Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([C:14]([F:17])([F:16])[F:15])=[N:11][NH:12][CH:13]=2)O1.Cl[C:20]1[C:29]([N:30]([CH:32]([CH3:34])[CH3:33])[CH3:31])=[N:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=2)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH:32]([N:30]([CH3:31])[C:29]1[C:20]([C:9]2[C:10]([C:14]([F:15])([F:16])[F:17])=[N:11][NH:12][CH:13]=2)=[N:21][C:22]2[C:27]([N:28]=1)=[CH:26][C:25]([C:35]([O:37][CH3:38])=[O:36])=[CH:24][CH:23]=2)([CH3:34])[CH3:33]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2c[nH]nc2C(F)(F)F)OC1(C)C
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: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3c[nH]nc3C(F)(F)F)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (536.0 mg, 2.05 mmol) in DME (5 mL) and water (0.5 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200.0 mg, 0.68 mmol), sodium carbonate (217.0 mg, 2.05 mmol) and Pd(PPh3)4 (39 mg, 0.03 mmol) with stirring for 0.5 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to get a residue, which was purified by a silica gel column with 2%-10% ethyl acetate in petroleum to afford methyl 3-(isopropyl(methyl)amino)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)quinoxaline-6-carboxylate as a light yellow solid (80 mg, 30%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)=[O:13].CCCCCC>CN(C)C=O>[CH2:1]([NH:8][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(CCCl)Nc1ccc2[nH]ncc2c1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(CCNCc1ccccc1)Nc1ccc2[nH]ncc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
N-benzylamine (4.0 ml, 36.5 mmol) was added to a solution of 3-chloro-N-(1H-indazol-5-yl)propanamide (1.70 g, 7.60 mmol) in N,N-dimethylformamide (2 ml), and the resulting mixture was stirred at 80° C. for 1 hour. Then, the reaction solution was cooled to 0° C. and hexane was added thereto to effect suspension. The solid precipitated was collected by filtration and purified by a silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N3-benzyl-N1-(1H-indazol-5-yl)-β-alaninamide (1.00 g, 45%).
Reaction SMILES: [Br:1][C:2]1[N:6](S(N(C)C)(=O)=O)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.FC(F)(F)C(O)=O>O.[OH-].[Na+]>[Br:1][C:2]1[NH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: CN(C)S(=O)(=O)n1nc(C(F)(F)F)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: FC(F)(F)c1cc(Br)[nH]n1

Procedure:
A solution of 5-bromo-N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide (i.e. the product of Example 11, Step A) (4.50 g, 14.0 mmol) and trifluoroacetic acid (2.0 mL, 26 mmol) was stirred at 25° C. for 4 h. The reaction mixture was diluted with water (20 mL), and sodium hydroxide was added to raise the pH to 12. The solution was extracted with chloroform, dried (MgSO4), and concentrated under reduced pressure to give 2.73 g of the title compound as a yellow light oil. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH:8](C(OCC)=O)[C:9]([O:11]CC)=[O:10])[CH:7]=1.Cl>C(O)(=O)C.O.CC#N>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(C)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(CC(=O)O)c1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Diethyl 2-(5-methyl-2-nitro-phenyl)propanedioate (9.50 g, 32.2 mmol) was suspended in glacial acetic acid (40 mL) and warmed until it had dissolved. Hydrochloric acid (40 mL of 6 M solution, 240.0 mmol) was added dropwise and the solution heated at reflux for 24 h. After cooling to room temperature the reaction was diluted with water and extracted with ether. The ether was dried over Na2SO4, filtered, and concentrated in vacuo to afford a light orange solid. The solid was dissolved in minimal CH3CN and added dropwise to stirring 0.05 N HCl (300 mL) resulting in a beige precipitate. The suspension was cooled in an ice bath, filtered, and washed with water to obtain 2-(5-methyl-2-nitro-phenyl)acetic acid as a beige crystalline solid (5.30 g, 84% yield). LC/MS m/z 391.4 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.01 (d, J=8.9 Hz, 1H), 7.36 (m, 2H), 3.95 (s, 2H), 2.40 (s, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[CH:10]=[CH:9][C:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:7][C:6]=2[C:5]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:4]1=2.C=O.[C:28]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C.C(OCC)(=O)C>[CH3:28][N:23]1[CH2:22][CH2:21][C:5]2[C:6]3[CH:7]=[C:8]([S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)(=[O:13])=[O:14])[CH:9]=[CH:10][C:11]=3[N:3]([CH3:2])[C:4]=2[CH2:25][CH2:24]1
Reactant: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCNCC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CCc2c(n(C)c3ccc(S(=O)(=O)c4ccccc4)cc23)CC1
Reaction time: 5 h

Procedure:
A mixture of 6-methyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (EXAMPLE 13, 341 mg, 1.00 mmol) in acetonitrile (5 mL) is treated with formaldehyde (37%, 0.400 mL, 5.00 mmol), sodium cyanoborohydride (101 mg, 1.60 mmol) and glacial acetic acid (1 drop). After 5 hr, the mixture is diluted with ethyl acetate and then washed with water and saline. The organic layer is dried, filtered, and concentrated. The concentrate is dissolved in methylene chloride/methanol and treated with methanolic hydrochloric acid. The solvent is then removed and the residual solid crystallized from hot ethyl acetate/methanol to give the title compound, mp=283–286°; IR (drift) 2523, 2477, 2453, 2428, 1479, 1311, 1304, 1283, 1150, 1094, 756, 730, 694, 644 and 623 cm−1; NMR (300 MHz, DMSO-d6) δ 11.00, 8.16, 7.85–7.95, 7.50–7.65, 3.70, 3.15–3.45 and 2.89; MS (FAB) m/z 355 (MH+), 354, 353, 58 and 44; HRMS (FAB) calculated for C20H23N2O2S=355.1480, found=355.1488.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.[H-].[Na+].Cl[C:12]1[C:13]([C:28]2([OH:32])[CH2:31][CH2:30][CH2:29]2)=[CH:14][C:15]2[N:16]([C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])=[N:19][N:20]=2)[N:17]=1.[NH4+].[Cl-].[Na+].[Cl-]>CN(C=O)C.ClCCl>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[N:16]2[N:17]=[C:12]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[CH:4][N:5]=3)[C:13]([C:28]3([OH:32])[CH2:31][CH2:30][CH2:29]3)=[CH:14][C:15]2=[N:20][N:19]=1
Reactant: OC1(c2cc3nnc(-c4ccccc4F)n3nc2Cl)CCC1
Reactant: Cn1ncnc1CO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C1(O)CCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.5 %

Procedure:
To a stirred solution of (2-methyl-2H-1,2,4-triazol-3-yl)methanol (0.2206 g, 1.95 mmol) in anhydrous DMF (6 ml) under nitrogen was added sodium hydride (60% dispersion in oil, 77.7 mg, 1.94 mmol) and the mixture was stirred at room temperature for 20 min. The mixture was then cooled in an ice-water bath and a solution of 6-chloro-3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-1,2,4-triazolo[4,3-b]pyridazine (0.2573 g, 0.807 mmol) in anhydrous DMF (5 ml) was added dropwise over min. The mixture was stirred for 20 min under nitrogen, then poured into saturated aqueous NH4Cl (50 ml), saturated aqueous NaCl (25 ml), and dichloromethane (75 ml). The aqueous layer was further extracted with dichloromethane (2×50 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3-5% MeOH/CH2Cl2) to afford 0.2793 g of 3-(2-fluorophenyl)-7-(1-hydroxycyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine (containing approximately 20% of (2-methyl-2H-1,2,4-triazol-3-yl)methanol starting material) as a colourless solid; 1H NMR (360 MHz, CDCl3) δ1.74 (1H, m), 2.17 (1H, m), 2.43 (2H, m), 2.60 (2H, m), 3.82 (3H, s), 5.58 (2H, s), 7.27 (1H, t, J=9.6 Hz), 7.36 (1H, t, J=7.5 Hz), 7.58 (1H, m), 7.82 (1H, m), 7.85 (1H, s), 8.01 (1H, s); MS (ES+) m/e 396 [MH]+, 114.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([OH:9])[C:3]=1[OH:10].[C:11](Cl)(Cl)=[S:12].[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]2[O:10][C:11](=[S:12])[O:9][C:4]=2[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Oc1c(F)ccc(Br)c1O
Reactant: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Fc1ccc(Br)c2oc(=S)oc12
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
3-Bromo-6-fluorobenzene-1,2-diol (8.9 g, 43 mmol) was dissolved in chloroform (100 mL), cooled to 0-5° C. and treated with thiophosgene (5.4 g, 47 mmol). Aqueous sodium hydroxide solution (10 wt %; 40 g, 99 mmol) was added in portions over 30 min with vigorous stirring. Stirring was continued for 60 min at 5-15° C. and then most of the chloroform was removed by rotary evaporation. The pH was adjusted to 2 by addition of 1 M HCl and the precipitated thione was taken up in ethyl acetate (150 mL). The organic phase was washed with water (25 mL), saturated NaCl (25 mL), dried (Na2SO4), and evaporated. The crude product was purified by flash chromatography, eluting with a 0-20% ethyl acetate-hexane gradient to give the title compound as a tan solid (6.2 g, 58%): mp 72-76° C.; 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J=9.2, 4.1 Hz, 1H), 7.04 (t, J=9.1 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −132.68; EIMS m/z 248.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10](I)[C:3]=12.[CH3:12][Si:13]([CH3:17])([CH3:16])[C:14]#[CH:15].CN(C=O)C.C1COCC1>C(Cl)Cl.[Cu]I.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.CC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([C:15]#[C:14][Si:13]([CH3:17])([CH3:16])[CH3:12])[C:3]=12
Reactant: Clc1ncnc2[nH]nc(I)c12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C[Si](C)(C)C#Cc1n[nH]c2ncnc(Cl)c12
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
Charge 4-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (5.4 g, 1.0 eq), trimethyl silyl acetylene (11.347 g, 6.0 eq), CuI (1.833 g, 0.5 eq), TEA (2.68 mL, 1.0 eq), DMF (67.5 mL), and THF (202.5 mL) in a round bottom flask under argon atmosphere. Stir the reaction mass under argon atm for 30 min. Charge (PPh3)4Pd (2.225 g, 0.1 eq) and stir the reaction mass at 35° C. for 3 h. Monitor the reaction by TLC (10% acetone in DCM). Concentrate the reaction mass under reduced pressure. Charge ethyl acetate and wash with saturated sodium bicarbonate solution, water and saturated aq. sodium chloride. Dry the organic layer over anhydrous sodium sulfate and concentrate the organic layer under reduced pressure. Purify the compound by column chromatography (silica 100-200 mesh, DCM-Acetone) to give desired product (1.81 g, 36.14%).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([OH:17])[C@H:6]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]=[CH2:8])=[N+:2]=[N-:3].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:1]([CH2:4][C@H:5]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:6]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH:7]=[CH2:8])=[N+:2]=[N-:3]
Reactant: C=C[C@@H](OCc1ccccc1)[C@@H](O)CN=[N+]=[N-]
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: C=C[C@@H](OCc1ccccc1)[C@H](CN=[N+]=[N-])OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a stirring solution of (2S,3R)-1-azido-3-benzyloxy-4-penten-2-ol (1) (250 μL, 1.07 mmol) in THF (50 mL) under argon was added tetrabutylammonium iodide (42 mg, 0.11 mmol) followed by benzyl bromide (155 μL, 1.27 mmol) and the reaction was cooled to 0° C. Sodium hydride (60% in mineral oil, 47 mg, 1.18 mmol) was added in small portions and the reaction was stirred overnight with warming to rt. The reaction was quenched with MeOH, filtered through Celite, and washed with Et2O. The organic solvent was removed under vacuum to give an oily residue, which was purified by flash chromatography (silica gel, 2% Et2O/hex) to yield (3R,4S)-5-azido-3,4-bisbenzyloxy-pent-1-ene (2, 237 mg, 65% yield) as a clear non-volatile liquid: Rf=−0.62 (1:4 EtOAc/hex); [α]D=−6.1° (c 1.50, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 7.35-7.24 (m, 10H), 5.81 (ddd, J=17.15, 10.58, 7.45 Hz, 1H), 5.37 (ddd, J=5.70, 1.65, 0.86 Hz, 1H), 5.33 (ddd, J=12.07, 1.44, 0.81 Hz, 1H), 4.63 (s, 2H), 4.61 (d, J=11.87 Hz, 1H), 4.35 (d, J=11.78 Hz, 1H), 3.90 (tdd, J=7.37, 5.65, 0.79, 0.79 Hz, 1H), 3.60 (ddd, J=6.39, 5.69, 3.64 Hz, 1H), 3.43 (dd, J=12.93, 6.42 Hz, 1H), 3.35 (dd, J=12.93, 3.60 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 138.25, 138.01, 135.43, 128.60 (4C), 128.29 (2C), 128.02, 127.99 (2C), 127.87, 119.97, 80.76, 80.23, 73.33, 70.79, 51.69; FTIR (NaCl): 2867, 2100, 1606, 1454, 1286, 1095, 1073.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[N:13](CC3C=CC(OC)=CC=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH:41][C:42](=[O:50])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[Ni]>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[NH:13][CH2:12][C:11]=2[S:10][C:9]=1[NH:41][C:42](=[O:50])[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(CN2Cc3sc(NC(=O)C(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c3CC2CNC(=O)C(=O)c2c[nH]c3ccccc23)cc1
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(=O)Nc1sc2c(c1C(=O)OC(C)(C)C)CC(CNC(=O)C(=O)c1c[nH]c3ccccc13)NC2
Reaction time: 18 h

Procedure:
2-(tert-Butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (101 mg, 0.143 mmol) was dissolved in dry tetrahydrofuran (6 ml) and passed through a pipette, plugged with cotton containing Raney 2800 Nickel (0.38 g). The pipette was flushed with dry tetrahydrofuran (6 ml) and the filtrate was concentrated in vacuo. Pd on carbon (10%, 102 mg, source: Avocado) and formic acid (10% in methanol, 5 ml) were added to the flask containing 2-(tert-Butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester. After stirring for 18 hours, the solution was filtered through a pad of celite and concentrated in vacuo. The residue was diluted in ethyl acetate, washed with saturated sodium bicarbonate (2×25 ml), brine (2×25 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was subjected to flash chromatography using a mixture of 10% methanol/dichloromethane as eluent, which afforded 2-(tert-butyoxyoxalyl-amino)-5-((2-(1H-indol-3-yl)-2-oxo-acetylamino)methyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([OH:17])=[O:16])[N:13]=1>C(O)=O>[CH:1]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([OH:17])=[O:16])[N:13]=1)=[O:3]
Reactant: CCCCON=C(C(=O)O)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.1 %

Procedure:
Formic acid (18.95 g.) was added dropwise to acetic anhydride (42.0 g.) under stirring at room temperature over 5 minutes, and stirred at 50° C. for an hour. 2-(2-Aminothiazol-4-yl)-2-n-butoxyiminoacetic acid (syn isomer, 25 g.) was added to the solution under ice cooling, and stirred at room temperature for 3 hours and additionally at 30° C. for an hour. After concentrating the resultant solution in vacuo, the residue was dissolved in diethyl ether. The solution was washed with water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and concentrated in vacuo. The obtained oil was triturated with a solution of n-hexane (1 part) and diisopropyl ether (1 part), and collected by filtration to give 2-(2-formamidothiazol-4-yl)-2-n-butoxyiminoacetic acid (syn isomer, 20.1 g.).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][CH:10]([CH2:15][C:16]23[CH2:31][CH2:30][CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=42)[C:22]2[C:17]3=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:15][C:16]23[CH2:31][CH2:30][CH:23]([C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=42)[C:24]2[C:29]3=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COC(CC23CCC(c4ccccc42)c2ccccc23)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCOC(CC34CCC(c5ccccc53)c3ccccc34)C2)cc1
Reaction time: 2 h

Procedure:
A mixture of 9-(4-benzyl-5-oxo-2-morpholinylmethyl)-9,10-dihydro-9,10-ethanoanthracene (1.07 g) and lithium aluminum hydride (400 mg) in dioxane was stirred at 50° -60° C. for 2 hours. Excess lithium aluminum hydride was decomposed by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(4-benzyl-2-morpholinylmethyl)-9,10-dihydro-9,10-ethanoanthracene, I.R., 3060, 3010, 2860, 2800, 1215, 1139, 1099, 1030, 980, 698, 660 cm-1.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:50]=[CH:51][CH:52]=1)[CH2:13][N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[CH:29]=[N:30][C:31]([N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[CH:32][CH:33]=4)[CH:26]=3)[N:21]([S:40]([C:43]3[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:20]=2)[CH:16]=[N:15]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:53][C@H:54]1[CH2:56][O:55]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:50]=[CH:51][CH:52]=1)[CH2:13][N:14]1[CH:18]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:35][CH2:36][N:37]([CH2:53][C@@H:54]([OH:55])[CH3:56])[CH2:38][CH2:39]5)=[N:30][CH:29]=4)[CH:26]=3)[N:21]([S:40]([C:43]3[CH:44]=[CH:45][C:46]([CH3:47])=[CH:48][CH:49]=3)(=[O:41])=[O:42])[CH:20]=2)[CH:16]=[N:15]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(OCc5ccccc5)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(OCc5ccccc5)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-(benzyloxy)benzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (200 mg. 0.273 mmol) was alkylated using (S)-2-methyloxirane (48 mg, 0.819 mmol), DIPEA (211 mg, 1.638 mmol) and ethanol (20 mL) to get 200 mg (crude) of the titled compound. MS: m/z=754.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:17][CH2:16][CH2:15][C@H:14]2[CH2:13][N:12]([CH3:18])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1>[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH2:13][N:12]([CH3:18])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@@]23CCC[C@H]2CN(C)CC3)c1
Agent: O=[Pt]
Product: COc1cccc([C@@]23CCC[C@@H]2CN(C)CC3)c1

Procedure:
Following the procedure set forth in Example 49, 4a-(3-methoxyphenyl)-2-methyl-3,4,4a5,6,7-hexahydro-2-pyrindine was hydrogenated over platinum oxide to provide a 60:40 mixture of trans-4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine and the corresponding cis-isomer. The trans isomer was crystallized as the picrate salt. The cis isomer was isolated as the free base, namely cis-4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine. M.P. 40°-43° C.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH:33]([CH3:35])[CH3:34])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl.[NH4+].[OH-].O>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH:33]([CH3:35])[CH3:34])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: CC(C)c1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1F
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)c1nc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of tert-butyl (3R,4R)-4-(6-carbamoyl-5-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (100 mg, 204 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (466 mg, 315 μL, 4.1 mmol) and the mixture stirred at room temperature for 16 h. The mixture was diluted with 25% aqueous NH4OH, dichloromethane, and water. The organic phase was separated and washed with water (2×), then concentrated in vacuo and purified by chromatography (silica, 3 to 10% methanol in dichloromethane) to give 6-((3R,4R)-3-aminotetrahydro-2H-pyran-4-ylamino)-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxamide (39 mg, 100 μmol, 49%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.76 (s, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 7.60 (t, J=9.2 Hz, 1H), 6.88 (dd, J=8.9, 2.9 Hz, 1H), 6.78 (d, J=7.7 Hz, 1H), 3.96 (br. s, 1H), 3.80 (m, 1H), 3.70 (dd, J=11.4, 2.8 Hz, 1H), 3.49 (dd, J=11.4. 1.7 Hz, 1H), 3.37 (m, 2H), 2.96 (s, 1H), 1.80 (m, 1H), 1.69 (m, 2H), 1.29 (d, J=6.8 Hz, 6H); MS (EI/CI) m/z: 390.2 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:31]([N+:32]([O-])=O)=[CH:30][C:29]([Cl:35])=[CH:28][C:3]=1[C:4]([O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:5]>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[C:31]([NH2:32])=[CH:30][C:29]([Cl:35])=[CH:28][C:3]=1[C:4]([O:6][CH2:7][C:8]1([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc([N+](=O)[O-])c2N)(c2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(Cl)cc(N)c2N)(c2ccc(F)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-((2-amino-5-chloro-3-nitrobenzoyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (700 mg, 1.4 mmol) in ethyl acetate (20 mL) under nitrogen was added palladium (10% on carbon, 140 mg). The flask was flushed with hydrogen and shaken under 60 psi of hydrogen overnight. The reaction was filtered through celite and concentrated to give 715 mg (quant.) as a foam semi-solid which was used without purification. tR=3.19 (Sunfire C18 4.6×50 mm, A=90% H2O/10% ACN, B=90% ACN/10% H2O, Modifier 0.1% TFA, 0.00 min=0% B, 4.0 min=100% B, 5.0 min=100% B, Flow rate=4 mL/min. Mass spec.: 377.88 (MH-Boc)+.