Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH2:14])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:15]=[C:5]2[C:6]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:23](=[O:25])[CH3:24])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c([C@@H]3C[C@H]3CN)cccn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@@H]1C[C@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
To a solution of trans-1-[2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine (200 mg, 0.994 mmol) and triethylamine (208 μL, 1.49 mmol) in tetrahydrofuran (10 mL) was added acetic anhydride (113 μL, 1.20 mmol) under ice-cooling, and the mixture was stirred at room temperature for 5 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) and recrystallization (ethyl acetate/hexane) to give the title compound (131 mg, yield 54%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1.I[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:19]([CH3:21])[CH3:20])[CH:10]=3)[O:8][C:4]=2[CH:3]=1
Reactant: Oc1cccc(-c2nc3ccc(Br)cc3o2)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
To a solution of 3-(6-bromobenzoxazol-2-yl)phenol (Compound of Example 272) (1.02 g) in N,N-dimethyl formamide (6 ml) were added 2-iodopropane (0.68 g) and potassium carbonate (0.63 g) at 50° C., and the mixture was stirred at 50° C. for 1.5 hour. To the mixture were further added 2-iodopropane (0.34 g) and potassium carbonate (0.31 g), and the mixture was further stirred at 50° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:20 to 1:6, v/v) was concentrated under reduced pressure to isolate 6-bromo-2-(3-isopropoxyphenyl)benzoxazole (896 mg, 77%).
Reaction SMILES: C([Li])CCC.[C:6]1([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>CCCCCC.O1CCCC1>[Cl:17][C:18]1[CH:32]=[CH:31][CH:30]=[CH:29][C:19]=1[CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][C:25]([CH:14]([CH3:15])[C:13]([NH:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:16])([OH:28])[CH2:26][CH2:27]1
Reactant: CCC(=O)Nc1ccccc1
Reactant: O=C1CCN(CCc2ccccc2Cl)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C(=O)Nc1ccccc1)C1(O)CCN(CCc2ccccc2Cl)CC1
Reaction time: 2 h

Procedure:
48 cc of n-butyl-lithium in hexane are added dropwise at 0°, in an atmosphere of nitrogen with stirring, to a solution of 9 g of N-phenylpropionamide in 90 cc of anhydrous tetrahydrofuran. The mixture is stirred at 45°-48° for 21/2 hours and a solution of 10.5 g of N-o-chlorophenethyl-4-piperidone in 25 cc of anhydrous tetrahydrofuran is added dropwise within 50 minutes. The heating (oil bath) is removed and the reaction mixture is stirred for a further hour while cooling slowly. 10 cc of a 20% potassium carbonate solution are subsequently added to the reaction solution while stirring and cooling with ice, dilution is effected with ether and the organic phase is decanted, dried over magnesium sulphate and concentrated by evaporation at reduced pressure. The resulting crude compound is filtered over silica gel resulting crude compound is filtered over silica gel (eluant: chloroform containing 3% of methanol) and an equivalent amount of fumaric acid is added to the resulting title compound in ethanol whereby this crystallizes as hydrogen fumarate. The hydrogen fumarate form of the title compound has a M.P. of 159°-161°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([O-:22])=[O:21].O>CN(C1C=CN=CC=1)C.O1CCCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 24 °C
Reaction time: 2 h

Procedure:
4-Nitrobenzoyl chloride (111.34 grams, 0.60 mole), triethylamine (72.86 grams, 0.72 mole), 4-(N,N'-dimethylamino)pyridine (1.94 grams, 1.0% wt. of the 4-nitrobenzoyl chloride and 4-nitroaniline used) and tetrahydrofuran (250 milliliters) are added to a reactor and stirred under a nitrogen atmosphere with cooling to provide a 5° C. solution. Dropwise addition of a solution of 4-nitroaniline (82.88 grams, 0.60 mole) in tetrahydrofuran (400 milliliters) commenced and is completed over the next 30 minutes while maintaining a reaction temperature of 5° C. to 8° C. After completion of addition of the 4-nitroaniline and tetrahydrofuran solution the reaction temperature is allowed to increase to room temperature (24° C.) over a 106 minute period. After the reaction is held at room temperature for two hours, the reactor contents are added to deionized water (1.5 gallons). The resultant precipitated product is recovered by filtration then washed with deionized water (500 milliliters). The wet filter cake is added to acetone (500 milliliters) and heated to boiling with stirring. The acetone suspension is held at 2° C. overnight followed by filtration to recover the crystalline precipitate. The recovered filter cake is dried in a vacuum oven at 110° C. and 5 mm Hg to a constant weight of 84.7 grams. The product is light yellow in color with a brilliant appearance. Additional solids precipitated from the acetone mother liquor from the initial filtration upon concentration by rotary evaporation, but no attempt is made to recover and process this material. Fourier transform infrared spectrophotometric analysis of a nujol mull of the product on a sodium chloride plate confirms the product structure (1538 and 1336 cm-1 absorbances observed for the conjugated nitro group, secondary amide N--H stretching (solid state) absorbance observed at 3368 cm-1, and secondary amide carbonyl stretching (solid state) absorbance observed at 1686 cm-1). Proton nuclear magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH:18]=[C:19]3[C:23]([CH3:25])([CH3:24])[O:22][C:21]([CH3:27])([CH3:26])[C:20]3=[O:28])[CH:9]=2)=[CH:4][CH:3]=1.[OH:29]O.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[C:10]([CH:18]3[C:19]4([C:20](=[O:28])[C:21]([CH3:27])([CH3:26])[O:22][C:23]4([CH3:24])[CH3:25])[O:29]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3)ccc2C(F)(F)F)C1=O
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3)ccc2C(F)(F)F)C1=O
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 99.6 %

Procedure:
To a solution of 4-[1-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (2.50 g, 6.12 mmol) in methanol (75 ml) at 35° C. is added 50% aqueous hydrogen peroxide solution (0.70 ml, 12.2 mmol), followed immediately by a solution of 2M aqueous lithium hydroxide (0.76 ml, 1.52 mmol). This mixture is stirred at 35° C. for 45 minutes, then allowed to cooled to room temperature and quenched with saturated sodium metabisulfite solution. The crude product is extracted with diethyl ether (×2), then all organics are combined and dried over magnesium sulfate. After filtration the filtrate is concentrated in vacuo to afford 2-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (2.59 g) as a yellow gum. This material is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:18].[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[CH3:18]
Reactant: COc1ccc(C(=O)c2ccc(Br)c(C)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C(=O)c2ccc(O)cc2)ccc1Br
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A mixture of 65 (2.00 g, 6.55 mmol) and AlCl3 (3.50 g, 26.2 mmol) were refluxed in benzene (50 mL) for 3 h and then cooled to RT. Water (100 mL) was cautiously added dropwise, and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration afforded 1.78 g (93%) of 66 that was used without further purification. 1H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H), 5.68 (br s, 1H), 6.90 (d, J=8.6 Hz, 2H), 7.40 (dd, J=8.2 Hz, 1.8 Hz, 1H), 7.63 (m, 2H), 7.75 (d, J=8.6 Hz, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH:74][CH2:75][CH2:76][N:77]1[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]1.[OH-].[Na+]>CN(C)C=O.O.C(O)(=O)C>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([N:80]4[CH2:81][CH2:82][N:77]([CH2:76][CH2:75][OH:74])[CH2:78][CH2:79]4)=[O:46])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: OCCN1CCNCC1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)N2CCN(CCO)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole (30 mg) in N,N-dimethylformamide (0.5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12 mg), 1-hydroxybenzotriazole (9 mg) and 1-(2-hydroxyethyl)-piperazine (54 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 5 mol/L aqueous sodium hydroxide solution (0.25 mL), and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (0.1 mL), and the mixture was diluted with water (1 mL). The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μL, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/acetonitrile=90/10-10/60) to give the title compound (4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[C:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[N+:23]([O-])=O)=[CH:7][CH2:6]2>O1CCCC1.CO.[Pd]>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2([CH3:14])[CH3:13])=[C:16]([NH2:23])[CH:17]=1
Reactant: COc1ccc2c(c1)CC=C(c1ccc(OC)cc1[N+](=O)[O-])C2(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2CCc3cc(OC)ccc3C2(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 79 %

Procedure:
To a solution of 6-methoxy-2-(4-methoxy-2-nitrophenyl)-1,1-dimethyl-1,4-dihydronaphthalene (433 mg) in tetrahydrofuran (6 ml) and methanol (6 ml) was added 10% palladium-activated charcoal (200 mg), and the solution was stirred for 3.5 hours at room temperature under a hydrogen atmosphere at 4 atmospheric pressures. After filtration through celite pad, the solvent was evaporated in vacuo, and the resulting solid was washed with hexane-diethyl ether system to provide the title compound (314 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:30]C)=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:32])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)[CH:9]=[CH:10][C:2]1=2.[Si](I)(C)(C)C>C(#N)C.ClCCl>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[C:27]([CH3:29])[C:26](=[O:30])[NH:25][CH:24]=5)[N:22]=4)=[O:15])[CH2:12][CH2:13]3)[CH:9]=[CH:10][C:2]1=2
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OCCO5)CC3)ccc2C)cc1C
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCCO4)CC2)nc1-c1c[nH]c(=O)c(C)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (16 mg, 0.037 mmol) in acetonitrile (1 mL) was added TMS-Iodide (21.10 μL, 0.148 mmol). The reaction was stirred at 50° C. for 20 minutes. The reaction solution was diluted with dichloromethane and washed with saturated NaHSO3 (2×), brine, dried over MgSO4 and concentrated. The crude product was dissolved in DMSO (1 mL) and purified by reverse phase HPLC (10-99% CH3CN in water). ESI-MS m/z calc. 417.5. found 418.3 (M+1)+. Retention time 1.40 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([CH3:13])[C:3]=1[OH:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:18][CH:17]=1>>[CH3:1][C:2]1[C:7]2[CH2:8][O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([CH3:13])[C:3]=1[O:14][CH2:26][CH2:25][CH2:24][CH2:23][S:22][C:19]1[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=1
Reactant: Cc1cc2c(c(C)c1O)COC(=O)N2
Reactant: Cc1ccc(SCCCCCl)cc1
Product: Cc1ccc(SCCCCOc2c(C)cc3c(c2C)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 4 from 5,7-dimethyl-6-hydroxy-4H-3,1-benzoxazin-2-one and 4-(4-methyl-phenylmercapto)-butylchloride.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(SSC2C=CC=CC=2)C=CC=CC=1>>[C:1]1([C:7]2[C:16]3[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccc2c1CCN=C2c1ccccc1
Agent: c1ccc(SSc2ccccc2)cc1
Product: Clc1cccc2c(-c3ccccc3)nccc12

Procedure:
1-Amino-2-(2-chlorophenyl)ethane and benzoyl chloride were reacted in the same way as in step (a) of Example 13 to afford 1-benzoylamino-2-(2-chlorophenyl)-ethane having a melting point of 70.1° to 71.0° C. (b) 1-Benzoylamino-2-(2-chlorophenyl)ethane, phosphorus oxychloride and phosphorus pentoxide were reacted in the same way as in step (b) of Example 13 to afford 1-phenyl-5-chloro-3,4-dihydroquinoline as an oil. (c) 1-Phenyl-5-chloro-3,4-dihydroisoquinoline and diphenyl disulfide were reacted in the same way as in step (c) of Example 13 to afford 1-phenyl-5-chloroisoquinoline as colorless needles having a melting point of 66.0° to 66.6° C. (d) 1-Phenyl-5-chloroisoquinoline, copper cyanide and hexamethylphosphotriamide were reacted in the same way as in step (d) of Example 13 to afford 1-phenyl-5-cyanoisoquinoline as an oil. (e) 1-Phenyl-5-cyanoisoquinoline was treated in the same way as in step (e) of Example 13 to afford 1-phenyl-5-methoxycarbonylisoquinoline as colorless needles having a melting point of 102.2° to 103.1° C. (f) 1-Phenyl-5-methoxycarbonylisoquinoline and dihydrobis(2-methoxyethoxy)aluminum sodium (in 70% benzene) were reacted in the same way as in step (f) of Example 13 to afford 1-phenyl-5-hydroxymethylisoquinoline as colorless plates having a melting point of 97.3° to 97.9° C. (g) 1-Phenyl-5-hydroxymethylisoquinoline was treated in the same way as in step (g) of Example 13 to afford 1-phenyl-5-chloromethylisoquinoline having a melting point of 104.0° to 104.2° C. (h) 1-Phenyl-5-chloromethylisoquinoline was treated by the same way as in step (h) of Example 13 to afford 1-phenylisoquinoline-5-acetonitrile as an oil.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:24]=1)[C:19](Cl)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH:40]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH2:41][C:42]([O:44][CH3:45])=[O:43]>>[CH3:50][O:49][C:47](=[O:48])[CH2:46][N:40]([C:19](=[O:20])[C:18]1[CH:17]=[C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:22]=1)[CH2:41][C:42]([O:44][CH3:45])=[O:43]
Reactant: CCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCC)cc(C(=O)Cl)c1
Reactant: COC(=O)CNCC(=O)OC
Product: CCCCCCCCCCCCCCOc1cc(OCCCCCCCCCCCCCC)cc(C(=O)N(CC(=O)OC)CC(=O)OC)c1

Procedure:
The reaction of 3,5-bis(tetradecyloxy)benzoyl chloride with dimethyl iminodiacetate as in Example 10 gave N-[3,5-bis (tetradecyloxy)benzoyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: C(=O)([O-])[O-].[Cu+2:5].C1COCC1.[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[CH2:13]>N1C=CC=CC=1>[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=[CH2:13].[Cu+2:5].[C:11]([O-:16])(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)O
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)[O-]

Procedure:
The method of Kuchen et al. (Angew. Chem. Int. Ed. Engl.), Vol. 27, #12, pp. 1695-1697 (1988) was followed with minor variation. For example, 1.01 g (4.5×10-3 mole) of basic copper carbonate was taken in a 100 ml round bottom flask. A mixture of 50 ml of THF and 2.4 g (0.028 mole) of methacrylic acid was added to it. The system was sonicated for 8 hrs. 30 Milligrams of pyridine was added to get a deep blue solution. The solution can be used directly to prepare the master solution
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8](COC)[C:7]=2[CH:20]=1.[ClH:22]>C(O)C>[ClH:22].[CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][C:7]=2[CH:20]=1
Reactant: COCn1c(=O)c2c(c3ccc(N(C)C)cc31)NCCC2
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc2c3c(c(=O)[nH]c2c1)CCCN3
Temperature: 80 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
The compound (100 mg, 0.34 mmol) prepared in step 3 was dissolved in ethanol (5 ml) and added with conc. hydrochloric acid (1.0 ml). The mixture was stirred overnight at 80° C., cooled to room temperature, and concentrated under reduced pressure to obtain the title compound (89.6 mg, yield: 92%, yellow solid).
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C(OCC)C>[C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(=O)C2)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(O)C2)O1
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 169 mg of the (2R,5R)-2-(t-butyl)-5-((1R)-3-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one, as obtained in Step 1 of Referential Example 1, in 2 ml of methanol, 71 mg of sodium borohydride was added under cooling with ice, followed by 30 minutes' stirring at the same temperature. The reaction liquid was diluted with diethyl ether, washed with water and with saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 157 mg of the title compound was obtained as a colorless oily substance.
Reaction SMILES: C([N:8]1[C@@H:13]2[CH2:14][CH2:15][C@@:9]1([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:10]([O:16][CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[F:26][C:24]([F:25])([F:27])[C:22]1[CH:23]=[C:18]([CH2:17][O:16][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:15][CH2:14]3)[CH:19]=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=1
Reactant: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3)cc(C(F)(F)F)c1
Yield: 80 %

Procedure:
(1R*,2R*,5R*)-8-Benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 59; 1.21 g, 2.33 mmol) was dissolved in ethyl acetate (20 ml) then 10% palladium hydroxide(0.13 mg) added. Glacial acetic acid (2 ml) was added and the mixture hydrogenated at room temperature at 40 psi overnight. The reaction mixture was filtered then concentrated in vacuo. The yellow oil was basified (saturated sodium hydrogen carbonate solution), and the solution extracted with dichloromethane (×3), dried (MgSO4) and concentrated in vacuo to give a yellow oil. The reaction mixture was purified by flash column chromatography [5%-15% methanol in dichloromethane] to give the title compound as a yellow oil (0.80 g, 80%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][C@H:20]([NH:26][C@@H:27]2[C:33](=[O:34])[N:32]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[C:31]3[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=3[S:29][CH2:28]2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[BrH:47].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:47].[BrH:47].[CH2:24]([O:23][C:21]([C@@H:20]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([OH:38])=[O:37])[C:31]2[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=2[S:29][CH2:28]1)[CH2:19][CH2:18][CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)[C@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 1.5 h

Procedure:
In 2 ml of acetic acid is dissolved 0.8 g of tert-butyl 3(R)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and 3 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 hours. Ethyl ether (50 ml) is added to the reaction solution, which is then allowed to stand. The supernatant is decanted, and the precipitate is washed with ethyl ether and dried to give 0.75 g of 3(R)-[1(S)-ethoxycarbonyl-4-(4-piperidyl)butyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid.dihydrobromide as a colorless powder.