Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCCCCCOC1C=CC(C2C=CC(C#N)=CC=2)=CC=1.O[C:24]1[CH:25]=[C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=[C:28]([CH:34]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].CC(C)=O>O>[C:29]([O:31][CH2:32][CH3:33])(=[O:30])[C:28]1[CH:34]=[CH:24][CH:25]=[C:26]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:27]=1
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)c1
Agent: N#Cc1ccc(-c2ccc(OCCCCCCBr)cc2)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cccc(C(=O)OCC)c1
Yield: 90 %

Procedure:
0.08 mol (28.8 g) of 4-(6-bromohexyloxy)-4′-cyanobiphenyl, 0.08 mol (16.6 g) of diethyl 5-hydroxyisophthalate, 0.12 mol (19.2 g) of potassium carbonate anhydride and 400 ml of acetone were placed in a 1 l three-neck flask and the mixture was reacted under reflux for 24 hours by using a water bath. After the reaction solution was allowed to cool, it was poured into about 4 l of purified water to take out a precipitate, which was to be a crude subject product, by filtration and the precipitate was dried under reduced pressure (yield: 90% (37 g)). The resulting precipitate was recrystallized from acetone to obtain diethyl isophthalate carrying cyanobiphenyl through a hexyl group as a target product (yield: 73% (30 g)). The resulting compound was subjected to nuclear magnetic resonance (NMR) measurement. The results of measurement are shown below. Also, the compound was subjected to mass spectrometry, with the result that a peak corresponding to a molecular weight of 515.6 was confirmed.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH:15]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1.FC1C=CC(N2CCN(C(=O)C(NC(=O)OC(C)(C)C)CC3C=CC=CC=3)CC2)=CC=1>>[ClH:1].[NH2:20][CH:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:13][CH2:12]1)=[O:28]
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccc2Cl)CC1
Agent: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1CCN(c2ccc(F)cc2)CC1
Product: CC(C)CC(N)C(=O)N1CCN(c2ccccc2Cl)CC1
Product: Cl
Yield: 62.6 %

Procedure:
Using 1,1-dimethylethyl 2-(4-(2-chlorophenyl)-1-piperazinyl)-2-oxo-1-(2-methylpropyl)ethylcarbamate in lieu of 1,1-dimethylethyl 2-(4-(4-fluorophenyl)-1-piperazinyl)-2-oxo-1-(phenylmethyl)ethylcarbamate, the procedure of Reference Example 13 was otherwise repeated to provide 1-(2-amino-4-methyl-1-oxopentyl)-4-(2-chlorophenyl)piperazine hydrochloride (1.54 g, 62.6%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1F
Reaction time: 0.05 h
Yield: 115.4 %

Procedure:
40% Methanolic Triton B (0.14 mL, 0.31 mM) was added to a solution of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (51.9 mg, 0.155 mM) in 5 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (110.5 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 72.8 mg (71%) of the {9-[(2-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ7.65 (d, 1H, J=8 Hz), 7.5 (s, 1H), 7.4-7.2 (m, 5H), 7.15 (s, 1H), 7.1 (d, 1H, J=8 Hz), 7.05 (t, 1H, J=8 Hz), 6.7 (t, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.85 (s, 2H), and 3.7 (s, 3H). IR (CHCl3, cm−1) 3436, 1763, 1675, 1457, 1327, 1208, 1198, 1150, 1102, 772, 756, and 719. MS (FD) m/e 407.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([S:36][CH2:37][CH2:38][CH2:39][C:40]([NH:42][C@H:43]([C:49]([O:51][CH3:52])=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])=[O:41])[NH:26][C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:1]12([C:11]([NH:48][CH2:47][CH2:46][CH2:45][CH2:44][C@@H:43]([C:49]([O:51][CH3:52])=[O:50])[NH:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][S:36][C:25]3[NH:26][C:27]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)[N:24]=3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)[C@H](CCCCN)NC(=O)CCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CCCCNC(=O)C12CC3CC(CC(C3)C1)C2)NC(=O)CCCSc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)[nH]1
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A solution of 1-adamantanecarbonyl chloride (0.159 g, 0.000804 mol) in methylene chloride (2 ml) was added to a mixture of N2-[4-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-ylthio]-1-oxobutyl]-L-lysine, methyl ester hydrobromide (0.5 g, 0.000804 mol), triethyl amine (0.24 g, 0.0024 mol) and methylene chloride (20 ml) at ambient temperature under a nitrogen atmosphere. The reaction mixture was stirred for 2 hours, poured into water and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous ammonium chloride, water, brine, dried over magnesium sulfate and concentrated to give a foam. The foam was purified by flash chromatography on silica gel (50 ml) eluting ethyl acetate to give the title compound (0.4 g, 0.00057 mol, 71% yield) as a white foam, mp 98°-104°. 1H NMR (DMSO-d6) δ8.22(d, 1H), 7.35-7.25(m, 5H), 6.87(d, 4H), 4.2-4.12(m, 1H), 3.75(s, 6H), 3.57(s, 3H), 3.1-2.93(m, 4H), 2.27(t, 2H), 1.97-1.5(m, 19H), 1.37-1.17(m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl.C(O)(=O)C.CO>[CH:17]1([NH:23][C:24](=[O:25])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=NC1CCCCC1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(C(=O)c2cccc(NC(=O)NC3CCCCC3)c2)CC1
Yield: 92.2 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and cyclohexyl isocyanate (44 μL, 0.344 mmol) in methylene chloride (2 mL) were mixed for 72 h at ambient temperature. The solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (2 mL). Cyclohexyl isocyanate (44 μL, 0.344 mmol) and poly(4-dimethyaminopyridine) (82 mg, 0.115 mmol) were added and the reaction mixture was mixed for 5 days. The reaction mixture was filtered and the filter cake was washed with methanol. The solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 36.4 mg (93%) of the title compound.
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:11]([N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)[CH3:12]>CCO>[CH2:11]([N:13]1[CH2:18][CH2:17][C:16]2[NH:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:15]=2[CH2:14]1)[CH3:12]
Reactant: CCN1CCC(=O)CC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCN1CCc2[nH]c3ccccc3c2C1
Temperature: 80 °C

Procedure:
To a solution of phenylhydrazine hydrochloride (1 equiv.) in EtOH is added 1-ethylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) and the reaction mixture is heated at 80° C. for 16 h. After completion of the reaction, e.g., as monitored by liquid chromatography-mass spectrometry (LCMS), the reaction mixture is concentrated to dryness and basified with aq. saturated NaHCO3 and extracted in EtOAc. The organic layer is separated, dried over sodium sulfate and concentrated to obtain 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[NH:9]1[CH2:12][CH2:11][CH2:10]1>>[Br:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: C1CNC1
Product: Brc1cccc(N2CCC2)c1

Procedure:
The title compound was prepared from 1,3-dibromobenzene and azetidine using a similar procedure to that described for D43. LCMS (A): m/z (M+H)+ 212/214, C9H10BrN requires 211/213 (acidic).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:41]1[CH:42]=[C:37]([Cl:36])[C:38]([OH:53])=[C:39]([Cl:52])[CH:40]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 75.9 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(3-acetyl-6-bromoquinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (60 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (48 mg, 0.166 mmol) to afford the desired product (52 mg, 76%) as an brown solid: ESI MS m/z 622, [C32H33Cl2N5O4+H]+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)=[O:13])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:17][CH:16]=3)=[O:13])=[CH:25][CH:26]=2)=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:37])=[O:36]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc1
Reaction time: 8 h

Procedure:
The product from Example 3 (300 mg, 0.87 mmol) and triethylamine (0.6 mL, 4.3 mmol) in CH2Cl2 (10 mL) were treated with methanesulfonyl chloride (0.2 mL, 2.58 mmol) at room temperature and stirred overnight. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with H2O (3×5 mL) and brine (5 mL), dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (99:1 CH2Cl2:CH3OH) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.81 (dd, J=4.6 Hz, 1.6 Hz, 1H), 8.25 (dd, J=8.1 Hz, 1.4 Hz, 1H), 8.11-8.14 (m, 2H), 7.61-7.77 (m, 5H), 7.37-7.41 (m, 2H), 3.19 (s, 6H), 1.29 (s, 9H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: [C-:1]#[N:2].[K+].C1(C)C=CC(S(O[CH2:14][C@H:15]2[CH2:23][C@@H:22]3[C@@H:18]([CH2:19][N:20]([C:24](=[O:35])[C@H:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[CH3:26])[CH2:21]3)[C@@:17]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])([OH:36])[CH2:16]2)(=O)=O)=CC=1>CS(C)=O.ClCCl>[C:1]([CH2:14][C@@H:15]1[CH2:23][C@@H:22]2[C@@H:18]([CH2:19][N:20]([C:24](=[O:35])[C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH3:26])[CH2:21]2)[C@@:17]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])([OH:36])[CH2:16]1)#[N:2]
Reactant: [C-]#N
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CC#N)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 149.6 %

Procedure:
0.35 g of potassium cyanide is added at room temperature to a solution of 1.55 g of (3aS,4S,6S,7aR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in 15 cm3 of dimethyl sulphoxide. The reaction mixture is stirred at 50° C. for 18 hours and then diluted with 100 cm3 of dichloromethane, and the organic phase is washed with twice 50 cm3 of water then with 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). Recrystallization from diisopropyl ether gives 1.74 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in the form of white crystals melting at 182° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][CH2:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C.[CH3:29][NH2:30]>CO>[F:27][C:23]1[CH:22]=[C:21]([S:18]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[CH:8]([CH2:7][NH:6][CH2:5][C:4]([NH:30][CH3:29])=[O:3])[CH2:9][CH2:10][CH2:11]3)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: CN
Reactant: CCOC(=O)CNCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Solvent: CO
Product: CNC(=O)CNCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-acetic acid ethyl ester (0.42 g) was dissolved in 20 m of 1.1 molar methylamin in methanol. The solution was stirred at room temperature for 24 hours and then concentrated to an oil under reduced pressure. The oil was dissolved in ethanol and 1N HCl in diethyl ether was added to precipitate 2-{[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-amino}-N-methyl-acetamide as a hydrochloride salt. Yield 0.045 gms, M+H=391.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][C@H:9]1[C:16]([OH:18])=O.F[P-](F)(F)(F)(F)F.[N:26]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:30]2C=CC=C[C:29]=2[N:28]=N1.Cl.NCC#N.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:13][CH2:12][C:11]([F:14])([F:15])[CH2:10][C@H:9]1[C:16]([NH:28][CH2:29][C:30]#[N:26])=[O:18]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)[C@@H]1CC(F)(F)CC[C@H]1c1ccccc1Br
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)[C@@H]1CC(F)(F)CC[C@H]1c1ccccc1Br
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A mixture of (1R,2R)-2-(2-bromophenyl)-5,5-difluorocyclohexanecarboxylic acid (820 mg, 2.58 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.49 g, 2.86 mmol) and aminoacetonitrile hydrochloride (530 mg, 5.73 mmol) in N, N-dimethylformamide (5.0 mL) was cooled to 0° C. and treated with triethylamine (1.26 mL, 9.04 mmol). The resulting slurry was stirred at room temperature for 2.5 hours and then poured into water and extracted with ethyl acetate (3×). The combined extracts were washed with brine and dried (Na2SO4). Concentration in vacuo and chromatography of the residue on silica eluting with 2/3 EtOAc/hexanes yielded (1R,2R)-2-(2-bromophenyl)-N-(cyanomethyl)-5,5-difluorocyclohexanecarboxamide as a faint-yellow foam.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[N+:12]([CH:15]=[C:16](SC)SC)([O-:14])=[O:13].[CH3:21][NH2:22]>>[N+:12]([CH:15]=[C:16]([NH:22][CH3:21])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[Br:1])([O-:14])=[O:13]
Reactant: CN
Reactant: NCCSCc1[nH]cnc1Br
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br

Procedure:
When 4-bromo-5-[(2-aminoethyl)thiomethyl]imidazole (from the dihydrobromide (4.8 g)) is reacted with 1-nitro-2,2-bis-methylthioethylene (2.0 g) according to the procedure of Example 4(i) and the resultant 1-nitro-2-methylthio-2- 2-((4-bromo-5-imidazolyl)methylthio)ethylamino ethylene treated with methlyamine by the procedure of Example 3(ii) there is produced 1-nitro-2-methylamino-2-[2-((4-bromo-5-imidazolyl)methylthio)ethylamino] ethylene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([N+:12]([O-])=O)[CH:5]=1>C(OCC)(=O)C.CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNc1ccc(C(=O)OC)cc1N
Reaction time: 4 h

Procedure:
After dissolving 4-methylamino-3-nitrobenzoic acid methyl ester (540 mg, 2.5 mmol) in ethyl acetate-methanol (2:1) (20 ml), 10% palladium-carbon powder (5 mol %) was added thereto under a nitrogen atmosphere. The mixture was stirred for 4 hours under a hydrogen atmosphere, and then the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain 3-amino-4-methylaminobenzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.CCCCCCC=CCCC.[CH3:22][N:23]=[C:24]=[O:25].CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[CH3:22][NH:23][C:24](=[O:25])[O:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2
Reactant: CN=C=O
Reactant: Oc1cccc2cc[nH]c12
Agent: CCCC=CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CNC(=O)Oc1cccc2cc[nH]c12
Temperature: 25 °C

Procedure:
3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-ol (2.2 g) was dissolved in CH2Cl2 (200 ml) with 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU; 0.21 g) and the solution was cooled to 0° C. A solution of methyl isocyanate (0.52 g in 30 ml CH2Cl2) was added slowly to the cooled solution and the reaction was monitored by thin layer chromatography (silica gel, 1:1 hexane/ethyl acetate). After warming to room temperature, the mixture was washed successively with water (2×100 ml), brine (1×100 ml) and again with water (1×100 ml). The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The crude material was recrystallized from acetonitrile. 3-(N-Cyclo-propyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent b!indol-7-yl methylcarbamate was isolated as light yellow/white plates (1.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C:9](=[O:26])[C@@:10]2([NH:22][C:23](=[O:25])[CH3:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].[Li+].[BH4-]>CCO.C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:26])[C@@:10]2([NH:22][C:23](=[O:25])[CH3:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@H:9]([OH:26])[C@@:10]2([NH:22][C:23](=[O:25])[CH3:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2CC(=O)[C@@](NC(C)=O)(C(=O)OCc3ccccc3)[C@@H]21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](NC(C)=O)(C(=O)OCc3ccccc3)[C@@H]21
Product: CCOC(=O)[C@H]1[C@@H]2C[C@H](O)[C@@](NC(C)=O)(C(=O)OCc3ccccc3)[C@@H]21
Temperature: -50 °C
Reaction time: 0.75 h

Procedure:
To a solution of (1S,2R,5R,6S)-2-acetylamino-3-oxo-bicyclo [3.1.0] hexane-2,6-dicarboxylic 2-benzyl ester 6-ethyl ester (XVI) (77 mg, 0.214 mmol) in EtOH (2 mL) and THF (1 mL) was added LiBH4 (5 mg, 0.23 mmol) at -50° C. and the mixture was stirred at -50° C. for 45 min. The reaction was quenched by addition of 1 N HCl (ca. 0.5 mL), warming up to 23° C. and stirring for 10 min. After dilution with ethyl acetate and extraction with sat. NaHCO3 -sol., brine and drying over MgSO4 the crude product was purified by silica gel column chromatography with toluene/acetone 3:1 to give (1S,2R,3R,5R,6S)-2-acetylamino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XVII) (33 mg, 43%, less polar product) as a colorless oil and (1S,2R,3S,5R,6S)-2-acetylamino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XVIII) (35 mg, 45%, more polar product) as a white solid. (XVII): 1H-NMR (250 MHz, CDCl3) □1.26 (3H, t, J=7.2 Hz), 1.76 (1H, t, J=3.5 Hz), 2.07 (1H, m), 2.10 (3H, s), 2.16 (1H, dd, J=6.1, 3.0 Hz), 2.30-2.41 (3H, m), 3.97-4.13 (3H, m), 5.24 (2H, bs), 6.19 (1H, bs), 7.26-7.38 (5H, m); MS[ISP] 362 (M+H+); □D20 -11.24° (c=1.18, CHCl3). (XVIII): 1H-NMR (250 MHz, CDCl3) □1.25 (3H, t, J=7.1 Hz), 1.98 (1H, m), 2.05-2.11 (1H, m),2.06 (3H, s), 2.18 (1H,t,J=3.5 Hz), 2.27-2.41 (2H, m), 2.59 (1H, ddd,J=13, 7, 5 Hz), 4.12 (2H, m), 4.68 (1H, dd, J=7, 5 Hz), 5.17 (2H, s), 6.30 (1H, bs), 7.26-7.40 (5H, m); MS[ISP] 362 (M+H+); mp 145-147° C.; □D20 +42.44° (c=1.01, CHCl3).
Reaction SMILES: [C:1]([C:9]1[CH:32]=[CH:31][C:12]2[N:13](CC3C=CC(OC)=CC=3)[C:14](=[O:21])[N:15]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.O>[C:1]([C:9]1[CH:32]=[CH:31][C:12]2[NH:13][C:14](=[O:21])[N:15]([CH2:16][CH2:17][N:18]([CH3:19])[CH3:20])[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2c(=O)n(CCN(C)C)c3cc(C(=O)c4ccccc4)ccc32)cc1
Solvent: CC#N
Solvent: O
Product: CN(C)CCn1c(=O)[nH]c2ccc(C(=O)c3ccccc3)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
To a solution of 1.11 g of 5-benzoyl-1,3-dihydro-3-(2-dimethylaminoethyl)-1-(4-methoxybenzyl)-2H-benzimidazol-2-one in 20 ml of acetonitrile and 7 ml of water was added 6.43 g of ceric ammonium nitrate. The reaction mixture was stirred at 60° C. for 4 hours, diluted with water and washed with ethyl acetate. After alkalization to pH 9 with 10% sodium hydroxide, the basic material was extracted with chloroform and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded the crude material which was chromatographed on silica gel. Elution with chloroformmethanol (10:1) gave 40 mg of 6-benzoyl-1,3-dihydro-1-(2-dimethylaminoethyl)-2H-benzimidazol-2-one.