Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.CO[CH:19](OC)[CH2:20][C:21]#[N:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:21]([C:20]1[CH:19]=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)#[N:22]
Reactant: COC(CC#N)OC
Reactant: Cc1ccc(C(=O)c2ccccc2N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2c(C#N)cnc3ccccc23)cc1

Procedure:
A mixture of 2-amino-4'-methylbenzophenone (10 g), 3,3-dimethoxypropionitrile (10.9 g), p-toluenesulfonic acid. monohydrate (1.0 g) in toluene (120 ml) was heated under reflux for 4 hours. After addition of water, the reaction mixture was extracted with ethyl acetate and the extract was concentrated to dryness. The residue was purified by column chromatography on silica gel. Recrystallization from isopropyl ether afforded pale yellow prisms (5.67 g, 49%), m.p. 96°-97° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C(=O)(O)[O-].[Na+].[I:16]Cl>C(Cl)Cl.CO>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([F:10])[C:7]([I:16])=[CH:8][CH:9]=1
Reactant: ClI
Reactant: N#Cc1c(N)cccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1c(N)ccc(I)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
To a solution of 2-amino-6-fluorobenzonitrile (3 g, 0.022 mol) in CH2Cl2 (200 mL) and MeOH (50 mL) was added sodium bicarbonate (3.7 g, 0.044 mmol) and ICl (3.75 g, 0.023 mol) in CH2Cl2 (20 mL). The suspension was stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue was partitioned between CH2Cl2 and water. The organic layer was washed with Na2S2O3, water, and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude material was triturated with ether. Filtration gave the title compound as a brown solid (2.5 g, 43% yield). LC/MS: Example 104A @ 2.86 min (RT) (Condition G). MS (ES): m/z=262.93, [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.60 (1 hr, dd, J=8.78, 7.03 Hz), 6.39 (1 hr, d, J=8 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([N:7]1[C@@H:13]([CH3:14])[C@H:12]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:18])[C:11](=[O:29])[NH:10][C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]1=2)=[O:6].[Br:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41]([CH2:45]Cl)=[C:40]([O:47][CH3:48])[CH:39]=[CH:38]2.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[C:41]([CH2:45][N:10]1[C:11](=[O:29])[C@@H:12]([NH:15][C:16](=[O:28])[C@@H:17]([N:19]([CH3:27])[C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:25])[CH3:23])[CH3:18])[C@H:13]([CH3:14])[N:7]([C:5](=[O:6])[CH2:4][CH2:3][O:2][CH3:1])[C:8]3[CH:33]=[CH:32][CH:31]=[CH:30][C:9]1=3)=[C:40]([O:47][CH3:48])[CH:39]=[CH:38]2
Reactant: COc1ccc2cc(Br)ccc2c1CCl
Reactant: COCCC(=O)N1c2ccccc2NC(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCC(=O)N1c2ccccc2N(Cc2c(OC)ccc3cc(Br)ccc23)C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-1-(3-methoxypropanoyl)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (46 mg, 99.5 μmol) in DMF (249 μl) was added 6-bromo-1-(chloromethyl)-2-methoxynaphthalene (34.1 mg, 119 μmol), cesium carbonate (42.1 mg, 129 μmol), and sodium iodide (19.4 mg, 129 μmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-5-(3-methoxypropanoyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (52.4 mg, 74%) as a white solid. MS m/z 733/735 (MNa)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:5]1[CH2:6][C:7](F)([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:9][CH:10]=1)[NH2:4].[C:18]([O:22][C:23]([NH:25][CH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[Cl:36])[NH:32][C:31]([C:37](O)=[O:38])=[CH:30]2)=[O:24])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C.O>[Cl:36][C:35]1[CH:34]=[C:33]2[C:29]([CH:30]=[C:31]([C:37](=[O:38])[NH:4][CH:3]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=3)[C:2]([F:17])([F:16])[F:1])[NH:32]2)=[CH:28][C:27]=1[CH2:26][NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1cc2cc(C(=O)O)[nH]c2cc1Cl
Reactant: NC(C1=CC=CC(F)(C(F)(F)F)C1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
2,2,2-Trifluoro-1-[3-fluoro-3-(trifluoromethyl)phenyl]ethanamine (0.75 g, 3.08 mmol) was dissolved in N,N-dimethylformamide (52 ml), and 5-{[(tert-butoxycarbonyl)amino]methyl}-6-chloro-1H-indole-2-carboxylic acid (1.00 g, 3.08 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (1.17 g, 3.08 mmol) and 4-methylmorpholine (0.93 g, 9.24 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then water and ethyl acetate were added. After phase separation, the organic phase was washed with dilute sodium hydrogencarbonate solution and saturated sodium chloride solution and dried over sodium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (5/1). 0.75 g (40% of theory) of tert-butyl {[6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indol-5-yl]methyl}carbamate was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[CH3:22][O:23][C:24]([C:26]1[S:27][C:28]([C:48]([CH3:54])=[CH:49][CH:50]=[CH:51][CH:52]=[CH2:53])=[CH:29][C:30]=1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:34](=[O:47])[CH2:33]1)=[O:25]>ClCCCl>[CH3:22][O:23][C:24]([C:26]1[S:27][C:28]([C:48]([CH3:54])=[CH:49][CH:50]=[CH:51][CH:52]=[CH2:53])=[CH:29][C:30]=1[N:31]([CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C:34](=[O:47])[CH2:33]1)[C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]1)=[O:10])=[O:25]
Reactant: C=CC=CC=C(C)c1cc(NC2CCN(Cc3ccc(OC)cc3)C(=O)C2)c(C(=O)OC)s1
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C=CC=CC=C(C)c1cc(N(C(=O)C2CCC(C)CC2)C2CCN(Cc3ccc(OC)cc3)C(=O)C2)c(C(=O)OC)s1
Yield: 10.8 %

Procedure:
A solution of trans 4-methylcyclohexane carboxylic acid (56 mg, 0.399 mmol, 1.2 eq) in 1,2-dichloroethane (1 ml) at 0°, under N2, was treated with oxalyl chloride (2.0M solution in CH2Cl2) (231 μl, 0.46 mmol, 1.4 eq), followed by dimethylformamide (8 μl, 7 mg, 0.1 mmol, 30 mol %). After 1 h the reaction was treated with a solution of 3-[1-(4-Methoxy-benzyl)-2-oxo-piperidin-4-ylamino]-5-(1-methyl-hexa-1,3,5-trienyl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.33 mmol) in DCE (2 ml). The reaction was then placed in bath at 90° and left at reflux overnight for 21 h. The reaction was stripped-off solvent and the residue (212 mg) was purified by bond elute chromatography using (Hexane:CH2Cl2:EtOAc=1:1:1) as eluent to give 3-[[1-(4-Methoxy-benzyl)-2-oxo-piperidin-4-yl]-(4-methyl-cyclohexanecarbonyl)-amino]-5-(1-methyl-hexa-1,3,5-trienyl)-thiophene-2-carboxylic acid methyl ester (21 mg, 11%) as a yellow foam; (300 MHz, CDCl3) 0.55-0.73 (m, 1H), 0.77 (d, J=5.4 Hz, 3H), 1.26-1.30 (m, 12H), 1.94-2.12 (m, 1H), 2.14-2.19 (m, 1H), 2.40 (dd, J=9.0 Hz, J=12.0 Hz, 1H), 2.64-2.70 and 2.80 and 2.84 (m, 1H), 3.10-3.15 (m, 3H), 3.79-3.82 (m, 1H), 3.78 (s, 3H), 3.83 and 3.87 (s, 3H), 4.32 (t, J=12.0 Hz, 1H), 4.62 (dd, J=5.7 Hz, J=10.8 Hz, 1H)′ 4.50-5.0 (m, 1H), 6.79-6.83 (m, 2H), 6.99-7.14 (m, 2H), 7.26-7.48 (m, 3H), 7.61-7.65 (m, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9])(=[O:4])=[O:3].C(Cl)Cl.[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][C:8]([C:7]1[CH:6]=[C:5]([S:2]([NH:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])(=[O:4])=[O:3])[CH:19]=[CH:18][CH:17]=1)=[O:9]
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)c1ccccc1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccccc1NS(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.2 %

Procedure:
To a mixture of 2.09 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate and 20 mL of methylene chloride were added 982 mg of methyl 2-aminobenzoate and 2.10 mL of pyridine under ice-cooling, followed by stirring at room temperature for 15 hours. To the reaction mixture was added a 10% aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.61 g of methyl 2-{[(3-{[2-(trimethylsilyl)ethoxy]carbonyl}phenyl)sulfonyl]amino}benzoate as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[C:3]([N:11]2[CH2:12][CH2:13][NH:14][CH2:15][C@H:10]2[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1ncccc1Br
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CNCCN1c1ncccc1Br
Temperature: 240 °C
Yield: 21.7 %

Procedure:
A mixture of 3-bromo-2-chloropyridine (2 g, 9 mmol, Aldrich), (R)-(−)-2-methylpiperazine (1.5 g. 15 mmol) and N,N-diisopropylethylamine (1 mL, 5.8 mmol) in NMP (1 mL) was heated in a microwave synthesizer for 60 min at 240° C. The reaction mixture was concentrated and purified by silica gel chromatography, eluting with 10% MeOH in dichloromethane to give 0.5 g (22%) of (2R)-1-(3-bromopyridin-2-yl)-2-methylpiperazine MS (ESI, pos. ion). MS m/z: 256 (M+1), and 0.75 g (33%) of (3R)-1-(3-bromopyridin-2-yl)-3-methylpiperazine. MS m/z: 256 (M+1).
Reaction SMILES: [NH2:1][C:2](=[NH:16])[N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cl:17][C:18]([SH:21])(Cl)Cl.[OH-].[Na+]>ClCCl.O>[Cl:17][C:18]1[S:21][N:1]=[C:2]([N:3]2[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]2)[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)N)CC1
Reactant: SC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nsc(Cl)n2)CC1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of tert-butyl 4-[amino(imino)methyl]piperazine-1-carboxylate (1.50 g, 5.67 mmol) and perchloromethyl mercaptan (0.609 ml, 5.67 mmol) in dichloromethane (20 ml) was added dropwise a solution of sodium hydroxide (0.907 g, 22.7 mmol) in water (2.5 ml) under ice-cooling. Then, the reaction mixture was stirred under ice-cooling for 1 hour and at room temperature for 1 hour. The organic layer was separated, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 1.03 g (59.5%) of the desired product as a solid.
Reaction SMILES: COC(=O)NC(C(N1CCCC1C1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([B:27]3[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=O)C(C)C.[C:37]([O:41][C:42]([N:44]1[CH:49]([C:50](O)=O)[CH:48]2[CH2:53][CH:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42]([N:44]1[CH:49]([C:50]2[NH:17][C:18]([C:21]3[CH:22]=[CH:23][C:24]([B:27]4[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]4)=[CH:25][CH:26]=3)=[CH:19][N:20]=2)[CH:48]2[CH2:53][CH:45]1[CH2:46][CH2:47]2)=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1

Procedure:
This compound was synthesized using the same procedure as [2-Methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester using 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester. LCMS-ESI+: calc'd for C26H36BN3O4: 465.28 (M+); Found: 466.41 (M+H+).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:22](I)=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH:32](=[O:34])[CH3:33]>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[C:22]([CH:32]([OH:34])[CH3:33])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([F:24])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: CC=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(C)O)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Temperature: -40 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a mixture of methyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoate (1.25 g, 2.80 mmol) in anhydrous tetrahydrofuran (10 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M solution in tetrahydrofuran, 3.2 mL, 4.20 mmol) at −40° C. The reaction mixture was stirred for 1 hour at −40° C., after which acetaldehyde (0.79 mL, 14.10 mmol) was added. The reaction mixture was allowed to warm to ambient temperature, stirred for 16 hours and then was quenched by addition of saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (2×50 mL) and the combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by silica gel column chromatography using 0-35% ethyl acetate in hexanes as eluent to afford the title compound as an amorphous solid (0.76 g, 75%): 1H NMR (300 MHz, CDCl3) δ 7.96 (d, J=8.5 Hz, 1H), 6.58 (d, J=12.7 Hz, 1H), 5.16-5.06 (m, 1H), 3.88 (s, 3H), 3.55 (d, J=8.9 Hz, 1H), 3.52 (d, J=9.3 Hz, 1H), 2.27 (d, J=4.8 Hz, 1H), 2.08-1.98 (m, 3H), 1.83-1.61 (m, 12H), 1.49 (d, J=6.5 Hz, 3H); MS (ES+) m/z 345.2 (M−17).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:14][CH2:13][CH:12]1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)C1C=CC=CC=1.[ClH:21].O1CCOCC1>CO.[Pd]>[ClH:21].[N:15]1([CH:12]2[CH2:13][CH2:14][CH:11]2[NH2:10])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(NC1CCC1N1CCCC1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCC1N1CCCC1

Procedure:
(2-Pyrrolidin-1-yl-cyclobutyl)-carbamic acid benzyl ester (intermediate AA, 475 mg, 1.7 mmol) was dissolved in 25 mL methanol and 4N HCl in dioxane (870 mL, 3.4 mmol) and palladium on charcoal (10%, 184 mg, 0.17 mmol) were added. The reaction mixture was hydrogenated at room temperature with a H2-balloon over night. The palladium on charcoal was filtered off and the solvent was evaporated. The crude product was used without any further purification, light yellow semisolid (525 mg, 99%). The 2 diastereomers were not separated.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[C:22]([OH:23])=[CH:21][CH:20]=[CH:19][N:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Br:16][C:17]1[C:22]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cccnc1Br
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cccnc3Br)c2cc1OC
Temperature: 140 °C
Reaction time: 2 h
Yield: 5.8 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (226 mg), 2-bromo-3-pyridinol (250 mg), and 4-dimethylaminopyridine (400 mg) were suspended in o-dichlorobenzene (10 ml), and the suspension was stirred at 140° C. for 2 hr. The reaction solution was cooled to room temperature, the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (21 mg, yield 6%).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:14]([C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([N:31]=O)[CH:27]([C:33]([OH:35])=[O:34])[CH2:26]2)=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C1COCC1>[N+:14]([C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22][C:23]([N:25]2[CH2:30][CH2:29][N+:28]3[C-:27]([C:33](=[O:35])[O:34][N:31]=3)[CH2:26]2)=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=NN1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1C(=O)O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[n+]2noc(=O)[c-]2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
The THF (10 mL) solution of trifluoroacetic anhydride (24.0 g) was added to the THF (371 mL) solution of crude 4-nitrosopiperazine-1,3-dicarboxylic acid 1-(4-nitrobenzyl) ester under a nitrogen atmosphere at 0° C. for 15 min. The solution was stirred for 1.5 h at 0° C. and for 1 h at room temperature. The THF (5 mL) solution of trifluoroacetic anhydride (8.0 g) was added to the solution for 5 min and stirred for 20 h at room temperature. To the solution was added trifluoroacetic anhydride (8.0 g) for 5 min and the solution was stirred for 4 h. The precipitate was filtered and washed with THF and Et2O. The filtrate was concentrated under reduced pressure. The residue was triturated with THF, filtered and washed with Et2O. These materials were combined and dried under reduced pressure to afford the titled compound as colorless crystals (22.3 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:25]2[CH2:24][CH2:23][N:22]([C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=3)[CH2:27][CH2:26]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(c2ccc(Cl)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 72.5 °C
Reaction time: 5 h
Yield: 86.7 %

Procedure:
(R)-2-Chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (20 g, 91.9 mmol) and 1-(4-chlorophenyl)piperazine (20.8 g, 0.11 mol) were added to DMF (200 ml) followed by stirring at 70-75° C. for 5 hours. The reaction mixture was allowed to return to room temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-chlorophenyl)piperazin-1-yl]propan-2-ol (33.0 g, yield 87%) as a yellow amorphous form.
Reaction SMILES: O1CCCCC1[S:7][CH2:8][CH:9]([CH3:20])[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11].Cl>CO>[SH:7][CH2:8][CH:9]([CH3:20])[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11]
Reactant: CC(CSC1CCCCO1)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CO
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 1-[3-(tetrahydropyran-2-ylthio)-2-methylpropanoyl]-L-proline (1 g.) in a mixture of methanol (25 ml.) and concentrated hydrochloric acid (25 ml.) is stored at room temperature for 30 minutes. The solvents are removed in vacuo to yield 1-(3-mercapto-2-methylpropanoyl)-L-proline. Rf : 0.35 (silica gel, Benzene/acetic acid, 3:1), Rf 0.5 (silica gel, Methyl-ethylketone/acetic acid/pyridine/water 14:1:2:1) identical to the compound of Example 34.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])C.[CH3:40][Li].[Cl-].[NH4+]>O1CCCC1>[C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10]([S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:37])=[CH:38][CH:39]=3)(=[O:32])=[O:31])[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[CH:13][CH:12]=3)(=[O:5])[CH3:40]
Reactant: CCOC(=O)c1ncc2c(c1COC)c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCc1c(C(C)=O)ncc2c1c1c(OCc3ccccc3)cccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
3.3 g of 5-benzyloxy-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid ethyl ester is suspended in 25 ml of absolute tetrahydrofuran (THF) and cooled to -60° C. under an N2 atmosphere. To this suspension is added dropwise 5.2 ml of a 1.5-molar ethereal methyllithium solution and the mixture is stirred for another 2 hours at -60° C. After heating to room temperature, the reaction mixture is combined with saturated ammonium chloride solution and extracted with ethyl acetate. The crude product is purified by chromatography on silica gel with toluene+ethyl acetate in a ratio of 95:5.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N+:9]([O-:32])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccccc1C1=NCc2cncnc2-c2ccc(Cl)cc21
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccccc2F)c2cc(Cl)ccc2-c2ncncc2C1

Procedure:
A solution of 3.2 g (10 mmoles) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine, 3 g (15 mmoles) of 85% m-chloroperbenzoic acid in 100 ml of methylene chloride was stirred at room temperature for 4 hours. The reaction mixture was washed with an excess of ice cold dilute sodium hydroxide, dried over anhydrous sodium sulfate and filtered over hyflo. The filtrate was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether to give the crude product, m.p. 185°-186° C. Recrystallization from a mixture of methylene chloride and ether gave the pure product, m.p. 187°-188° C.