Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[N:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.Cl.C(O)(C)C>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[N:5]=[N:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nnc(C(F)(F)F)cc2Cl)CC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: FC(F)(F)c1cc(Cl)c(NC2CCNCC2)nn1
Yield: 8.6 %

Procedure:
A solution of D8 (1.1 g, 2.9 mmol) and hydrochloric acid/isopropanol (6N, 20 ml) in methanol (100 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was evaporated in vacuo, the residue re-dissolved in methanol and the solution made alkaline with methanolic ammonia. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (silica gel; 5%-15% methanolic ammonia in dichloromethane) to give D9 (70 mg, 9%). C10H12ClF3N4 requires 280; Found 281 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:18])[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:16][CH2:17][CH:12]([N:11]([CH3:18])[CH3:10])[CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CN(C)C1CCNCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(Cc2ccc(Br)cc2)CC1
Yield: 85.8 %

Procedure:
4-Bromobenzyl bromide (0.5 g, 2.0 mmol) was stirred with 4-dimethylaminopiperidine (0.51 g, 4.0 mmol) and triethylamine (0.42 mL, 3.0 mmol) in THF (20 mL) at ambient temperature for 96 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound (0.51 g, 86%). 1H NMR (CDCl3, 400 MHz): 7.44-7.40 (m, 2H), 7.21-7.16 (m, 2H), 3.43 (s, 2H), 2.91-2.85 (m, 2H), 2.27 (s, 6H), 2.17-2.07 (m, 1H), 2.00-1.91 (m, 2H), 1.80-1.72 (m, 2H), 1.58-1.45 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CBr)c1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(CC2(c3cccc(OC)c3)C(=O)Nc3cc(Cl)ccc32)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 3-methoxybenzyl bromide (0.15 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(3-methoxy-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as orange plates. (Yield 0.19 g, 80.4%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].[Cl:15][C:16]1[CH:17]=[C:18]([NH:23][CH:24]([C:26](O)=[O:27])[CH3:25])[CH:19]=[CH:20][C:21]=1[Cl:22].N[C@H](C(O)=O)C>>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[NH:5][C:26](=[O:27])[CH:24]([CH3:25])[NH:23][C:18]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: C[C@H](N)C(=O)O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-tyrosine methyl ester (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a mixture of stereoisomers about alanine. The reaction was monitored by tlc (Rf=0.29 in 10% MeOH/CH2Cl2) and purification was by flash chromatography (10% methanol/methylene chloride).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]2[CH2:36][CH2:35][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH:21][CH:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[O:20])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:48]([C:50]1[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1)#[N:49].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:48]([C:50]1[CH:51]=[CH:52][C:53]([S:56]([N:25]2[CH2:26][CH2:27][CH:22]([NH:21][C:19]([C:16]3[CH:15]=[CH:14][C:13]4[NH:12][C:11]5[CH2:35][CH2:36][N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([C:2]([F:40])([F:1])[F:39])=[CH:38][CH:37]=6)[CH2:9][C:10]=5[C:18]=4[CH:17]=3)=[O:20])[CH2:23][CH2:24]2)(=[O:58])=[O:57])=[CH:54][CH:55]=1)#[N:49]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(Cc2ccc(C(F)(F)F)cc2)CC4)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)N2CCC(NC(=O)c3ccc4[nH]c5c(c4c3)CN(Cc3ccc(C(F)(F)F)cc3)CC5)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl 4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (9, 50 mg, 90 μmol) in DCM (1.0 mL), TFA (1.0 mL) was added. After allowing the reaction mixture to stir at room temperature for 2 h, the volatiles were evaporated, DCM and toluene (10 mL) were added and the volatiles evaporated (2×). The resulting residue was dissolved in DMF (2.0 mL) and triethylamine (0.5 mL, 0.36 g, 3.6 mmol) and 4-cyanobenzenesulfonyl chloride (22 mg, 110 μmol) were added. The resulting reaction mixture was allowed to stir at room temperature overnight, poured into saturated sodium bicarbonate solution (20 mL) to give a tan solid which was triturated with ethyl ether to provide N-(1-(4-cyanophenylsulfonyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 21, 54 mg, 97%). 1H NMR (DMSO-d6, 300 MHZ) 11.04 (br s, 1H), 8.12 (d, J=8.5 Hz, 2H), 8.04 (d, J=7.7 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.79 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.62 (d, J=7.7 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 3.86 (s, 2H), 3.82-3.72 (m, 1H), 3.70-3.59 (m, 4H), 2.90-2.78 (m, 4H), 2.56-2.44 (m, 2H), 1.90-1.80 (m, 2H), 1.64-1.48 (m, 2H) ppm; MS (ES) 622 (M+H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)([OH:19])N.[Na]>C(O)(=O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:19])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)O)cc1OC1CCCC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (66 g) and sulfamic acid (39.6 g) in glacial acetic acid (500 mL) is treated dropwise during 1 hour with a solution of sodium chicrite (35 g) in water (150 mL). The mixture is stirred at 20° C. during 1 hour and then it is treated with water (500 mL) dropwise during 30 minutes. The resulting solid is filtered, washed with water and dried, to give 3-cyclopentyloxy-4-methoxybenzoic acid (60.9 g) in the form of white crystals [Elemental analysis: C,65.8; H,6.7%; calculated: C,66.1; H,6.8%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C([Li])CCC.[CH2:27]1[O:29][CH2:28]1.O>C(COC)OC>[CH3:14][C:12]1([CH3:15])[CH2:11][O:10][C:9]([C:6]2[C:5]([CH:28]([OH:29])[CH3:27])=[C:4]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13]1
Reactant: CCCCCOc1cc(C2=NC(C)(C)CO2)ccc1OC
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Product: CCCCCOc1c(OC)ccc(C2=NC(C)(C)CO2)c1C(C)O
Temperature: -60 °C
Yield: 38.2 %

Procedure:
2-(4-Methoxy-3-pentyloxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (373 mg, 1.28 mmol, 1 eq) was dissolved in dimethoxyethane (7 ml). The solution was cooled to -60° C., and n-butyllithium (1.6M hexane solution)(1.76 ml, 2.82 mmol, 2.2 eq) was added dropwise. The mixture was stirred at said temperature for 1.5 hours. Ethylene oxide was added dropwise, and the mixture was stirred for 1.0 hour. The mixture was heated to room temperature, and further stirred for 2 hours. Water (50 ml) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layers were combined, washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=3/1-2/1) to give [6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methoxy-2-pentyloxyphenyl]ethanol (164 mg, 38.2%) as an oil.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:32]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][C:35]=2[F:41])=[C:31]([CH3:42])[C:30](=[O:43])[N:29]([CH3:44])[CH:28]=1)=O)#[N:21].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Si]([N:63]=[N+:64]=[N-:65])(C)(C)C>CC#N.C(OCC)(=O)C>[Br:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:32]2[C:27]([C:25]3[N:24]([CH2:23][CH2:22][C:20]#[N:21])[N:65]=[N:64][N:63]=3)=[CH:28][N:29]([CH3:44])[C:30](=[O:43])[C:31]=2[CH3:42])=[C:35]([F:41])[CH:36]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NCCC#N)cn(C)c1=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(Nc2ccc(Br)cc2F)c(-c2nnnn2CCC#N)cn(C)c1=O
Reaction time: 22 h
Yield: 61 %

Procedure:
PPh3 (83 mg, 0.32 mmol) was added to a stirred suspension of 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-cyano-ethyl)-amide (51 mg; 0.12 mmol) in MeCN (1.5 mL). DIAD (0.065 mL, 0.31 mmol) and TMSN3 (0.045 mL, 0.32) were added dropwise. After 22 hours, the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography gave clean desired product (33 mg, 61%).
Reaction SMILES: O[C@@H:2]([C:6]1[CH:11]=CC=C[CH:7]=1)C(O)=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:24][C:23](=[O:25])[CH2:22][CH2:21][NH:20]2)=[C:15]([CH3:26])[CH:14]=1.ClCCl.[C:30]([O-])([OH:32])=[O:31].[Na+]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:24][C:23](=[O:25])[CH2:22][CH2:21][N:20]2[C:30]([O:32][C:6]([CH3:2])([CH3:7])[CH3:11])=[O:31])=[C:15]([CH3:26])[CH:14]=1
Reactant: Cc1cc(F)ccc1[C@H]1CC(=O)CCN1
Reactant: O=C([O-])O
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(F)ccc1[C@H]1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of (2S)-hydroxy(phenyl)ethanoic acid—(2R)-2-(4-fluoro-2-methylphenyl)-4-piperidinone (1:1) (WO 2008090117 published on 31 Jul. 2008) (50 g, 139 mmol) in dry Dichloromethane (DCM) (550 ml) TEA (29.1 ml, 209 mmol) was added and then BOC-Anhydride (38.8 ml, 167 mmol). The reaction mixture was stirred overnight at r.t. The reaction was diluted with NaHCO3 sat. sol. (400 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by a small pad of silica panel eluting with Cy to 7:3 Cy/EtOAc to afford the title compound (37.6 g, 122 mmol, 88% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.08-7.18 (m, 1H) 6.80-6.92 (m, 2H) 5.62 (br. s., 1H) 4.16-4.32 (m, 1H) 3.09-3.30 (m, 1H) 2.79 (d, 2H) 2.39-2.62 (m, 2H) 2.33 (s, 3H) 1.33-1.51 (m, 9H); UPLC: Rt=0.77 mins, m/z=251 [M−56+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:32])=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[C:28](=[O:29])[N:27]([CH3:30])[CH2:26][CH2:25][N:24]4[CH3:31])=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[O:33]=[C:34]1[C:39]2[S:40][C:41]([C:43](O)=[O:44])=[CH:42][C:38]=2[CH2:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O.CN(C=O)C>[CH3:31][N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[C:28](=[O:29])[CH:23]1[C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:10]2[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=[C:8]([C:4]3[C:3]([CH3:32])=[C:2]([NH:1][C:43]([C:41]4[S:40][C:39]5[C:34](=[O:33])[CH2:35][CH2:36][CH2:37][C:38]=5[CH:42]=4)=[O:44])[CH:7]=[CH:6][CH:5]=3)[N:9]=2)=[CH:22][CH:21]=1
Reactant: Cc1c(N)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Reactant: O=C(O)c1cc2c(s1)C(=O)CCC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)c2cc3c(s2)C(=O)CCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc(C3C(=O)N(C)CCN3C)cc2)n1
Reaction time: 4 h
Yield: 52.2 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 15 (249 mg, 1.27 mmol), 16 (500 mg, 1.16 mmol), N,N-diisopropylethylamine (600 mg, 4.64 mmol) and anhydrous DMF (5 mL). Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 616 mg, 1.39 mmol) was added, and the reaction was stirred for 4 h. After this time, the reaction was diluted with water (10 mL), and the resulting suspension was filtered. The filter cake was dissolved in methylene chloride (20 mL), and the solution was washed with 10% aqueous citric acid (10 mL), saturated aqueous sodium bicarbonate (10 mL), and water (10 mL), and dried over sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography to afford a 52% yield of 17 (370 mg) as a white solid: mp 154-155° C.; 1H NMR (500 MHz, CD2Cl2) δ 8.31 (s, 1H), 7.81 (dd, 1H, J=7.5, 1.5 Hz), 7.76-7.72 (m, 3H), 7.50 (s, 1H), 7.28-7.23 (m, 4H), 6.73 (s, 1H), 3.64 (td, 1H, J=11.5, 4.5 Hz), 3.57 (s, 1H), 3.55 (s, 3H), 3.14 (dt, 1H, J=11.5, 3.5 Hz), 2.93 (m, 1H), 2.88-2.86 (m, 5H), 2.62-2.57 (m, 3H), 2.36 (s, 3H), 2.17 (m, 2H), 2.09 (s, 3H); MS (ESI+) m/z 611.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([N:37]3[CH2:43][C:42]4[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][C:41]=4[O:40][CH2:39][CH2:38]3)=[N:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1>>[NH2:16][C@H:13]1[CH2:14][CH2:15][N:11]([S:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:45]3[CH:46]=[CH:47][C:41]4[O:40][CH2:39][CH2:38][N:37]([C:31]5[C:30]6[C:35](=[CH:36][C:27]([O:26][CH3:25])=[CH:28][CH:29]=6)[N:34]=[CH:33][N:32]=5)[CH2:43][C:42]=4[CH:44]=3)[CH:6]=2)(=[O:9])=[O:10])[CH2:12]1
Reactant: COc1ccc2c(N3CCOc4ccc(B(O)O)cc4C3)ncnc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Product: COc1ccc2c(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)N6CC[C@H](N)C6)c5)cc4C3)ncnc2c1

Procedure:
Synthesized according to the method of example 5 using (S)-tert-butyl 1-(2-amino-5-bromopyridin-3-ylsulfonyl)pyrrolidin-3-ylcarbamate (reagent preparation 25) and {4-[7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1 and BOC group deprotection. 1H NMR (400 MHz, d6-DMSO): 8.80 (s, 1H), 8.65 (d, 1H), 8.41 (m, 2H), 8.22 (m, 1H), 8.04 (d, 1H), 7.78 (s, 1H), 7.53 (d, 1H), 7.35 (m, 2H), 6.98 (br m, 2H), 5.43 (S, 2H), 4.62 (s, 2H), 4.49 (s, 2H), 3.92 (s, 3H), 3.79 (m, 1H), 3.69 (m, 1H), 3.55-3.45 (m, 3H), 3.32 (m, 2H), 2.20 (m, 1H), 1.91 (M, 1H); MS (EI) for C27H29N7O4S: 548 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3].N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O>[C:7]1([CH2:6][O:5][CH2:4][CH:2]([O:3][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(O)COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 73.9 %

Procedure:
CH3CH(OH)CH2OCH2Ph (50.0 g) and pyridine (150 ml) were put into a flask, and under cooling with ice, p-toluenesulfonic acid chloride (63.2 g) was added over a period of 30 minutes. The mixture was stirred at room temperature for 4 days, and then water (150 ml) was added, followed by extraction twice with dichloromethane (100 ml). The extracted organic phase was washed twice with a KHCO3 saturated aqueous solution (100 ml) and twice with water (100 ml), dried over magnesium sulfate, filtered and further concentrated to obtain PhCH2OCH2CH(CH3)OTs (71.2 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]CC)=[O:12])[CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[C:5]2[CH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH:25]([CH:31]([CH3:33])[CH3:32])[CH2:24]1.O.[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:23]1[CH2:28][CH2:27][S:26](=[O:29])(=[O:30])[CH:25]([CH:31]([CH3:33])[CH3:32])[CH2:24]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C(C(C)C)C3)cn(C(=O)OC(C)(C)C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C1CC(c2c[nH]c3c(C(=O)O)cc(Br)cc23)CCS1(=O)=O
Temperature: 80 °C

Procedure:
1-(1,1-dimethylethyl) 7-ethyl 5-bromo-3-[2-(1-methylethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]-1H-indole-1,7-dicarboxylate (1.46 g, 2.69 mmol) was dissolved in methanol (12 mL) and then water (6.00 mL) was added and then 6 N aqueous NaOH (6.73 mL, 40.4 mmol was added and the mixture was heated in a microwave 30 mins at 80° C. The mixture was neutralized with 1 N aqueous HCl until pH=1 and a small amount of yellow solid precipitated which was set aside. The aqueous solution was extracted with ethyl acetate, the organic layers were combined, dried (MgSO4) and solvent was removed under vacuum to afford the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH:9]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1[F:27])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:6])([CH3:5])[CH3:4].[CH3:28]I>CN(C=O)C>[C:3]([O:7][CH2:8][CH:9]([N:17]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1[F:27])[CH3:28])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OCC(NCc1ccc(C#N)cc1F)C(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C#N)cc1F)C(COC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of sodium hydride (1.8 g, 0.038 mol) in dry DMF (10 mL) at 0° C., tert-butyl 3-tert-butoxy-2-[(4-cyano-2-fluorobenzyl)amino]propanoate (6.7 g, 0.019 mol) in DMF (20 mL) was added dropwise. The resulting mixture was allowed to stir for 20 min at RT. Methyl iodide (3.5 mL, 0.0057 mol) was then added dropwise at 000 and the mixture was allowed to stir for 3 hr at RT. The reaction mixture was quenched in ice water and extracted with ethyl acetate (250 mL). The organic layer was washed with water (3×100 mL), dried over sodium sulphate and concentrated under reduced pressure. The crude was purified by column chromatography using petroleum ether and ethyl acetate as eluent, affording the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, J=9.8 Hz, 1H), 7.67 (t, J=2.5 Hz, 2H), 3.92 (d, J=15.2 Hz, 1H), 3.81-3.70 (d, J=15.0 Hz, 1H), 3.63 (m, 1H), 3.52 (m, 2H), 2.26 (s, 3H), 1.42 (s, 9H), 1.08 (s, 9H).
Reaction SMILES: C([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([O:24][Si:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:17][CH2:16]4)[CH2:13][CH:12]=[C:11]1[CH2:10][C@@H:9]([O:44][Si:45]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:8][CH2:7]2)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[C:58]1([Si:45]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[O:44][C@H:9]2[CH2:8][CH2:7][C@@:6]3([CH2:5][OH:4])[C:11](=[CH:12][CH2:13][C@@H:14]4[C@@H:23]3[CH2:22][CH2:21][C@@:19]3([CH3:20])[C@H:15]4[CH2:16][CH2:17][C@@H:18]3[O:24][Si:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH2:10]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: CC(=O)OC[C@]12CC[C@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)CC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@@]43CO)[C@@H]1CC[C@@H]2O[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To an ether solution of 3β,17β-di(triphenylsiloxy)androst-5-en-19-ol acetate is added a suspension of lithium aluminum hydride in ether. After refluxing for a period of one hour, water is cautiously added, the ether solution is separated, dried over sodium sulfate and evaporated under reduced pressure. The residue when purified from an acetone-hexane mixture results in the preparation of the desired 3β,17β-di(triphenylsiloxy)-androst-5-en-19-ol.