Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>CO>[ClH:19].[CH3:18][O:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COCCOC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COCCOC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methoxyethoxy)-piperidine-1-carboxylic acid tert-butyl ester (Preparation 81, 114 mg, 0.44 mmol) in methanol (3 mL) was added 4M HCl in dioxane (550 μL, 2.20 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude residue dissolved in water (10 mL). The aqueous solution was extracted with ethyl acetate (2×10 mL) then concentrated in vacuo. Purification by trituration in ethyl acetate gave the title compound as the hydrochloride salt. δH (CD3OD): 3.74-3.67 (1H, m), 3.64 (2H, m), 3.56 (2H, m), 3.40-2.39 (7H, m), 2.11-1.96 (2H, m), 1.93-1.83 (2H, m).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+:28]>C(O)C>[Na+:28].[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([O-:26])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reaction time: 0.08 h

Procedure:
A mixture of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (3.2 g) in 95% ethanol (700 mL) was heated at reflux and 1N sodium hydroxide (15 mL) was added dropwise. Heating was continued for five minutes and the resulting mixture was chilled in ice, filtered, washed with water and dried at 80° C. over phosphorus pentoxide at 0.1 mm to give 3.2 g of colorless 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alphaoxobenzeneacetic acid sodium salt, mp>295° C. with decomposition.
Reaction SMILES: [CH:1]([N:4]([CH:9]1[CH:14]=[C:13]([CH3:15])[CH2:12][CH2:11][CH:10]1[C:16]#[N:17])[C:5](OC)=[O:6])([CH3:3])[CH3:2].[OH-:18].[Na+].OO>C(O)C>[CH:1]([N:4]1[CH:9]2[CH:10]([CH2:11][CH2:12][C:13]([CH3:15])=[CH:14]2)[C:16](=[O:18])[NH:17][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: COC(=O)N(C(C)C)C1C=C(C)CCC1C#N
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CC1=CC2C(CC1)C(=O)NC(=O)N2C(C)C

Procedure:
To a solution of 100 g 2-(N-isopropyl-N-carbomethoxyamino)-4-methyl-3-cyclohexene-nitrile in 700 ml 95% ethanol are added 90 ml of concentrated aqueous sodium hydroxide. To this mixture are added dropwise within 4 hours under stirring and at an internal temperature of 40° 600 ml 40% hydrogen peroxide. Stirring is continued over night at room temperature. The reaction mixture is concentrated in vacuo and the residue treated with water and toluene. The water layer is extracted twice with toluene and the combined toluene extracts are washed with water and evaporated in vacuo to give the title compound.
Reaction SMILES: CC(OC([NH:8][C@@H:9]([CH2:14][CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:25]1([CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[CH2:15][CH2:14][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[N:8]=3)=[CH:18][CH:19]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3)cc2)=N1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
To a solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-oxo-5-{4-[(phenylmethyl)oxy]phenyl}pentanoate (D2, 323 mg, 0.75 mmol) in dry DCM (4 ml) at 0° C., under nitrogen atmosphere, was added trifluoroacetic acid (1 ml) dropwise. The resulting pale pink solution was allowed to warm to room temperature over 1 hour, then it was evaporated under vacuum, affording the title compound (D3, 291 mg, 0.68 mmol, 91%) as a greenish oil which may be used in the next step without further purification; MS: (ES/+) m/z: 310 [MH]); C19H19NO3 requires 309; Rt (HPLC): 3.69 min.
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12])=[O:6])(=O)C.[C:36](Cl)(=O)OCOC(=O)C(C)C>ClCCl>[O:33]=[S:30]1(=[O:34])[CH2:31][CH2:32][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH:11]([CH3:36])[CH3:12])=[O:6])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:28][CH2:29]1
Reactant: CC(C)C(=O)OCOC(=O)Cl
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Solvent: ClCCl
Product: CC(C)C(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 91 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (344.1 mg, 1.00 mmol), dichloromethane (9 mL) and isobutyroyloxymethyl carbonochloridate (7c) gave the titled product in 91% yield (446.3 mg, 0.92 mmol). 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H), 7.23 (t, 1H), 7.16 (dd, 1H), 5.73 (q, 2H), 5.28 (t, 1H), 4.80 (sept, 1H), 4.05 (t, 1H), 3.79 (dd, 1H), 3.67 (ddd, 1H), 3.57 (dt, 1H), 3.12-3.19 (m, 4H), 3.09 (dt, 1H), 2.55 (sept, 1H), 2.34-2.46 (m, 2H), 2.15-2.22 (m, 2H), 1.14 (dd, 6H). MS-APCI (m/z+): 487 (M+H).
Reaction SMILES: O[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].CN(C=O)C.O=P(Cl)(Cl)[Cl:30]>C(Cl)Cl>[Cl:30][C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(O)c(F)cn2c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Under nitrogen, ethyl 8-hydroxy-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (7A, 1.52 g, 5 mmol) was dissolved in methylene chloride (10 mL), and treated with DMF (0.73 g, 10 mmol) and POCl3 (1.53 g, 10 mmol). After stirring overnight, the mixture was poured into 10 mL of ice water. The organic layer was separated, and the aqueous layer was extracted with methylene chloride (10 mL×2). The organic layers were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered and concentrated to give the crude product which was chromatographed (silica gel, 50% ethyl acetate/hexane) to give the title compound (IIA, 1.3 g, 80%). 1H NMR (300 MHz, CDCl3): δ0.75 (m, 2H), 1.08 (m, 2H), 1.42 (t, 3H), 2.30 (m, 1H), 3.19 (s, 3H), 4.42 (q, 4H), 8.39 (s, 1H), 9.43 (d, 1H): MS (DCI/NH3) m/e 324 (M+H)+. Anal. Calcd for C16H15ClFNO3 : C, 59.35; H, 4.67; N, 4.32. Found C, 59.68; H, 4.76; N, 4.22.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].I[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[CH:34][CH:33]=1.C(OCC)(=O)C>CN(C=O)C>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[CH:33][CH:34]=1)(=[O:42])[CH2:39][CH2:40][CH3:41]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: CCCC(=O)c1ccc(OCCOCCOCCI)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(=O)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 48.8 %

Procedure:
Di-tert-butyliminodicarboxylate (3.05 g, 14.07 mmol) and potassium tert-butoxide (1.58 g, 14.07 mmol) were stirred in DMF (50 mL) for 15 minutes followed by the addition of 1-(4-(2-(2-(2-iodoethoxy)ethoxy)ethoxy)phenyl)butan-1-one (43; 3.81 g, 9.38 mmol). The resulting mixture was stirred under nitrogen for 18 hours, and then poured into 200 mL of ethyl acetate. This solution was washed with water (2×) and sat. brine, dried over sodium sulfate, and concentrated to afford a liquid that was purified by flash silica gel column chromatography, eluting with 3:1 hexanes/ethyl acetate to afford 44 (2.27 g, 49%) as a clear oil: MS (ES+) m/z 496.2 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: CS(=O)(=O)Cl
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)nc2)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
1-(2-Chloro-phenyl)-5-[6-(piperazin-1-yl)-pyridin-3-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 357, methanesulfonyl chloride (7.0 uL, 0.09 mmol), and triethylamine (41.0 uL, 0.30 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][N:21]([CH3:34])S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][CH3:34])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CN(C[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1

Procedure:
The crude 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{methyl[(2-nitrophenyl)sulfonyl]amino}butanoate from the previous step (31.8 g), phenyl hydrosulfide (1.5 equiv., 10.32 g, 94 mmol), and K2CO3 (325 mesh, 3 equiv., 25.9 g, 188 mmol) in DMF (100 mL) were stirred at room temperature for 30 min. The reaction mixture was diluted with H2O (300 mL) and extracted with Et2O (4×). The organic extracts were washed with H2O, and 10% aq. Na2CO3, dried, and concentrated to give the titled product which contaminated with the 2-nitrophenyl phenyl sulfide by product (31.7 g). This contaminated product was used directly in the next step.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17]([N:19]1[CH2:27][CH2:26][CH2:25][C:21]2([NH:24][CH2:23][CH2:22]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[N:24]1([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[C:21]2([CH2:25][CH2:26][CH2:27][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20]2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCCC2(CCN2)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CCN2C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of benzyl chloroformate (0.148 mL, 1.039 mmol) in DCM (1 mL) was added to a mixture of tert-butyl-1,6-diazaspiro[3.5]nonane-6-carboxylate (200 mg, 0.866 mmol) and DIPEA (0.378 mL, 2.165 mmol) in DCM (3 mL) and the mixture was stirred at RT for 16 h. The solvent was evaporated off under reduced pressure and the crude product was purified by flash chromatography (Silica gel column, 4 g, n-hexane/DCM from 20% to 100% DCM) to give the title product as a yellow resin. UPLC-MS (Condition 3) tR=1.21 min, m/z=361.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Cl[CH2:25][C:26]([C:28]1[O:29][CH:30]=[CH:31][C:32]=1[CH2:33][O:34][CH3:35])=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[O:29][CH:30]=[CH:31][C:32]=1[CH2:33][O:34][CH3:35])=[O:27]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: COCc1ccoc1C(=O)CCl
Product: COCc1ccoc1C(=O)c1[nH]c2cc(Cl)ccc2c1CC(=O)OC

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(penylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-chloroacetyl-3-(methoxymethyl)furan*.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:20]([N-]C(C)C)(C)C.[Li+].IC.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[C:9]([CH3:20])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(I)c2c(Cl)ncnc2n1COCC[Si](C)(C)C
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a −78° C. solution of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (15.0 g, 36.6 mmol) in tetrahydrofuran (500 mL) was added lithium diisopropylamide (2 M solution in heptane/tetrahydrofuran/ethylbenzene, 183 mL, 366 mmol), and the reaction mixture was stirred at −20° C. for 2 hours, then re-cooled to −78° C. Iodomethane (52.1 g, 367 mmol) was added at −78° C., and the reaction mixture was allowed to stir at −20° C. for 2 hours. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water (100 mL) and with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via chromatography on silica gel (Eluent: 10:1 petroleum ether/ethyl acetate) afforded the product as a yellow oil. Yield: 10 g, 24 mmol, 66%. LCMS m/z 424.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 5.69 (s, 2H), 3.48-3.54 (m, 2H), 2.60 (s, 3H), 0.88-0.95 (m, 2H), −0.05 (s, 9H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[C:42]([N:22]1[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]2[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[CH2:10][CH:9]([N:8]2[C:7]4[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=4[N:5]=[C:4]2[CH3:3])[CH2:15]3)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a stirred solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (0.53 g, 1.06 mmol) in dichloromethane (10 mL) and triethylamine (0.32 g, 3.18 mmol) was added benzoyl chloride (0.156 g, 1.11 mmol) at 0° C. The ice bath was then removed and the mixture allowed to stir for 30 min. The solvents were then removed in vacuo and the resulting solid was partitioned between ethyl acetate and water (3×). The organic layer was dried with magnesium sulfate and the solvent removed in vacuo, yielding crude 17, which was them purified using the supercritical fluid chromatography, resulting in 525 mg of pure 1-{(1R,5S)-8-[2-(1-benzoyl-4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methyl-1H-benzimidazole 17 (yield 93%). 1H NMR (400 MHz, CDCl3) δ 7.20 (1H, m), 6.94 (7H, m), 6.82 (4H, m), 6.70 (2H, m), 4.15 (1H, m), 3.75 (1H, m), 3.11 (1H, m), 2.98 (4H, m), 2.93 (1H, m), 2.78 (3H, m), 2.05 (3H, s), 2.04 (2H, m), 1.88 (3H, m), 1.70 (1H, m), 1.59-1.24 (4H, m), 1.14 (2H, m). HRMS m/z (M+H)+Calc 533.3280; (M+H)+Obs 533.3300.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[S:27]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].N1CCCCC1>CO>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])/[C:8](=[CH:46]/[C:39]3[C:40]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=4)(=[O:29])=[O:28])[CH:38]=3)/[O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.488 g, 1.35 mmol) obtained in Example A40, Step 1 in methanol (5 mL) was added with 1-tosyl-1H-indole-3-carboxaldehyde (0.404 g, 1.35 mmol) obtained in Example A33, Step 1 and piperidine (0.0115 g, 0.135 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, and then added with methanol (2 mL), and the precipitated solid was suspended in methanol and thereby washed. The reaction mixture was filtered to obtain tert-butyl (Z)-4-({6-methoxy-3-oxo-2-[(1-tosyl-1H-indol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.485 g, 55%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+]>CO>[OH:11][CH2:10][CH2:9][O:8][C:7]1[C:2]([O:13][CH3:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[O-]
Reactant: OCCOc1cccnc1Br
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1OCCO
Yield: 44.7 %

Procedure:
A mixture of the product obtained in Step 1 (2.33 g, 10.7 mmol) and NaOMe (0.634 mg, 11.8 mmol) in MeOH (50 mL) was refluxed overnight. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica, using CH2Cl2/MeOH/heptane (4:1:5) as eluent, to give 0.81 g (45%) of the title compound as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:21]=[C:19]1[C:18]2[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16](=[O:26])[N:20]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)C1(CCCCBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(CCCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Under argon, 4.2 g (15.15 mmol) of tert-butyl 1-(4-bromobutyl)cyclopropanecarboxylate were initially charged in 50 ml of DMF, 3.34 g (22.72 mmol) of phthalimide and 4.19 g (30.3 mmol) of potassium carbonate were added and the mixture was stirred at 90° C. for 2 h. The reaction mixture was then filtered, and the filtrate was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 4.23 g (81.3% of theory) of the target compound.
Reaction SMILES: Cl[Si@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([F:18])[CH:9]=2)[CH2:4][CH2:3]1.[CH2:19]1[CH2:23]O[CH2:21][CH2:20]1>>[F:18][C:10]1[CH:9]=[C:8]([C@H:5]2[CH2:6][CH2:7][Si@H:2]([CH2:21][CH2:20][CH2:19][CH2:23][C@H:19]3[CH2:23][CH2:3][C@H:4]([CH2:5][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:21][CH2:20]3)[CH2:3][CH2:4]2)[CH:13]=[CH:12][C:11]=1[O:14][CH:15]([F:17])[F:16]
Reactant: Fc1cc([C@H]2CC[Si@H](Cl)CC2)ccc1OC(F)F
Reactant: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](CCCC[Si@H]2CC[C@H](c3ccc(OC(F)F)c(F)c3)CC2)CC1

Procedure:
28.9 g (0.1 mol) of trans-4-(4-bromobutyl)-1-n-pentylcyclohexane was dropped in a mixture of 2.5 g (0.11 mols) of magnesium and 300 ml of THF to obtain a Grignard reagent. The resultant solution was then dropped in a solution, in 500 ml of THF, of 29.5 g (0.1 mol) of 4-(trans-4-chloro-4-silacyclohexyl)-2-fluoro-1-difluoromethoxybenzene. The resultant product consisted of a mixture of trans and cis isomers with respect to the cyclohexane ring. The product was subjected to ordinary aftertreatments to obtain trans-4-(4-(trans-4-(3-fluoro-4-difluoromethoxyphenyl)-1-silacyclohexyl)butyl)-1-n-pentylcyclohexane, followed by isolation through chromatography to obtain 41.8 g (yield: 89%) of the intended trans isomer product.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].CO.[H][H]>[Rh].C(O)(=O)C>[C:1]([CH:9]1[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)CC(C)(C)C1CCC(O)CC1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
4-t-octylphenol (250 g, used as received from Rohm and Haas), methanol (250 ml), acetic acid (2.5 ml) and rhodium on carbon catalyst (5.0 g, 5% rhodium, MCB Chemicals) were added to a 3 L glass lined autoclave. The autoclave was charged to 60 psig H2 and heated at 60° C. until hydrogen uptake was complete (about 10 hrs.). The mixture was cooled to room temperature and the catalyst was removed by filtration in a glove bag under a nitrogen atmosphere (CAUTION: pyrophoric catalyst). The solvent was removed on a rotary evaporator and the residue was dissoved in dichloromethane and extracted with 10% sodium carbonate solution (3×250 ml) to remove phenolic contamination, thus avoiding the formation of a yellow impurity in the subsequent oxidation step. The dichloromethane solution was washed with 25% sulfuric acid (2×100 ml) distilled water (1×250 ml), and dried over anhydrous magnesium sulfate, after which the solvent was evaporated to isolate 4-t-octylcyclohexanol as a low melting off-white solid (182 g, 81%).