Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH2:24])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[CH:39]=[C:38]([CH3:43])[C:37]=1[S:44](Cl)(=[O:46])=[O:45]>CN(C)C=O>[C:2]([O:6][C:7](=[O:25])[C@@H:8]([NH:24][S:44]([C:37]1[C:38]([CH3:43])=[CH:39][C:40]([CH3:42])=[CH:41][C:36]=1[CH3:35])(=[O:46])=[O:45])[CH2:9][NH:10][C:11]([C:13]1[S:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)=[O:12])([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2c(C)cc(C)cc2C)C(=O)OC(C)(C)C)s1
Reaction time: 5 h
Yield: 83.8 %

Procedure:
0.490 g (1.38 mmol) of (2S)-2-amino-3-((5-(2-methoxycarbonyl-ethyl)-thiophene-2-carbonyl)-amino)-propionic acid tert-butyl ester hydrochloride (example 15, step a) were dissolved in 15 ml of anhydrous dimethylformamide. Under stirring, 0.47 ml of N,N-diisopropyl-N-ethylamine and 0.302 g of 2,4,6-trimethylphenylsulfonyl chloride were added. Stirring was continued for 5 hours until the reaction was complete (thin layer chromatography). The solvents were removed in vacuo, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and with brine. After drying with anhydrous magnesium sulfate and filtration, the solvents were removed in vacuo to give 0.623 g of a yellow oil which was sufficiently pure for use in the subsequent step.
Reaction SMILES: [CH3:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>ClCCl>[CH3:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: Cc1c(O)ccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(O)ccc2c1cnn2C1CCCCO1
Reaction time: 48 h
Yield: 60.9 %

Procedure:
Under nitrogen, the 4-methyl-1H-indazol-5-ol (500 mg, 3.37 mmol) obtained in Example 402 was suspended in dichloromethane (20 ml), followed by adding thereto 3,4-dihydro-2H-pyran (239 μl, 3.71 mmol) and p-toluenesulfonic acid monohydrate (64 mg, 0.337 mmol). Tetrahydrofuran (25 ml) was added thereto to effect dissolution, and the reaction was carried out at room temperature for 2 days. The solvent was distilled off under reduced pressure and water was added to the residue, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to obtain 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-ol (477 mg, yield 60.9%).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[SH:5])(C)C.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:25](=[O:26])[C@@H:24](OS(C(F)(F)F)(=O)=O)[C@H:23]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:18][CH:17]=1>C1COCC1>[SH:5][C@H:24]1[C:25](=[O:26])[N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[C@@H:23]1[C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)[C@@H]1[C@H](OS(=O)(=O)C(F)(F)F)C(=O)N1c1ccc(OC)cc1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1[C@@H](S)C(=O)N1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of triisopropylsilane thiol (0.91 mmol) in anhydrous THF (2 ml) was added sodium hydride (0.68 mmol, 60% in mineral oil) and the reaction mixture was stirred at room temperature for 15 min. Afterwards, compound 109 (0.45 mmol, dissolved in 2 ml THF) was added to the reaction and the mixture was stirred at room temperature for 1 h. Then it was concentrated in vacuo, diluted with ethyl acetate and washed with sodium bicarbonate. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated in vacuo. Column chromatography purification (12 g pre-packed silica column, hexane/ethyl acetate) afforded the protected thiol. The thiol (0.126 mmol) was then diluted with anhydrous methanol (2 ml) and ammonium fluoride (0.15 mmol, 0.5 M in methanol) and acetic acid (0.454 mmol) were added to the reaction and the mixture was stirred at room temperature for 2 h. Afterwards, it was concentrated in vacuo and the residual acetic acid was azeotroped with toluene. The solid was diluted with dichloromethane and was filtered through a syringe filter. The solution was concentrated in vacuo to give compound 110 as a clear oil (23% yield for both steps). LS/MS M+H 282.3, calc. 282.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Cl)[CH:18]=2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].N1C=CC=CC=1.[CH3:32][CH:33]([OH:40])[CH2:34][NH:35][CH2:36][CH:37]([OH:39])[CH3:38].ClCC1C=C(C=CC=1)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:35]([CH2:36][CH:37]([OH:39])[CH3:38])[CH2:34][CH:33]([OH:40])[CH3:32])[CH:18]=2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccccc2cc1NC(=O)c1cccc(CCl)c1
Reactant: CC(O)CNCC(C)O
Agent: O=C(O)c1cccc(CCl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc2ccccc2cc1NC(=O)c1cccc(CN(CC(C)O)CC(C)O)c1
Reaction time: 48 h

Procedure:
Subsequently, 3-(3-chloromethyl-benzoylamino)-naphthalene-2-carboxylic acid methyl ester (870 mg) was dissolved in anhydrous methylene chloride (15 ml). Pyridine (400 μl) and diisopropanolamine (compound B′) (1.0 g) were added to the solution at room temperature, and the mixture was then stirred at that temperature for 48 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a hexane-acetone system to give 3-(3-{[bis-(2-hydroxy-propyl)-amino]-methyl}-benzoylamino)-naphthalene-2-carboxylic acid methyl ester as a useful intermediate (640 mg).
Reaction SMILES: O[C:2]1([CH2:14][CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]([CH3:13])[CH2:5][CH2:4][CH2:3]1.C(OCC)C.N.[Li]>C(O)C>[CH2:18]([N:17]([CH2:16][CH2:15][CH2:14][CH:2]1[C:8]2[CH2:9][CH:10]=[CH:11][CH2:12][C:7]=2[CH:6]([CH3:13])[CH2:5][CH2:4][CH2:3]1)[CH2:20][CH3:21])[CH3:19]
Reactant: CCN(CC)CCCC1(O)CCCC(C)c2ccccc21
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: CCN(CC)CCCC1CCCC(C)C2=C1CC=CC2
Reaction time: 0.5 h

Procedure:
The crude 5-hydroxy-5-diethylaminopropyl-9-methyl-6,7,8,9-tetrahydro-5H-benzocycloheptene is dissolved in 100 ml. of diethyl ether and added to 500 ml. of liquid ammonia. The solution is treated with 20 g. of lithium in small portions. After 1/2 hr., the mixture is treated slowly dropwise with absolute ethanol until the color discharges completely. After removal of NH3, the residue is cooled, treated with water and extracted with ether. The dried extracts are freed of solvent leaving crude 5-diethylaminopropyl-9-methyl-1,4,6,7,8,9-hexahydro-5H-benzocycloheptene, which is converted to the corresponding tetrol as described hereinbefore.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:14]=[C:10]1[N:11]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)ccn2)C(=O)C1
Reaction time: 18 h

Procedure:
A mixture of 1-Boc-3-oxopiperazine (1.0 eq.), 2-bromo-4-(trifluoromethyl)pyridine (1.5 eq.) and Cs2CO3(1.5 eq.) in 1,4-dioxane (0.5M) was degassed under Argon flow for 30 min, then Pd(OAc)2(0.1 eq.) and Xantphos (0.15 eq.) were added, the vial was sealed and stirring was continued at 110° C. for 18 hr. Reaction mixture was diluted with EtOAc and filtered through a pad of SolcaFloc® 200 FCC. After removal of the solvent, the crude product was purified by flash column chromatography on silica gel using 10-40% EtOAc/Petroleum ether as eluent to afford the desired product I1 as yellow solid (92% yield). 1H NMR (400 MHz, CDCl3, 300K) δ 8.57 (1H, d, J=4.8 Hz), 8.40 (1H, bs), 7.32 (1H, d, J=4.8 Hz), 4.31 (2H, s), 4.17 (2H, t, J=5.3 Hz), 3.76 (2H, t, J=5.3 Hz), 1.50 (9H, s). MS (ES) C15H18F3N3O3 requires: 345, found: 346 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9](=[C:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH:16]=[CH:15][C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]2=3)[CH2:8][CH2:7]1.[C:27]([O:31][C:32]([N:34]1[CH2:42][CH2:41][CH:37]([C:38](O)=[O:39])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>>[C:27]([O:31][C:32]([N:34]1[CH2:42][CH2:41][CH:37]([C:38]([NH:3][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][C:9](=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[CH:16]=[CH:15][C:14]4[CH:23]=[CH:24][CH:25]=[CH:26][C:13]3=4)[CH2:8][CH2:7]2)=[O:39])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCCN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Aminoethyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene) piperidine dihydrochloride (2.3 g, 6.0 mmol), 1-t-butoxycarbonylisonipecotic acid (1.6 g, 7.2 mmol), triethylamine (3.0 ml, 21.6 mmol) and 1-ethyl-3-(3-dimethlaminopropyl) carbodiimide hydrochloride (1.4 g, 7.2 mmol) were mixed, and the mixture was stirred at room temperature overnight. After evaporating the solvent, the residue was dissolved in 100 ml of dichloromethane, washed with 100 ml of 1 N hydrochloric acid, 100 ml of a 1 N aqueous, sodium hydroxide solution, and 50 ml of a saturated aqueous sodium chloride solution. The solvent was evaporated and the residue was purified by silica gel chromatography to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4](F)[CH:3]=1.[F:17][CH:18]([F:21])[CH2:19][OH:20].[H-].[Na+].C1COCC1>CN(C=O)C>[NH2:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:20][CH2:19][CH:18]([F:21])[F:17])[CH:3]=1
Reactant: OCC(F)F
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OCC(F)F

Procedure:
The sub-title compound was prepared in accordance with Example 59 (f) using ethyl 4-amino-2-fluoro-5-nitrobenzoate (4.80 g; 21.0 mmol), 2,2-difluoroethanol (1.73 g; 21.0 mmol), sodium hydride (0.841 g; 60%; 21.0 mmol), THF (100 mL) and DMF (50 mL).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.P(Br)(Br)[Br:27]>C(Cl)Cl.C(OC)(C)(C)C>[Br:27][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CO)cc1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1.20 g (3.57 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 3.1a) in 25 mL of DCM is added at 0° C. 0.24 mL (2.50 mmol) phosphorus tribromide. After warming to RT, the mixture is stirred 2 h at RT and is diluted with 30 mL tertbutylmethylether. The precipitate is collected and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH2:15]
Reactant: NN
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: O
Solvent: CCO
Product: NN=C1C(=O)Nc2ccc(Cl)cc21
Reaction time: 8 h

Procedure:
To a stirred slurry of 100 g (0.55 mol) of 5-chloroisatin in 930 ml of ethanol was added 40 ml (0.826 mol) of hydrazine hydrate, resulting in a red solution. The solution was heated under reflux for 3.5 hours, during which time a precipitate appeared. The reaction mixture was stirred overnight, and then the precipitate was recovered by filtration to give 5-chloro-3-hydrazono-2-oxindole as a yellow solid, which was dried in a vacuum oven. The dried solid weighed 105.4 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])[C:10](=[O:21])[CH2:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.OS([O-])(=O)=O.[Na+]>CCO>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29])[CH:10]([OH:21])[CH2:11][C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(=O)Cc1ncccc1C(=O)O
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1F)C(O)Cc1ncccc1C(=O)O
Reaction time: 0.33 h

Procedure:
To a solution of 2-[3-tert-butoxycarbonylamino-4-(2-fluoro-phenyl)-2-oxo-butyl]-nicotinic acid (14 g, 35 mmol) in 100 mL of EtOH at 0° C. is added NaBH4 (5.3 g, 140 mmol). After 20 min, 30 mL of water is added to the reaction and the reaction poured into 300 ml of water. The pH is adjusted to ˜pH3 with 2M NaHSO4 at which point a white solid precipitates and isolation by filtration gives the title compound.
Reaction SMILES: [OH:1][C:2]1([CH3:25])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:3]1>CO.[Pd]>[NH2:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:4]1[CH2:3][C:2]([OH:1])([CH3:25])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Agent: [Pd]
Solvent: CO
Product: Cn1ncc(N)c1N1CCN(C(=O)OC(C)(C)C)CC(C)(O)C1
Reaction time: 16 h

Procedure:
To a solution of Intermediate 44, tert-butyl 6-hydroxy-6-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate (70 mg, 0.20 mmol) in MeOH (5 mL), was added 10% palladium on carbon (10 mg) and the mixture was stirred under an atmosphere of H2 (60 psi) for 16 hr. The mixture was filtered through Celite® and the solvent was removed under reduced pressure to afford tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as an oil. To a solution of this amine in DCM (5 mL), DIPEA (0.1 mL, 9.6 mmol), PyBOP (0.16 g, 0.3 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (78 mg, 0.22 mmol) were added and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (30 mL) and washed with water (10 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as a solid (122 mg). To this solid (122 mg, 0.18 mmol) in MeOH (1 mL), a solution of HCl (4 M in 1,4-dioxane, 3.2 mL, 12.9 mmol) was added and the resulting solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the crude residue was dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH. Purification by preparative HPLC gave 190 as an off-white solid (40 mg, 44% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 9.19 (s, 1H), 8.24 (s, 1H), 7.59-7.48 (m, 3H), 7.33-7.23 (m, 2H), 3.69 (s, 3H), 3.26-3.02 (m, 4H), 2.98-2.73 (m, 4H), 1.01 (s, 3H). Alkyl NH and OH not observed. LCMS (ES+) m/z 464 (M+1).
Reaction SMILES: [C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][C@H:22]([O:23]C(=O)C)[C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@@H:13]([CH2:14][C@H:15]([O:27]C(=O)C)[CH2:16][CH2:17]1)[CH2:12][C@H:11]3[O:31]C(=O)C)(=[O:3])[CH3:2].O.[OH-].[Li+]>CO.O.O1CCCC1>[C:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][C@H:22]([OH:23])[C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@@H:13]([CH2:14][C@H:15]([OH:27])[CH2:16][CH2:17]1)[CH2:12][C@H:11]3[OH:31])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](OC(C)=O)[C@@H]1[C@@H]2C[C@H](OC(C)=O)[C@]2(C)[C@@H](C(C)=O)CC[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 17β-acetyl-3α,7α,12α-triacetoxy-5β-androstane (9.48 g) and lithium hydroxide monohydrate (4.0 g) in methanol (20 ml), water (20 ml) and tetrahydrofuran (20 ml) is stirred at room temperature for about 19 hours, concentrated in vacuo, diluted with ethyl acetate and washed with brine. The organic solution is dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude is purified by flash chromatography in ethyl acetate to give the desired product.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH2:10][C:9](=[O:18])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:19]I>CN(C=O)C.C(Cl)Cl.O>[CH3:19][CH:10]1[C:9](=[O:18])[NH:8][C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]1=2
Reactant: CI
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC1C(=O)Nc2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A round bottom flask was charged with sodium hydride (0.295 g, 7.46 mmol) in 9.0 ml of DMF and treated with 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.3 g, 6.22 mmol) (CAS # 20011-90-9, prepared as described in Brown, et. al., Tetrahedron Letters, No. 8, 667-670, (1971) and references cited therein, which are incorporated herein by reference). After stirring at 60° C. for 1 h, the solution was treated with methyl iodide (1.16 ml, 18.6 mmol) and stirring continued for 17 h with the exclusion of light. After cooling, the reaction was diluted with CH2Cl2/H2O, washed with NaHSO4 solution, H2O, and dried over Na2SO4. Evaporation and flash chromatography (SiO2, CHCl3) gave 0.885 g (63%) of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:25][C:24]2[CH:23]=[C:22]([OH:26])[CH:21]=[CH:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][C@@H:17]2[F:27])([CH3:15])[C:13](=[O:28])[CH2:12][CH2:11]1.[BH4-].[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:25][C:24]2[CH:23]=[C:22]([OH:26])[CH:21]=[CH:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][C@@H:17]2[F:27])([CH3:15])[CH:13]([OH:28])[CH2:12][CH2:11]1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCl)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCl)[C@H]3[C@@H]1CCC2O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
611 mg of 7α-(6-chlorohexyl)-11β-fluor-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 10 ml of methanol and carefully mixed with 166 mg of sodium borohydride. After 15 minutes of stirring at room temperature, the batch is added to saturated common salt solution, extracted with methylene chloride, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 599 mg of 7α-(6-chlorohexyl)-11β-fluor-estra-1,3,5(10)-triene-3,17-diol is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][CH:7]=[C:8]([O:10][S:11]([CH3:14])(=[O:13])=[O:12])[N:9]=1)([CH3:3])[CH3:2].[Br:15]Br.S([O-])(O)=O.[Na+]>CCOCC>[CH:1]([S:4][C:5]1[S:6][C:7]([Br:15])=[C:8]([O:10][S:11]([CH3:14])(=[O:12])=[O:13])[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Sc1nc(OS(C)(=O)=O)cs1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)Sc1nc(OS(C)(=O)=O)c(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
3.5 g of 2-isopropylthio-4-methylsulfonyloxy-1,3-thiazole was dissolved in 50 ml of ether, and 0.8 ml of bromine was added dropwise to the solution keeping the temperature below 0° C. After the addition, the solution was stirred at room temperature for 2 hours, then 5% solution of sodium hydrogen sulfite was added thereto to separate ether layer, which was washed with water and dried over anhydrous sodium sulfate, followed by concentration to an oil. The oil was purified by silica-gel column chromatography to obtain 3.7 g of the objective compound as a yellow oil (yield: 80.7%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[CH2:14]=[CH:15][C:16](=[O:20])/[CH:17]=[CH:18]/[CH3:19]>C(#N)C>[CH2:1]([N:8]1[CH2:14][CH2:15][C:16](=[O:20])[CH2:17][CH:18]1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)/C=C/C
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC1CC(=O)CCN1Cc1ccccc1
Temperature: 16 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a stirred solution of benzylamine (5.2 mL, 47 mmol) in acetonitrile (30 mL) was added aqueous NaHCO3 solution (20 mL, 1.8 M, 36 mmol). After cooling to 16° C., the crude product obtained in step A (3.46 g, 32.9 mmol) dissolved in acetonitrile (30 mL) was added slowly over 40 minutes. After addition, the solution was heated to reflux for 1 h. The solvent was evaporated in vacuo to approximate 25 mL volume and ethyl acetate (60 mL) added. The resulting solution was stirred for 15 minutes. The organic layer was separated, washed with water (60 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (SiO2, 8:1 to 7:3 hexanes/ethyl acetate) to give 1-benzyl-2-methylpiperidin-4-one (3.9 g, 54%) as a brown oil: 1H NMR (CDCl3, 300 MHz) δ 7.39-7.26 (m, 5H), 3.96 (d, J=13.5 Hz, 1H), 3.45 (d, J=13.2 Hz, 1H), 3.03-2.95 (m, 2H), 2.56-2.51 (m, 2H), 2.39-2.31 (m, 2H), 2.28-2.24 (m, 1H), 1.17 (d, J=6.3 Hz, 3H).