Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1.[CH2:11](O)[CH2:12][OH:13]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[C:3]2([CH2:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH:7]=1)[O:13][CH2:12][CH2:11][O:10]2
Reactant: CC1(C)C=C(I)C(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)C=C(I)C2(CC1)OCCO2
Yield: 90.1 %

Procedure:
A solution of 2-iodo-4,4-dimethylcyclohex-2-en-1-one (Synlett, 2005, 1263-1266; 5.46 g, 21.8 mmol), ethylene glycol (3.00 g, 48.3 mmol), p-toluenesulfonic acid hydrate (100 mg) in benzene (100 mL) was stirred for 7 hours under reflux, and the solvent was subjected to azeotropic distillation with water. After allowing to cool, a saturated aqueous solution of sodium hydrogencarbonate (100 mL) was added to the reaction solution, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=95:5) to yield the title compound (5.78 g, 90%) as a colorless oil.
Reaction SMILES: C(O[C:6](=[O:41])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:39])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[CH2:23][CH2:22]2)[C:18]([Cl:40])=[CH:17][N:16]=1)(C)(C)C.[C:42](O)([C:44](F)(F)F)=O.NC1C=CC=CC=1NC1N=C(N2CCN(C(NC3C=CC=C(C(F)(F)F)C=3)=O)CC2)C(Cl)=CN=1.C(Cl)(=O)C=C.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=3)=[O:39])[CH2:25][CH2:26]2)[C:18]([Cl:40])=[CH:17][N:16]=1)(=[O:41])[CH:42]=[CH2:44]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Agent: C=CC(=O)Cl
Agent: Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccccc1Nc1ncc(Cl)c(N2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)n1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of tert-butyl(2-((5-chloro-4-(4-((3-(trifluoromethyl)phenyl)carbamoyl)piperazin-1-yl)pyrimidin-2-yl)amino)phenyl)carbamate (0.025 g, 0.043 mmol) in DCM (1.0 mL) was added TFA (1.0 mL) and the mixture was stirred for 1 h. An aliquot of the reaction mixture was analyzed by LCMS, which indicated that the reaction had proceeded to completion. The solvents were removed and the residue was dried on high vacuum. The crude product was used for the next step without further purification. To a solution of 4-(2-((2-aminophenyl)amino)-5-chloropyrimidin-4-yl)-N-(3-(trifluoromethyl)phenyl)piperazine-1-carboxamide (0.043 mmol) in DCM (0.5 mL) was added acryloyl chloride (0.004 mL, 0.052 mmol) and DIEA (0.018 mL, 0.11 mmol) and the mixture was stirred at 0° C. for 1 h. The crude reaction mixture was loaded onto silica gel and purified using 0-7% MeOH/DCM gradient to give the title compound (10 mg, 43%). MS (ES+) C25H23ClF3N7O2 requires: 545. Found: 546 [M+H]+
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([CH3:31])[C:29]=1[CH3:30])[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[C:11]=1[O:25][CH3:26])=[O:8])=[N+:2]=[N-:3].[C:32]([O:36][CH3:37])(=[O:35])[C:33]#[CH:34].O>CC(N(C)C)=O>[CH3:37][O:36][C:32]([C:33]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]3[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:13]=[C:12]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[C:11]=3[O:25][CH3:26])[CH:27]=[C:28]([CH3:31])[C:29]=2[CH3:30])[CH:34]=1)=[O:35]
Reactant: C#CC(=O)OC
Reactant: COc1c(NC(=O)c2cc(C)c(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cn(-c2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)cc(C)c2C)nn1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
A mixture of 0.112 g (0.252 mmol) of 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4,5-dimethyl-benzamide and 0.069 mL (0.756 mmol) of methyl propiolate was stirred in 0.5 mL of DMA at 110° C. overnight. The vial was cooled to room temperature, and the contents were poured into stirring water. The precipitate was collected and chromatographed (10–60% EtOAc in hexanes). Fractions containing predominantly the major product were collected and further purified by precipitating from dichloromethane with hexanes to provide 57 mg of a white powder. The filtrate was combined with the mixed fractions from the first chromatography, and the resulting mixture was chromatographed again to provide 22 mg of the title compound as a pale yellow solid for a total yield of 79 mg (0.149 mmol; 59%), mp: 199° C. ESI MS (m/z 528, 100, M−H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:14])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[F:15][CH:16]([CH2:18][C:19](Cl)=[S:20])[F:17]>O1CCCC1>[C:8]([O:14][C:19](=[S:20])[CH2:18][CH:16]([F:17])[F:15])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: FC(F)CC(=S)Cl
Reactant: CC(C)CC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CC(=O)OC(=S)CC(F)F
Reaction time: 1 h

Procedure:
To a stirred solution of triethylamine (1.4 equivalents) and isovaleric acid (1.3 equivalents) in tetrahydrofuran (5 parts by weight) is dropwise added difluoromethylthioacetyl chloride at -30° C., and the mixture is left standing for 1 hour. After removing separated crystals by filtration, the reaction mixture is concentrated in vacuum to leave difluoromethylthioacetic isovaleric anhydride.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:17]2[CH2:18][C:19]3[C:24]([C:16]2=[N:15][N:14]=1)=[C:23](Br)[CH:22]=[CH:21][CH:20]=3.Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:17]2[CH2:18][C:19]3[C:24]([C:16]2=[N:15][N:14]=1)=[C:23]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH:22]=[CH:21][CH:20]=3
Reactant: Brc1cccnc1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1cccc(Br)c1-2
Product: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1cccc(-c3cccnc3)c1-2
Yield: 3 %

Procedure:
Prepared in a similar manner to Example 7 from 3-(5-methyl-3-phenylisoxazol-4-yl)-9-bromo-5H-[1,2,4]triazolo[3,4-a]isoindole (100 mg) (prepared using 7-bromo-2,3-dihydroisoindol-1-one by analogy with Example 4) and 3-bromopyridine (0.06 ml) to give the title compound (7 mg, 3%). 1H NMR (360 MHz, CDCl3) δ 8.90 (1H, s), 8.71 (1H, s), 8.40 (1H, d, J=5.8 Hz), 7.56–7.40 (8H, m), 7.30 (1H, d, J=7.3 Hz), 4.08 (2H, s), 2.68 (3H, s), miz (ES+) 392 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F-].[Cs+].CS(O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(=O)=O>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-ol (500 mg, 1.565 mmol) was dissolved in DMA (20 ml). tert-Butyl (4-methanesulfonyloxy)piperidine-1-carboxylate (436.6 mg, 1.565 mmol) and cesium fluoride (236.3 mg, 1.565 mmol) were added, and the mixture was heated to 60° C. with stirring. After 18 hours, tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride were again added in the same quantities to the reaction mixture and heating was continued at 60° C. for a further 18 hours. The solvent was evaporated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution (50 ml) and EtOAc (2×50 ml). The organics were combined, dried over MgSO4 and evaporated. The resulting product was then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/EtOAc (100/0 to 0/100). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate as a colourless foam (757 mg, 96%); 1H NMR Spectrum: (DMSO-d6): 1.52 (s, 9H), 1.60-1.80 (m, 2H), 2.02-2.20 (m, 2H), 3.20-3.45 (m, 2H), 3.75-3.92 (m, 2H), 4.05 (s, 3H), 4.95 (m, 1H), 7.32-7.45 (m, 2H), 7.55-7.70 (m, 2H), 7.92 (s, 1H), 8.50 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)+ 503.
Reaction SMILES: CO.Cl.[CH:4]1([C:7]([CH:39]2[CH2:41][CH2:40]2)([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=4)[CH:24]=[C:23]([CH3:38])[CH:22]=3)=[CH:17][N:16]=2)[NH:8][S@@](C(C)(C)C)=O)[CH2:6][CH2:5]1>O1CCOCC1.C([O-])(O)=O.[Na+]>[NH2:8][C:7]([CH:39]1[CH2:41][CH2:40]1)([CH:4]1[CH2:6][CH2:5]1)[C:15]1[N:16]=[CH:17][C:18]([C:21]2[CH:26]=[C:25]([NH:27][C:28]3[N:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=3)[CH:24]=[C:23]([CH3:38])[CH:22]=2)=[CH:19][CH:20]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(N[S@](=O)C(C)(C)C)(C3CC3)C3CC3)nc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C(N)(C3CC3)C3CC3)nc2)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Methanol (5.00 mL) and HCl (4 M in dioxanes, 0.584 mL, 2.34 mmol) were added to (R)—N-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]methyl}-2-methylpropane-2-sulfinamide (317.5 mg, 0.584 mmol) and the reaction mixture was stirred for 25 minutes at room temperature. An additional 150 uL of 4 M HCl in dioxane was added to the reaction mixture, stirred for 45 minutes, diluted with saturated aqueous NaHCO3 (20.0 mL) and extracted with ethyl acetate (30.0 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered, and was concentrated under reduced pressure to yield N-(3-{6-[amino(dicyclopropyl)methyl]pyridin-3-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine. MS APCI calc'd for C24H25F3N5 [M+H]+ 440. found 440.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([OH:12])[CH3:11].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([O:12][S:22]([CH3:21])(=[O:24])=[O:23])[CH3:11]
Reactant: CC(O)C(=O)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)C(=O)c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
2',4'-Difluoro-2-hydroxypropiophenone (2.8 g) was dissolved in methylene chloride (28 ml), to which were added triethylamine (2.5 ml) and methanesulfonyl chloride (1.3 ml) at 0° C. After stirring for 15 minutes, the mixture was washed with water (30 ml), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3 cm×10 cm) and eluted with methylene chloride. The desired fraction was concentrated, to give 2',4'-difluoro-2-methanesulfonyloxypropiophenone (3.0 g) as a colorless oil. This compound (3.0 g) was dissolved in 30 ml of N,N-dimethylformamide, to which were added 1H-1,2,4-triazole (0.94 g) and then 60% sodium hydride suspension in oil (0.5 g) at -10° C. After stirring at 0° C. for 50 minutes, the reaction mixture was added to a mixture of ethyl acetate (100 ml) and water (200 ml) for extraction. The water layer was extracted with ethyl acetate (100 ml) and the ethyl acetate layers were combined, washed with saturated aqueous solution of sodium chloride (30 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3 cm×10 cm) and eluted with ethyl acetate. The desired fraction was concentrated, to give 2',4'-difluoro-2-(1H-1,2,4-triazol-1-yl)propiophenone (1.5 g) as a colorless oil. This compound (1.24 g) was added to a mixture of dimethyl sulfoxide (30 ml), 60% sodium hydride suspension in oil (0.25 g) and trimethylsulfoxonium iodide (1.38 g) at 10° C. and then the temperature was raised to 25° C. Two hours later, the reaction mixture was added to a mixture of diethyl ether (100 ml) and water (150 ml), diethyl ether layer was separated, and the water layer was extracted with diethyl ether (100 ml×2). The organic layers were combined, washed with saturated aqueous solution of sodium chloride (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (3 cm×10 cm) and eluted with ethyl acetate-hexane (3:1), to give 2-(2,4-difluorophenyl)-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane as a colorless oil (0.87 g).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[F:16])[N:3]=1.[O:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C@@H:29]3[O:34][CH2:33][CH2:32][NH:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:18]1.C(N(CC)CC)C>O1CCCC1>[O:17]1[CH2:21][CH2:20][C@@H:19]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C@@H:29]3[O:34][CH2:33][CH2:32][N:31]([C:2]4[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]5[CH:15]=[CH:14][N:13]=[CH:12][C:11]=5[F:16])[N:3]=4)[CH2:30]3)=[CH:27][CH:28]=2)[CH2:18]1
Reactant: c1cc([C@H]2CNCCO2)ccc1N[C@@H]1CCOC1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCO[C@@H](c3ccc(N[C@@H]4CCOC4)cc3)C2)nc(-c2ccncc2F)cc1=O
Temperature: 95 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A solution of 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.08 g, 0.35 mmol), (2S)-2-(4-(N-((3R)-tetrahydrofuran-3-yl)amino)phenyl)morpholine obtained in Reference Example 7 (0.11 g, 0.44 mmol) and triethylamine (0.22 g, 2.2 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for 3 hours. The mixture was partitioned between water and dichloromethane, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 5-10% methanol in chloroform to furnish 2-((2S)-2-(4-(N-((3R)-tetrahydrofuran-3-yl)amino)phenyl)-morpholin-4-yl)-3-methyl-6-(3-fluoropyridin-4-yl)-3H-pyrimidin-4-one (0.07 g, 47%) as pale yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:39]=[C:38]([CH3:40])[C:37]([O:41]CC4C=CC=CC=4)=[C:36](Cl)[CH:35]=3)[C:19](=[O:32])[N:20]3[CH2:25][CH2:24][N:23]([CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1.[H][H]>CO.C(N(CC)CC)C.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:33][C:34]3[CH:35]=[CH:36][C:37]([OH:41])=[C:38]([CH3:40])[CH:39]=3)[C:19](=[O:32])[N:20]3[CH2:21][CH2:22][N:23]([CH:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH2:24][CH2:25]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:50]=[CH:51][CH:52]=[CH:53][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)ccc1O

Procedure:
A suspension of 108 mg (0.15 mmol) (R)-1-(4-benzyloxy-3-chloro-5-methyl-benzyl)-2-oxo-2-[4-(tetrahydropyran-4-yl)-piperazin-1-yl]-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 30 mg 10% Pd/C in 10 mL MeOH and 0.5 mL triethylamine was hydrogenated at RT and 3000 hPa hydrogen pressure until the theoretical amount of hydrogen had been taken up. The catalyst was filtered off, the residue was dissolved in 1 mL DMF and purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.CCOC(C)=O>[N:36]1([C:21]2[CH:20]=[C:19]([C:17]3[S:18][C:14]4[C:13]([C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=5)=[C:12]([C@H:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:27]([CH3:28])=[CH:26][C:15]=4[N:16]=3)[CH:24]=[CH:23][N:22]=2)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[N:37]1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: c1ccc2[nH]ncc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ncc5ccccc54)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 160 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (30 mg, 0.057 mmol) and 1H-indazole (6.0 mg, 0.052 mmol) in DMF (0.5 mL) was added K2CO3 (16.0 mg, 0.117 mmol) and 18-crown-6 (0.1 mg, 5.1×10−4 mmol). The reaction mixture was heated in a microwave at 160° C. for 1 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 60% ethyl acetate/hexanes) and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C34H32ClN4O3S: 611.2; found: 611.3.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH:10]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[OH:9][CH:10]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(O)c1cccc(N)c1
Reactant: BrCc1ccccc1
Product: CCCCCC(O)c1cccc(NCc2ccccc2)c1

Procedure:
For compounds in which X is --NR2 --(CHR1)n --, the corresponding amino starting compounds are employed to form the desired amino compound. Thus, aniline is condensed with 3-(1-hydroxyhexyl)benzylbromide to form 2-[3-(1-hydroxyhexyl)benzylamino]benzene. Alternatively, benzyl bromide is condensed with 3-(1-hydroxyhexyl)aniline to form 2-[3-(1-hydroxyhexyl)anilinomethyl]benzene.
Reaction SMILES: [CH2:1]([C@H:6]([N:10]([CH2:15][C:16]([O-:18])=[O:17])[CH2:11][C:12]([O-:14])=[O:13])[C:7]([O-:9])=[O:8])[CH2:2]C([O-])=O.[Na+].[Na+].[Na+].[Na+].[OH2:23]>>[C:12]([OH:14])(=[O:13])[CH2:11][N:10]([CH2:15][C:16]([OH:18])=[O:17])[C@H:6]([C:7]([OH:9])=[O:8])[C@@H:1]([CH3:2])[OH:23]
Reactant: O=C([O-])CC[C@@H](C(=O)[O-])N(CC(=O)[O-])CC(=O)[O-]
Reactant: O
Agent: [Na+]
Product: C[C@@H](O)[C@@H](C(=O)O)N(CC(=O)O)CC(=O)O
Yield: 85 %

Procedure:
The solution obtained in example 1 was acidified using an ion exchange resin. Acidification took place using Amberlite IR-120, a strong acid ion exchange resin: 55 g of GLDA solution, 110 g of Amberlite IR-120 as such, and ca 100 g of water were stirred in a 500 ml round-bottomed flask for at least 48 h. After filtering off the resin the solution was dried by evaporation of water at reduced pressure at 70° C. The light-coloured crispy foam obtained was further dried in a vacuum oven at 65° C. This resulted in a solid product in a yield of circa 85%.
Reaction SMILES: [OH-].[Na+].C([N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:16]([O:18]C)=[O:17])=[C:12]([CH3:15])[CH:13]=2)[CH:8]=[N:7]1)(=O)C.[OH-].[Li+]>O1CCCC1.O>[CH3:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[N:7][NH:6]2)=[CH:10][C:11]=1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1cc2cnn(C(C)=O)c2cc1C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2[nH]ncc2cc1C(=O)O
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A 2N-aqueous sodium hydroxide solution (0.63 ml, 1.3 mmol) was added to a solution of methyl 1-acetyl-6-methyl-1H-indazole-5-carboxylate (0.0731 g, 0.315 mmol) in tetrahydrofuran (1 ml), and the resulting mixture was stirred for 3 hours with heating under reflux. Then, a 2N-aqueous lithium hydroxide solution (0.63 ml, 1.3 mmol) was added thereto and stirred for another 3 hours. The resulting solution was diluted with water and washed with diethyl ether, and the aqueous layer was adjusted to pH 1 to 2 with 1N-hydrochloric acid to precipitate a solid. The solid precipitated was collected by filtration and the precipitate on a filter was washed with water and dried under reduced pressure to obtain 6-methyl-1H-indazole-5-carboxylic acid (0.0514 g, 93%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10](OS(C(F)(F)F)(=O)=O)[C:11]2=[O:21])[CH2:3]1.C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[C@@H](O)C2=O)C1.FC(F)(F)S(O)(=O)=O.[Cl-:60].[Li+]>CN(C=O)C.O>[CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@@H:10]([Cl:60])[C:11]2=[O:21])[CH2:3]1
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](OS(=O)(=O)C(F)(F)F)C[C@@H]32)C1
Reactant: [Cl-]
Agent: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](O)C[C@@H]32)C1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](Cl)C[C@@H]32)C1
Reaction time: 21 h
Yield: 96.5 %

Procedure:
800 mg of 3β-methyl-16β-trifluoromethylsulfonyloxy-5-androsten-17-one, prepared from 3β-methyl-16α-hydroxy-5-androsten-17-one and trifluoromethane sulfonic acid was placed in 16 ml DMF and was treated with 100 mg Lithium chloride at room temperature. The reaction mixture was stirred magnetically for 21 hours. Water is then added and the resulting crystalline ppt was collected. The crystals were washed with additional water and were then dissolved in CH2Cl2, filtered through anhydrous sodium sulfate and the solvent was evaporated off. The resulting crystals were recrystallized from CH3OH, yielding 570 mg of final product. m.p. 159°-165° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:8][CH:7]=[C:6]([F:15])[C:3]=1[CH:4]=[O:5].ClC1C(OCC(F)(F)F)=CC=C(Cl)C=1C(C1C2C(=NC=C(C3C=NN(C)C=3)C=2)NC=1)O.[Cl:47][C:48]1[CH:49]=[C:50]2[CH:56]=[CH:55][NH:54][C:51]2=[N:52][CH:53]=1>>[Cl:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:8][CH:7]=[C:6]([F:15])[C:3]=1[C:4]([C:56]1[C:50]2[C:51](=[N:52][CH:53]=[C:48]([Cl:47])[CH:49]=2)[NH:54][CH:55]=1)=[O:5]
Reactant: COCCOc1ccc(F)c(C=O)c1Cl
Reactant: Clc1cnc2[nH]ccc2c1
Agent: Cn1cc(-c2cnc3[nH]cc(C(O)c4c(Cl)ccc(OCC(F)(F)F)c4Cl)c3c2)cn1
Product: COCCOc1ccc(F)c(C(=O)c2c[nH]c3ncc(Cl)cc23)c1Cl

Procedure:
Additional compounds were prepared using the protocol of Scheme 41, optionally substituting 2-chloro-6-fluoro-3-(2-methoxy-ethoxy)-benzaldehyde 123 with a suitable aldehyde (prepared as described in Examples 36, 39 or 40), and/or optionally replacing 5-chloro-1H-pyrrolo[2,3-b]pyridine 4 with an appropriate substituted 7-azaindole (5-methoxy-7-azaindole per Example 8, 5-(1-methyl-1H-pyrazol-4-yl)-7-azaindole per Example 35) in Step 1. The following compounds were made following this procedure: