Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[C:6](=[O:17])[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4](=[O:25])[C:3]=1[C:26](OCC)=[O:27].C1(CNC([CH:41](C(OCC)=O)[C:42]([O:44]CC)=[O:43])=O)C=CC=CC=1.[H-].[Na+].[N+:54](C1C=CC=CC=1N=C=O)([O-])=O>O1CCOCC1.ClCCl>[OH:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])[C:6](=[O:17])[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4](=[O:25])[C:3]=1[C:26]([NH:54][CH2:41][C:42]([OH:44])=[O:43])=[O:27]
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)C(=O)OCC
Reactant: CCOC(=O)c1c(O)n(-c2ccccc2[N+](=O)[O-])c(=O)n(Cc2ccccc2)c1=O
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CNC(=O)c1c(O)n(-c2ccccc2[N+](=O)[O-])c(=O)n(Cc2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 7 %

Procedure:
Ethyl 6-hydroxy-1-(2-nitrophenyl)-2,4-dioxo-3-(phenylmethyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate. Diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (420 mg, 1.43 mmoles) was added to a suspension of sodium hydride (60% suspension in mineral oil, 220 mg, 5.5 mmoles) in dry dioxan (10 mL) and stirred for 10 minutes under argon. 2-Nitrophenyl isocyanate (360 mg, 2.20 mmoles) was added and the mixture sealed in a pressure flask heated in a microwave reactor at 110° C. for 1 hour. The mixture was taken up in dichloromethane, washed with 1 molar hydrochloric acid and evaporated onto silica gel. Flash chromatography (hexane to 0.5% formic acid in ethyl acetate) gave the title compound (59 mg, 7%) 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (s, 1 H), 7.81 (s, 1 H), 7.68 (s, 1 H), 7.47 (s, 1 H), 7.08-7.38 (m, 5 H), 4.77-5.16 (m, 2 H), 4.12 (q, J=5.31 Hz, 2 H), 0.97-1.31 (m, 3 H)
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:12](O)(=[O:14])[CH3:13]>[Zn]>[C:12]([NH:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:11][CH:10]=1)(=[O:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC(=O)O
Agent: [Zn]
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Yield: 81 %

Procedure:
A mixture of 20 g (134 mmol) of 4-tert-butyl aniline and 0.044 g (0.67 mmol) of zinc powder in 20 ml acetic acid is heated under reflux for 7 hours. Then the crude product is poured into 350 ml of ice water and filtered. Recrystallization in ethanol-water affords 20.83 g (81%) of the title compound.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16]([OH:18])=O)[CH2:6]1)(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[O:23][CH2:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([C:16](=[O:18])[NH:19][C:20]2[CH:33]=[CH:32][CH:31]=[C:22]([O:23][CH2:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH:21]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)COc1cccc(N)c1
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)COc1cccc(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCC=C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.5 %

Procedure:
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine (1.59 g, 5.82 mM), allyl 3-aminophenoxyacetate (2.5 g, 0.012M), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (3.88 g, 0.016M) were dissolved in toluene (50 ml) and stirred 18 h at ambient temperature. The reaction mixture was diluted with ethyl acetate (150 ml) and washed with 2M hydrochloric acid (2×30 ml), water, saturated NaHCO3, and brine. Crude product was purified by chromatography on silica, using a gradient from dichloromethane to dichloromethane/diethyl ether (4:1), to give title compound (3.0 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C@@H:8]([O:24][CH3:25])[C@@H:9]([N:15](CC1C=CC=CC=1)[CH3:16])[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:26])[CH2:7][C@@H:8]([O:24][CH3:25])[C@H:9]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)[NH:15][CH3:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: CO[C@H](CC(=O)OC(C)(C)C)[C@H](C1CCCC1)N(C)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN[C@@H](C1CCCC1)[C@@H](CC(=O)OC(C)(C)C)OC
Yield: 33.7 %

Procedure:
(3R,4S)-tert-butyl4-(benzyl(methyl)amino)-4-cyclopentyl-3-methoxybutanoate (8) (3.0 g, 8.3 mmol) in ethanol (30 mL) was hydrogenated with Pd/C (1.3 g) for overnight. After the removal of residual Pd/C by filtration, the filtrate was concentrated to afford the desired product 9 (760 mg, 33.6.0%). LC-MS: m/z 272.1[M+H+]+.
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Br:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Br:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:10]3([CH:9]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[F:35])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.2 %

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1.4 g, 2.5 mmol) in dichloromethane (18 mL) was added trifluoroacetic acid (6 g). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′S)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a light yellow solid (1.5 g, 97%).
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2C(OC)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Br>[CH:1]1([C@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][NH:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1C1CCCCC1
Agent: Br
Product: O=c1cc([C@H]2CCN[C@@H](C3CCCCC3)C2)o[nH]1
Yield: 66 %

Procedure:
(2R,4S)-Methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.427 g, 1.38 mmol) was stirred in HBr (33% in AcOH) overnight (19 hours). Evaporation of solvents and the residue purified by preparative HPLC (Instrument: FractionLynx I, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4S)-2-cyclohexylpiperidin-4-yl)isoxazol-3(2H)-one (228 mg, 66%). 1H NMR (400 MHz, cd3od) δ 1.05-1.42 (m, 5H), 1.49-1.66 (m, 2H), 1.67-1.91 (m, 6H), 2.17-2.26 (m, 1H), 2.26-2.35 (m, 1H), 2.97-3.19 (m, 3H), 3.43-3.52 (m, 1H), 5.70 (s, 1H), 8.51 (s, 1H). HRMS Calcd for [C14H22N2O2+H]+: 251.1760. Found: 251.1750.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:7])[C:3]([CH3:6])([OH:5])[CH3:4].F[C:9]1[C:10]([C:19]#[C:20][Si](C)(C)C)=[C:11]([C:17]#[N:18])[C:12](=[CH:15][CH:16]=1)[C:13]#[N:14].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O>[OH:5][C:3]([CH3:6])([CH3:4])[C@@H:2]([N:1]1[C:9]2[C:10](=[C:11]([C:17]#[N:18])[C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)[CH:19]=[CH:20]1)[CH3:7]
Reactant: C[C@H](N)C(C)(C)O
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H](n1ccc2c(C#N)c(C#N)ccc21)C(C)(C)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
An oven-dried vial was charged with (S)-3-amino-2-methylbutan-2-ol (Example 21G) (0.064 g, 0.622 mmol), 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (0.126 g, 0.518 mmol), and K2CO3 (0.143 g, 1.036 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 30 min, the vial was sealed with a PTFE-faced crimp top and the mixture was subjected to microwave heating (140° C.) for 15 min. The mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (S)-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-4,5-dicarbonitrile (0.0659 g, 50% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.7 Hz, 1H), 7.69 (d, J=3.3 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 6.84 (d, J=3.2 Hz, 1H), 4.47 (q, J=7.0 Hz, 1H), 1.63 (d, J=7.0 Hz, 3H), 1.53 (s, 1H), 1.34 (s, 3H), 1.11 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19]C(Cl)Cl.ClCCl>>[C:1]([C:5]1[CH:14]=[C:13]([CH:18]=[O:19])[C:12]2[CH2:11][CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[C:6]=1[OH:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1O)C(C)(C)CCC2
Reactant: COC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=O)c2c(c1O)C(C)(C)CCC2
Temperature: 0 °C
Yield: 90 %

Procedure:
To a solution of 2-tert-butyl-8,8-dimethyl-5,6,7,8-tetrahydronaphthol (9.5 g, 40.5 mmole) and 1,1-dichloromethyl methyl ether (5.17 g, 45 mmole) in dry dichloromethane (200 ml) stannic chloride (15.63 g, 60 mmole) was added dropwise at -58°. The mixture was warmed to 0° over 45 minutes, poured into ice water (300 ml) and extracted with diethyl ether (3×150 ml). The ether extracts were washed with water and aqueous saturated sodium chloride, dried and evaporated to give 3-tert-butyl-5,5-dimethyl-4-hydroxy-5,6,7,8-tetrahydro-1-naphthaldehyde as a crystalline solid (9.49 g, 90%), m.p. 143°-45°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.OC(C(F)(F)F)=O.N[C@H](CC1C=CC(Cl)=CC=1)C(N1C[CH2:44][N:43]([C:46]2[CH:51]=[CH:50]C=C[C:47]=2[NH:52]S(C)(=O)=O)CC1)=O.C(N1CCC[C@H]1C=O)(OC(C)(C)C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[NH:43]1[CH2:44][CH2:50][CH2:51][C@@H:46]1[CH2:47][NH:52][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]1)=[O:11]
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)CCc2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC[C@H]2CCCN2)CC1

Procedure:
Following the procedure of Example 38, Step 3, (2R)-2-{[(2R)-pyrrolidin-2-yl)methyl]amino}-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperazinyl)propan-1-one TFA salt (0.6 g, 1.1 mmol) in ClCH2Cl2Cl (10 mL), N-Boc-L-prolinal (Aldrich) (280 mg, 1.4 mmol), and NaBH(OAc)3 (Aldrich) (340 mg , 1.9 mmol). The desired compound (TFA salt) was purified by preparative TLC (60% Hexane, 38% CH2Cl2 and 2% 2N NH3 in MeOH), followed by preparative HPLC (TFA buffer) yielding a white solid (14.8 mg). MS (ESI, pos. ion) m/z: 520 (M+H); MS (ESI, neg. ion) m/z: 518 (M−H). Calc'd for C25H34ClN5O3S: 519.21.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][O:13]2)=[CH:4][C:3]=1[F:9]
Reactant: OCC1CCCO1
Reactant: Oc1ccc(Br)c(F)c1
Product: Fc1cc(OCC2CCCO2)ccc1Br

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and rac-2-hydroxymethyl-tetrahydrofuran in analogy to Example 9c): MS (EI): 274 and 276 M+.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[NH:18][CH2:19][C:20]([O:22]C)=O)=O)(C)(C)C.C([O-])(O)=O.[Na+]>O1CCOCC1.Cl>[O:22]=[C:20]1[NH:8][C:9]2[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=2[N:18]=[CH:19]1
Reactant: COC(=O)CNc1cc(C(=O)OC)sc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc2ncc(=O)[nH]c2s1
Temperature: 80 °C
Yield: 99.2 %

Procedure:
To a solution of 90 (0.035 mmol, 12 mg) in dioxane (0.5 mL), HCl 4N in dioxane (1.742 mmol, 436 μl) was added and the solution was heated overnight at 80° C. The reaction was neutralized with a saturated solution of NaHCO3 and extracted with CH2Cl2 (2×). The organic layer was dried with phase separator and concentrated to give methyl 3-oxo-3,4-dihydrothieno[2,3-b]pyrazine-6-carboxylate 91 (7.3 mg, 100%). NMR (400 MHz, CDCl3) 3.96 (s, 3H), 8.05 (s, 1H), 8.29 (s, 1H). (m/z)=211 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([CH3:33])[C:16]([CH3:18])([CH3:17])[O:15]C(N[C@H](C3C=CC=CC=3F)CCO)=[N:13][S:12]2(=[O:32])=[O:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(C2(C)C(C)(C)OC(OC)=NS2(=O)=O)=CC=1)(C)(C)C.BrC1C=C(C2(C)C(C)(C)OC(N[C@H](C3C=CC=CC=3)CCO)=NS2(=O)=O)C=CC=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([S:12]([NH2:13])(=[O:31])=[O:32])([C:16]([OH:15])([CH3:17])[CH3:18])[CH3:33])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C2(C)C(C)(C)OC(N[C@@H](CCO)c3ccccc3F)=NS2(=O)=O)cc1
Agent: CC1(C)OC(N[C@@H](CCO)c2ccccc2)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Agent: COC1=NS(=O)(=O)C(C)(c2ccc(C(C)(C)C)cc2)C(C)(C)O1
Product: CC(C)(C)c1ccc(C(C)(C(C)(C)O)S(N)(=O)=O)cc1

Procedure:
The further conversion to (S)-3-[5-(4-tert-butylphenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino]-3-(2-fluorophenyl)propan-1-ol was effected via the 5-(4-tert-butylphenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide intermediate in analogy to the preparation of (S)-3-[5-(3-bromophenyl)-5,6,6-trimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-2-ylamino]-3-phenylpropan-1-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH:21][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:19])=[O:20])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCCc2ccccc2)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 4-phenylbutyryl chloride, gave 3′-amino-5-formyl-6-methoxy-N-(4-phenylbutyryl)-biphenyl-3-sulfonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-])=O.[NH:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1>>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH:15]([N:19]3[CH2:24][CH2:23][S:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(=O)CC1
Reactant: C1CSCCN1
Product: N#Cc1cc(N)ccc1N1CCC(N2CCSCC2)CC1

Procedure:
Reductive amination was conducted according to J. Org. Chem., vol. 55, p. 2552 (1990) using 5-nitro-2-(4-oxopiperidin-1-yl) benzonitrile and thiomorpholine. Then, the nitro group was reduced in the same manner as in Starting Material Synthesis Example 40 to give the title compound, melting point: 138° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:10]1[CH2:9][CH2:8][CH:7]([NH2:23])[CH2:6][C:5]2=1.Cl.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C(N(CC)CC)C>CN1CCCC1=O.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[C:10]1[CH2:9][CH2:8][CH:7]([NH:23][C:27](=[O:28])[N:26]([CH3:30])[CH3:25])[CH2:6][C:5]2=1
Reactant: CN(C)C(=O)Cl
Reactant: NC1CCc2c(c3cc(Br)ccc3n2Cc2cccc(F)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NC1CCc2c(c3cc(Br)ccc3n2Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Mix 6-bromo-9-(3-fluoro-benzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-ylamine.HCl (Preparation 51) (200 mg, 0.49 mmol), N,N-dimethylcarbamoyl chloride (54 μL, 63 mg, 0.59 mmol), triethylamine (205 μL, 149 mg, 1.47 mmol), CH2Cl2 (6 mL), and N-methylpyrrolidinone (2 mL). Stir at room temperature for 18 h, then add more N,N-dimethylcarbamoyl chloride (54 μL, 63 mg, 0.59 mmol). Stir at room temperature for 60 h, then evaporate the solvents. Dilute the residue with EtOAc (80 mL) and wash the organic solution with HCl (<1N in water, 40 mL) and aqueous NaHCO3. Dry (MgSO4), filter, and concentrate the organic portion to obtain 308 mg crude product as a brown oil. Purify on silica gel (12 g), eluting with 80-100% EtOAc/hexanes to afford 164 mg (75%) of the title compound as a white foam. MS (ES): 444, 446 (M+1); HPLC: Rt=3.27 min, (92%).
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[F:1][C:2]1([F:7])[CH2:6][CH2:5][N:4]([C:22]([C:21]2[CH:25]=[CH:26][N:27]=[CH:28][C:20]=2[NH:19][C:17]([C:15]2[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=[C:11]([CH:8]3[CH2:10][CH2:9]3)[N:16]=2)=[O:18])=[O:23])[CH2:3]1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: FC1(F)CCNC1
Product: O=C(Nc1cnccc1C(=O)N1CCC(F)(F)C1)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 27 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 3,3-difluoro-pyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (27%) as amourphous light yellow solid.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1>N1C=CC=CC=1>[I:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:7])=[O:6])=[CH:12][CH:11]=1
Reactant: Nc1ccc(I)cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butanesulphonyl chloride (7.8 g) was added dropwise to a stirred solution of 4-iodobenzeneamine (10 g) in pyridine (50 ml) at 0°. The bright red mixture was stirred at room temperature for 1 h, then concentrated to an oil which was partitioned between 2N hydrochloric acid (100 ml) and EA (100 ml). The organic layer was washed with 2N hydrochloric acid, water and brine, dried (MgSO4) and concentrated to a pale brown solid which was recrystallised from CX to give the title compound as white flakes (10.5 g) m.p. 80°-81°.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].Cl.C(O[C:10](=N)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])C>>[NH2:5][C:3]1[S:4][C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:1][N:2]=1
Reactant: NNC(N)=S
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Product: CCOC(=O)Cc1nnc(N)s1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
Thiosemicarbazide (1.0 g, 11.0 mmol) and ethyl 3-ethoxy-3-iminopropionate hydrochloride (2.0 g, 10.0 mmol) were mixed in glacial acid (2 mL) for 10 min at 55° C. and then boiled for 1.5 h. The reaction mixture was evaporated, diluted with cold water, carefully neutralized with NaHCO3, and cooled to 5° C. The precipitate was collected and crystallized from water to yield 0.88 g (4.70 mmol, 47%) of the product, mp 149-150° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.19 (t, 3H, J=7.2 Hz), 3.96 (s, 2H), 4.10 (q, 2H, J=6.9 Hz), 7.11 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 14.0, 35.4, 60.9, 150.4, 168.9, 169.6.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(OC([NH:70][CH2:71][CH2:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][NH:74]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:74]1[CH2:75][CH2:76][CH2:77][CH2:78][CH:73]1[CH2:72][CH2:71][NH2:70])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)NCCC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CCN)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(2-tert.-butyloxycarbonylamino-ethyl)-piperidine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:16](=[O:20])[CH2:17][CH2:18]Cl)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O1CCOCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:16](=[O:20])[CH2:17][CH2:18][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccccc2N(C(=O)CCCl)c2ccc(Cl)cc21
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2N(C(=O)CCN2CCCCC2)c2ccc(Cl)cc21
Yield: 50.4 %

Procedure:
5.0 gm (0.015 mol) of 2-chloro-5-(3-chloropropionyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 4.3 gm (0.05 mol) of piperidine were refluxed in 100 ml of dioxane for 1 hour. The reaction mixture was evaporated in vacuo, the residue was dissolved in dilute acetic acid, and the solution was filtered after addition of activated charcoal. The filtrate was made alkaline with ammonia and extracted with chloroform. The chloroform solution was evaporated in vacuo, and the residue was crystallized from isopropanol and recrystallized from methanol. 2.9 gm of the title compound, m.p. 170°-172° C., were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:26]([N+:27]([O-])=O)=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O>[CH2:1]([O:8][C:9]1[C:26]([NH2:27])=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:30])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4cc([N+](=O)[O-])c(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC[C@@H]3c4cc(N)c(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a suspension of 3-benzyloxy-2-nitroestra-1,3,5(10)-trien-17-one (79, 1.82 g, 4.5 mmol) in acetone (250 mL) were added 0.5 N aqueous NaOH (60 mL, 30 mmol) and sodium hydrosulfite (85%, 6.0 g) at 80° C., and stirred for 1 h. After the reaction mixture was cooled to room temperature, H2O (150 mL) was added, acetone was removed at reduced pressure, and the remainder allowed to stand for 3 h at 0° C. The precipitate was collected by filtration and washed with H2O to afford 1.15 g of 80 (68% yield) mp: 205-207° C.