Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:27][CH2:26][C@:4]2([N:8]=[C:7]([C:9]3[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:28].C(N)(C)(C)C.B.Cl.CC(C)=O.C(=O)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:27][CH2:26][C:4]2([NH:8][CH:7]([C:9]3[N:14]=[C:13]([CH3:15])[CH:12]=[C:11]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=4)[N:10]=3)[CH2:6][CH2:5]2)[C:3]1=[O:28]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C2=N[C@@]3(CC2)CCN(C)C3=O)n1
Agent: B
Agent: Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CC(C)(C)N
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C2CCC3(CCN(C)C3=O)N2)n1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
(5S)-7-Methyl-2-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 9) (78.34 g, 201.7 mmol) was added to a 5 L three necked round bottomed flask containing an overhead stirrer, 500 ml pressure-equalising dropping funnel with a nitrogen inlet and thermometer. To this was added DCM (1000 mL) and the stirred mixture cooled to approx. −70° C. The dropping funnel was charged with a pre-sonicated solution of borane tert-butylamine (19.3 g, 221.87 mmol) in DCM (200 mL). The borane complex was added slowly maintaining the temperature below −70° C. over approx. 30 minutes. After addition the reaction was stirred at below −70° C. for 90 minutes. The dropping funnel was charged with 6M HCl (400 ml) and this was added dropwise over approx. 15 minutes. The reaction temperature warmed to −50° C. during the addition. After addition was complete the acetone/dry-ice bath was removed and the reaction mixture warmed to room temperature then stirred for a further 30 minutes. In a separate 10 L flask was added sodium carbonate (200 g) and water (1 L). To this flask was added an overhead stirrer. The reaction mixture was carefully added (note: gas evolution) to the sodium carbonate solution and stirring was maintained until gas evolution ceased. The mixture was transferred to a 6 L separating funnel and the phases were separated. The aqueous layer was washed with DCM (2×200 ml) and the combined organics were dried (MgSO4). The solvent was evaporated to afford 7-methyl-2-[4-methyl-6-[4-(trifluoromethyl)-phenyl]pyrimidin-2-yl]-1,7-diazaspiro[4.4]nonan-6-one as an amber oil (77.8 g), a 96:4 ratio of (2R,5S) and (2S,5S) isomers.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C:11]1([CH3:17])[CH2:16][CH2:15][N:14]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CC1(NC(=O)OCc2ccccc2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC1(NC(=O)OCc2ccccc2)CCN(c2ccc(Cl)cn2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (4-methyl-piperidin-4-yl)-carbamic acid benzyl ester (0.5 g, 2.02 mmol, Example 30B) in dioxane (5.0 mL) at room temperature was added 2,5-dichloro-pyridine (0.4 g, 2.79 mmol) and diisopropylethyl amine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 80° C. for 48 hours, concentrated under reduced pressure and purified by flash chromatography with 10% to 40% ethyl acetate in hexane to provide (5′-chloro-4-methyl-3,4,5,6-tetrahydro-2H-(1,2′)bipyridinyl-4-yl)-carbamic acid benzyl ester. MS (CI) m/z 360 (M+1)+; 1H NMR (300 MHz, CDCl3) δ ppm 8.01 (d, 1H), 7.49 (dd, 1H), 7.36-7.27 (m, 5H), 7.26 (m, 1H), 6.78 (d, 1H), 5.04 (s, 2H), 3.82 (m, 2H), 3.21 (m, 2H), 2.15 (m, 2H), 1.58 (m, 2H), 1.35 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.[Li+].[CH3:24]C([N-]C(C)C)C.CI>C1COCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:13][CH2:14][C:15]([CH3:24])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A solution of ethyl 4-(1,3-dioxoisoindolin-2-yl)cyclohexanecarboxylate (0.30 g, 1.00 mmol) in THF (10 mL) was cooled to −78° C. followed by dropwise addition of LDA (1.60 M in THF, 1.88 mL, 3.00 mmol) at −78° C. The mixture was stirred at the same temperature for 30 minutes followed by addition of MeI (0.311 mL, 5.00 mmol) at −78° C. The temperature of the reaction was slowly raised up to rt and left to stir overnight. The reaction was then cooled to 0° C. and quenched by dropwise addition of saturated NH4Cl solution (30 mL), extracted with EtOAc (3×50 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product as a viscous liquid (0.30 g, 97%). MS: 316.12 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18](=[O:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CC#N>[C:18]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)[N:14]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[N:13]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1n[nH]c2ccc(OCc3ccccc3)cc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1nc(C(C)=O)c2cc(OCc3ccccc3)ccc21
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To 1-(5-(benzyloxy)-1H-indazol-3-yl)ethanone (3.50 g, 13.1 mmol) in CH3CN (100 mL) was added K2CO3 (4.54 g, 32.9 mmol) and methyl 2-bromoacetate (1.33 mL, 14.5 mmol). The reaction mixture was stirred at 90° C. for 90 min. The reaction mixture was filtered and the solid was washed with CH3CN. Volatiles were evaporated and then the crude mixture was purified by flash column chromatography on silica gel (gradient: c-hexane/EtOAc 1:1 to 1:3). TLC, Rf (c-hexane/EtOAc 1:3)=0.64; MS (LC/MS): 339.0 [M+H]+, 361.0 [M+Na]+; tR (HPLC conditions c): 5.09 min.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][S:6][CH:7](Cl)[C:8]([O:10][CH3:11])=[O:9].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH3:11][O:10][C:8]([CH:7]1[C:13]2[C:3](=[C:2]([Br:1])[CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:5][S:6]1)=[O:9]
Reactant: COC(=O)C(Cl)SCCc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1SCCc2c(Br)cccc21
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of methyl 2-((2-bromophenethyl)thio)-2-chloroacetate (4.7 g), aluminum trichloride (2 g) and DCM (15 ml) was stirred in ice bath and allowed to warm up to ambient temperature and stirred 3.5 hrs. Separation method B and E yielded the title compound (2.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11](=O)[CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:25][OH:26]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11](=[N:25][OH:26])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(C2=CC(=O)CCC2c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(C2=CC(=NO)CCC2c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 188.6 g. of 3,4-bis(4-methoxyphenyl)-2-cyclohexen-1-one and 84.8 g. of hydroxylamine hydrochloride in 1.5 liters of methanol was heated to reflux for three hours. The reaction was then stirred overnight at room temperature and evaporated in vacuo. To the residue were added one liter of ethyl acetate and 600 ml. of water. The layers were separated and the organic layer was washed three times each with 500 ml. of water. The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to provide 192.59 g. of the title oxime intermediate.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:16](OS(C(F)(F)F)(=O)=O)=[CH2:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CCCC)CCCC)CCC.C(O)=O.C(OCC)(=O)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([O:5][C:6]([C:8]1([CH:16]=[CH2:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OS(=O)(=O)C(F)(F)F)C1(C(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC1(C(=O)OC(C)(C)C)COC(C)(C)OC1
Temperature: 60 °C
Yield: 45 %

Procedure:
A solution of N,N-diisopropylamine (1.51 g, 2.1 mL, 15 mmol) in anhydrous tetrahydrofuran (30 mL) was stirred at −78° C. under nitrogen. n-Butyl lithium (2.5 M in hexanes, 5.6 mL, 14 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 30 min. A solution of 5-acetyl-2,2-dimethyl-[1,3]dioxane-5-carboxylic acid tert-butyl ester (2.58 g, 10 mmol) in tetrahydrofuran (5 mL) was added and the reaction mixture was stirred at −78° C. for 15 min. A solution of N-phenyl-(bis-trifluoromethanesulfonamide) (3.93 g, 11 mmol) in tetrahydrofuran (30 mL) was added and the reaction mixture was stirred at −78° C. for 15 min. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 min. The solvent was evaporated and diethyl ether (50 mL) was added. The solution was cooled to 5° C. and was washed with cold sodium hydroxide solution (1 M, 3×30 mL) and brine. The organic solution was separated, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated to afford 2,2-dimethyl-5-(1-trifluoromethanesulfonyloxy-vinyl)-[1,3]dioxane-5-carboxylic acid tert-butyl ester (3.84 g, 10 mmol) as a yellow oil. A solution of 2,2-dimethyl-5-(1-trifluoromethanesulfonyloxy-vinyl)-[1,3]dioxane-5-carboxylic acid tert-butyl ester (3.84 g, 10 mmol) and tri-n-butylamine (5.55 g, 7 mL, 30 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature under nitrogen. Bis(triphenylphosphine)palladium(II) dichloride (350 mg, 0.5 mmol) and formic acid (920 mg, 0.77 mL, 20 mmol) were added and the reaction mixture was heated at 60° C. for 90 min. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic extracts were washed with water (5×) and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 9:1 followed by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 19:1 to 9:1 to afford the title compound (1.09 g, 45%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.41 (s, 3H), 1.45 (s, 3H), 1.50 (s, 9H), 3.82 (d, J=11.8 Hz, 2H), 4.25 (d, J=11.8 Hz, 2H), 5.25 (d, J=17.2 Hz, 1H), 5.26 (d, J=10.7 Hz, 1H), 5.73 (dd, J=17.2, 11.7 Hz, 1H).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:8](CC)[CH2:9]C)C.O[CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[I-].[Na+].Cl.CNC.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O.ClCCl>[CH3:6][N:8]([CH2:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:9]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CNC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CN(C)C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
With cooling with ice, methanesulfonyl chloride (923 μl, 11.9 mmol) and triethylamine (1.94 ml, 13.9 mmol) were added to a dichloromethane (100 ml) solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.00 g, 9.94 mmol), followed by stirring for 30 minutes with cooling with ice. The reaction liquid was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was dissolved in acetone (50 ml), then sodium iodide (1.49 g, 9.94 mmol) was added, followed by heating under reflux in an oil bath at 85° C. for 5 hours. The reaction liquid was concentrated under reduced pressure, the residue was suspended in ethyl acetate, washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, the residue obtained by concentration was dissolved in dimethylformamide (30 ml), then dimethylamine hydrochloride (2.43 g, 29.8 mmol) and potassium carbonate (2.75 g, 19.9 mmol) were added, followed by stirring at room temperature for 24 hours. The reaction liquid was concentrated under reduced pressure, the residue was suspended in ethyl acetate, and washed with water and saturated brine. After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=10:1, v/v) to obtain the entitled compound (92.0 mg, 4%) as a colorless oily substance.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[Cl:22]>CN(C=O)C>[Cl:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[CH:4]([C:3]([O:10][CH3:11])=[O:9])[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
NaH (288 mmol) was suspended in DMF (370 mL) at 0° C. under an atmosphere of nitrogen. Dimethyl malonate (261 mmol) in DMF (30 mL) was added dropwise over a period of 20 min. at 0° C. and stirring was continued at 0° C. for 30 min. Then 1,2-dichloro-4-nitrobenzene (130 mmol) in DMF (35 mL) was added dropwise at 0° C. over a period of 20 min. The mixture was stirred at 70° C. for 15 h. The reaction mixture was cooled to room temperature and quenched with NH4Cl. The solution was successively washed with EtOAc (1×100 mL, 1×250 mL) and water (2×150 mL). To facilitate separation of the layers, sat. aq. NaCl (20 mL) was added. The organic layer was separated and washed with sat. aq. NaCl (2×100 mL). The aqueous layer was backextracted with EtOAc (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was recrystallized from EtOH to give dimethyl 2-(2-chloro-4-nitrophenyl)malonate as a solid (74%).
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[N:12]([CH3:29])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=3)=[N:14][C:15]=2I)=[O:10])[CH2:5]1)[CH3:2]>CO.[Pd]>[CH2:30]([N:3]([CH2:1][CH3:2])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[N:12]([CH3:29])[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=3)=[N:14][CH:15]=2)=[O:10])[CH2:5]1)[CH3:31]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N(CC)CC)C3)n2C)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCc1cccc(-c2ncc(C(=O)N3CCC(N(CC)CC)C3)n2C)c1
Reaction time: 2 h
Yield: 96.3 %

Procedure:
A solution of 0.230 g (0.43 mmol) of (rac)-(3-diethylamino-pyrrolidin-1-yl)-[2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-methanone (example 1) in 10 ml of MeOH was treated with 0.091 g (0.1 mmol) of Pd—C (10%) and the reaction mixture was then hydrogenated with H2 (1 bar) at RT for 2 hours. After removal the catalyst by filtration, the solvent was evaporated completely to give 0.17 g (96%) of the title compound as light yellow oil. MS: 411.2 (MH+).
Reaction SMILES: C([NH:4][C@@H](CS)C(O)=O)(=O)C.[C:11]([C:13]1([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)#[N:12].C([O-])(=O)C.[NH4+]>CO>[C:11]([C:13]1([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:14]1)(=[NH:4])[NH2:12]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(NS(=O)C(C)(C)C)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(NS(=O)C(C)(C)C)(C(=N)N)C1
Temperature: 70 °C
Yield: 38 %

Procedure:
A mixture of (R)-2-acetamido-3-mercaptopropanoic acid (N-acetylcycteine, 0.812 g, 4.98 mmol), tert-butyl 3-cyano-3-(1,1-dimethylethylsulfinamido)azetidine-1-carboxylate (1.5 g, 4.98 mmol), and ammonium acetate (1.918 g, 24.88 mmol) in MeOH (5 ml) in a 15 ml sealed tube was heated at 70° C. overnight. Analysis of the reaction mixture by LCMS showed 38% desired product with other impurities but no starting material present. The reaction mixture was used for the next step without workup.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[CH3:41][C@@H:42]1[C@@H:47]([NH2:48])[CH2:46][C@H:45]2[CH2:49][C@@H:43]1[C:44]2([CH3:51])[CH3:50]>>[CH3:41][C@@H:42]1[C@@H:47]([NH:48][C:30]([CH:29]2[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]2[CH2:24][C:23]2[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=3[F:38])[C@H:10]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:22]=2)=[O:31])[CH2:46][C@H:45]2[CH2:49][C@@H:43]1[C:44]2([CH3:50])[CH3:51]
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Reactant: C[C@@H]1[C@@H](N)C[C@H]2C[C@@H]1C2(C)C
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)N[C@H]4C[C@H]5C[C@@H]([C@@H]4C)C5(C)C)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 72.3 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7 (Epimer 1), 0.070 g, 0.117 mmol) was reacted with (1S,2S,3S,5R)-2,6,6-Trimethyl-bicyclo[3.1.1]hept-3-ylamine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 25 μL, 0.148 mmol) to form 2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid((1S,2S,3S,5R)-2,6,6-trimethyl-bicyclo[3.1.1]hept-3-yl)-amide (Epimer 1) (0.062 g, 72%). m/z=733 (M+1); HRMS: calcd for C39H59ClFN4O4S. Calc [M+H+] 1733.3924. found 733.3925.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH2:11]([O:13][CH2:14][CH2:15][NH2:16])[CH3:12]>C(OCC)(=O)C>[CH2:11]([O:13][CH2:14][CH2:15][NH:16][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:12]
Reactant: CCOCCN
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: CCOC(C)=O
Product: CCOCCNc1ccccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 3 h
Yield: 107.2 %

Procedure:
A mixture of o-nitrochlorobenzene (30 g) and 2-ethoxyethylamine (51 g) is stirred at 130° C. for 3 hours. After allowing to cool, ethyl acetate (150 ml) is added to the reaction mixture, and the ethyl acetate layer is separated, washed three times with saturated aqueous saline, dried over anhydrous magnesium sulfate, and then concentrated. The residue is distilled under reduced pressure to give N-(2-ethoxyethyl)-o-nitroaniline (42.9 g) as a reddish brown liquid, b.p. 144°-145.5° C./1.0 mmHg.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]([C:14]1[CH:19]=[CH:18][C:17]([O:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[C:16]([O:28][CH3:29])[CH:15]=1)(O)[CH2:11][CH3:12])[CH3:9].[C:30]1([CH3:37])[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:8]([C:10]([C:14]1[CH:19]=[CH:18][C:17]([O:20][S:21]([C:24]([F:27])([F:26])[F:25])(=[O:23])=[O:22])=[C:16]([O:28][CH3:29])[CH:15]=1)([C:32]1[CH:33]=[CH:34][C:35]([OH:36])=[C:30]([CH3:37])[CH:31]=1)[CH2:11][CH3:12])[CH3:9]
Reactant: Cc1ccccc1O
Reactant: CCC(O)(CC)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Trifluoromethanesulfonic anhydride (0.8 mL, 4.76 mmol) was added to a solution of 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenol (Example 176-(3); 1.0 g, 4.76 mmol) in pyridine (4 mL) at room temperature, and the mixture was stirred at room temperature for one hour. The reaction solution was extracted with ethyl acetate. The organic layer was washed with 1 N hydrochloric acid aqueous solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=1:1) to give trifluoromethanesulfonic acid 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenyl ester (1.51 g, 93%). Trifluoroacetic acid (0.1 mL) was added to a mixture of trifluoromethanesulfonic acid 4-(1-ethyl-1-hydroxy-propyl)-2-methoxy-phenyl ester (100 mg, 0.292 mmol) with o-cresol (68.2 mg, 585 mmol) at room temperature, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. Then, the resulting residue was purified by silica gel chromatography (hexane only to hexane:ethyl acetate=4:1) to give the title compound (0.12 g, 95%).
Reaction SMILES: [Li].[CH2:2](I)[CH3:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]23[CH2:22][CH:17]([N:18]([CH3:21])[C:19]2=O)[CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:11][CH:12]=1.O>CCOCC.C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:13]23[CH2:22][CH:17]([N:18]([CH3:21])[C:19]2=[CH:2][CH3:3])[CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:11][CH:12]=1
Reactant: CCI
Reactant: COc1cccc(C23CCCC(C2)N(C)C3=O)c1
Agent: [Li]
Solvent: O
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC=C1N(C)C2CCCC1(c1cccc(OC)c1)C2
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
0.17 g of lithium is added to 8 ml of absolute ether in a nitrogen atmosphere, and a solution of 1.8 g of ethyl iodide in 3 ml of absolute ether is added dropwise thereto at 0° to -5°C. The mixture is stirred at the same temperature for 30 minutes. Then, a solution of 0.8 g of 1-(3-methoxyphenyl)-6-methyl-6-azabicyclo[3,2,1]octane-7-one in 30 ml of benzene is added dropwise to the mixture at room temperature for 5 minutes. The mixture is refluxed for 3 hours. Water is added to the mixture under ice-cooling, and the aqueous mixture thus obtained is extracted with ether. The ether extract is washed with water, dried and then evaporated to remove solvent, whereby 0.8 g of 1-(3-methoxyphenyl)-6-methyl-7-ethylidene-6-azabicyclo[3,2,1]octane is obtained. The product thus obtained is dissolved in 60 ml of ethanol. 300 mg of sodium borohydride are added to the ethanol solution at 10° to 15°C. Then, the mixture is stirred at room temperature for 20 hours. After the reaction, the mixture is concentrated under reduced pressure. Water is added to the residue, and the aqueous mixture is extracted with chloroform. The chloroform extract is washed with water, dried and then evaporated to remove solvent. Methanolic hydrogen chloride is added to the residue in ether, and the crystalline precipitate is collected by filtration. The precipitate is recrystallized from a mixture of ethanol and ether. 0.4 g of 1-(3-methoxyphenyl)-6-methyl-7-ethyl-6-azabicyclo[3,2,1]octane hydrochloride is obtained. M.p. 176° - 178°C.