Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:36]=[CH:35][C:13]2[N:14]([CH2:17][C:18]3[CH:34]=[CH:33][C:21]4[N:22]=[C:23]([NH:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]5[OH:32])[S:24][C:20]=4[CH:19]=3)[CH:15]=[N:16][C:12]=2[CH:11]=1.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C:38]1=[O:43]>CS(C)=O.[Cu](I)I>[OH:32][C@@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]1[NH:25][C:23]1[S:24][C:20]2[CH:19]=[C:18]([CH2:17][N:14]3[C:13]4[CH:35]=[CH:36][C:10]([N:37]5[CH2:42][CH2:41][CH2:40][CH2:39][C:38]5=[O:43])=[CH:11][C:12]=4[N:16]=[CH:15]3)[CH:34]=[CH:33][C:21]=2[N:22]=1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Reactant: O=C1CCCCN1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CCCCN1c1ccc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 125 °C
Yield: 2.1 %

Procedure:
To a stirred mixture of copper iodide (23 mg, 0.12 mmol) and tripotassium phosphate (190 mg, 0.90 mmol) in DMSO (3 mL) were added (1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (150 mg, 0.30 mmol) from Step 5 of Example 183 and piperidin-2-one (200 mg, 2.02 mmol). The mixture was flushed with argon and heated in a sealed reaction vessel at 125° C. for 15 h. The reaction mixture was cooled to rt and filtered, and the filtrate was purified directly by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 1-(1-((2-(((1R,2R)-2-Hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)piperidin-2-one (3 mg, 7%) as a solid. 1H NMR (500 MHz, DMSO-d6) δ 8.31 (br s, 1H), 7.69 (br s, 1H), 7.62 (s, 1H), 7.44-7.53 (m, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.9 Hz, 1H), 5.45 (s, 2H), 3.62 (t, J=5.4 Hz, 2H), 3.51 (br s, 1H), 3.37-3.46 (m, 2H), 2.36-2.43 (m, 2H), 2.06 (m, 1H), 1.82-1.93 (m, 5H), 1.61-1.70 (m, 2H), 1.20-1.36 (m, 4H); LCMS (ESI) m/z 476 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:9]2)[O:7][NH:33]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(OC(F)(F)F)cc1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 95.9 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (679 mg, 1.57 mmol) (from example 113, step 1) was dissolved in MeOH (10 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.463 mL, 1.57 mmol) dissolved in water (1.000 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.096 mL, 1.57 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8.11 mL, 48.63 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. Crude trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(4-(trifluoromethoxy)benzyl)piperidine-1-carboxylate (603 mg, 96%) was isolated. MS m/z 401 (M+H)+
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:30]=[CH:29][C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=2)[CH:8]=1)(=O)=O.[CH:33]1[C:41]2[C:40]3[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=3[S:38][C:37]=2[C:36](B(O)O)=[CH:35][CH:34]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:14]1[C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]=2[CH:29]=[CH:30][C:13]=1[C:9]1[CH:8]=[C:7]([C:36]2[C:37]3[S:38][C:39]4[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=4[C:41]=3[CH:33]=[CH:34][CH:35]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: O=S(=O)(Oc1cccc(-c2ccc3c4ccccc4c4ccccc4c3c2)c1)C(F)(F)F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc(-c2cccc3c2sc2ccccc23)c1
Yield: 88.4 %

Procedure:
4.52 g (10.0 mmol) of 3-(triphenylen-2-yl)phenyl trifluoromethanesulfonate, 3.0 g (13.0 mmol) of 4-dibenzothiopheneboronic acid, 0.46 g (0.5 mmol) of Pd2(dba)3, 0.82 g (2.0 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, 12.7 g (60.0 mmol) of K3PO4 and 150 mL of toluene and 15 mL of water were charged in a 250 mL round bottom flask. The reaction mixture was heated up to reflux under nitrogen for overnight. The reaction mixture was cooled and the organic extracts were purified by column chromatography and recrystallization. 4.3 g (88%) of white solid was obtained as product which was confirmed by proton NMR.
Reaction SMILES: [S:1]([C:5]1[S:13][C:12]2[C:7](=[N+:8]([O-:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C(#N)C>[CH3:17][N:18]([CH3:20])[CH:19]=[N:2][S:1]([C:5]1[S:13][C:12]2[C:7](=[N+:8]([O-:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=[O:3])=[O:4]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1cc2c(ccc[n+]2[O-])s1
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1cc2c(ccc[n+]2[O-])s1
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To a partial suspension of 2-sulfamoylthieno[3,2-b]pyridine-4-oxide (1.64 g, 7.1 mmol) in acetonitrile (45 ml), under a nitrogen atmosphere at room temperature was added dimethylformamide dimethyl acetal (1.5 ml, 11 mmol). The product began to precipitate after initial complete solution. After stirring for 18 hours, the reaction mixture was diluted with chloroform to dissolve the product. The solution was washed with water, dried over anhydrous sodium sulfate, filtered through charcoal and evaporated to give nearly pure product (1.9 g, 94% yield). Recrystallization from hot chloroform gave pure product (1.6 g), m.p. 224°-225.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=O)[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:11]([F:30])=[CH:12][C:13]([F:29])=[C:14]([C@:16]4([CH3:28])[C:22]([F:24])([F:23])[C:21]([CH3:26])([CH3:25])[O:20][CH2:19][C:18](=[S:41])[NH:17]4)[CH:15]=3)=[N:7][C:6]=2[CH:31]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(-c3nc4cc(Cl)ccc4o3)c(F)cc2F)C1(F)F
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3nc4cc(Cl)ccc4o3)c(F)cc2F)C1(F)F

Procedure:
In a manner analogous to that described in Example 2b), the reaction of (R)-5-[5-(5-chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepan-3-one (35 mg, 77 μmol) with Lawesson's reagent (34 mg, 84 μmol) yielded the title compound in quantitative yield as a white powder. MS (ISP): m/z=473.0 [M+H]+.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][CH:8]=2)[CH:2]=1.F[B-](F)(F)F.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([I+]C2C(C)=CC(C)=CC=2C)=[CH:26][CH:25]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:4]2[CH:5]=[CH:6][C:1]([CH3:17])=[CH:2][C:3]=2[C:7]2[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:26][CH:25]=1
Reactant: Cc1cc(C)c([I+]c2ccc(Cl)cc2)c(C)c1
Reactant: CC(=O)Nc1ccc(-c2cccc(C)c2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccc(Cl)cc2)c(-c2ccc(N)cn2)c1
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To acetic acid (17 ml), N-(6-m-tolylpyridine-3-yl)acetamide (0.50 g, 2.2 mmol), (4-chlorophenyl)(2,4,6-trimethylphenyl)iodonium tetrafluoroborate (1.13 g, 2.5 mmol) synthesized in (ii) and palladium acetate (0.025 g, 0.11 mmol) were added, and reacted at 100° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography. The solvent was distilled off under reduced pressure. Methanol and 35% hydrochloric acid were added, and the hydrolysis was carried out at 65° C. for 2 hours. Methanol was distilled off under reduced pressure. Purification by column chromatography gave the title compound (0.47 g, 72.5%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#N)=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.Cl.C([O-])(O)=[O:24].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:24])=[N:6][CH:7]=1
Reactant: CC(C)(C#N)c1ccc(Br)cn1
Reactant: O=C([O-])O
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(5-bromopyridin-2-yl)-2-methylpropanenitrile (2.0 g, 8.9 mmol) in dichloromethane (20 mL) under nitrogen was added DIBAL-H (12.4 mL, 12.4 mmol, 1.0 M in THF) dropwise at −30° C. The resulting solution was stirred at ambient temperature for 3 hours before the addition of 2 N aqueous HCl (10 mL) at 0° C. The resulting solution was stirred at ambient temperature for 10 minutes, the solution was basified with saturated aqueous NaHCO3 to pH 8-9, and then extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by MPLC on Silica gel (eluting with 2-4% EtOAc/hexane) to afford the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 9.73 (s, 1H), 8.66 (s, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 1.47 (s, 6H). MS ESI: [M+H]+ m/z 228, 230.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18]CC)=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.O.[OH-].[Li+]>O1CCOCC1.O>[C:12]([O:11][C:9]([N:6]1[C@H:5]([C:16]([OH:18])=[O:17])[C@H:4]2[CH2:8][C@@H:7]1[C@H:2]([OH:1])[CH2:3]2)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H](C2)N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)O
Temperature: 43 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a solution of 2-tert-butyl 3-ethyl (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 5-5 (249 mg) in dioxane (4.5 mL) and water (1.5 mL), was added lithium hydroxide monohydrate (110 mg). The mixture was stirred at 43° C. for 12 hrs and then 60° C. for 3 hrs. The resulting mixture was evaporated in vacuo. 1N Hydrochloric acid (2.7 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over NaSO4, and evaporated in vacuo. The residue was triturated with ether to give the target compound (164 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:16]([O:18][C:19]1[C:20](=O)[C:21](=[O:26])[C:22]=1[O:23]CC)[CH3:17]>C(O)C>[CH2:16]([O:18][C:19]1[C:22](=[O:23])[C:21](=[O:26])[C:20]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]2)=[O:9])[CH:3]=1)[CH3:17]
Reactant: Nc1cccc(C(=O)N2CCC(O)C2)c1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2cccc(C(=O)N3CCC(O)C3)c2)c(=O)c1=O
Temperature: 60 °C
Yield: 63 %

Procedure:
A mixture of the 30 ml of the solution of (3-aminophenyl)-(3-hydroxypyrrolidin-1-yl)methanone in ethanol and 6.81 g of 3,4-diethoxycyclobut-3-ene-1,2-dione (40.0 mmol, 2.5 eq) was heated at 60° C. overnight. The reaction medium was evaporated and the residue was chromatographed on silica gel eluted with heptane/ethyl acetate at 4/1, 2:1, then dichloromethane/methanol (6%). 3.03 g of 3-ethoxy-4-[3-(3-hydroxypyrrolidine-1-carbonyl)phenylamino]cyclobut-3-ene-1,2-dione were obtained. Yield=63%.
Reaction SMILES: CS(O[CH:6]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1)[C@@H:7]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8])(=O)=O.[C:31](=[S:34])([O-:33])[CH3:32].[K+]>CN(C=O)C.CCOC(C)=O.CCCCCC>[C:31](=[O:33])([S:34][CH:6]([C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:20]=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:18]=1)[C@@H:7]([NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH3:8])[CH3:32]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(OS(C)(=O)=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)SC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propyl methanesulfonate (1.0 g, 2.15 mmol) and potassium ethanethioate (0.736 g, 6.45 mmol) were combined in DMF (5 ml). The reaction was stirred at room temperature for 5 hours under a N2 atmosphere. The reaction was diluted with 30% EtOAc in hexane, washed with water, then brine, dried over Na2SO4, filtered and concentrated. The compound was purified by column chromatography to yield S-((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propyl) ethanethioate. 1H NMR (500 MHz, CDCl3): δ 7.84 (s, 2H); 7.79 (s, 1H); 4.91 (s, 1H); 4.51 (s, 1H); 4.21 (s, 1H); 2.40 (s, 3H); 1.38 (s, 9H); 1.19 (d, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:23][C:24]([C:26]2[C:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][NH:13][C@H:12]([CH2:21][OH:22])[CH2:11]1)=[O:9].[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl.C(Cl)Cl>[CH2:38]([N:13]1[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([NH:23][C:24]([C:26]3[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:25])=[CH:3][C:2]=2[Cl:1])=[O:9])[CH2:11][C@H:12]1[CH2:21][OH:22])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccc(C(=O)N2C[C@@H](CO)NCc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1ccc(C(=O)N2C[C@@H](CO)N(Cc3ccccc3)Cc3ccccc32)c(Cl)c1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a solution of (S)-biphenyl-2-carboxylic acid [3-chloro-4-(3-hydroxymethyl-2,3,4,5-tetrahydrobenzo[e][1,4]diazepine-1-carbonyl)-phenyl]-amide (1.02 g; 1.95 mmol) dissolved in ClCH2CH2Cl (11 mL) was added benzaldehyde (2.92 mmol) followed by sodium triacetoxyborohydride (0.824 g; 3.89 mmol) in one-portion and the reaction was stirred for 18 h at rt. The reaction was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, filtered, and the solvent removed under reduced pressure to afford a crude residue which was purified by flash chromatography (SiO2) eluting with EtOAc-MeOH gradient to afford 0.949 g (81%) of the title compound as a white solid. [α]23D: −75° (c 1.4, MeOH); 1H NMR (300 MHz, CDCl3): δ 7.81-7.83 (d, 1H), 7.28-7.56 (m, 13H), 6.71-7.20 (m, 7H), 4.77-4.82 (m, 1H), 4.40-4.46 (m, 1H), 3.85-4.10 (m, 2H), 3.52-3.69 (m, 3H), 3.31-3.36 (m, 1H), 3.14 (s, 1H); LC/MS m/z 602 (M+1). Calcd for C33H32ClN3O3.0.88% H2O; C, 72.08; H, 5.31; N, 6.80; Cl, 6.91.
Reaction SMILES: CN(C=O)C.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:18][C@H:17]2[C:19]([OH:21])=O)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(Cl)CCl.Cl.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([F:40])[CH:30]=1>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:18][CH:17]2[C:19]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[C:31]([F:40])[CH:30]=2)=[O:21])=[CH:14][CH:15]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(C2CC2C(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 9.5 %

Procedure:
To a DMF (10 ml) solution of trans-2-(4-tert-butylphenyl)cyclopropanecarboxylic acid (435 mg, 1.89 mmol)) [Journal of medicinal chemistry, 2005, vol. 48, 71-90], EDC (572 mg, 3.0 mmol), DMAP (73 mg, 0.6 mmol), triethylamine (0.836 ml) and N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (507 mg, 1.89 mmol) were added and the mixture was stirred for 5 hours at room temperature. Then, the reaction was quenched with saturated sodium bicarbonate aqueous solution and the whole was extracted with EtOAc/hexane (3:1), and dried over sodium sulfate. Then, filtration, evaporation, and purification by silica gel column chromatography, eluting with hexane/EtOAc (1:2), gave title compound (75 mg, 9% yield) as white solids.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:29][S:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)(=[O:32])=[O:31]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[CH3:17])=[O:9])=[CH:6][N:5]=[C:4]([NH:39][CH:36]2[CH2:37][CH2:38][N:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:34][CH2:35]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)ccc2C)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The compound was prepared from (4-amino-2-ethylsulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methyl-phenyl)-methanone (Example 198) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C18H23N5O3SF [(M+H)+] 408.1500, observed 408.1504.
Reaction SMILES: [Na].N.[CH3:3][O:4][C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:14](I)([CH3:16])[CH3:15]>O1CCCC1.[N+]([O-])([O-])=O.[Fe+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH3:3][O:4][C:5](=[O:13])[CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)I
Reactant: COC(=O)Cc1ccccc1
Agent: [Fe+3]
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)C(C)C
Yield: 86.2 %

Procedure:
23 g of sodium in small portions were added at -35° within 90 minutes to 1500 ml of liquid ammonia. After completion of the addition, 150 mg of iron-(III) nitrate.9H2O were added. To this suspension were added, while stirring vigorously, 150 g (1 mol) of phenylacetic acid methyl ester in 500 ml of absolute tetrahydrofuran and, half an hour later, 100 ml (1 mol) of isopropyl iodide were added dropwise. After completion of the addition, the ammonia was distilled off overnight. Water was added slowly to the liquid residue and the mixture was extracted with ether. The organic extracts were washed with water, dried over sodium sulfate and evaporated under reduced pressure, to obtain 165.8 g (87%) of 2-phenyl-3-methylbutyric acid methyl ester as a yellow oil which was used directly in the next step.
Reaction SMILES: [Na].[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:16])[CH:12]=[CH:13][C:14]#[N:15]>C(O)C>[NH2:15][C:14]1[CH2:13][CH:12]([CH:11]([CH3:16])[CH3:10])[N:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: CC(C)C=CC#N
Reactant: NNc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CC(C)C1CC(N)=NN1c1ccccc1

Procedure:
A 0.31 g. amount of sodium metal is dissolved in 150 ml. of absolute ethanol, then 6.3 g. of phenylhydrazine is added followed by 5.5 g. of 4-methyl-2-pentenonitrile. The reaction mixture is refluxed for 16 hours. The solvent is removed in vacuo, water is added to the residue and the mixture is extracted with dichloromethane. The extract is dried over anhydrous magnesium sulfate and evaporated to give a gum. The gum is chromatographed on a column containing 400 g. of a synthetic magnesium silicate absorbent. The column is eluted first with portions of 21/2% acetone-hexane and 5% acetone-hexane to remove exteraneous colored material, then with portions of 25% and 10% acetone-hexane to remove the product. The product cuts are evaporated to give 2.7 g. of a dark gum which solidifies on standing. This material is recrystallized twice from ether-hexane to give 1.7 g. of the product of the Example as tan crystals, m.p. 115°-117° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[CH:22]1([CH2:28][CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:34]([O:33][C:31]([C@H:30]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:28][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)=[O:32])[CH3:35]
Reactant: CCOC(=O)C(=O)CCC1CCCCC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Product: CCOC(=O)[C@@H](CCC1CCCCC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 12.2 %

Procedure:
In a manner similar to that described in Example 1, the reaction of 1.5 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate with 5 g of ethyl 4-cyclohexyl-2-oxobutyrate obtained in Reference Example 5 is carried out, and the product is purified by silica gel column chromatography (hexane:ethyl acetate=4:1). From the first fraction is obtained 0.3 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C:57]3([NH2:61])[CH2:60][CH2:59][CH2:58]3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.C(OCC)(=O)C.C(O)C>[Cl:49][C:50]1[CH:63]=[CH:62][C:53]2[NH:54][C:55]([C:57]3([NH:61][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][C:10]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][CH2:14]5)=[O:12])=[C:2]([CH3:1])[CH:3]=4)[CH2:58][CH2:59][CH2:60]3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NC1(c2nc3cc(Cl)ccc3[nH]2)CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2(c3nc4cc(Cl)ccc4[nH]3)CCC2)ccc1C(=O)N1CCCC1
Yield: 88 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and 1-(5-chloro-1H-benzimidazol-2-yl)cyclobutylamine in tetrahydrofuran. Yield: 88%; Rf value: 0.42 (silica gel; ethyl acetate/ethanol=9:1); C24H25ClN4O2 (436.94); mass spectrum: (M+H)+=437/439 (chlorine isotope).