Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=O)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C>C(OCC)(=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C@H:18]2[NH:9][C@@H:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][CH2:17]2)=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](CCCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@@H](c2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
To a solution of 1-tert-butyl(R)-6-oxopiperidine-1,2-dicarboxylate (CAS No. 183890-36-0, 9.00 g) in THF (120 ml), 4-chlorophenylmagnesium bromide (1.0 M solution in diethyl ether, 42 ml) was added in a nitrogen atmosphere at −78° C. over 20 minutes. The reaction solution was stirred at −78° C. to −40° C. for 1.5 hours, and then quenched with a saturated ammonium chloride solution at −40° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain methyl(R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (9.53 g). A solution of 4 N hydrogen chloride in ethyl acetate (90 ml) was added to a solution of methyl(R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (9.53 g) in ethyl acetate (90 ml) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. Sodium cyanoborohydride (3.29 g) and then acetic acid (4.27 ml) were added to a solution of the residue in methanol (150 ml) at 0° C., and the reaction solution was stirred at 0° C. for one hour and at room temperature for one hour. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and solidified with a heptane-diisopropyl ether system to obtain 2.47 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CCN(CC)CC.Br.[NH2:22][C:23]1[S:24][C:25]([Br:28])=[CH:26][N:27]=1>CN(C=O)C.C1COCC1>[Br:28][C:25]1[S:24][C:23]([NH:22][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=2)=[N:27][CH:26]=1
Reactant: Nc1ncc(Br)s1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(C(=O)Nc2ncc(Br)s2)cc1
Reaction time: 1 h

Procedure:
To a mixture of 4-sulfamoylbenzoic acid (1.0 g, 4.97 mmol), Et3N (1.5 ml, 10.78 mmol), DMF (5 ml) and THF (5 ml) isobutyl choroformate (0.70 ml, 5.36 mmol) was added dropwise at −10° C. After stirring for 1 h, a solution of 2-amino-5-bromothiazole hydrobromide (1,55 g, 5.96=mol) and Et3N (0.83 ml, 5.96 mmol) in DMF (6 ml) and THF (4 ml) was added dropwise to the mixture at the same temperature.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:25][C:26]1[CH:36]=[CH:35][C:29](/[CH:30]=[CH:31]/[N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH:30]([C:29]2[CH:35]=[CH:36][C:26]([F:25])=[CH:27][CH:28]=2)[CH2:31][N+:32]([O-:34])=[O:33])[CH2:7][CH2:8][N:9]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN([C@@H]2CCCC[C@@H]2c2ccc(F)cc2)CC1
Reactant: O=[N+]([O-])/C=C/c1ccc(F)cc1
Product: CCOC(=O)C1(C(C[N+](=O)[O-])c2ccc(F)cc2)CCN([C@@H]2CCCC[C@@H]2c2ccc(F)cc2)CC1
Yield: 77 %

Procedure:
As described for example 1b, cis-rac-1-[2-(4-fluoro-phenyl)-cyclohexyl]-piperidine-4-carboxylic acid ethyl ester (1.0 g, 3 mmol) (using 4-fluoro-trans-beta-nitrostyrene instead of trans-beta-nitrostyrene) was converted to the title compound (1.2 g, 77%) which was obtained as a white solid. MS: m/e=501.4 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].CCOCC>C(O)C.[Pd]>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccccc2)cc1
Reaction time: 6 h

Procedure:
A mixture of 2-hydroxy-2-phenylethanamine (17.7 g) and 1-(4-carbomethoxyphenyl) propan-2-one (24.8 g) in ethanol (300 ml) was refluxed for one hour. When cooled, 10% Pd/C (1.0 g) was added and the mixture was hydrogenated on a Parr Hydrogenator at 60° and 60 psi for six hours. The mixture was filtered and the filtrate was evaporated to an oil which was taken up in methanol (75 ml). The solution was allowed to stand at 4° to give crystals (Batch 1). Ether (75 ml) was added to the mother liquors to obtain subsequent crops (Batches 2 & 3). The mother liquors were evaporated to an oil, which was crystallised from ether (Batch 4).
Reaction SMILES: [NH:1]=[C:2]1[C:15]([NH:16][C:17]([NH:19][C:20]([O:22][CH3:23])=[O:21])=[S:18])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.[H-].[Ca+2].[H-].[CH3:36]OS(OC)(=O)=O>COCCOC>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:19][C:20]([O:22][CH3:23])=[O:21])[S:18][CH3:36])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6])[CH:3]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)NC(=S)NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccc(OC)cc2)C1=N
Agent: [Ca+2]
Agent: [H-]
Solvent: COCCOC
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccc(OC)cc2)C1=N)SC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-imino-(4-methoxyphenyl)methyl-4-(3-carbomethoxythioureido)benzophenone (4.47 g.; 0.01 mol) in 1,2-dimethoxyethane (50 ml.) there is added calcium hydride (0.42 g.; 0.01 mol). The mixture is refluxed for one hour and is cooled to room temperature. To the mixture there is added dimethylsulfate (1.26 g.; 0.01 mol). The mixture is stirred at room temperature for one hour and is poured into an excess of ice water. The suspension formed is filtered and the filter cake dried to afford 3-imino-(4-methoxyphenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>CN(C)C(=O)C>[C:12]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[Cl:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CC(=O)N(C)C
Product: CC(=O)n1cnc2c(Cl)nc(N)nc21
Temperature: 55 °C
Reaction time: 4 h
Yield: 99.3 %

Procedure:
2-Amino-6-chloropurine (150 g, 0.89 mol) and acetic anhydride (108 g, 1.06 mol) were added to N,N-dimethylacetamide (350 ml), and the mixture was heated to 50-60° C. and stirred for 4 hr. The reaction mixture was cooled and filtrated. The obtained crystals were washed with isopropanol (400 ml) and dried at 80° C. under reduced pressure to give 9-acetyl-2-amino-6-chloropurine as a pale-yellow powder (187 g, yield 99.0%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:8][CH3:9])[NH:5][C:6]=1[Br:7].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][O:18][CH3:19]>CN(C)C=O.[Cl-].[Na+].O>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][CH3:9])[N:5]([CH2:17][O:18][CH3:19])[C:6]=1[Br:7]
Reactant: COCCl
Reactant: CCc1nc(Br)c(Br)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(Br)c(Br)n1COC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
4,5-Dibromo-2-ethylimidazole (451.3 g) was dissolved in N,N-dimethylformamide (2.25 L), and potassium carbonate (368 g) was added. (Chloromethyl)methyl ether (200 g) was gradually added dropwise under ice-cooling and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into ice-cooled brine and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Hexane was added to the residue and the mixture was heated and allowed to cool. The precipitated crystals were collected by filtration and dried by heating under reduced pressure to give 4,5-dibromo-2-ethyl-1-(methoxymethyl)imidazole (461.7 g) as brown crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:27][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.C(N=C=NCCCN(C)C)C.[OH:39][C:40]1[C:48]2[N:47]=NN[C:44]=2[CH:43]=[CH:42]C=1.C(N(CC)CC)C.[C@@H]12O[C@@H](CC1)CNC2>CN(C)C=O.CN(C)C1C=CN=CC=1>[C@@H:43]12[CH2:44][C@@H:48]([N:47]([C:24]([C@@H:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:15]4[N:14]=[C:13]5[NH:27][C:10]([C:8]6[CH:7]=[CH:6][N:5]=[C:4]([CH:1]7[CH2:3][CH2:2]7)[N:9]=6)=[N:11][C:12]5=[CH:17][CH:16]=4)[CH2:19]3)=[O:25])[CH2:42]1)[CH2:40][O:39]2
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Reactant: Oc1cccc2[nH]nnc12
Agent: C1C[C@H]2CNC[C@@H]1O2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C([C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1)N1C[C@H]2C[C@@H]1CO2
Temperature: 0 °C
Reaction time: 18 h
Yield: 10.5 %

Procedure:
To a solution of (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (70 mg, 0.192 mmol) in N,N-dimethylformamide (10 mL) were added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCl) (73.2 mg, 0.383 mmol), hydroxybenzotriazole (52 mg, 0.383 mmol), triethylamine (58.2 mg, 0.575 mmol), (1R,5S)-8-oxa-3-azabicyclo[3.2.1]octane (186 mg, 1.64 mmol) and 4-dimethylaminopyridine (3 mg) at room temperature. The reaction mixture was stirred for 18 h, poured into ice water, extracted with ethyl acetate, washed with cold water and concentrated. The crude was purified via preparative TLC (3% methanol in dichloromethane) to afford the title compound (9 mg). MS (ES+) (M+H) 446.3; LCMS retention time 1.816 min (Method F)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:11](N(OC)C)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[CH:24]([Mg]Br)=[CH2:25].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:17][CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:11](=[O:12])[CH:24]=[CH2:25])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A solution of 2-[3-fluoro-4-(methylsulfanyl)phenyl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide (1.33 g) in tetrahydrofuran (15.6 mL) was cooled to 0° C., and vinylmagnesium bromide (1.0M tetrahydrofuran solution, 15.6 mL) was added dropwise thereto. The reaction mixture was stirred at room temperature for 4 hr and poured into 1M hydrochloric acid, and the mixture was stirred for 30 min. The reaction mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.12 g, yield 93%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[NH:4][N:3]=1.Cl[C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:13][C:5]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([CH3:1])[N:3]([C:15]2[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][N:16]=2)[N:4]=1
Reactant: Cc1n[nH]c(C)c1-c1ccccc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-n2nc(C)c(-c3ccccc3)c2C)nc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 52.1 %

Procedure:
A mixture of 3,5-dimethyl-4-phenyl-1H-pyrazole (2.50 g, 14.5 mmol), ethyl 6-chloronicotinate (5.39 g, 29.0 mmol), potassium carbonate (8.02 g, 58.1 mmol) and dimethyl sulfoxide (100 mL) was stirred at 160° C. for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and toluene (2:1) and washed with water. The organic fraction was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with hexane/ethyl acetate (8:1) to afford 2.43 g (52%) of the title compound: MS (ESI) m/z 322 [M+H]+, 1H-NMR (CDCl3) δ 9.06-9.05 (1H, m), 8.39-8.36 (1H, m), 8.04-8.01 (1H, m), 7.48-7.29 (5H, m), 4.42 (2H, q, J=7.2 Hz), 2.67 (3H, s), 2.32 (3H, s), 1.43 (3H, t, J=7.2 Hz).
Reaction SMILES: C[Si](C)(C(C)(C)C)[O:3][C@@H:4]([CH2:16][NH2:17])[CH2:5][O:6][C:7]1[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:3][C@@H:4]([CH2:16][NH2:17])[CH2:5][O:6][C:7]1[C:15]2[NH:14][CH:13]=[N:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)COc1cccc2nc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: NC[C@H](O)COc1cccc2nc[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(S)-4-[2-(Dimethyl tert-butylsilyl)oxy-3-aminopropoxy]benzimidazole (10 mg, 31 mmol) was dissolved in THF (1 mL) and the mixture cooled to 0° C. Tetrabutylammonium fluoride (1 mL, 1.0M solution in THF) was added. The reaction stirred at this temperature for 4 hours. The reaction was quenched by addition of water. Evaporation of the aqueous layer provided the desired alcohol. NMR. MS.
Reaction SMILES: [P:1]([O:9]CC)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].COC(=O)[O-].[CH2:17]([N+:19]1[CH:23]=[CH:22][N:21]([CH3:24])[CH:20]=1)[CH3:18].O>CO>[CH2:4]([O:3][P:1]([O-:9])([O:6][CH2:7][CH3:8])=[O:2])[CH3:5].[CH2:17]([N+:19]1[CH:23]=[CH:22][N:21]([CH3:24])[CH:20]=1)[CH3:18]
Reactant: CCOP(=O)(OCC)OCC
Agent: CC[n+]1ccn(C)c1
Agent: COC(=O)[O-]
Solvent: CO
Solvent: O
Product: CCOP(=O)([O-])OCC
Temperature: 100 °C
Reaction time: 20 h

Procedure:
By adding triethyl phosphate (TEP, produced by Daihachi Chemical Industries Co., Ltd.) (0.1 mol) to a methanol solution of 1-ethyl-3-methylimidazolium methyl carbonate salt (0.1 mol), adding water (0.3 mol) and stirring the mixture at 100° C. for 20 hours, the triethyl phosphate was hydrolyzed and, at the same time, a salt exchange reaction was performed. As a result, a methanol solution of 1-ethyl-3-methylimidazolium diethyl phosphate monoanion was obtained. The resulting solution was heated at a pressure reduction degree of 1.0 kPa or less at 50° C., so that methanol was evaporated until methanol was no longer distilled off. By increasing the temperature from 50° C. to 100° C. and heating the mixture for 30 minutes to distill by-products off, an electrolyte (c10) {1-ethyl-3-methylimidazolium diethyl phosphate monoanion} was obtained. The yield was 98 wt %. The content of diethyl phosphate in the anions was 99% by mol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.O/[N:53]=[C:54](\[NH2:62])/[CH2:55][C:56]1[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=1>ClCCl.O>[NH2:62]/[C:54](=[N:53]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[CH2:55][C:56]1[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=1
Reactant: N/C(Cc1ccncc1)=N\O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)Cc1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.6 %

Procedure:
A solution of (2R)-2-(2-tert-butoxy-2-oxoethyl)-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.67 mmol) in dichloromethane (20 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (354 mg, 1.85 mmol), N-methylmorpholine (203 μl, 1.85 mmol) and 1-hydroxybenzotriazole hydrate (227 mg, 1.67 mmol). (1Z)-N′-hydroxy-2-(4-pyridinyl)ethanimidamide (WO 9600720) (374 mg, 1.67 mmol) followed by N-methylmorpholine (369 μl, 3.34 mmol) were added to the reaction mixture which was stirred at room temperature for 18 hours. The reaction mixture was diluted with water (10 ml) and stirred for 20 minutes. The layers were separated via a 5 micron filter cartridge. The organic solvent was removed under reduced pressure to afford the title compound as a yellow oil (840 mg). This was used without further purification in the following step.
Reaction SMILES: C(C(Cl)CC1C=CC=CC=1)C.[CH3:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]([CH2:23][CH3:24])[NH:14]1.C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].[Cl:37][CH:38]([Cl:42])[C:39](Cl)=[O:40]>O.C(Cl)Cl.C(#N)C>[Cl:37][CH:38]([Cl:42])[C:39]([N:14]1[CH:15]([CH2:23][CH3:24])[CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]1[CH3:12])=[O:40]
Reactant: CCC1Cc2ccccc2C(C)N1
Reactant: O=C(Cl)C(Cl)Cl
Agent: CCC(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: c1ccc2cnccc2c1
Product: CCC1Cc2ccccc2C(C)N1C(=O)C(Cl)Cl

Procedure:
By procedures described in Example 1, α-ethylphenethyl chloride and acetonitrile were converted to 1-methyl-3-ethyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 3 g of this isoquinoline compound, 10 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 1.1 equivalents dichloroacetyl chloride was added dropwise to the mixture. The mixture was stirred for 15 minutes, then water was added. The organic extract was dried with magnesium sulfate, stripped of solvent and chromatographed. A yellow oil product was recovered having the following elemental analysis:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-fluoro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.6 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.91 g, 4.8 mmol). The product was isolated as a white foam. Yield 0.75 g (40%). mp 94-97° C. FDMS m/e=407 (M+ of free base). α[D]589=+7.97 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.Cl.[NH2:21][C@H:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1)[CH2:23][OH:24].C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH2:15]([O:14][C:12]1[NH:11][N:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([NH:21][C@H:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=3)[CH2:23][OH:24])[CH:3]=[CH:4][C:5]=2[N+:17]([O-:19])=[O:18])[CH:13]=1)[CH3:16]
Reactant: N[C@@H](CO)c1ccc(F)cn1
Reactant: CCOc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 70.3 %

Procedure:
A mixture of 6-chloro-N-(5-ethoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 26, 0.2 g) and (2R)-2-amino-2-(5-fluoropyridin-2-yl)ethanol hydrochloride (Intermediate 23, 0.15 g) in n-BuOH (5 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.2 g of the title compound. MS (electrospray): 404 (M+1) for C17H18FN7O4.