Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH:10]=[N:9]2)=[C:4]([F:17])[CH:3]=1.Cl[CH2:19][C:20]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:21]=1[O:22][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][N:12]1[C:11](=[O:16])[CH:10]=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:19][C:20]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:21]=3[O:22][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:3][C:4]=2[F:17])[C:13]1=[O:14]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Reactant: Cn1c(=O)cnn(-c2ccc(O)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-n2ncc(=O)n(C)c2=O)c(F)c1
Yield: 78.9 %

Procedure:
By the method of Example 1, Step I, 0.47 g (0.002 mole) of 2-(4-hydroxy-2-fluorophenyl)-4-methyl-1,2,4-triazine-3,5-dione and 0.73 g (0.003 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate were reacted in the presence of 0.41 g (0.003 mole) of anhydrous potassium carbonate in 30 mL of N,N-dimethylformamide, yielding 0.70 g of methyl 2-[2-[4-(4-methyl-1,2,4-triazine-3,5-dion-2-yl)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as a syrup. The IR and NMR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH=8.0 Hz); 2.30 (s, 3H); 3.40 (s, 3H); 3.78 (s, 3H); 4.84 (q, 1H, JHH=8.0 Hz); 5.18 (dd, 2H, JHH=10 Hz); 6.58 (s, 1H); 6.8-7.3 (m, 5H); 7.54 (s, 1H).
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1)(=O)=O.[F:11][C:12]1[C:13]([CH3:28])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=2)[C:15]([CH3:19])=[CH:16][C:17]=1O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[F:11][C:12]1[C:13]([CH3:28])=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][OH:27])[CH:21]=2)[C:15]([CH3:19])=[CH:16][C:17]=1[O:5][C@H:6]1[CH2:10][CH2:9][O:8][CH2:7]1
Reactant: Cc1cc(O)c(F)c(C)c1-c1cccc(CO)c1
Reactant: CS(=O)(=O)O[C@@H]1CCOC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O[C@H]2CCOC2)c(F)c(C)c1-c1cccc(CO)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 50.7 %

Procedure:
The crude (R)-tetrahydrofuran-3-yl methanesulfonate 1b (202 mg, 1.22 mmol), the crude 3-fluoro-3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-ol 19b (200 mg, 0.81 mmol) and cesium carbonate (527 mg, 1.62 mmol) were dissolved in 5 mL of N,N-dimethylformamide. The reaction mixture was heated to 80° C. and stirred for 12 hours. The resulting mixture was mixed with 20 mL of water and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with water (30 mL) and saturated sodium chloride solution (30 mL) successively, dried with anhydrous magnesium sulphate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound (S)-(3′-fluoro-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 19c (130 mg, yield 50.8%) as a colorless slime.
Reaction SMILES: [CH3:1][Mg]Cl.[S:4]1[CH:8]=[C:7]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[N:6]=[N:5]1>O1CCCC1>[S:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH:13]([OH:14])[CH3:1])=[CH:15][CH:16]=2)[N:6]=[N:5]1
Reactant: O=Cc1ccc(-c2csnn2)cc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2csnn2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Methylmagnesium chloride (3 M in tetrahydrofuran) (0.83 mL, 2.5 mmol) was added to a −78° C. solution of 4-(1,2,3-thiadiazol-4-yl)benzaldehyde (473 mg, 2.5 mmol) in tetrahydrofuran (10 mL). After stirring at −78° C. for 2 h, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 1-[4-(1,2,3-thiadiazol-4-yl)phenyl]ethanol.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:11])[CH2:7][C:8]([CH3:10])=[O:9].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21]>CN(C)C=O>[C:6]([NH:5][CH2:4][CH2:3][NH:2][C:19](=[O:23])[C:20]([CH3:22])=[CH2:21])(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9]
Reactant: CC(=O)CC(=O)NCCN
Reactant: C=C(C)C(=O)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)C(=O)NCCNC(=O)CC(C)=O
Temperature: 20 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
Crude N-(2-aminoethyl)acetoacetamide hydrobromide (50 g, 0.18 mole) was dissolved in N,N-dimethylformamide (500 ml). Triethylamine (78 g, 0.4 mole) and methacryloyl chloride (19 g, 0.18 mole) were added simultaneously at 0° C. The reaction solution was then stirred at 0° C. for 1 hour and at 20° C. for 20 hours. The resulting solution was filtered, the solvent removed, and the residue dissolved in chloroform (500 ml). The solution was then washed with 10% hydrochloric acid (200 ml), then water (200 ml) and dried over anhydrous magnesium sulfate. The solvent was then removed. The residue was recrystallized from ethanol/ether (1:1). The resulting compound had a m.p. of 86°-90° C. The yield was 25%.
Reaction SMILES: I[C:2]1[CH:28]=[CH:27][C:5]2[N:6]([CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]5[OH:24])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1.C(=O)([O-])[O-].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N>[Cu]I.CN(C=O)C>[N:29]1([C:2]2[CH:28]=[CH:27][C:5]3[N:6]([CH2:9][C:10]4[CH:26]=[CH:25][C:13]5[N:14]=[C:15]([NH:17][C@@H:18]6[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]6[OH:24])[S:16][C:12]=5[CH:11]=4)[CH:7]=[N:8][C:4]=3[CH:3]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(-n5ccnc5)ccc43)cc2s1
Temperature: 120 °C
Yield: 35.1 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (250 mg, 0.50 mmol) from Step 5 of Example 183, imidazole (80 mg, 1.18 mmol), potassium carbonate (82 mg, 0.59 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (9 mg, 0.063 mmol), copper (I) iodide (30 mg, 0.158 mmol) and DMF (2 mL) was heated at 120° C. for 3 h. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 20:1 DCM: MeOH, to afford (1R,2R)-2-((6-((5-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (78 mg, 35%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.18 (s, 1H), 7.91-7.96 (m, 2H), 7.72-7.86 (m, 3H), 7.47 (dd, J=8.4, 1.8 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.21 (dd, J=8.1, 1.5 Hz, 1H), 7.07 (d, J=1.2 Hz, 1H), 5.52 (s, 2H), 4.71 (d, J=5.1 Hz, 1H), 3.51 (m, 1H), 3.38 (m, 1H), 2.02 (m, 1H), 1.88 (m, 1H), 1.60-1.80 (m, 2H), 1.15-1.28 (m, 4H); LCMS (ESI) m/z 445 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:31])[N:14]([CH3:30])[C:15]([CH:24]([OH:29])[C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O>C(OC(C)(C)C)(=O)C.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[C:13](=[O:31])[N:14]([CH3:30])[C:15]([CH:24]([O:29][C:2]([CH3:7])([CH3:3])[CH3:1])[C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(O)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 206.2 %

Procedure:
A solution of methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (3.3 g, 4.53 mmol) in t-Butyl acetate (30 mL) was treated with perchloric acid (0.423 mL, 7.04 mmol) and the resultant was stirred at room temperature for 3 hours. The mixture was diluted with Ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-70% ethyl acetate/hexanes) to afford methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (2.3 g, 4.67 mmol, 73% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.43-7.47 (m, 3H) 7.37-7.41 (m, 1H) 7.32-7.35 (m, 4H) 7.01-7.05 (m, 1H) 5.92-5.96 (m, 1H) 5.83-5.88 (m, 2H) 5.21-5.24 (m, 1H) 3.82 (s, 3H) 3.67 (s, 3H) 0.96 (s, 9H); LCMS (m/z) ES+=493 (M+1).
Reaction SMILES: [NH:1]1CCCC[CH2:2]1.[NH2:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([OH:19])=[CH:13][C:9]=1[C:10](O)=[O:11].N1C=CC=NN=1>CO>[CH3:18][O:17][C:15]1[CH:16]=[C:8]2[C:9]([C:10]([OH:11])=[N:1][CH:2]=[N:7]2)=[CH:13][C:14]=1[OH:19]
Reactant: COc1cc(N)c(C(=O)O)cc1O
Reactant: C1CCNCC1
Agent: c1cnnnc1
Solvent: CO
Product: COc1cc2ncnc(O)c2cc1O
Reaction time: 6 h
Yield: 107.1 %

Procedure:
Piperidine (3 mL, 31 mmol) was added to a mixture of 2-Amino-5-hydroxy-4-methoxy-benzoic acid (8.1 g, 44.26 mmol) and triazine (5.38 g, 66.4 mmol) in MeOH (60 mL). The reaction was then heated to reflux and stir for 6 hours. The reaction was cool to 0oC. The product was isolated by filtration and washed with cold MeOH to give 6.37 g (33.2 mmol, 75%) of desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH:8]=[C:9]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)[CH:10]=1)=[O:4].[OH-].[Na+]>CO>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:7]1[CH:8]=[C:9]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2OC)cc(-n2cnnn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1cc(C(=O)O)cc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
A mixture of 2′-methoxy-5-tetrazol-1-yl-biphenyl-3-carboxylic acid methyl ester (8.6 g, 27.7 mmol), 3N aqueous NaOH (28.5 mL) and MeOH (28.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was filtered and the collected solid was partitioned between 1N aqueous HCl and methylene chloride. A white precipitate formed in the methylene chloride layer and was collected by filtration, washed with water and methylene chloride, and dried to give 4.2 g (46%) of 2′-methoxy-5-tetrazol-1-yl-biphenyl-3-carboxylic acid, MP=214.0-215.3° C., MS (M+H)=297.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=O)=[CH:10][CH:9]=1.O=S(Cl)Cl.[OH-].[Na+]>ClCCl.C(OCC)C>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([CH:12]2[NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4]2)=[CH:10][CH:9]=1
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.4 %

Procedure:
To a solution of 2-amino-2-methyl-propan-1-ol (59 g, 0.66 mol) in dichloromethane (120 mL) at 0° C. was added dropwise a solution of 4-chloro-benzoyl chloride (53 g, 0.3 mol) in dichloromethane (75 mL). The resulting mixture was stirred at r.t. for 2.5 h, then filtered and the filtrate was concentrated. Then SOCl2 (120 g, 1 mol) was added dropwise. The mixture was stirred at room temperature for overnight, then diluted with ethyl ether (150 mL). The resulting mixture was cooled in an ice bath, neutralized with aqueous NaOH (20%). The organic layer was separated, and aqueous layer was extracted with ethyl ether for 3 times. The organic lays were combined and washed with water twice, dried over anhydrous Na2SO4 and concentrated. The residue was distilled in vacuo to give the title product (25 g) as oil.
Reaction SMILES: [C:1]([O:5]O)([CH3:4])([CH3:3])[CH3:2].[C:7]([O:12]C)([CH2:10][CH3:11])([CH3:9])[CH3:8]>>[C:7]([O:12][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH2:10][CH3:11])([CH3:8])[CH3:9]
Reactant: CCC(C)(C)OC
Reactant: CC(C)(C)OO
Product: CCC(C)(C)OOC(C)(C)C

Procedure:
In similar manner, although optimal conditions may vary, hydrogen peroxide may be reacted with methyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with methyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with ethyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with ethyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with ethyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with n-propyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with n-propyl t-amyl ether to provide t-amyl hydroperoxide or di t-amyl peroxide; or with n-propyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide. Illustrative of reactions employing hydroperoxide reactants are the reaction of t-butyl hydroperoxide with methyl t-butyl ether to provide di-t-butyl peroxide; the reaction of t-hexyl hydroperoxide with methyl t-hexyl ether to provide di-t-hexyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-amyl ether to provide t-butyl t-amyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-hexyl ether to provide t-butyl t-hexyl peroxide; and the reaction of t-amyl hydroperoxide with ethyl t-hexyl ether to provide t-amyl t-hexyl peroxide.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][CH2:7][C@H:3]1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.[C:41]1([CH2:51][NH2:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1>ClCCl>[CH3:1][N:2]1[C:9](=[O:10])[CH2:8][CH2:7][C@H:3]1[C:4]([NH:52][CH2:51][C:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[CH:43][CH:42]=1)=[O:6]
Reactant: NCc1cccc2ccccc12
Reactant: CN1C(=O)CC[C@H]1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1C(=O)CC[C@H]1C(=O)NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-methyl-5-oxoproline (0.050 g, 0.35 mmol, prepared in a manner analogous to that described above for example 51), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.081 g, 0.42 mmol), 1-hydroxybenzotriazole (0.057 g, 0.42 mmol), N-ethyl morpholine (0.166 ml, 1.05 mmol) and (1-naphthalenylmethyl)amine were combined in dichloromethane (˜8 ml) and the mixture was stirred for ˜20 hrs at room temperature. The mixture was then washed with 2M aqueous hydrogen chloride (5 ml) and the organic layer was separated using a phase separator. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, separated as before, and then evaporated. The residue was purified by mass-directed automated HPLC to give pure 1-methyl-N-(1-naphthalenylmethyl)-5-oxoprolinamide as a white solid (0.062 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][C@@H:16]([C:19]([O:21]C)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][C@@H:16]([C:19]([OH:21])=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1CC[C@H](N2CCN(c3ccc(Cl)cc3)CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1CC[C@H](N2CCN(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.6 %

Procedure:
To a stirred solution of (1R,3S)-methyl 3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentanecarboxylate (1.5 g, 4.65 mmol) in tetrahudrofuran:water (4:1) was added a solution of lithium hydroxide monohydrate (0.58 g, 13.94 mmol) in 5 ml water. Reaction mixture was allowed to stir at room temperature for 20 h. Upon completion, the reaction mixture was concentrated under reduced pressure to remove tetrahudrofuran. The resulting residue was diluted with 10 ml of water followed by washing with diethyl ether (3×20 ml). The aqueous layer was acidified at 0° C. with 1N hydrochloric acid to pH 6-7 and the mixture was extracted with ethyl acetate (2×50 ml). The organic layer was separated and dried over sodium sulphate and concentrated under reduced pressure to obtain (1R,3S)-3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentanecarboxylic acid (1.0 g, 69.7%).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:17]1([CH3:30])[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1>C(OCC)C>[SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:16])[C:13]([N:27]3[CH2:28][CH2:29][CH:24]([O:23][C:20]4[CH:21]=[CH:22][C:17]([CH3:30])=[CH:18][CH:19]=4)[CH2:25][CH2:26]3)=[O:15])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)C(=O)Nc1ccc2nc(S)[nH]c2c1
Solvent: CCOCC
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4nc(S)[nH]c4c3)CC2)cc1

Procedure:
The title compound is prepared from N-(2-mercapto-3H-benzimidazol-5-yl)-oxalamic acid (Example 60b) and 4-p-tolyloxy-piperidine according to the method described in Example 1c. Melting Point: 311-314° C. (diethylether)
Reaction SMILES: P([O-])(OCC)(SCC)=[S:2].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[CH2:31][N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]#[N:39])[C:33]2=[O:40])=[CH:13][C:12]=1[F:41].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.O>C(OCC)(=O)C.Cl.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[C:38]([C:34]1[C:33](=[O:40])[N:32]([CH2:31][C@H:18]2[C@H:17]([C:14]3[CH:15]=[CH:16][C:11]([Cl:10])=[C:12]([F:41])[CH:13]=3)[O:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:19]2)[CH:37]=[CH:36][CH:35]=1)(=[S:2])[NH2:39]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2cccc(C#N)c2=O)C1
Reactant: CCOP([O-])(=S)SCC
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](Cn2cccc(C(N)=S)c2=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
Diethyl dithiophosphate (0.189 mL, 1.13 mmol) was added to a solution (5 mL, 20.00 mmol) of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-[(3-cyano-2-oxopyridin-1(2H)-yl)methyl]-1,4-oxazepane-4-carboxylate (348 mg, 0.75 mmol) in 4 N hydrogen chloride-ethyl acetate. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 ml), and di-tert-butyl dicarbonate (0.210 mL, 0.90 mmol) was added. The reaction mixture was stirred at room temperature for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (225 mg, 0.454 mmol, 60.2%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[C:26](O)(=[O:30])[CH2:27][CH2:28][CH3:29]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CCCC(=O)O
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, light yellow solid (12.9 mg, 46%), MS (ISP) m/z=401.4[(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.07 mmol) and butyric acid
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[C@H:21]([C:22]([OH:24])=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (8.0 g, 13.3 mmol) was suspended in 30 mL DCM and 1R-2S-5R (−)-menthol (26.6 mmol), EDC (26.6 mmol) and DMAP (cat.) added. The mixture was stirred at r.t. for 6 h and the mixture was diluted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue purified over silica with hexanes-EtOAc gradient (0% EtOAc to 30%) to provide (3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 741R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl) ester (2.4 g, 1H NMR (400 MHz, CDCl3): 8.2 (m, 1H), 7.5 (m, 1H), 7.42 (d, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 6.9 (m, 2H), 6.7 (m, 1H), 6.6 (s, 1H), 5.55 (m, 1H), 4.8-5.1 (m, 1H), 5.0 (s, 2H), 4.3-4.6 (m, 3H), 3.1 (m, 2H), 1.8 (m, 1H), 1.6 (m, 3H), 1.5 (d, 9H), 1.3 (m, 2H), 0.7-1.0 (m, 9H), 0.4 (m, 3H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[F:28][C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[C:29]([F:28])=[CH:35][CH:34]=[CH:33][C:32]=1[F:36])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Nc1c(F)cccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(CNc1c(F)cccc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 30.6 %

Procedure:
17.0 g of sodium triacetoxyborohydride (80.0 mmol) was added to a solution of 15.0 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (80.0 mmol), 5.16 g of 2,6-difluoroaniline (40.0 mmol) and 2.09 ml of acetic acid (40.0 mmol) in methylene chloride (400 ml) under ice-cooling, and the mixture was stirred at room temperature for 19 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=20/1-10/1) to obtain 3.68 g of the title compound (yield: 31%).