Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH:15]([NH2:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:42][CH:43]([Cl:47])[C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[Cl:42][CH:43]([Cl:47])[C:44]([NH:20][C@H:15]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:22][CH2:23][N:24]2[C@H:29]3[CH2:30][CH2:31][C@@H:25]2[CH2:26][CH:27]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[CH2:28]3)[CH2:9][CH2:10]1)=[O:21])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:45]
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(N)C(C)(C)C)CC1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)C(Cl)Cl)C(C)(C)C)CC1
Yield: 59.6 %

Procedure:
2,2-dichloro-N-{(1S)-1-[(4-(3-fluorophenyl-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}carbamate, example 915, (0.591 g, 0.90 mmol) with HCl as outlined in the procedure for Example 890 to form (2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.500 g, 99%). 2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Dichloro-acetyl chloride (0.013 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2-dichloro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl) carbonyl]-2,2-dimethylpropyl}acetamide (0.036 g, 60%) as an oil. ES-LCMS m/z 670 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@@:11]3([CH3:25])[N:12]=[C:13]([NH:16]C(=O)C4C=CC=CC=4)[S:14][CH2:15][C@H:10]3[CH2:9][O:8][C:6]=2[CH:7]=1.N1C=CC=CC=1.CO[NH3+].[Cl-]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@@:11]3([CH3:25])[N:12]=[C:13]([NH2:16])[S:14][CH2:15][C@H:10]3[CH2:9][O:8][C:6]=2[CH:7]=1
Reactant: C[C@]12N=C(NC(=O)c3ccccc3)SC[C@H]1COc1cc(F)ccc12
Agent: CO[NH3+]
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: C[C@]12N=C(N)SC[C@H]1COc1cc(F)ccc12
Temperature: 50 °C
Yield: 70.2 %

Procedure:
A mixture of rel-N-((4aR,10bS)-8-Fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-yl)benzamide from step F5 (1.27 g, 3.56 mmol), pyridine (1.0 mL, 12.36 mmol), and hydroxylamine methyl ether hydrochloride (1.0 g, 12.0 mmol) in ethanol (100 mL) was heated at 50° C. for 24 h. The mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using silica gel column chromatography (5-10% MeOH/dichloromethane) to afford rel-(4aR,10bS)-8-fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-amine (644 mg, 2.50 mmol, 70% yield) as a viscous yellow oil. LCMS (M+H)+=253.1. 1H NMR (500 MHz, chloroform-d) δ 7.59 (dd, J=8.8, 6.6 Hz, 1H), 6.73-6.65 (m, 1H), 6.51 (dd, J=10.1, 2.6 Hz, 1H), 4.40 (dd, J=11.4, 2.8 Hz, 1H), 4.21 (dd, J=11.4, 5.7 Hz, 1H), 3.15-3.02 (m, 2H), 2.14 (dddd, J=8.4, 5.7, 3.7, 2.9 Hz, 1H), 1.60 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH2:12]2)=[C:7](Br)[N:6]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(Cl)Cl.[Pd](Cl)Cl.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH2:12]2)=[C:7]([C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:15])[CH:21]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C2CC2)c(Br)n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Temperature: 110 °C
Reaction time: 12 h
Yield: 69.5 %

Procedure:
6-Bromo-5-cyclopropyl-pyridine-2-carboxylic acid methyl ester (0.1 g, 0.4 mmol), 3-chlorophenylboronic acid (CAN 63503-60-6, 0.08 g, 0.5 mmol), 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride methylene chloride adduct (CAN 95464-05-4, 50 mg) and cesium carbonate (CAN 534-17-8, 0.2 g, 0.6 mmol) was added into 1,4-dioxane (10 mL) under nitrogen atmosphere. The mixture was stirred for 12 h at 110° C. Subsequently, the mixture was concentrated to give crude product. The crude product was purified by a flash column chromatography (silica gel, 5 g, 20% ethyl acetate in petroleum ether) to give product (80 mg, 71%); MS: (EI) m/e 288.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][NH:3][C:4](=[O:31])[CH2:5][NH:6][C:7](=[O:30])[CH2:8][C@H:9]1[CH2:20][CH2:19][C:18]2[S:17][C:16]3[N:15]=[CH:14][N:13]=[C:12]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([NH:28][CH3:29])[CH2:24][CH2:23]4)[C:11]=3[C:10]1=2.C=O.[C:34]([BH3-])#N.[Na+]>CO>[CH3:29][N:28]([CH3:34])[CH:25]1[CH2:24][CH2:23][CH:22]([O:21][C:12]2[C:11]3[C:10]4[C@@H:9]([CH2:8][C:7]([NH:6][CH2:5][C:4]([NH:3][CH3:2])=[O:31])=[O:30])[CH2:20][CH2:19][C:18]=4[S:17][C:16]=3[N:15]=[CH:14][N:13]=2)[CH2:27][CH2:26]1
Reactant: CNC(=O)CNC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(NC)CC4)c3c21
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNC(=O)CNC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N(C)C)CC4)c3c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A solution of N-methyl-2-[2-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]acetamido]acetamide hydrochloride (105 mg, 0.22 mmol, 1.00 equiv) in 5 mL of methanol was added formaldehyde (37%, 1.0 mL) at room temperature under nitrogen for 1 h. Then sodium cyanoborohydride (59 mg, 0.97 mmol, 4.32 equiv) was added and stirred overnight at ambient temperature. The solvent was removed under reduced pressure and the crude product (100 mg, crude) was purified by preparative HPLC under the following conditions (SHIMADZU): column: SunFire Prep C18, 19*150 mm 5 um; mobile phase: water with 0.05% NH4CO3 and CH3CN (6.0% CH3CN up to 50.0% in 25 min); UV detection at 254/220 nm. The product containing fractions were collected and evaporated to remove the water and CH3CN to give 2-[2-[(3R)-12-[[4-(dimethylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetamido]-N-methylacetamide (40 mg) as a white solid. MS: m/z 446 [M+H]+. 1H NMR (300 MHz, CD3OD) δ 8.37 (s, 1H), 5.20-5.12 (m, 1H), 3.74-3.68 (m, 3H), 3.20-2.84 (m, 3H), 2.65-2.47 (m, 4H), 2.36-2.17 (m, 11H), 1.95 (d, 2H), 1.59-1.51 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:14][CH2:13]3)[N:9]=[C:10]([C:34]3[CH:33]=[CH:32][C:31]([NH:45][C:46]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:52])=[C:30]([O:29][CH3:28])[CH:35]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(C3CCN(C(=O)OCc4ccccc4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Temperature: 75 °C
Reaction time: 16 h
Yield: 95.9 %

Procedure:
A mixture of benzyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (7.0 g, 0.0146 mol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (6.15 g, 0.0176 mol), tetrakis(triphenylphosphine)palladium (1.0 g, 0.000876 mol) and sodium carbonate (3.9 g, 0.0365 mol) in ethylene glycol dimethyl ether (170 mL) and water (70 mL) was heated at 75° C. for 16 hours under an atmosphere of nitrogen. After addition of tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (6.15 g, 0.0176 mol, 1.2 eq.) and tetrakis(triphenylphosphine)palladium (1.0 g, 0.000876 mol) the mixture was stirred at 85° C. for additional 16 hours. The mixture was allowed to cool to ambient temperature and ethylene glycol dimethyl ether was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 20%-40% ethyl acetate/dichloromethane followed by 2%-5% methanol/dichloromethane as a mobile phase to give benzyl 4-(4-amino-3-{4-[(tert-butoxycarbonyl)amino]-3-methoxyphenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (8.0 g, 0.014 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 12.6 min. MS: MH+ 574.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[NH:10][C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([O-:24])=[O:23]>O1CCOCC1.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.[Pd]>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([C:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[NH:10][C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1[nH]c2cccnc2c1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c2cccnc2c1-c1ccc([N+](=O)[O-])cc1
Yield: 22.5 %

Procedure:
3 g of potassium carbonate and 0.8 g of palladium tetrakis(triphenylphosphine) are added to a solution of 2 g of ethyl 3-bromo-1H-pyrrolo[3,2-b]pyridine-2-carboxylate and 1.5 g of 4-nitrophenylboronic acid in 50 ml of dioxane. The mixture is refluxed for 20 hours, and then filtered. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a silica column, elution being carried out with a mixture of cyclohexane and ethyl acetate (50/50 by volume), to give 0.52 g of ethyl 3-(4-nitrophenyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([NH:12][C:13](=[O:16])[CH:14]=[CH2:15])O.CC(C)=O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:1][C:2]1[C:3]([OH:9])=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:10][NH:12][C:13](=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)NCO
Reactant: Cc1ccc(O)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: C=CC(=O)NCc1cc(C)cc(C)c1O
Yield: 84.9 %

Procedure:
A flask equipped with a condenser and a stirrer was charged with 122 g of 2,4-dimethylphenol, 101 g of N-methylolacrylamide, 1.80 g of p-toluenesulfonic acid and 100 ml of acetone, and the mixture was reacted at 60° C. for 60 minutes with stirring. The obtained reaction mixture was poured into excess water to separate an organic layer. The organic layer was dissolved in 200 ml of methylene chloride, which was washed with three 100 ml portions of water to give 174 g of N-(3,5-dimethyl-2-hydroxybenzyl)acrylamide.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](OC)=[O:7].[H-].C([Al+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: OCc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 3-(bromomethyl)benzoate (10.0 g) in toluene (100 mL) was added a 1.5 M solution (100 mL) of diisobutylaluminum hydride in toluene at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added methanol at 0° C., and the resulting white precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure to give a crude product of the title compound (8.83 g) as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[C:6]([S:19]C#N)=[CH:7][C:8]([CH3:18])=[C:9]([O:11][S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].SC[C@H]([C@@H](CS)O)O.OP([O-])(O)=O.[K+]>CCO>[C:1]([C:5]1[C:6]([SH:19])=[CH:7][C:8]([CH3:18])=[C:9]([O:11][S:12](=[O:16])(=[O:17])[N:13]([CH3:14])[CH3:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1OS(=O)(=O)N(C)C
Agent: O=P([O-])(O)O
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CCO
Product: Cc1cc(S)c(C(C)(C)C)cc1OS(=O)(=O)N(C)C

Procedure:
To a round bottom flask equipped with a magnetic stirrer and condenser were added 1.1 g (3.3 mmol) of dimethyl-sulfamic acid 5-tert-butyl-2-methyl-4-thiocyanato-phenyl ester (prepared in Example SSS), dithiothreitol (1.29 g, 8.35 mmol), EtOH (40 mL), and 0.02M KH2PO4 buffer solution (5 mL), respectively. The reaction was refluxed overnight. The mixture was then quenched with H2O (250 mL) and extracted with a 1:1 mixture of hexanes:Et2O. The organic layer was again washed with H2O and brine, dried (MgSO4) and concentrated. The residue was dried under high vacuum to yield the title compound. 1H NMR (CDCl3) δ 1.45 (s, 9 H), 2.25 (s, 3 H), 3.02 (s, 6 H), 3.57 (s, 1 H), 7.01 (s, 1 H), 7.28 (s, 1 H).
Reaction SMILES: CCOCC.[CH3:6][O:7][C:8]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C@H:12]1[CH2:14][O:13]1.CNC.B.O>C(Cl)Cl>[CH3:6][O:7][C:8]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:9]=1[O:10][CH2:11][C@H:12]([OH:13])[CH3:14]
Reactant: COc1cc([N+](=O)[O-])ccc1OC[C@H]1CO1
Agent: B
Agent: CNC
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc([N+](=O)[O-])ccc1OC[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To 160 mL of Et2O cooled to 0° C. was added LiClO4 (80 g; 752 mmol) in portions over 20 min. The mixture was allowed to warm to rt and (R)-2-((2-methoxy-4-nitrophenoxy)methyl)oxirane (9.55 g; 42.5 mmol) was added. The suspension was stirred for 10 min, borane dimethylamine (3.40 g; 46.6 mmol) was added and the suspension was stirred at rt for 2.5 h. The suspension was diluted with CH2Cl2 and stirred in a beaker with H2O until gas evolution ceased. The organic layer was washed with H2O, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was triturated in CH2Cl2, filtered and the filtrate purified by flash chromatography (silica gel, Hexanes/EtOAc; 100:0 to 100:0 gradient) to afford 6.83 g (70%) of the title compound as a yellow solid. 1H NMR (CDCl3) δ 1.31 (d, J=6.59 Hz, 3H), 2.77 (br s, 1H), 3.90-3.94 (m, 4H), 4.05-4.08 (m, 1H), 4.24-4.32 (m, 1H), 6.92 (d, J=9.35 Hz, 1H), 7.74 (d, J=2.75 Hz, 1H), 7.88 (dd, J=8.79 Hz, 2.74 Hz, 1H); 13C NMR (CDCl3) δ 18.64, 56.18, 65.87, 74.85, 106.73, 111.66, 117.60, 141.76, 149.20, 153.63; HPLC (Method #1) 2.17 min retention time; LCMS (ES): m/z 228 [M+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@H:25]([CH2:54][C:55]3[CH:60]=[C:59]([C:61]([F:64])([F:63])[F:62])[C:58]([NH2:65])=[C:57]([Cl:66])[CH:56]=3)[C:26]([N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:39][CH2:38][CH:37]([N:40](C(OCC)=O)[CH2:41][C:42]([O:44][C:45](C)(C)[CH3:46])=[O:43])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)=[O:27])=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:67]=[CH:68][CH:69]=[CH:70][C:11]=2[NH:10]1>C(Cl)Cl>[O:8]=[C:9]1[N:15]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C@H:25]([CH2:54][C:55]3[CH:60]=[C:59]([C:61]([F:62])([F:63])[F:64])[C:58]([NH2:65])=[C:57]([Cl:66])[CH:56]=3)[C:26]([N:28]3[CH2:29][CH2:30][CH:31]([N:34]4[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:36][CH2:35]4)[CH2:32][CH2:33]3)=[O:27])=[O:23])[CH2:20][CH2:21]2)[CH2:14][CH2:13][C:12]2[CH:67]=[CH:68][CH:69]=[CH:70][C:11]=2[NH:10]1
Reactant: CCOC(=O)N(CC(=O)OC(C)(C)C)C1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CNC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
0.5 mL TFA were added to a solution of 330 mg (0.36 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(tert-butoxycarbonyl-ethoxycarbonyl-methylamino)-1,4′-bipiperidinyl-1′-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 5 mL DCM cooled to 0° C. and the reaction mixture was stirred overnight at RT. It was evaporated down i. vac. and the residue was purified by HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([OH:23])=[O:21])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: Cc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: Cc1ccc2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10](O)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>C(Cl)Cl.C(OCC)(=O)C.O>[N:29]([CH:10]([C:4]1[CH:5]=[C:6]([Cl:9])[C:7]([CH3:8])=[C:2]([Br:1])[C:3]=1[O:13][CH3:14])[CH3:11])=[N+:30]=[N-:31]
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1Br
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C(C)N=[N+]=[N-])cc(Cl)c(C)c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol (13.4 g, 47.9 mmol) in methylene chloride (150 mL), cooled at 0° C. was added N,N-diisopropylethylamine (14 mL, 80 mmol) followed by methanesulfonyl chloride (5.5 mL, 71 mmol). The mixture was stirred for 1 hour at 0° C. Water (100 mL) was added while cold. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. The resulting crude mesylate was dissolved in N,N-dimethylformamide (140 mL) and sodium azide (6.2 g, 96 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine, dried over MgSO4, filtered and concentrated. The residue was purified on silica gel (eluting with 0-30% of ethyl acetate in hexanes) to afford the desired product (12.2 g, 82%). LCMS calculated for C10H11BrClO (M−N3)+: m/z=261.0, 263.0. found: 261.0, 263.0.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1I)=O)C1C=CC=CC=1.[CH:29]1[CH2:33][CH2:32][CH2:31][CH:30]=1.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CC([O-])=O.CC([O-])=O.[Pd+2].CO.CCOC(C)=O.CCCCCC.CCN(CC)CC>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C@@H:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH2:11])=[C:15]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:16]=1
Reactant: C1=CCCC1
Reactant: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1I)NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)[C@@H](N)Cc1ccc(N)cc1C1CCCC1
Reaction time: 24 h

Procedure:
According to example 151, 1.65 g of ethyl N-((benzyloxy)carbonyl)-2-iodo-4-nitro-L-phenylalaninate was subjected to Heck coupling with 20 mL of cyclopentene using 60 mL of toluene, 0.074 g of Pd(OAc)2, 0.20 g of tri-ortho-tolylphosphine, and 0.51 mL of Et3N. The reaction was carried out at 110° C. for 24 h. Analysis of the crude product by tlc (SiO2, 8:2 hexane:EtOAc) indicated a major product at Rf =0.40 and minor components at Rf =0.38, 0.60, and 0.95. The Rf =0.40 material was isolated by flash chromatography on silica gel (8:2 hexane:EtOAc). This afforded 1.03 g (71%) of the desired olefin mixture as a clear liquid. This material was subjected to catalytic hydrogenation at 45 psi for 18 h using 55 mL of MeOH and 0.25 g of 10% Pd(C). The crude product was purified by flash chromatography (SiO2, 99:1 EtOAc:MeOH) to give 0.56 g (61% for both steps) of ethyl 4-amino-2-cyclopentyl-L-phenylalaninate as a thick transparent oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH2:10][C:11](O)([CH2:13][O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:27]3[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:32]=3)[CH:10]=[C:11]([CH2:13][O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(COCc3ccc4ccccc4n3)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(COCc3ccc4ccccc4n3)nc2-c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(2-quinolylmethoxy)methyl]-4,5-dihydro-1H-imidazole (1 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in toluene (70 mL) is heated to reflux for 48 hours. The reaction mixture is cooled and the solvent removed under reduced pressure. The crude residue is redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture is purified by chromatography on silica gel using hexane/ethyl acetate to give 2-(4-chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-4-[(2-quinolylmethoxy)methyl)-1H-imidazole.