N#Cc1ncc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ncc(N)cc1F
Yield: 94.2 %

Procedure:
2-Cyano-3-fluoro-5-nitropyridine (0.12g, 0.72 mmol) and iron powder (0.21g, 3.6 mmol, 325 Mesh) were reacted in 1:1 EtOAc/AcOH (10 mL) utilizing the procedure described in example 762D. Trituration of the crude product with ether gave compound 771D (0.093g, 94%) as a pale yellow solid. HPLC: 99% at 1.27 min(YMC S5 ODS column) eluting with 10–90% aqueous methanol containing 0.2% phosphoric acid over a 4 min gradient monitoring at 220 mm. MS (ES): m/z 138.02 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]#[N:20])[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[Cl:21][CH2:22][C:23](OCC)(OCC)OCC>C(O)(=O)C>[Cl:21][CH2:22][C:23]1[N:11]([C@H:12]2[CH2:13][CH2:14][C@H:15]([CH2:18][C:19]#[N:20])[CH2:16][CH2:17]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Solvent: CC(=O)O
Product: N#CC[C@H]1CC[C@H](n2c(CCl)nc3cnc4ccsc4c32)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (51.9 mg, 0.181 mmol) (Example 2, Step 4) and 2-chloro-1,1,1-triethoxyethane (from Aldrich, 0.105 mL, 0.549 mmol) in acetic acid (0.5 mL) was stirred at 120° C. for 30 min. The solvent was removed and the resultant residue dissolved in dichloromethane and purified on silica gel (eluting with 0-5% MeOH in dichloromethane) to give 22 mg (35.5%) of {trans-4-[2-(Chloromethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]cyclohexyl}acetonitrile. LCMS calculated for C17H18ClN4S (M+H)+: m/z=345.1. Found: 345.0. Also eluted was 8 mg (12%) of {1-[trans-4-(cyanomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}methyl acetate, LCMS calculated for C19H21N4O2S (M+H)+: m/z=369.1. Found: 369.0. The acetate compound was treated with lithium hydroxide to give compound the desired product after HPLC purification (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min). LCMS calculated for C17H19N4OS (M+H)+: m/z=327.1. Found: 327.1. 1H NMR (500 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.01 (d, J=5.5 Hz, 1H), 7.67 (d, J=5.5 Hz, 1H), 5.80 (t, J=5.6 Hz, 1H), 4.85 (d, J=5.3 Hz, 2H), 4.74 (m, 1H), 2.61 (d, J=6.1 Hz, 2H), 2.42 (m, 2H), 2.09-1.99 (m, 5H), 1.41 (m, 2H) ppm.
Reaction SMILES: [N:1]1([C:5]2[C:10]([C:11]#[N:12])=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=3)[C:8]([C:23]#[N:24])=[C:7]([S:25][CH2:26][C:27]3[N:28]=[C:29]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[S:30][CH:31]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49](O)=[O:50])[CH3:48])=[O:45])([CH3:42])([CH3:41])[CH3:40].C1COCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49]([O:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:23]#[N:24])=[C:7]([S:25][CH2:26][C:27]3[N:28]=[C:29]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[S:30][CH:31]=3)[N:6]=[C:5]([N:1]3[CH2:2][CH2:3][CH2:4]3)[C:10]=2[C:11]#[N:12])=[CH:14][CH:15]=1)=[O:50])[CH3:48])=[O:45])([CH3:41])([CH3:42])[CH3:40]
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCC2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
350 mg (0.625 mmol) of 2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 8), 354.7 mg (1.875 mmol) of N-(tert-butoxycarbonyl)-L-alanine and 38.17 mg (0.312 mmol) of 4-dimethylaminopyridine were initially charged in 3.3 ml of DMF. 3.3 ml of THF and 155.7 mg (0.812 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the reaction solution was then stirred at 40° C. overnight. After cooling, the reaction solution was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 377 mg (83% of theory) of the target compound.
Reaction SMILES: [OH:1][C@H:2]([CH3:21])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:22][S:23]([O:1][C@H:2]([CH3:21])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:9][CH:10]=1)=[O:4])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(COc2ccc(C(=O)[C@@H](C)O)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C(=O)[C@@H](C)OS(C)(=O)=O)cc2)cc1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
The compound (1.53 g, 5.34 mmol) synthesized in the above (3) was dissolved in dichloromethane (15 mL), and with cooling with ice, methanesulfonyl chloride (0.62 mL, 8.0 mmol) and triethylamine (1.11 mL, 8.0 mmol) were added in that order. The reaction solution was stirred for 20 minutes with cooling with ice. The reaction solution was poured into aqueous saturated sodium hydrogencarbonate solution, and extracted with chloroform. The organic layer was washed with aqueous saturated ammonium chloride solution and water in that order, then dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting pale yellow solid was washed with chloroform and n-hexane to obtain the entitled compound (1.8 g, 93%) as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([CH3:8])[NH:6][CH2:5][CH2:4][NH:3]1.C[C@H]1[C@@H](C)NCCN1.CS(O)(=O)=O.C([O-])(=O)C.[K+].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>O.C(O)C>[CH3:1][CH:2]1[CH:7]([CH3:8])[NH:6][CH2:5][CH2:4][N:3]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]
Reactant: C[C@@H]1NCCN[C@H]1C
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: C[C@@H]1NCCN[C@@H]1C
Solvent: CCO
Solvent: O
Product: CC1NCCN(C(=O)OCc2ccccc2)C1C
Temperature: 20 °C
Yield: 41 %

Procedure:
A 100 mL, three-necked round-bottom flask was charged with a mixture of trans-2,3-dimethylpiperazine and cis-2,3-dimethylpiperazine (Yakugaku Zasshi, 1958, 78, 229-232) (3.571 g, 31.1 mmol). The flask was cooled in an ice bath, and a solution of methanesulfonic acid (3.95 mL, 60.9 mmol) in 2.7 mL of water was added slowly, maintaining the temperature below 40° C. The solution was cooled to 20° C., and 4 mL of ethanol was added. The pH was adjusted to 4 with 60% aqueous potassium acetate, and then benzyl chloroformate (3.86 mL, 27.4 mol in 2 mL of THF) and potassium acetate solutions were simultaneously added dropwise with adjustment of the rate to maintain the reaction solution at pH 4, with cooling to maintain the temperature at 25° C. After the mixture was stirred an additional hour, the organic solvents were removed, and the remaining aqueous solution was washed with ethyl acetate. The ethyl acetate wash was extracted with 1 M HCl twice to recover the desired product. The acid extracts were combined with the original aqueous solution, and the pH was adjusted to 11 by addition of 6 N NaOH, with cooling to maintain the temperature below 40° C. The aqueous solution was then extracted with ethyl acetate, and the ethyl acetate extraction was dried over magnesium sulfate. Filtration and removal of the solvent provided all four stereoisomers of phenylmethyl 2,3-dimethyl-1-piperazinecarboxylate as a dark brown oil (3.11 g, 41%). LCMS: (M+H)+: 249.1.
Reaction SMILES: NC[C@@H]1[C@H](C)CCCN1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[C:27]([C:53]2[N:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[C:28]([CH:50]=[CH:51][CH:52]=1)[C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([CH3:37])[C@H:32]1[CH2:38][N:39]1C(=O)C2C(=CC=CC=2)C1=O)=[O:30]>>[NH2:39][CH2:38][C@@H:32]1[C@H:33]([CH3:37])[CH2:34][CH2:35][CH2:36][N:31]1[C:29]([C:28]1[CH:50]=[CH:51][CH:52]=[C:26]([F:25])[C:27]=1[C:53]1[N:54]=[CH:55][CH:56]=[CH:57][N:58]=1)=[O:30]
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-c2ncccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 2-(((2S,3R)-1-(3-fluoro-2-(pyrimidin-2-yl)benzoyl)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione. MS (ESI) 329 (M+H).