Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[S:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=O.[CH3:14][C:15]1[CH:29]=[CH:28][C:18]([CH2:19]P(=O)(OCC)OCC)=[CH:17][CH:16]=1.C[O-].[Na+]>CN(C)C=O>[CH3:14][C:15]1[CH:29]=[CH:28][C:18]([CH:19]=[CH:1][C:3]2[S:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(-c2ccccc2)s1
Reactant: CCOP(=O)(Cc1ccc(C)cc1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C=Cc2ccc(-c3ccccc3)s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
To a stirred solution of 1.52 gram (0.008 mole) of 2-formyl-5-phenylthiophene and 2.0 grams (0.00820 mole) of diethyl 4-methylbenzylphosphonate in 40 mL of N,N-dimethylformamide was added 0.53 gram (0.0098 mole) of sodium methoxide. The reaction mixture was stirred at room temperature for approximately 18 hours and then was quenched with 50 mL of an aqueous solution saturated with ammonium chloride. A precipitate formed and was collected by filtration. The filter cake was washed with water. The washed solid was purified by column chromatography on silica gel, eluting with chloroform:n-hexane (10:90) yielded 1.1 gram of 2-(4-methylphenyl)-1-(5-phenylthien-2-yl)ethene as a solid, m.p. 159°-160° C.
Reaction SMILES: [C:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][CH2:9][CH:10]([OH:38])[CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22]([C:24]3[N:28](CC4C=CC(OC)=CC=4)[N:27]=[N:26][N:25]=3)=[O:23])[C:16]([CH3:20])=[CH:17][C:18]=2[Br:19])=[C:6]([CH2:41][CH2:42][C:43]([F:46])([F:45])[F:44])[C:5]=1[OH:47])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:40]=[CH:39][C:7]([O:8][CH2:9][CH:10]([OH:38])[CH2:11][O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[O:23])[C:16]([CH3:20])=[CH:17][C:18]=2[Br:19])=[C:6]([CH2:41][CH2:42][C:43]([F:45])([F:46])[F:44])[C:5]=1[OH:47])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cc(OCC(O)COc3ccc(C(C)=O)c(O)c3CCC(F)(F)F)c(Br)cc2C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)c1ccc(OCC(O)COc2cc(NC(=O)c3nnn[nH]3)c(C)cc2Br)c(CCC(F)(F)F)c1O

Procedure:
A solution of 6.2 g of N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propoxy}-4-bromo-6-methyl-phenyl}}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 130 ml of trifluoroacetic acid and 14 ml of anisole is refluxed for 30 minutes. The reaction mixture is concentrated under reduced pressure, about 200 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. N-{{3-{3-[4-Acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-2-hydroxy-propoxy}-4-bromo-6-methyl-phenyl}}-1H-tetrazole-5-carboxamide is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH:19]([O-])=[O:20].[Na+].[C]=O>CN(C)C=O.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:19]([C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20]
Reactant: O=C[O-]
Reactant: COc1ccc(Br)cc1CNC(=O)OC(C)(C)C
Agent: [C]=O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)cc1CNC(=O)OC(C)(C)C
Yield: 75.1 %

Procedure:
1.015 g of tertiary butyl N-(5-bromo-2-methoxybenzyl)carbamate, 45 mg of dichlorobis(triphenylphosphine) palladium (II), 330 mg of sodium formate and 17 mg of triphenyl phosphine were dissolved in anhydrous N,N-dimethylformamide and stirred at 110° C. for 2 hours in a carbon monoxide atmosphere. The reaction mixture was diluted with ethyl acetate, and successively washed with water and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (3:1), 640 mg of tertiary butyl N-(5-formyl-2-methoxybenzyl)carbamate was obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.[CH2:13]([OH:16])[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[O:15]1[CH2:14][CH2:13][O:16][CH:1]1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(C2OCCO2)c1

Procedure:
A stirred solution of methyl 3-formylbenzoate (10.0 g., 61 mmol), ethylene glycol (5.0 ml, 91 mmol) and p-toluene sulphonic acid (10 mb) in toluene (100 ml) was refluxed under a Dean and Stark water trap for 4 hours. The cooled solution was washed with sodium bicarbonate solution, dried and evaporated to a pale oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH:11]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=1[CH3:22])[CH3:12].ClC(C)[CH2:25][NH:26]C1C(C)=CC=CC=1C.CC1C=C(C)C=C(C)C=1N>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:10][CH:11]([CH3:12])[N:13]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:25]1=[NH:26]
Reactant: Cc1cc(C)c(NC(C)CNc2c(C)cccc2C)c(C)c1
Reactant: Cc1cccc(C)c1NCC(C)Cl
Agent: Cc1cc(C)c(N)c(C)c1
Product: Cc1cc(C)c(N2C(=N)N(c3c(C)cccc3C)CC2C)c(C)c1
Yield: 87.6 %

Procedure:
1-(2',6'-Dimethylphenyl-amino)-2-(2',4',6'-trimethylphenyl-amino)-propane, applied as starting substance, is prepared by reacting N-(β-chloropropyl)-2,6-dimethyl-aniline, a compound prepared according to Example 3, Method (b), point (a), with 2,4,6-trimethylaniline under the conditions specified in Example 16, point (c). The aimed compound is obtained with a yield of 87.6%; m.p.: 128°-130° C. (dihydrochloride).
Reaction SMILES: C(=NC(N)=S)=O.C(Cl)(=O)[C:8]1[CH:13]=[CH:12]C=[CH:10][CH:9]=1.Cl[C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][C:18]=1[CH:24]([NH:31]C([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=NC(C1C=CC=CC=1)=O)[CH2:25]N1C=CN=C1>>[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[C:25]1([CH:24]([NH2:31])[C:18]2[CH:17]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(N=C(Nc1ccccc1)NC(Cn1ccnc1)c1ccc(Cl)cc1Cl)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: NC(=S)N=C=O
Product: NC(c1ccccc1)c1ccccc1
Product: Nc1ccccc1

Procedure:
N-[1-(2,4-Dichlorophenyl)-2-(imidazol-1-yl)-ethyl]-N′-phenyl)carbonyl thiourea. Compound A was prepared by following the procedure of Example 190, Step A, except benzoyl chloride was used instead of 4-chlorobenzoyl chloride. B. N-[1-(2,4-Dichlorophenyl)-2-(imidazol-1-yl)-ethyl]—N′-phenyl-N″-phenylcarbonylguanidine. Step B of Example 190 was followed using Compound A, above, and aniline (instead of diphenylmethylamine) to obtain Example 191. MS (ES): m/z 478 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCOCC1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(F)c(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(F)c(OC3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A6(a) from 5-fluoro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A84(f)) and tetrahydro-4H-pyran-4-ol. Yellow solid. MS (m/e): 282.3 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].C=O.CN.[CH3:23][N:24]1[CH2:29]COC[CH2:25]1>CO.CCO.O>[CH2:1]([N:3]1[CH2:25][N:24]([CH3:29])[CH2:23][N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[C:4]1=[O:5])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CCNC(=O)Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: C=O
Agent: CN
Solvent: CO
Solvent: O
Solvent: CCO
Product: CCN1CN(C)CN(c2nc3ccc([N+](=O)[O-])cc3s2)C1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
N-Ethyl-N′-(6-nitro-1,3-benzothiazol-2-yl)urea (2.8 g) was suspended in about 100 mL 1:1 EtOH/H2O at room temperature. About 8 mL of a 37% aqueous solution of formaldehyde is added followed by addition of about 15 mL of a 2M solution of MeNH2 in MeOH, then about 2.2 mL of N-methylmorpholine. The solution was warmed to about 80° C. then allowed to stir for about 16 hours. The slurry was then cooled to room temperature, filtered and washed well with water. After drying in vacuo, about 3.2 grams was isolated. 1H NMR 1.13 (t, 3H, J=7.1 Hz), 2.55 (s, 3H), 3.38 (q, 2H, J=7.1 Hz), 4.39 (s, 2H), 5.16 (s, 2H), 7.81 (d, 1H, J=8.9 Hz), 8.22 (dd, 1H, J=2.4 Hz, J=8.9 Hz), 8.95 (d, 1H, J=2.4 Hz) LC/MS=3.33 min, 322 (MH+), 320(M−H−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[I-].[Na+].[CH3:14][O:15][CH2:16][CH2:17]Br.[OH2:19]>CN(C=O)C>[CH3:14][O:15][CH2:16][CH2:17][O:19][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH2:1])[CH:7]=1
Reactant: COCCBr
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc([N+](=O)[O-])c(N)c1
Temperature: 0 °C

Procedure:
4-Amino-3-nitrophenol (58.53 g, 379.7 mMol) was dissolved in 600 mL of anhydrous DMF under an atmosphere of dry N2 and the solution was mechanically stirred. The reaction mixture was then cooled to 0° C. and to this mixture was added CS2CO3 (177.4 g, 455.7 mMol), sodium iodide (5.7 g, 37.9 mMol) and 2-bromoethyl methyl ether (39.3 mL, 417.7 mMol). After stirring for 15 minutes, the reaction mixture was then warmed up to ambient temperature and then stirred overnight. The reaction mixture is then poured into 6 L of water. The precipitate was collected via suction filtration. The wet precipitate was taken up in toluene and then concentrated under vacuum to remove the water. Finally, the solid was recrystallized from 2-propanol to give 57.93 g of 5-(2-Methoxy-ethoxy)-2-nitro-phenylamine 42A as an orange solid. A second crop of 12.5 g of compound 42A was also obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24](Cl)=[O:25])[CH:19]=1.ClC1N=CN=C(C(NC2C=CC(O)=CC=2)=O)C=1>ClCCl>[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[O:25])[CH:19]=1
Reactant: O=C(Cl)c1cc(Cl)ncn1
Reactant: Cc1cc(O)ccc1N
Agent: O=C(Nc1ccc(O)cc1)c1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A cooled (0° C.) solution of 4-amino-m-cresol (Fluka, 4.17 g, 33.9 mmol) and triethylamine (23.6 mL, 0.170 mol) in dry dichloromethane (100 mL) was treated with 6-chloropyrimidine-4-carbonyl chloride, obtained as described above for Intermediate 7, step 1 (6.0 g, 34 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo, diluted with water and extracted with EtOAc. The combined organic layers were dried on magnesium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (silica) using as eluent petroleum ether/EtOAc to afford the title compound as yellow solid.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]>>[F:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][C:46]=1[F:47])[CH2:28][N:29]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][C:36]([C:40]([NH2:7])=[O:41])=[C:37]([CH3:39])[N:38]=2)[C:30]1=[O:43]
Reactant: Cc1nc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)c(F)c3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(3,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 221-223° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.47-7.37 (m, 4H), 7.20-7.15 (m, 1H), 4.43 (s, 2H), 4.03-3.98 (m, 2H), 3.50-3.45 (m, 2H), 2.46 (s, 3H); MS (ES+) m/z 352.7 (M+1).
Reaction SMILES: [CH3:1][Si:2]1([CH3:12])[O:7][Si:6]([CH3:9])([CH3:8])[O:5][Si:4]([CH3:11])([CH3:10])[O:3]1.[C:13]([O:18][Si:19](C)([CH3:21])[CH3:20])(=[O:17])[C:14]([CH3:16])=[CH2:15].[C:23]1(C)C=CC=CC=1>>[CH3:23][Si:2]([CH3:12])([CH3:1])[O:3][Si:4]([CH3:11])([CH3:10])[O:5][Si:6]([CH3:9])([CH3:8])[O:7][Si:19]([CH3:21])([CH3:20])[O:18][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)O[Si](C)(C)C
Reactant: Cc1ccccc1
Reactant: C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O1
Product: C=C(C)C(=O)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C

Procedure:
5 g of hexamethylcyclotrisiloxane, 3.5 g of trimethylsilyl methacrylate and 0.3 g of Amberlyst A15 resin catalyst were stirred in 2.5 ml of toluene. After 7 h at room temperature the catalyst was filtered and the solvent evaporated under reduced pressure to furnish nonamethyl-1-methacryloyloxy-tetrasiloxane.
Reaction SMILES: [OH:1][C:2]([C:9](=[O:27])[NH:10][C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)([CH2:6][CH2:7][CH3:8])[C:3](O)=[O:4].[F:28][C:29]([F:33])([CH3:32])[CH2:30]N.O.O[N:36]1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[F:28][C:29]([F:33])([CH3:32])[CH2:30][N:10]([C@@H:11]1[C:17](=[O:18])[NH:16][C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]1=2)[C:9](=[O:27])[C:2]([OH:1])([CH2:6][CH2:7][CH3:8])[C:3]([NH2:36])=[O:4]
Reactant: CC(F)(F)CN
Reactant: CCCC(O)(C(=O)O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(O)(C(N)=O)C(=O)N(CC(C)(F)F)[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 48.1 %

Procedure:
A solution of 50.0 mg (0.14 mmol) 2-hydroxy-2-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-pentanoic acid and 14.2 mg (0.15 mmol) 2,2-difluoropropylamine in 2.5 ml tetrahydrofuran were cooled to 0° C. and 20.2 mg (0.15 mmol) 1-hydroxy-benzotriazole hydrate, 39 μl (0.3 mmol) diisopropylethylamine and 28.6 mg (0.15 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight. Removal of the solvent by distillation and chromatography on silicagel with heptane/ethylacetate (gradient 90:10 to 50:50) yielded 30.0 mg (50%) (R/S)-N-(2,2-Difluoro-propyl)-2-hydroxy-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-propyl-malonamide: MS (m/e): 446.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([Cl:24])[C:10]3[O:15][CH2:14][CH2:13]C(C#N)(O[Si](C)(C)C)[C:11]=3[CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:26]([OH:29])(=[O:28])[CH3:27]>>[C:1]1([C:7]2[CH:8]=[C:9]([Cl:24])[C:10]3[O:15][CH2:14][CH2:13][CH:27]([C:26]([OH:29])=[O:28])[C:11]=3[CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)OC1(C#N)CCOc2c(Cl)cc(-c3ccccc3)cc21
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C1CCOc2c(Cl)cc(-c3ccccc3)cc21
Temperature: 25 °C

Procedure:
To a 500 ml. single neck reaction flask equipped with a magnetic stirrer, reflux condenser, and nitrogen inlet was added 6-phenyl-8-chloro-4-cyano-4-trimethylsilyloxy-3,4-dihydro-2H-1-benzopyran (3.0 g.). In one portion was added stannous chloride dihydrate (15 g.) followed by glacial acetic acid (20 ml.) and concentrated hydrochloric acid (20 ml.). The reaction flask was immediately flushed with nitrogen and plunged into a preheated (140° C.) oil bath. With vigorous stirring the reaction mixture was heated at reflux for 65 hrs., cooled to room temperature, diluted with 500 ml. chloroform, the layers separated, and the aqueous layers again saturated with chloroform. The combined organic layers were extracted with three 150 ml. portions of 2 N aqueous potassium hydroxide, and the combined basic aqueous layers back-extracted with one 150 ml. portion of ether. Acidification of the basic aqueous layer with ice bath cooling, extraction with three 250 ml. portions of chloroform, drying of the combined organic layers over magnesium sulfate, filtration, and removal of the volatiles afforded 6-phenyl-8-chloro-3,4-dihydro-2H-1-benzopyran-4-carboxylic acid. Filtration of a chloroform solution of the acid through 400 ml. of silica gel (EM Reagents, 70-230 mesh) with elution by three liters of chloroform removes a small amount of an -hydroxy acid impurity. Recrystallization from cyclohexane yielded 0.93 g. (38%) of the acid, m.p. 187°-188° C.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Br[CH2:14][CH2:15][Cl:16]>C(O)C>[CH3:2][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:15][Cl:16])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCBr
Agent: [Na]
Solvent: CCO
Product: COC(=O)c1ccc(OCCCl)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To 35 mL of ethanol was added sodium pellets (2.27gm, 98.6 mmol). After all the sodium had disappeared methyl-4-hydroxybenzoate (15 gm, 98 mmol) was added in one portion at room temperature. The reaction mixture was then heated to 60° C. and treated dropwise with 1-bromo-2-chloroethane (10.2 gm, 123 mmol) in 15 mL of ethanol. The reaction was stirred for 16 hrs then cooled to room temperature and concentrated. The residue was taken up in ethyl acetate and washed with water, 2N NaOH, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel using 1:10 Ethyl acetate:Hexanes to 1:6 Ethyl acetate:Hexanes as the gradient eluant to yield 11.9 gm of the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].Cl.[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([OH:37])([C:31]4[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=4)[C:23]4[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=4)[CH:20]=3)[NH:15][C:14](=[O:38])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1.C([O-])([O-])=O.[K+].[K+].[CH2:45](O)[CH3:46]>>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:37][CH2:45][CH3:46])([C:31]4[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=4)[C:23]4[CH:30]=[CH:29][C:26]([CH:27]=[N:2][OH:3])=[CH:25][CH:24]=4)[CH:20]=3)[NH:15][C:14](=[O:38])[CH:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCO
Reactant: NO
Reactant: Cn1cncc1C(O)(c1ccc(C=O)cc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(c1ccc(C=NO)cc1)(c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1)c1cncn1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydroxylamine, hydrochloride (0.0131 mol) was added to a solution of (±)-4-[[4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzaldehyde monohydrochloride (described in Example B1) (0.0087 mol) in ethanol (45 ml). The mixture was stirred at room temperature for 1 hour and 30 minutes then refluxed for 2 hours, poured out into K2CO3 10% and extracted with EtOAc. The organic layer was separated, dried MgSO4), filtered and the solvent was evaporated. The residue (4.86 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1; 15–40 μm). The pure fractions were collected and the solvent was evaporated, yielding: two fractions. The first fraction was crystallized from CH3CN/diethyl ether. The precipitate was filtered off and dried, yielding 1.69 g (38%) of -4-[[4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-quinolinyl]ethoxy(1-methyl-1H-imidazol-5-yl)methyl]benzaldehyde oxime, of indeterminate E/Z configuration mp. 232° C. The second fraction was crystallized from CH3CN/diethyl ether. The precipitate was filtered off and dried, yielding 1.91 g (45%) of -4-[[4-(3-chlorophenyl)-1,2-dihydro-2-oxo-6-quinolinyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]benzaldehyde oxime, of indeterminate E/Z configuration, mp. 230° C.
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1)=O)C>C1COCC1>[C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C:25]2([CH:16]([C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[NH:6][C:23]2=[O:22])[CH2:26]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NC2c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A solution of 1M LHMDS (8.55 mL, 8.55 mmol) in THF was cooled to −78° C. and to this mixture 4-fluorobenzaldehyde (839 ul, 7.77 mmol) in THF (25 mL) was added dropwise. The mixture was left to stir for 50 minutes and allowed to warm to 0° C. for 10 minutes and cooled again to −78° C. In a different flask a solution of 1M LHMDS (8.55 mL, 8.55 mmol) was cooled to −78° C. and a solution of piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (2 g, 7.77 mmol) in THF (25 mL) was added dropwise. The mixture was left to stir for 40 minutes and allowed to warm to 0° C. for 10 minutes and cooled again to −78° C. The solution of trimethylsilylenamine was added dropwise to the solution of enolate maintaining the temperature below 0° C. After the addition was complete, the reaction was left to stir for 3 hours at 0° C. and allowed to warm to room temperature overnight. The reaction was quenched with water (5 ml) and the resulting solution was extracted using ethyl acetate. The organic portion was separated, dried (MgSO4) and concentrated in vacuo to yield a yellow oil. Purification by flash chromatography on silica (80 g column) eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].C(N(C(C)C)CCC(C1C=C(COC(=O)CCC=C)C=CC=1OC(=O)CCC=C)C1C=CC=CC=1)(C)C>ClCCl>[C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCCCCCC(=O)O
Agent: C=CCCC(=O)OCc1ccc(OC(=O)CCC=C)c(C(CCN(C(C)C)C(C)C)c2ccccc2)c1
Solvent: ClCCl
Product: O=C(O)CCC=CCCC(=O)O
Yield: 71 %

Procedure:
Intramolecular cyclic diester of octane-1,8-dioic acid and 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol Grubbs catalyst (benzylidene-bis-(tricyclohexylphosphine)dichlororuthenium, 16 mg, 0.002 mmol, 2 mol-%) was added to a solution of (±)-pent-4-enoic acid 2-(3-diisopropylamino-1-phenylpropyl)-4-(pent-4-enoyloxymethyl)-phenyl ester (483 mg, 0.96 mmol) in dichloromethane (150 ml) and the mixture was refluxed for 96 hrs. under an atmosphere of nitrogen gas, after which all of the starting material was consumed as indicated by tlc. The mixture was filtered through a short pad of basic alumina, and the solvent was removed an vacuum. Flash chromatography (solvent system (4)) afforded the intermediate intramolecular cyclic diester of oct-4-ene-1,8-dioic acid and 2-(3-diisopropylamino)-1-(phenylpropyl)-4-hydroxymethyl-phenol (324 mg) as a colourless syrup (tlc: (4) Rf 0.68) in 71% yield, mixture of two geometrical isomers. NMR (CDCl3, major isomer): 19.24, 20.61, 23.11, 25.62, 30.55, 33.53, 35.02, 42.41, 48.29, 50.20, 65.30, 114.46, 124.33, 125.58, 127.15, 128.70, 129.29, 131.10, 132.46, 139.54, 146.76, 147.98, 173.76, 174.39.