Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[N:16]\[OH:17])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](=[N:16]\[O:17][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:29][C:30]=3[CH3:31])=[CH:38][CH:39]=2)/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)/C(=N/O)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Sodium hydride (60% in oil, 225 mg) was added under a nitrogen atmosphere to a solution of ethyl E-2-(4-bromophenyl)-2-hydroxyiminoacetate (1.73 g) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (2.00 g) in N,N-dimethylformamide (20 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (10 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain ethyl E-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (2.54 g, yield 73%) as crystals from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization was performed from ethyl acetate-hexane. m.p. 105-106° C.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[C:2]1=[O:14].Cl.[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:2](=[O:14])[CH2:1][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:3][C:4](=[O:13])[CH2:5][CH2:6]2)[CH3:17]
Reactant: CCO
Reactant: O=C1CCc2cccc3c2N1C(=O)C3
Agent: Cl
Product: CCOC(=O)Cc1cccc2c1NC(=O)CC2

Procedure:
A solution of 5,6-dihydro-4H-pyrrolo [3,2,1-ij]-quinoline-2,4(1H)-dione (1.87 g, 0.01 mole) in ethanol (10 ml) is treated with a drop of concentrated hydrochloric acid. The mixture is refluxed 24 hours (or until the dione starting material can no longer be detected by thin layer chromatography). The solution is cooled and concentrated at reduced pressure. The product is purified by flash chromatography to yield 1,2,3,4-tetrahydro-2-oxo-8-quinoline acetic acid ethyl ester.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:39]=[CH:38][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=3)[S:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49].[Cl-].[NH4+]>C(Cl)Cl>[CH3:47][S:48]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:39]=[CH:38][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=3)[S:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])=[CH:7][CH:6]=1)(=[O:50])=[O:49]
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2CCCOc2ccc(OCCO)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2CCCOc2ccc(OCCOS(C)(=O)=O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
4-{3-[4-(2-Hydroxyethoxy)phenoxy]propyl}-7-methoxymethoxy-3-[4-(methoxymethoxy)phenyl]-3-methylthiochroman (7) prepared in Step 5 (45.6 mg, 0.082 mmol) was dissolved in CH2Cl2 (0.4 ml), which was then cooled down to 0° C. Triethylamine (23 μl, 0.17 mmol) and methanesulfonylchloride (16 μl, 0.21 mmol) were added thereto, and the mixture was stirred for 30 minutes. Saturated aqueous ammonium chloride solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and subjected to silica gel column chromatography to give 4-{3-[4-(2-methanesulfonyloxyethoxy)phenoxy]propyl}-7-methoxymethoxy-3-[4-(methoxymethoxy)phenyl]-3-methylthiochroman (8) (49.2 mg, yield 95%) as a colorless oily substance.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCCCCCOCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To sodium metal (1.32 g, 0.0573 mol) dissolved in dry ethanol (150 ml) under argon at room temperature was added diethyl malonate (14.13 g, 0.088 mol) over a period of 10 minutes and the solution left for 2 hours. B1 (10.0 g 0.044 mol) was then added dropwise over 2 hours and this solution heated at reflux overnight. Excess salts were quenched by the addition of 50 ml of water and the total solvent volume reduced to 50-100 ml. Diethyl ether (100 ml) and water (50 ml) were added and the aqueous layer extracted 3 times with diethyl ether. The organic fractions were combined, dried (K2CO3), and the solvent removed to yield the crude product as a yellow oil. Distillation of the oil (0.5 mBar, 220° C.) gave the title compound (10.52 g, 68%) as a colourless viscous oil. δH (CDCl3) 1.32 (6H, t, Me), 1.43 (6H, br s, (CH2)3CH2CH), 1.69 (2H, p, CH2CH2O), 1.99 (2H, q, CH2CH), 3.39 (1H, t, CH), 3.53 (2H, t, CH2OCH2Ph), 4.25, 4.28 (4H, 2×q, OCH2Me), 4.57 (2H, s, CH2Ph), 7.3-7.4 (5H, m, Ph). δC (CDCl3) 13.9 (2 C, Me), 25.7 (1 C, CH2(CH2)2CH), 27.1 (1 C, CH2(CH2)2O), 28.5 (1 C, CH2CH2CH), 28.9 (1 C, CH2CH2O), 29.5 (1 C, CH2CH), 51.8 (CHCO2Et), 61.0 (2C, OCH2Me), 70.1, 72.7 (2C, CH2OCH2), 127.3 (1C, CH(CH)2C), 127.4 (2C, CGC), 128.1 (2C, CHCHC), 138.5 (1C, CCH2O) 169.3 (2C, CO2).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][C:19]([S:23]([CH3:26])(=[O:25])=[O:24])=[N:20][CH:21]=3)[N:16]([CH3:27])[N:15]=2)=[CH:10][CH:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:26][S:23]([C:19]1[N:18]=[C:17]2[N:16]([CH3:27])[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=3)[C:22]2=[CH:21][N:20]=1)(=[O:25])=[O:24]
Reactant: Cn1nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)c2cnc(S(C)(=O)=O)nc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2ccc(N)cc2)c2cnc(S(C)(=O)=O)nc21

Procedure:
[4-(6-Methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-phenyl]carbamic acid tert-butyl ester (1.49 g, 3.70 mmol) was treated with TFA (30% in CH2Cl2, 40 ml) at room temperature for 1 hr. Solvent was removed on rotavap and the residual was taken into 5% Na2CO3 (50 ml) and the product was extracted by CH2Cl2×10, the organic extracts were combined and washed by brine, drying and concentration left 750 mg as a light brown solid; LC/MS(m/e)=304 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](=O)[CH3:12])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C1C=C(C=CC=1)C=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C@H:36]([NH2:38])[CH3:37])[CH:33]=[CH:34][CH:35]=1.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C@H:11]([NH:38][C@@H:36]([C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=2)[CH3:37])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)CCc1cccc(C(F)(F)F)c1
Reactant: COc1cccc([C@@H](C)N)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=Cc1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cccc([C@@H](C)N[C@H](C)CCc2cccc(C(F)(F)F)c2)c1

Procedure:
In a similar fashion an equal molar amount of 4-(3-trifluoromethylphenyl)-2-butanone, prepared from m-trifluoromethylbezaldehyde, (R)-1-(3-methoxyphenyl)ethylamine and 1.25 equivalents titanium(IV) isopropoxide were mixed and the intermediate imine reduced with ethanolic sodium cyanoborohydride. Work-up and repetitive preparative thin-layer chromatography using 5% methanol in chloroform afforded (R,R)-N-[4-(3-trifluoromethylphenyl)-2-butyl]-1-(3-methoxyphenyl)ethylamine, 21Y [m/z (rel. int.) 351 (M+, 2), 336 (18), 216 (4), 202 (3), 178 (45), 135 (100), 105 (13), 91(9), 77 (8)] and (S,R-N-[4-(3-trifluoromethylphenyl)-2-butyl]-1-(3-methoxyphenyl)ethylamine, 21X.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH:4]1[C:11]2[CH:10]=[C:9]([C:12]([O:14]C)=[O:13])[NH:8][C:7]=2[CH2:6][CH2:5]1.[OH-].[Li+]>>[F:17][C:2]([F:1])([F:16])[CH2:3][CH:4]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[NH:8][C:7]=2[CH2:6][CH2:5]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cc2c([nH]1)CCC2CC(F)(F)F

Procedure:
The title compound was synthesized from methyl 4-(2,2,2-trifluoroethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.2888 g, 1.2 mmol, 1 equiv) and lithium hydroxide (1.1 mL, 2 M aqueous, 5.3 equiv) according to General Procedure 7. The resulting product was purified by preparative HPLC (using the Chromeleon purification system (0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 50% methanol and increasing to 100% over 7 minutes)) to afford the title compound. 60.2 mg, (63%), with purity by HPLC of 98.9% (UV). LCMS m/e 232 (M−H). 19F NMR (376 MHz, METHANOL-d4) δ ppm −66.50 (t, J=9.94 Hz, 3F). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.05-2.17 (m, 1H), 2.19-2.33 (m, 1H), 2.44 (ddd, J=14.88, 11.45, 6.56 Hz, 1H), 2.59-2.83 (m, 3H), 3.23 (quin, J=6.79 Hz, 1H), 6.65 (s, 1H).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=CC=1[O-])([O-])=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])=[CH:17][CH:16]=1.[C:30]([O:34][CH3:35])(=[O:33])[C:31]#[CH:32].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:23]([O:22][CH2:21][C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[CH:32][C:31]([C:30]([O:34][CH3:35])=[O:33])=[C:16]2[CH:17]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc[n+](N)cc1
Reactant: C#CC(=O)OC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnn2ccc(CO[Si](C)(C)C(C)(C)C)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-amino-4-((tert-butyldimethylsilyloxy)methyl)pyridinium 2,4-dinitrophenolate Y-4 (13.4 g, 31.6 mmol) in DMF (60 mL) were added methyl propiolate (2.7 g, 31.6 mmol) and K2CO3 (6.5 g, 47.4 mmol). The reaction was stirred at room temperature for 24 h, then treated with water. The resulting mixture was extracted with ethyl acetate (100 ml×3), the combined organic layers were washed with water, brine and dried over Na2SO4, then concentrated in vacuo, the residue was purified by silica gel chromatography to afford the title compound (2.9 g). MS (m/z): 321 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1([Cl:12])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.Cl>CC(C)=O.O>[Cl:1][C:2]1([Cl:12])[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: ClC1(Cl)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(Cl)(Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 8,8-dichloro-1,4-dioxaspiro[4.5]decane (0.27 g, 1.28 mmol) in acetone (3.5 mL), aqueous 2N hydrochloric acid (5 mL) was added and the reaction mixture was stirred at room temperature overnight, diluted with water and extracted twice with diethyl ether. The combined organic phases were washed with water, brine, dried over sodium sulfate and evaporated to dryness. The resulting crude 4,4-dichlorocyclohexanone, obtained as a white solid, was used in the next steps without any further purification (0.17 g, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:36]=[CH:35][C:24]([O:25][CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][C:28]([CH3:33])([CH3:34])[C:29]([OH:31])=[O:30])=[CH:35][CH:36]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)C(C)C)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)cc2)c2ccccc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[(4-chlorophenyl)(isobutyryl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoate was dissolved in methanol/tetrahydrofuran/water (2/1/1) then sodium hydroxide (3 equivalents) was added and reaction mixture stirred at 40° C. overnight. The mixture was concentrated, the residue acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-(4-{[(2S,4R)-4-[(4-Chlorophenyl)(isobutyryl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=5[N:21](C(C)=C)[C:20]4=[O:32])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Cl.C(O)C>O>[OH2:9].[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:32])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:32])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4cc(Cl)ccc43)CC2)c2cc(C)ccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2[nH]c(=O)n(CCCN3CCC(n4c(=O)[nH]c5cc(Cl)ccc54)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 6.4 parts of 3-{3-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2-one, 24 parts of a concentrated hydrochloric acid solution, 80 parts of ethanol and 50 parts of water is stirred for 1 hour at room temperature. The reaction mixture is evaporated and the residue is stirred in ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 4-methyl-2-pentanone. The product is filtered off and crystallized from a mixture of N,N-dimethylformamide and water, yielding 2.5 parts (40%) of 5-chloro-1-{1-[3-(2,3-dihydro-6-methyl-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one hemihydrate; mp. 195.4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH:22]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(Cc1ccc(Cl)c(Cl)c1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(3,4-dichlorobenzyl)-4-phenyl-5-oxohexanoic acid (5.48 g., 0.015 mole) and sodium hydroxide (0.80 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. Then the reaction solution is cooled to room temperature, diluted with water (250 ml.), and extracted with ether to remove the excess p-chlorobenzaldehyde. The aqueous phase is then acidified with dilute hydrochloric acid (15 ml.). The organic material which separates is extracted into ether, washed with saturated brine, and dried over Na2SO4. The ether is removed in vacuo, and trituration of the residue with ethanol (25 ml.) produces 1.6 g. of solid. Recrystallization from butyl chloride gives material with m.p. 155°-156.5°C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH2:7])=[O:6].[C:14]1([CH2:24][CH2:25][OH:26])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[C:14]1([CH2:24][CH2:25][O:26][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[N+:11]([O-:13])=[O:12])[C:5]([NH2:7])=[O:6])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: OCCc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc([N+](=O)[O-])c(OCCc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
To a solution of 3-fluoro-4-nitro-benzamide (1.0 g, 5.43 mmol) in tetrahydrofuran (55 mL) at room temperature was added 1-napthaleneethanol (1.02 g, 5.97 mmol) followed by potassium tert-butoxide (0.67 g, 5.97 mmol). The reaction was allowed to stir overnight at room temperature. The reaction was then diluted with ethyl acetate and washed with 1N hydrochloric acid (50 mL), saturated sodium bicarbonate (50 mL), and saturated sodium chloride (50 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a pale yellow solid. The powder was collected and washed with ether, followed by drying under reduced pressure to yield 3-(2-naphthalen-1-yl-ethoxy)-4-nitro-benzamide 1.09 g (60%). 1HNMR(300 MHz, DMSO) 8.13 (d, 2H), 7.91 (t, 2H), 7.88 (dd, 1H), 7.72(s, 1H), 7.64 (s, 1H), 7.41 (m, 5H), 4.50 (t, 2H), 3.54 (t, 2H). MS(APCI) m/z 335.1 (M−H). Anal. Calcd. for C19H16N2O4: C, 67.85; H, 4.79; N, 8.33. Found: C, 67.35; H, 4.53; N, 8.06.
Reaction SMILES: COC1C=CC(C[CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][NH:20][C:21]([CH:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26](=[O:33])[N:25]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]4[OH:40])[CH:24]3[C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][C:42]=3[Cl:48])=[O:22])[CH:13]=2)[C:9]([O-:11])=[O:10])=CC=1.FC(F)(F)C(O)=O>C(Cl)CCl>[Cl:48][C:42]1[CH:43]=[C:44]([Cl:47])[CH:45]=[CH:46][C:41]=1[CH:24]1[CH:23]([C:21]([NH:20][CH2:19][CH2:18][C:14]2[CH:13]=[C:12]([CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:16][CH:15]=2)=[O:22])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[OH:40]
Reactant: COc1ccc(CC(C(=O)[O-])c2cccc(CCNC(=O)C3c4ccccc4C(=O)N(C4CCCCC4O)C3c3ccc(Cl)cc3Cl)c2)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cccc(CCNC(=O)C2c3ccccc3C(=O)N(C3CCCCC3O)C2c2ccc(Cl)cc2Cl)c1
Reaction time: 4 h
Yield: 41.1 %

Procedure:
To a mixture of 990 mg of 4-methoxybenzyl(3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetate and 10 ml of ethylene chloride was added 10 ml of trifluoroacetic acid at room temperature, followed by stirring for 4 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 20 mL of methanol, and 20 mL of a saturated aqueous sodium hydrogen carbonate solution was added thereto at room temperature, followed by stirring for 30 minutes. The organic solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and neutralized with 1 M hydrochloric acid. The product was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 339 mg of (3-{2-[({(3RS,4RS)-3-(2,4-dichlorophenyl)-2-[(1SR,2SR)-2-hydroxycyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl}carbonyl)amino]ethyl}phenyl)acetic acid as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:38](=[O:39])[CH2:37][O:36][CH3:35])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: COCC(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, methoxyacetyl chloride.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O.O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.8 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (10 g, 52.8 mmol) produced in Example A7(ii) in tetrahydrofuran (100 mL) were added N,N-dimethylformamide (4 drops) and oxalyl chloride (6.28 mL, 72.0 mmol), and the mixture was stirred at room temperature for 1.5 hr. The solvent was evaporated under reduced pressure to give a residue. To a solution of 3-aminophenol (5.24 g, 48.0 mmol) in tetrahydrofuran (40 mL) was added a suspension of sodium hydrogencarbonate (6.05 g, 72.0 mmol) in water (60 mL), and the mixture was stirred vigorously at room temperature. To this mixture was added dropwise a solution of the residue obtained above in tetrahydrofuran (60 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was filtered off through a pad filled with two layers of silica gel and celite. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate-hexane mixture to give the title compound (13.03 g, 96%) as a white powder.