Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[Cu][C:33]#[N:34]>CN(C)C=O.[Cu]I>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:33]#[N:34])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Reactant: N#C[Cu]
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(C#N)cc3)oc2C)cc1
Temperature: 150 °C
Yield: 86.8 %

Procedure:
2-(4-{2-[2-(4-Bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (170 mg, 0.35 mmol), copper (I) cyanide (96 mg, 1.07 mmol), and copper (I) iodide (120 mg, 0.63 mmol) were dissolved in dimethylformamide (1.5 mL) and heated to 150° C. for 20 h. The mixture was cooled ambient temperature and partitioned between EtOAc (20 mL) and saturated aqueous FeCl3 (20 mL). The organic phase was washed with FeCl3 solution, H2O, brine and then dried (MgSO4), filtered and concentrated. The product was purified by flash chromatography (15 mL SiO2, 40% EtOAc/hexanes) and obtained as a clear, colorless oil (132 mg, 87%). Rf=0.32 in 35% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 6.81-6.76 (m, 4H), 4.21 (q, J=6.4 Hz, 2H), 4.18 (t, J=6.4 Hz, 2H), 2.95 (t, J=6.4 Hz, 2H), 2.38 (s, 3H), 1.51 (s, 6H), 1.26 (t, J=7.2 Hz, 3H); MS (EI) 457.2 (M+Na)+; 435.2 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:7][C:8]2[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][C:14]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:13][C:9]=2[C:10](=[O:12])[CH:11]=1)=[O:5])C.[OH-].[Na+:26]>C(O)C>[Na+:26].[C:21]([C:14]1[CH:15]=[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]2[O:7][C:6]([C:4]([O-:5])=[O:3])=[CH:11][C:10](=[O:12])[C:9]=2[CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1cc(=O)c2cc(C(C)(C)C)cc(C(C)(C)C)c2o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1cc(C(C)(C)C)c2oc(C(=O)[O-])cc(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a chilled solution of 1.02 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester in 100 parts of ethanol was added 3.1 parts of N sodium hydroxide solution. After the solution had been stirred at room temperature for one hour the solvent was evaporated and the remaining solid was triturated with ether and filtered off to yield 0.93 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid sodium salt.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1>>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: COc1cccc(C(=O)O)c1N
Product: COc1cccc(C(=O)NCCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c1N
Yield: 82 %

Procedure:
Starting from 2-amino-3-methoxybenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (179 mg; 82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH:12]1[CH:17]=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=C[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C=C>C1COCC1>[CH2:17]([O:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[CH:12]=[CH2:13]
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Reactant: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C=CCO
Product: C=CCOc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.4 %

Procedure:
To a mixture of 5-chloro-3-nitro-pyridin-2-ol (0.600 g, 3.4 mmol), DBAD (1.19 g, 5.16 mmol), triphenylphosphine-polymer supported (3 mmol/g, 1.70 g, 5.16 mmol) in THF (18 mL) was added allyl alcohol (0.42 mL, 6.12 mmol). The reaction mixture was stirred at room temperature overnight, filtered through celite, and concentrated. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (95:5 to 1:1) to give 0.120 g (15%) of the desired product. MS (DCI/NH3) m/z: 214.9 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 5.01 (ddd, J=5.34, 1.40, 1.40 Hz, 2 H) 5.32 (dd, J=10.51, 1.36 Hz, 1 H) 5.49 (dd, J=17.12, 1.53 Hz, 1 H) 6.06 (m, 1 H) 8.28 (d, J=2.37 Hz, 1 H) 8.34 (d, J=2.37 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[CH:32][C:27]5[O:28][CH2:29][CH2:30][O:31][C:26]=5[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>>[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[CH:32][C:27]5[O:28][CH2:29][CH2:30][O:31][C:26]=5[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:38]
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: O=C(Cl)c1ccccc1Cl
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1)c1ccccc1Cl

Procedure:
{4-[2-(3-Amino-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine (150 mg, 0.34 mmol) was acylated with 2-chlorobenzoyl chloride (47 μL, 0.37 mmol) in a manner analogous to Example 3 above, to give the title compound as a yellow solid. HRMS calculated C32H23ClN6O3 [M+H]+ 575.1598 found 575.1600.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[C:18]1[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=1.[Br:25]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(#N)C>[Br:25][C:22]1[CH:23]=[C:18]([C:10]2[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[C:17]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:11]=2)[C:19]([NH2:24])=[N:20][CH:21]=1
Reactant: Nc1ncccc1-c1nc2cnccc2n1-c1cccc(F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(Br)cc1-c1nc2cnccc2n1-c1cccc(F)c1F
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
A solution of 3-(1-(2,3-difluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-amine (2.4 g, 7.43 mmol) in acetonitrile (70 mL) was treated with N-bromosuccinimide (1.45 g, 18.17 mmol) at 0° C. and the reaction mixture stirred for 30 min. reaction mixture was treated with saturated aq. NaHCO3 solution (150 mL), stirred for 30 min, and the resulting precipitate filtered and dissolved in CHCl3 (200 mL). The combined organics were washed with water (3×70 mL), brine (70 mL), and dried (Na2SO4). Filtration and evaporation of solvent in vacuo gave a solid, which was purified by silica gel chromatography (4% methanol/chloroform) to give 5-bromo-3-(1-(2,3-difluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl)pyridin-2-amine (2.2 g, 75% yield) as a light yellow solid; LC-MS: 402.0, 404.0 (M+H).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[CH:8][CH:7]=1.[S:25]1(=[O:33])(=[O:32])[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[ClH:1].[O:32]=[S:25]1(=[O:33])[CH2:30][CH2:29][CH:28]([NH:2][C@@H:3]2[CH2:5][C@H:4]2[C:6]2[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:23])[F:21])[CH:15]=3)=[CH:10][CH:11]=2)[CH2:27][CH2:26]1
Reactant: O=C1CCS(=O)(=O)CC1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NC2CCS(=O)(=O)CC2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-(trifluoromethyl)benzamide hydrochloride (75 mg), tetrahydro-4H-thiopyran-4-one 1,1-dioxide (37.4 mg) and acetic acid (0.2 mL) in methanol (2 mL) was added 2-picoline-borane complex (38.2 mg). The mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling. The mixture was m extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, ethyl acetate/methanol) and 10% hydrochloric acid methanol solution was added. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (32.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][O:24][CH2:23][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[C:27]1(B(O)O)[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][O:24][CH2:23][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1
Reactant: OB(O)C1=CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1

Procedure:
Nitrogen was bubbled through a solution of 5-bromo-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (15 mg, 0.034 mmol) containing cyclohexen-1-ylboronic acid (8 mg, 0.063 mmol) in 2M aqueous Na2CO3 (0.9 mL) and DME (1.8 mL) for 10 min. Pd(PPh3)4 (3 mg) was added and the mixture was refluxed for 1 h 10 min. It was cooled, diluted with ethyl acetate (50 mL), washed with water and brine, dried and evaporated yielding the crude 5-cyclohex-1-enyl-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (24 mg) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][C:36]([O:38]C)=[O:37])=[O:33])=[CH:4][N:3]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:33])=[CH:4][N:3]=1
Reactant: COC(=O)CNC(=O)c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2csc3c(C(=O)NCC(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 50 °C
Yield: 50.6 %

Procedure:
To a mixture of methyl ({[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]carbonyl}amino)acetate (0.130 g, 0.239 mmol) in 1,4 dioxane (10 mL) was added 2M sodium hydroxide in water (0.260 mL, 0.521 mmol). The resulting solution was heated at 50° C. for 3 hours. 1M hydrochloric acid was added until pH of the mixture was 4 and solvent was removed under reduced pressure. The resulting white solid was washed with water (2 mL) and filtered and dried to furnish the title compound (64 mg, 0.121 mmol): LCMS (Conditions b): MH+=530 RT=2.03 min; 1H NMR (DMSO-d6, 400 MHz) δ 12.65 (1H), 9.50 (1H), 8.95 (1H), 8.60 (1H), 8.02 (1H), 7.71 (2H), 7.58 (1H), 7.35 (2H), 7.21 (1H), 7.15 (1H), 7.09 (1H), 6.29 (2H), 4.04 (3H), 3.97 (2H), 3.92 (3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([N:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1.[CH3:15][NH2:16]>CO>[CH3:13][N:12]([CH3:14])[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:16][CH3:15])[CH:7]=1
Reactant: CN
Reactant: CN(C)c1cccc(OCCCCl)c1
Solvent: CO
Product: CNCCCOc1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
The crude (3-(3-chloropropoxy)phenyl)dimethylamine (4.06 g, 19.01 mmol) was dissolved in methanol (30 mL) and added to a 40 wt % aqueous solution of methylamine (75 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred at ambient temperature for 16 h, followed by heating at 87° C. (oil bath temperature) for 3 h. After cooling, the solution was concentrated by rotary evaporation to a lavender-brown semi-solid. Saturated NaCl solution (35 mL) was added. The mixture was acidified to pH 1 with 10% HCl solution and extracted with CHCl3 (5×30 mL) to remove impurities. The dark-brown aqueous layer was basified to pH 7 with 30% NaOH solution and extracted with ether (4×40 mL) to remove impurities. The brown aqueous layer was basified with 30% NaOH solution to pH 12 and extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation, producing an oil. The product was dried briefly under high vacuum to afford 2.24 g (56.6%) of a dark-brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CC#N>[CH:15]([C:14]1[CH:17]=[C:18]([C:21]([F:22])([F:23])[F:24])[CH:19]=[CH:20][C:13]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:16]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)O)c1

Procedure:
3-Hydroxyphenylacetic acid (1 g, 5.2 mmol), 2-fluoro-5-(trifluoromethyl)benzaldehyde (1 g, 6.6 mmol), and potassium carbonate (2.2 g, 15.6 mmol) were combined in THF (20 mL) and MeCN (20 mL), and the reaction was stirred at 70° C. for 3 days. After acidic workup, the crude material was purified by silica gel chromatography (20-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C:5](=[S:7])[NH2:6])[CH3:2].Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCO>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C:5]1[S:7][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:6]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOC(OCC)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(C(OCC)OCC)n1

Procedure:
A mixture of 2,2-diethoxyethanethioamide (2 g), ethyl bromopyruvate (1.61 ml), MS-4A (2 g) and EtOH (15 ml) was heated under reflux for 1 h. The mixture was concentrated, and the residue was diluted with AcOEt. The mixture was washed with water and brine successively, dried with MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (2.5 g) as an off-white solid.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH2:36][CH:37]=[CH2:38])([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]=[CH2:17])=[CH:10][CH:9]=1.[Li+].[OH-].Cl>C1COCC1>[CH2:15]([C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:39])=[CH:13][CH:12]=1)([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[CH2:36][CH2:37][CH3:38])[CH2:16][CH3:17]
Reactant: C=CCC(CC=C)(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC(CCC)(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of 3-{4-[1-allyl-1-(4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-benzoylamino}-propionic acid methyl ester (0.0703 g, 0.120 mmol) in THF (2.0 mL) is treated with 1N LiOH (2.0 mL) and stirred overnight at room temperature. The reaction mixture is acidified with 1N HCl (2.2 mL) and extracted with EtOAc (3×10 mL). The combined extracts are dried over MgSO4, filtered, and concentrated to provide 0.0401 g, (58%) of the title compound as a white solid. MS (ES): 570.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[N:3]=1.[NH2:12][NH2:13]>C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][NH2:13])=[O:7])=[C:4]([CH3:11])[N:3]=1
Reactant: NN
Reactant: Cc1nc(Cl)ccc1C(=O)O
Solvent: CCO
Product: Cc1nc(Cl)ccc1C(=O)NN
Temperature: 80 °C

Procedure:
6-Chloro-2-methylnicotinic acid (Example 425, Step 1) (480 mg, 2.59 mmol) was taken up in ethanol (5.2 ml). Hydrazine (0.8 ml, 12.93 mmol) was added and the reaction was heated to 80° C. overnight. It was then concentrated under reduced pressure and purified via silica gel chromatography (0-3% methanol in ethyl acetate) to yield the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[C:12]([NH:21][C@H:22]4[CH2:27][CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23]4)=[N:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:15][CH:16]=3)[N:9]=2)[N:4]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:3]=1.[C:40]([Zn]C#N)#[N:41].CN(C)C=O>[Cl-].[Na+].O.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][S:17]([C:14]1[N:13]=[C:12]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23]2)[C:11]([C:8]2[N:9]=[C:10]3[C:2]([C:40]#[N:41])=[CH:3][N:4]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:5]3=[N:6][CH:7]=2)=[CH:16][N:15]=1)(=[O:19])=[O:18]
Reactant: N#C[Zn]C#N
Reactant: C[Si](C)(C)CCOCn1cc(I)c2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C#N)c2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Temperature: 120 °C
Yield: 63.4 %

Procedure:
A solution of {5-[7-Iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-2-methanesulfonyl-pyrimidin-4-yl}-((S)-1-methanesulfonyl-piperidin-3-yl)-amine (65 mg, 0.091 mmol) and dicyanozinc (11 mg, 0.092 mmol) was combined with dimethylformamide (0.5 ml) (1% water) and the solution thoroughly degassed. To this was added 1,1′-bis(diphenylphosphino)ferrocene (dppf) (1.0 mg, 1.84 μmol) and Tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (4.2 mg, 4.6 μmol) and the mixture was heated to 120° C. for 1.5 hours. This was cooled, diluted with brine and water, extracted with ethyl acetate, dried and purified by flash chromatography (silica gel, 0% to 50% ethyl acetate/dichloromethane) to give 2-[2-methanesulfonyl-4-((S)-1-methanesulfonyl-piperidin-3-ylamino)-pyrimidin-5-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonitrile (35 mg, 63%). MS: (ES+): 607.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([N:11]([CH3:10])[C:2]2[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1c(I)ccnc1F
Reactant: CNC1CCCCC1
Product: Cc1c(I)ccnc1N(C)C1CCCCC1

Procedure:
2-Fluoro-4-iodo-3-methylpyridine (700 mg) in N-methylcyclohexanamine (2.2 ml) was heated at 180° C. in a Biotage Initiator microwave reactor for 18 hours. The reaction mixture was loaded onto a silica gel cartridge, and was eluted with 0-100% dichloromethane in hexanes to provide the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([CH3:9])=[C:6]([CH3:8])[N:7]=1.[CH2:10]([N:12]([CH2:15]C)[CH2:13]C)C.COC(OC)N(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:6]1[N:7]=[C:3]([N:2]=[CH:10][N:12]([CH3:15])[CH3:13])[S:4][C:5]=1[CH3:9]
Reactant: CCN(CC)CC
Reactant: Cc1nc(N)sc1C
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(N=CN(C)C)sc1C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A suspension of 2-amino-4,5-dimethylthiazole hydrochloride (4.92 g, 30 mmol) (Formula A-1) in toluene (60 mL) was treated with triethylamine (4.5 mL, 35 mmol) and vigorously stirred for 30 minutes. The mixture was treated with dimethylformamide dimethyl acetal (7.3 mL, 60 mmol) and heated at reflux temperature for 2 hours. The solution was cooled, diluted with ethyl acetate, washed with saline, dried and evaporated. The residue was crystallized from hexane to provide pure N′-(4,5-Dimethyl-2-thiazolyl)-N,N-dimethyl-methanimidamide (Formula A-2) (4.31 g, 77%), m.p. 47-58°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: O=S(=O)(NCC(F)(F)F)c1ccc(Br)cc1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NCC(F)(F)F)cc1
Reaction time: 16 h
Yield: 41.5 %

Procedure:
According to general procedure B, 4-bromo-N-(2,2,2-trifluoroethyl)benzenesulfonamide (127 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-(2,2,2-trifluoroethyl)benzenesulfonamide (57 mg, 42%) was provided after purification. MS (ESI) m/z 343. HPLC purity 97.2% at 210-370 nm, 10.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)=[O:4].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:19][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)=[O:4])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN
Reactant: COC(=O)C1CNc2ccccc2C1
Product: CCCCNC(=O)C1CNc2ccccc2C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 500 mg of 3(R,S)-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (Example 1r) and 1 ml of n-butylamine is stirred at 60° C. for 1 h. Purification of the crude product by means of FC over 50 g of silica gel (mobile phase Z) gives 3(R,S)-butylaminocarbonyl-1,2,3,4-tetrahydroquinoline: Rf (Z)=0.21.