Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:37][CH3:38])[C:35]=1[F:36].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[C:34]([O:37][CH3:38])[C:35]([F:36])=[C:30]([F:29])[CH:31]=1
Reactant: COc1cc(B(O)O)cc(F)c1F
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(F)c1F
Temperature: 100 °C
Yield: 57.6 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (200 mg, 0.3 mmol) was treated with (3,4-difluoro-5-methoxyphenyl)boronic acid (93 mg, 0.49 mmol), 1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (29 mg, 0.03 mmol) and aqueous solution of sodium carbonate (2M, 492 μl, 0.98 mmol) in dioxane. The reaction mixture was submitted at vacuum-argon cycles and heated at 100° C. overnight. The solvent was cooled at room temperature and diluted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse phase using SP1® Purification System to obtain 87 mg (53% yield) of the title compound.
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][N:7]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[NH2:19]>O1CCOCC1>[Br:15][C:16]1[CH:17]=[C:18]([NH:19][C:6]2[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:8][N:7]=2)[CH:20]=[C:21]([CH3:23])[CH:22]=1
Reactant: Cc1cc(N)cc(Br)c1
Reactant: CC(C)c1ccnc(Cl)n1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1cc(Br)cc(Nc2nccc(C(C)C)n2)c1
Temperature: 120 °C
Yield: 98.1 %

Procedure:
Acetic acid (0.192 mL, 3.35 mmol) was added to commercially available 2-chloro-4-(propan-2-yl)pyrimidine (0.5 g, 3.19 mmol) and 3-bromo-5-methylaniline (0.900 g, 3.19 mmol) suspended in dioxane (6.39 mL). Reaction was heated to 120° C. (bath temp) overnight. Then, the reaction was cooled to room temperature and purified by column chromatography on silica gel eluting with ethyl acetate and hexanes to give N-(3-bromo-5-methylphenyl)-4-(propan-2-yl)-pyrimidin-2-amine (959.8 mg, 3.13 mmol, 98%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[F:11][C:12]([F:25])([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)[CH:13]([F:15])[F:14].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([O:16][C:12]([F:11])([F:25])[CH:13]([F:14])[F:15])[CH:18]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.9 %

Procedure:
EX-528A) 3-nitroaniline (1.87 g, 13.51 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)-benzaldehyde (3 g, 13.5 mmol) were dissolved in 25 mL of dichloroethane and acetic acid (0.85 mL, 14.9 mmol), then solid NaBH(OAc)3 (3.73 g, 17.6 mmol) was added. The mixture was stirred at room temperature for 48 hours, then quenched with aqueous saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane 1:7 to give 3.25 g (70%) of the desired N-(3-nitrophenyl)-3-(1,1,2,2-tetrafluoroethoxy) benzenemethan-amine product as a brown oil. HRMS calcd. for C15H13F4N2O3: 345.0862 [M+H]+, found: 345.0864. 1H NMR (CDCl3) δ4.4 (s, 2H), 4.5 (s, 1H), 5.9 (tt, 1H), 6.9 (d, 1H), 7.1 (d, 1H), 7.2-7.3 (m, 3H), 7.4 (m, 2H), 7.5 (d, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([F:52])([F:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([F:51])([F:52])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:22]([OH:34])([CH2:30][CH2:31][O:32][CH3:33])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(F)(F)CCCCCCC)[C@@](O)(CCOC)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(F)(F)CCCCCCC)[C@@](O)(CCOC)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoate (No. 6804236; 28.9 mg, 0.0393 mmol) was dissolved in dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added. The mixture was stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure. To the residue was added dichloromethane, and the solvent was again distilled off under reduced pressure. This operation was repeated twice and the residue was then purified by HPLC (water with 0.05% TFA-acetonitrile with 0.05% TFA) to obtain (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-(2-methoxy-ethyl)-nonadec-4-enoic acid (No. 5513213; 20.1 mg, 75% yield, white powder).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[CH:20]=[C:19]([CH:21]([F:23])[F:22])[N:18]=[C:17]([S:24][CH3:25])[N:16]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:15]1[CH:20]=[C:19]([CH:21]([F:23])[F:22])[N:18]=[C:17]([S:24][CH3:25])[N:16]=1)[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1nc(Cl)cc(C(F)F)n1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nc(C(F)F)cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.100 g, 0.534 mmol) and 4-chloro-6-(difluoromethyl)-2-(methylthio)pyrimidine (0.124 g, 0.587 mmol, 1.10 equiv) in DMF (2.7 mL) was treated with NaH (60%, 0.026 g, 0.64 mmol, 1.20 equiv), then the resulting mixture (yellow) was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(6-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)oxazolidin-2-one (0.164 g, white solid) in 85% yield. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 6.45 (t, J=54 Hz, 1H), 4.80-4.72 (m, 1H), 4.66 (dd, J=9.4, 3.0 Hz, 1H), 4.49-4.34 (m, 2H), 2.58 (s, 3H), 1.25 (s, 9H), 1.02 (d, J=6.5 Hz, 3H); MS m/z 362.3 (M+H)+; Rt-1.09 min.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:19]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1)=[O:8].Cl>C(OCC)C.O1CCCC1>[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:19]([C:33]3[CH:41]=[CH:40][C:36]4[O:37][CH2:38][O:39][C:35]=4[CH:34]=3)[C:20]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[O:21])=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1)(=[O:8])[CH3:1]
Reactant: CON(C)C(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3)c3ccc4c(c3)OCO4)cn(C)c2c1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Methylmagnesium bromide (0.23 ml of a 3M solution in diethyl ether) was added dropwise to a stirred solution of N6-methoxy-N6,1-dimethyl-3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-1H-6-indolecarboxamide (from Example 103, 174 mg, 0.32 mmol) in anhydrous tetrahydrofuran (5 ml) at −70° C. under a nitrogen atmosphere. The mixture was stirred at −70° C. for an additional 2 hours before warming to room temperature. Aqueous hydrochloric acid (5 ml of 1M solution) was slowly added to the mixture, and then it was extracted with ethyl acetate (100 ml). The organic phase was separated and washed with brine, dried (magnesium sulphate) and the solvent were removed in vacuo. The residue was flash chromatographed using a gradient elution of a mixture of 90% hexane and 10% ethyl acetate, through to 100% ethyl acetate, to give the title compound (18 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([N:25]=[C:26]=[O:27])[CH2:23][CH3:24]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:26]([NH:25][CH2:22][CH2:23][CH3:24])=[O:27])[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCN=C=O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)CC1
Solvent: ClCCl
Product: CCCNC(=O)NCCCCCN1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(4-tert-Butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (1.1 g) was dissolved in methylene chloride (20 ml) and a solution of n-propyl isocyanate (0.34 ml) in methylene chloride was dropwise added under ice-cooling. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure to give 4-tert-butoxycarbonylaminomethyl-1-(5-(3-n-propylureido)pentyl)piperidine.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH2:4](Br)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>ClCCl>[CH2:4]([N:2]([CH3:1])[NH2:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: CNN
Solvent: ClCCl
Product: CN(N)Cc1ccccc1
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
Methylhydrazine (0.1 ml, 2.0 mmol) in dichloromethane (5 ml) was treated dropwise with a solution of benzyl bromide (0.12 ml, 1.0 mmol) in dichloromethane (2 ml). After addition was complete the mixture was stirred for 10 min. and evaporated to dryness under reduced pressure. The residue was diluted with brine (5 ml) and ethyl acetate (5 ml). The organic phase was separated, dried over magnesium sulphate and evaporated to dryness under reduced pressure to give N-benzyl-N-methylhydrazine (0.082 g, 60%); υmax (CH2Cl2) 1650 cm-1 ; δH (CDCl3) 2.49 (3H, s), 3.41 (2H, s), 3.60 (2H, s), and 7.27 (5H, s).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:36]/[O:37][CH3:38])/[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[I-:39].[Na+]>CC(C)=O>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:36]/[O:37][CH3:38])/[C:8]([NH:10][C@@H:11]2[C:34](=[O:35])[N:13]3[C:14]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20][I:39])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: [I-]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(/C=C\CCl)CS[C@H]12)c1nsc(N)n1
Agent: [Na+]
Solvent: CC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(/C=C/CI)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
To a solution of p-methoxybenzyl 7β[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[(Z)-3-chloro-1-propen-1-yl]3-cephem-4-carboxylate(1.5 g) dissolved in acetone(20 ml), sodium iodide (0.82 g) was added thereto under ice-cooling. The resulting solution was stirred for 15 minutes under ice-cooling and for additional an hour at room temperature. The solvent was distilled off, and the residue was extracted with ethyl acetate. The extract was washed with a 10%-sodium thiosulfate and with a saturated brine, followed by drying with addition of anhydrous magnesium sulfate. The dried extract was concentrated under reduced pressure and the resulting precipitates were collected by filtration to obtain 1.1 g of p-methoxybenzyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[(E)-3-iodo-1-propen-1-yl]3-cephem-4-carboxylate. The powder was dissolved in N,N-dimethylformamide(2.5 ml), and 4-ethylmethylamino-2-butenylamide(0.2 g) was added thereto at -10° C. The resulting solution was stirred for 4 hours at -10° C. 10%-sodium thiosulfate(70 ml) was added to the reaction solution, and the resulting precipitates were collected by filtration to obtain the yellowish brown powder. The powder was stirred in 88%-formic acid(1.3 ml) for 3 hours at room temperature, and acetone(400 ml) was added thereto. The resulting precipitates were collected by filtration and washed with acetone. The precipitates were chromatographed over silicagel[acetonitrile:distilled water 4:1 (v/v)], Sephadex LH-20(or Amberlite XAD-2), and then lyophilized to obtain the target product (180 mg) as white solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:25])[CH2:18]4)(=O)=O)=CC=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH2:34].O>CS(C)=O>[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH:34][CH2:11][CH:12]1[O:26][C:16]2=[C:17]3[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:25])[CH2:18]3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3cc(C)c4c(c3O2)CC(=O)N4)cc1
Reactant: NCc1cccs1
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)C3)OC(CNCc1cccs1)CO2
Temperature: 90 °C
Yield: 31.8 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-6-methyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.00 g,2.57 mmole) and thiophene-2-methylamine (1.42 g, 12.6 mmole) were combined in 15 ml of dry DMSO and heated to 90° C. for 6 hours under a nitrogen atmosphere. After cooling to room temperature, 250 ml of water was added and a brown solid precipitated This was dissolved in methylene chloride, dried over MgSO4, filtered and concentrated in vacuum to yield an flaky orange solid, which was column chromatographed on silica gel using 1.5% methanol/CH2Cl2 as eluant. The free base of the title compound (0.27 g) thus obtained was crystallized from isopropanol with the addition of fumaric acid (0.10 g, 0.90 mmole) to give 0.28 g of the (S) enantiomer of the title compound as a light orange solid fumarate, m.p. 211-212° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6](O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.P(Br)(Br)[Br:14].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([Br:14])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: BrP(Br)Br
Reactant: Cc1cnc2c(c1)CCCC2O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cnc2c(c1)CCCC2Br

Procedure:
1.50 Grams of 3-methyl-8-hydroxy-5,6,7,8-tetrahydroquinoline was dissolved in 20 ml of chloroform, to this solution was added dropwise a solution consisting of 1.35 g of phosphorus tribromide and 5 ml of chloroform under ice-cooled condition, then the mixture was stirred under ice-cooled condition for 2 hours, next was stirred at room temperature overnight. To the reaction mixture was added 5%-sodium hydroxide aqueous solution, then was extracted with chloroform. The chloroform layer was washed with an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain 1.80 g of 3-methyl-8-bromo-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].C(N(C(C)C)C(C)C)C.[C:19]([O:23][C:24](=[O:39])[NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH3:34])[C:30]2[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=2[NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[C:19]([O:23][C:24](=[O:39])[NH:25][C@@H:26]1[C:32](=[O:33])[N:31]([CH3:34])[C:30]2[CH:35]=[CH:36][CH:37]=[CH:38][C:29]=2[N:28]([S:2]([CH3:1])(=[O:5])=[O:3])[CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(S(C)(=O)=O)c2ccccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
A mixture of 623 mg (3.4 mmol) of methanesulfonic acid anhydride and 0.12 ml (0.7 mmol) of N-ethyl-diisopropylamine was cooled to 0° C. and treated with a solution of 200 mg (0.7 mmol) of (S)-(1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 2 ml of dichloromethane. The reaction mixture was left to warm to room temperature and stirred during 18 h. For the working-up, the reaction mixture was cooled to 0° C. and treated with a saturated solution of sodium carbonate. The organic layer was separated, washed with a saturated solution of ammonium hydrochloride and water, finally dried over sodium sulphate and evaporated. For purification, the crude material was chromatographed on silical gel using a 96:4-mixture of dichloromethane and ethyl acetate as the eluent. There were obtained 100 mg (40% of theory) of the ((S)-5-methanesulfonyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester as a white foam;
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH2:14][CH3:15])[CH:8]=1.N1C=CC=CC=1>ClCCl>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][S:2]([CH3:1])(=[O:4])=[O:3])=[C:9]([CH2:14][CH3:15])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(Br)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(Br)ccc1NS(C)(=O)=O
Reaction time: 1 h

Procedure:
Methane sulfonyl chloride (1.93 ml, 0.025M) was added to a solution of 4-bromo-2-ethylaniline (5.0 g, 0.025M) and pyridine (2.02 ml, 0.025M) in dichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1 hr, after which time it was partitioned between dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The organics were separated and dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a clear oil (4.77 g). 1H NMR (CDCl3): δ 1.12 (t, J=8.60 Hz, 3H), 2.91 (q, 2H), 3.06 (s, 3H), 6.81 (d, J=7.54 Hz, 1H), 7.05 (d, J=7.54 Hz, 1H), 7.26 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.B(F)(F)F.[CH3:25]COCC>C1(C)C=CC=CC=1>[CH3:25][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][CH2:17][CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CCOCC
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Yield: 101 %

Procedure:
A dry 1-L, one-necked, round-bottomed flask was equipped with a Liebig condenser fitted with a rubber septum and a magnetic stirrer. The condenser was temporarily removed, and the flask was charged with 33.7 g (0.135 mol) of N-benzyloxycarbonyl-(S)-proline and 400 mL of anhydrous methanol (Mallinckrodt). The flask was flushed with nitrogen through the septum. The mixture was stirred, and 24.6 mL (28.4 g, 0.2 mol) of boron trifluoride etherate was added via cannula. The resulting mixture was stirred and refluxed for 1 hr under nitrogen. After the solvent was removed under reduced pressure, the residue was vigorously stirred with 200 mL of ice-water. The mixture was extracted with ethyl acetate (3×100 mL). The extacts were combined and successively washed with brine (2×20 mL), a 1M aqueous sodium hydrogen carbonate solution (3×20 mL), and brine (2×20 mL), and dried over anhydrous sodium sulfate. After the removal of the solvent under reduced pressure, a colorless oil was obtained. The oil was dissolved in 100 mL of dry toluene (distilled over CaH2), and the solvent was removed under reduced pressure to remove water from the oil. This treatment was repeated to give 35.9 g of N-benzyloxycarbonyl-(S)-proline methyl ester is a colorless oil (containing a small amount of toluene), [α]D21 -53.9° (methanol, c 1.0).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:18]CC1C=C(C=CC=1)CN.O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([NH2:18])[C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: NCc1cccc(CN)c1
Reactant: O=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: NC(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reaction time: 12 h
Yield: 65.9 %

Procedure:
To a solution of 24.5 g of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (88 mmol, 1 eq) in 200 ml of toluene were added 13.6 g of m-(aminomethyl)benzylamine (100 mmol, 1.13 eq). After the addition of a catalytic amount of p-TsOH.H2O (˜100 mg), the mixture was refluxed on a water separator for 12 h (approx. 5 ml of water were removed). Thereafter, another 5.5 g of m-(aminomethyl)benzylamine (40 mmol) were added and the mixture was boiled for a further 11 h. Subsequently, the toluene was distilled off (760 Torr). The resulting crude product was distilled under high vacuum (30-105° C. at 0.5 Ton). Further distillation by means of a Vigreux column (b.p. 105-108° C. at 25 Torr) gives 16.0 g of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanamine (58 mmol, 65%) as a clear liquid.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:17]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:18]2[F:25])[C:11]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[O:6])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10]([C@@H:17]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:18]2[F:25])[C:11]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])=[O:6]
Reactant: CN(C)C=Nc1c(C(=O)CN=[N+]=[N-])ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)C=Nc1c(C(=O)CN)ncn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F
Yield: 89.2 %

Procedure:
The compound (23) (52 mg) obtained in item (12) above was dissolved in methanol (6 ml), and the solution was subjected to catalytic reduction by blowing hydrogen therein in the presence of palladium black as catalyst at room temperature for 30 minutes. The resulting reaction solution was filtered and the filtrate was concentrated to give a solid. The solid material thus obtained was washed with ethyl acetate to yield the titled compound (24) (43 mg) as an insoluble substance. Yield: 89%.