Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O-])(=O)=O.[CH2:6]1[CH2:11][CH2:10][C:9]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[CH2:8][CH2:7]1.C(=O)(O)[O-].[Na+].C(Cl)(Cl)=S.CS(O)(=O)=O>C(Cl)(Cl)Cl.O.O1CCCC1>[CH2:6]1[CH2:11][CH2:10][C:9]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:1]=[S:2])[CH:13]=2)[CH2:8][CH2:7]1
Reactant: Nc1cccc(C2(N3CCCCC3)CCCCC2)c1
Reactant: CS(=O)(=O)[O-]
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: S=C(Cl)Cl
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: S=C=Nc1cccc(C2(N3CCCCC3)CCCCC2)c1
Reaction time: 0.08 h

Procedure:
Metaphit was prepared as methanesulfonate and hydrochloride salts. To a vigorously stirred two-phase system consisting of 4.65 g (18 mmol) of m-amino-PCP (1-(1-(3-aminophenyl)cyclohexyl)piperidine) in 50 ml of chloroform and 756 mg (90 mmol) of sodium bicarbonate in 25 ml water, was added a solution of 1.45 ml (2.29 g, 19 mmol) of freshly distilled thiophosgene in 10 ml of chloroform. The mixture was stirred for 5 minutes, then the phases were separated and the aqueous phase was washed once with chloroform. The combined organic layers were dried (over sodium sulfate) and evaporated to a clear glass (5.43 g). This substance was dissolved in tetrahydrofuran (20 ml) and treated with a solution of methanesulfonic acid (1.73 g, 18 mmol) in tetrahydrofuran. The resulting crystalline solid was filtered and dried in vacuo to give 7.01 g (98%) of methanesulfonate salt, mp 175°-178° C. (dec). The material could be recrystallized from isopropanol/isopropyl ether if necessary. It was stored at 0° C. in a dessicator. The hydrochloride salt prepared in isopropanol and recrystallized from methanol-ether showed mp 214°-216 ° C. The methanesulfonate salt was considerably more soluble in water than the hydrochloride.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][C:23]#N>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:8][CH2:7][CH2:10][CH2:11][C:22]3[CH:23]=[CH:6][CH:5]=[CH:4][CH:9]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2CCNCC2)cc1
Reactant: CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C2CCN(CCCCc3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-methoxyphenyl)piperidine hydrochloride (1.00 g, 4.39 mmol), 4-phenyl-p-tosylbutane (1.40 g, 4.61 mmol) and K2CO3 (1.24 g, 9.00 mmol) in CH3CN (25 mL) as a beige solid (979 mg, 69%): mp 48-50° C.; 1H NMR (CDCl3) 1.52-1.86 (m, 8H), 2.01 (td, J=11 and 3.6 Hz, 2H), 2.34-2.50 (m, 3H), 2.65 (t, J=7.2 Hz, 2H), 2.98-3.08 ((m, 2H), 3.79 (J, 3H), 6.85 (d, J=8.7 Hz, 2H), 7.12-7.32 (m, 7H).
Reaction SMILES: [CH:1]1(Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Mg].[CH2:9]([O:16][CH2:17][C@@H:18]1[CH2:20][O:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+].N>O1CCCC1.C1(C)C=CC=CC=1>[CH:1]1([CH2:20][C@H:18]([OH:19])[CH2:17][O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCCC1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Agent: N
Agent: [Cl-]
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O[C@H](COCc1ccccc1)CC1CCCCC1
Reaction time: 0.17 h
Yield: 80.5 %

Procedure:
A solution of a Grignard reagent, prepared from 9.79 g (60.0 mmol) of cyclohexyl bromide and 1.46 g (60.0 mmol) of magnesium, in 85 ml of tetrahydrofuran was added dropwise over a period of 10 minutes to a suspension of 1.90 g (9.98 mmol) of cuprous iodide in 50 ml of tetrahydrofuran at -75° C. The mixture was allowed to stand for 10 minutes, and then a solution of 8.21 g (50.0 mmol) of (S)-benzyloxymethyloxirane, [α]D =+4.82° (c=1, toluene), in 20 ml of tetrahydrofuran was added dropwise over a period of 15 minutes. The resulting mixture was stirred for 3 hours at the same temperature and then for 30 minutes at 0° C. At the end of this time, the reaction was stopped by adding a saturated aqueous solution of ammonium chloride. The reaction mixture was then mixed with 20 ml of concentrated aqueous ammonia, after which it was extracted with diethyl ether. The extract was washed with a saturated aqueous solution of ammonium chloride, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 250 g of silica gel, using a 1:4 by volume mixture of ethyl acetate and methylene chloride as the eluent, to give 10.0 g (yield 82%) of the title alcohol derivative as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:59])[C@H:12]([CH3:58])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:57])[CH2:22][C@@H:23]([O:55][CH3:56])[C@@H:24]([N:29]([CH3:54])[C:30](=[O:53])[C@H:31]([CH:50]([CH3:52])[CH3:51])[NH:32]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1.C(NCC)C>ClCCl>[CH:1]1([CH2:8][CH2:9][NH:10][C:11](=[O:59])[C@H:12]([CH3:58])[C@H:13]([C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21](=[O:57])[CH2:22][C@@H:23]([O:55][CH3:56])[C@@H:24]([N:29]([CH3:54])[C:30](=[O:53])[C@H:31]([CH:50]([CH3:51])[CH3:52])[NH2:32])[C@@H:25]([CH3:28])[CH2:26][CH3:27])[O:14][CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCNCC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](N)C(C)C
Yield: 86.4 %

Procedure:
According to the general procedure A, from #175 (560 mg, 0.690 mmol, 1 eq.) in dichloromethane (9 mL), and N,N-diethylamine (6.0 mL), was synthesized the crude desired compound, which was purified by by silica gel chromatography (Gradient: 0 to 50% methanol in dichloromethane) to afford #176 (351 mg, 87%) as a yellow oil. LC-MS (Protocol Q1): m/z 589.5 [M+H+], retention time=0.72 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1
Reactant: O=Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(O)C1CCN(Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of 3-fluoro-4-nitrobenzaldehyde (0.5 g, 2.96 mmol) and 2-(piperidin-4-yl)propan-2-ol (0.466 g, 3.25 mmol) in DCM (25 mL) was added AcOH (0.017 mL, 0.296 mmol) and sodium triacetoxyborohydride (0.689 g, 3.25 mmol), and the reaction was stirred at RT for 1 hour. After 1 hour, the reaction was quenched by the addition of 1 N aqueous NaOH (15 mL), and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residual product was adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide 2-(1-(3-fluoro-4-nitrobenzyl)piperidin-4-yl)propan-2-ol as a yellow oil (0.75 g, 86% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[C:4]([CH3:11])[CH:3]=1.Cl.[CH3:13][NH:14][O:15][CH2:16][C:17]([OH:19])=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:14]([CH3:13])[O:15][CH2:16][C:17]([OH:19])=[O:18])=[S:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: CNOCC(=O)O
Reactant: Cc1cc(Cl)ccc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)ccc1NC(=S)N(C)OCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A mixture of 4-chloro-2-methylphenyl-isothiocyanate (12.8 g), N-methyl aminooxy acetic acid hydrochloride (10 g), triethylamine (7.5 g) and chloroform (100 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (200 mL) and extracted with sodium bicarbonate saturated solution (2×200 mL). The aqueous extract was acidified with 6N HCl and extracted with ethyl acetate (2×300 mL). The organic phase was washed with water (200 mL), dried over anhydrous magnesium sulfate and evaporated to dryness to give 13.9 g of [[[[(4-Chloro-2-methylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as a solid, m.p. 110-113° C. Mass spectrum (El, M.+) m/z 288/290. 1H-NMR (DMSO-d6; 400 MHz) δ□13.20 (br s, 1H), 10.12 (s, 1H), 7.34-7.19 (m, 3H),4.69 (q, 2H), 3.55 (s, 3H), and 2.17 ppm (s, 3H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:21]1[CH2:22][CH2:23][N:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N+:9]([O-:11])=[O:10])[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
Benzyl bromide (3.1 mL, 26 mmol) was added to a mixture of 1-(2-nitrophenyl)piperazine (4.91 g, 24 mmol) and potassium carbonate (8.2 g, 59 mmol) in dimethylformamide (30 mL) and the mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with xylene. The residue was diluted with ethyl acetate, washed with brine (×3), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (60:40) to give the title compound as an orange oil (4.0 g, 57%). δH (250 MHz, CDCl3) 7.75 (1H, dd, J 1.6, 8.1 Hz), 7.46 (1H, dt, J 1.6, 7.3 Hz), 7.34-7.24 (5H, m), 7.12 (1H, dd, J 7.1, 8.3 Hz), 7.01 (1H, dt, J 1.2, 8.3 Hz), 3.57 (2H, s), 3.10-3.05 (4H, m), and 2.63-2.58 (4H, m).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1)[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>CO>[CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:15])[CH3:16])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(SC)c1ccc(N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC(C(=O)O)c1ccc(N(C)C)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 83.1 %

Procedure:
Methyl α-methylthio(p-dimethylaminophenyl)acetate (1.215 g) was dissolved in 20 ml of methanol, and 30 ml of a 10% aqueous solution of sodium hydroxide was added. The mixture was stirred at 70° C. for 14 hours. The mixture was acidified to a pH of 5 with conc. hydrochloric acid, and continuously extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to afford 0.951 g of α-methylthio(p-dimethylaminophenyl)acetic acid in a yield of 83%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:29]([NH:31][NH2:32])[CH3:30].CCN(CC)CC>CCO>[CH2:29]([N:31]1[C:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[N:32]1)[CH3:30]
Reactant: N#Cc1cccc(C(=O)CC(=O)CCc2ccc(F)cc2)c1
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCn1nc(-c2cccc(C#N)c2)cc1CCc1ccc(F)cc1
Yield: 25.9 %

Procedure:
A mixture of 3-[5-(4-fluorophenyl)-3-oxo-pentanoyl]-benzonitrile (1.0 g, 3.39 mmol), ethyl hydrazine oxalate (763 mg, 5.08 mmol) and Et3N (709 □L, 5.08 mmol) in EtOH (50 mL) was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and H2O (50 mL). The organics were separated, washed with brine (50 mL), concentrated under reduced pressure, and the residue purified by column chromatography on silica eluting with 40% EtOAc/iso-hexanes to yield first 3-{1-ethyl-5-[2-(4-fluorophenyl)-ethyl]-1H-pyrazol-3-yl}-benzonitrile (280 mg, 26%) (by-product) and then 3-{1-ethyl-3-[2-(4-fluorophenyl)-ethyl]-1H-pyrazol-5-yl}-benzonitrile (380 mg, 35%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2([CH2:14][O:15][CH3:16])[CH2:13][O:12][CH2:11]2)=[C:6]([O:17][CH3:18])[C:5]([O:19][CH:20]([F:22])[F:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[C:42](=[O:46])[NH:41][CH2:40]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][CH:20]([F:22])[O:19][C:5]1[CH:4]=[CH:3][C:2]([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[C:42](=[O:46])[NH:41][CH2:40]3)=[C:7]([O:8][CH2:9][C:10]2([CH2:14][O:15][CH3:16])[CH2:13][O:12][CH2:11]2)[C:6]=1[O:17][CH3:18]
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: COCC1(COc2c(Br)ccc(OC(F)F)c2OC)COC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCC1(COc2c(-c3ccc4c(c3)CNC4=O)ccc(OC(F)F)c2OC)COC1
Temperature: 85 °C
Yield: 22 %

Procedure:
To a stirring solution of 3-((6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)-3-(methoxymethyl)oxetane (200 mg, 0.521 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h. To this cesium carbonate (507 mg, 1.563 mmol), tetrakis(triphenylphosphine) palladium(0) (30 mg, 0.026 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (162 mg, 0.626 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (50 mg, 22%).
Reaction SMILES: [OH:1][CH:2]1[CH:8]([NH:9][C:10]([C@@H:12]([NH:17][C:18]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH:24]=2)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.CO>[C:29]([N:4]1[CH2:5][CH2:6][CH2:7][CH:8]([NH:9][C:10]([C@@H:12]([NH:17][C:18]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH:24]=2)=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:11])[CH:2]([OH:1])[CH2:3]1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCNCC1O
Reactant: O=C(O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(C(=O)c2ccccc2)CC1O

Procedure:
To a solution of benzofuran-2-carboxylic acid [(S)-1-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-amide of Example 78c (0.2 ) in dichloromethane was added benzoic acid (0.12 g), HOBt (0.07 g) and EDC (0.99 g). The reaction was stirred until complete. Workup and column chromatography (5% methanol:dichloromethane) provided the title compound (0.2 g): 1H NMR (CDCl3): δ 1.0 (m, 6H), 1.5-2.2 (m, 6H), 2.7 (m, 1H), 3.8 (m,1H), 4.1 (m, 1H), 4.7 (m, 2H), 5.1 (m, 1H), 7.0-7.7 (m, 10H), 8.7 (m, 1H); MS(EI): 492 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:58]([CH3:60])C)[C:7]([N:9]1[C@H:14]([C:15]2[NH:19][C:18]3[C:20]4[C:25]([CH:26]=[CH:27][C:17]=3[N:16]=2)=[CH:24][C:23]([C:28]2[CH:29]=[C:30]3[C:54](=[CH:55][CH:56]=2)[C:34]2[NH:35][C:36]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49](=[O:52])[O:50][CH3:51])[CH:45]([CH3:47])[CH3:46])=[N:37][C:33]=2[CH:32]=[CH:31]3)=[CH:22][CH:21]=4)[C@@H:13]2[CH2:57][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4].[CH3:61][O:62]C(N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:58]([O:62][CH3:61])[CH3:60])[C:7]([N:9]1[C@H:14]([C:15]2[NH:19][C:18]3[C:20]4[C:25]([CH:26]=[CH:27][C:17]=3[N:16]=2)=[CH:24][C:23]([C:28]2[CH:29]=[C:30]3[C:54](=[CH:55][CH:56]=2)[C:34]2[NH:35][C:36]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43](=[O:53])[C@@H:44]([NH:48][C:49](=[O:52])[O:50][CH3:51])[CH:45]([CH3:47])[CH3:46])=[N:37][C:33]=2[CH:32]=[CH:31]3)=[CH:22][CH:21]=4)[C@@H:13]2[CH2:57][C@H:10]1[CH2:11][CH2:12]2)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c65)c4)ccc3c2[nH]1)C(C)C

Procedure:
Title compound was prepared by methods analogous to those described for methyl (S)-1-((S)-2-(2′-((1R,3S,4S)-2-((S)-2-methoxycarbonylamino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid. (ESI) m/z 830 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([N+:32]([O-])=O)[CH:26]=3)=[O:24])[CH2:16][CH2:15]2)=[O:12])=[CH:4][C:3]=1[Cl:35].O=[Si]=O>O1CCCC1.[Pt]>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([NH2:32])[CH:26]=3)=[O:24])[CH2:16][CH2:15]2)=[O:12])=[CH:4][C:3]=1[Cl:35]
Reactant: Nc1ccc(C(=O)CCCN2CCC(OC(=O)c3cc(Cl)c(N)c4c3OCC4)CC2)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: O=[Si]=O
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)CCCN2CCC(OC(=O)c3cc(Cl)c(N)c4c3OCC4)CC2)cc1N
Yield: 70.4 %

Procedure:
A mixture of intermediate (11) (8.2 g) in tetrahydrofuran (150 ml) was hydrogenated with platinum on activated carbon (5%) (2 g) as a catalyst. After uptake of H2 (3 equiv), the catalyst was filtered off over dicalite and the filtrate was evaporated. The residue was diluted with water and this mixture was extracted twice with CH2Cl2. The separated organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated. The residue (8 g) was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 92/8). The pure fractions were collected and the solvent was evaporated. The residue (7.5 g) was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 5.43 g (70.5%) of 1-[4-(3,4-diaminophenyl)-4-oxobutyl]-4-piperidinyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate; mp. 173.4° C. (intermediate 12).
Reaction SMILES: C([O:8][C:9]1[C:10]([O:43][CH3:44])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][C:30](=[O:41])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:17]=4[CH2:18]3)[C:13]=2[CH:42]=1)C1C=CC=CC=1>[Ni]>[OH:8][C:9]1[C:10]([O:43][CH3:44])=[CH:11][C:12]2[CH2:21][CH2:20][N:19]3[CH:14]([CH2:15][C:16]4[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][C:30](=[O:41])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:17]=4[CH2:18]3)[C:13]=2[CH:42]=1
Reactant: CCCCCCCCCCC(=O)Oc1c(OC)cc(Cl)c2c1CN1CCc3cc(OC)c(OCc4ccccc4)cc3C1C2
Agent: [Ni]
Product: CCCCCCCCCCC(=O)Oc1c(OC)cc(Cl)c2c1CN1CCc3cc(OC)c(O)cc3C1C2

Procedure:
A product obtained in Example 39 (0.07 g, 0.1 mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The product was given as pale brown oil (0.05 g, 85.8%). 1HNMR (CDCl3) δ: 0.95 (3H, s, CH3), 1.32˜1.56 (16H, m, CH2), 2.12˜2.21 (2H, m, CH2) 2.58˜2.70 (3H, m, CH2), 3.04˜3.24, 3.38˜3.39 (3H, m, CH2), 3.54˜3.66 (2H, m, CH2 and N—CH), 3.87 (3H, s, Ar—OCH3), 3.88 (3H, s, Ar—OCH3), 4.25 (1H, d, CH2), 5.52 (1H, brs, Ar—OH), 6.60 (1H, s, ArH), 6.87 (1H, s, ArH), 6.93 (1H, s, ArH).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>CO.[Pd]>[C:12]1([C@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]([OH:23])=[O:22])[CH2:19][CH2:20]2)[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Palladium (10 wt. %) on carbon (50 g) and triethylamine (90 mL, 0.65 mol) were added sequentially, each in one portion, to a stirred solution of 4-(4-chlorophenyl)cyclohexanecarboxylic acid (150 g, 0.63 mol) in MeOH (1.5 L). The reaction mixture was stirred under a hydrogen atmosphere for 4 h at 50° C. at a pressure of 5 bar then cooled, filtered and then concentrated in vacuo to give the title compound (160 g, 83%) as a solid, which was contaminated with triethylamine hydrochloride (0.65 mol) and used with no further purification; 1H NMR δ 1.23 (9H, t), 1.44-1.53 (4H, m), 1.8-1.9 (2H, m), 1.96-2:05 (2H, m), 2.22-2.32 (1H, m), 2.45-2.58 (1H, m), 3.05 (6H, q), 7.1-7.35 (5H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:18]([CH:29]([CH3:31])[CH3:30])[C:17]1=O.CCN(CC)CC.[Si](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl.CCOC(C)=O>[CH:29]([C@H:18]1[N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:20][CH2:21][N:16]2[C:3]3[CH:4]=[C:5]([S:12]([CH3:15])(=[O:13])=[O:14])[C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=3[N:1]=[C:17]12)([CH3:30])[CH3:31]
Reactant: COC(=O)c1cc(N)c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Agent: Cl[Si](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a 1 L round-bottom flask containing (R)-tert-butyl 4-(2-amino-4-(methoxycarbonyl)-5-(methylsulfonyl)phenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (25 g, 0.0532 mol) in dichloromethane (500 mL) was added Et3N (64.5 g, 0.638 mol, 12 eq.) and SiCl4 (27.1 g, 0.160 mol, 3 eq.). The mixture was stirred at rt overnight. The mixture was added dropwise to aq. NaHCO3 solution (54.1 g in 1 L of water, 0.644 mol, 12.1 eq.) at 0° C. slowly and adjusted to pH=8. The mixture was filtered and the aqueous layer was extracted with dichloromethane (3×600 mL). The combined organic layers were washed with brine, and then dried over anhydrous Na2SO4. The mixture was filtered and concentrated under vacuum to give the residue. The residue was purified by column chromatography on silica gel eluting with PE:EtOAc 2:1 to give (R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate (13.2 g, 55% yield) as a pale yellow solid. Analytical chiral HPLC: tR=9.03 min in 15 min chromatography (Method: OD-3—3—5—40—2.5 ML). LC-MS MS (ESI) m/z 452.2 [M+H]+. 1H NMR (CD3OD 400 MHz): δ 8.31 (s, 1H), 8.01 (s, 1H), 5.30-5.18 (m, 1H), 4.70-4.52 (m, 1H), 4.47 (dd, J=3.2 and 12.4 Hz, 1H), 4.18 (dt, J=5.2 and 11.6 Hz, 1H), 3.98 (s, 3H), 3.70-3.52 (m, 1H), 3.44 (s, 3H), 2.50-2.38 (m, 1H), 1.53 (s, 9H), 1.25 (d, J=6.8 Hz, 3H), 1.06 (d, J=6.8 Hz, 3H).