Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:24](OC(C)(C)C)(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][N:6]1[C:24](=[O:29])[CH2:25][C:26](=[O:27])[CH3:28])=[O:4]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with tert-butyl acetoacetate to give the title compound as yellow oil. MS (ESI): m/z=440.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:36][CH2:37][C:38]1[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=1[CH3:44]>ClCCl>[OH:46][C:39]1[C:38]([CH2:37][NH:36][C:8](=[O:10])[C:7]2[CH:6]=[CH:5][C:4]([CH:3]([O:2][CH3:1])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][CH:11]=2)=[C:43]([CH3:44])[CH:42]=[C:41]([CH3:45])[N:40]=1
Reactant: COC(c1ccccc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(c1ccccc1)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Yield: 19.9 %

Procedure:
A mixture of 4-(methoxy(phenyl)methyl)benzoic acid (0.26 g, 1.07 mmol), 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride (309 mg, 1.61 mmol), 1-hydroxybenzotriazole (218 mg, 1.61 mmol), triethylamine (0.45 mL) and dichloromethane (15 mL) was stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (163 mg, 1.07 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(methoxy(phenyl)methyl)benzamide (Compound I-53) as a white solid (80 mg, 20%). LRMS (M+H+) m/z: calcd 376.18. found 376. HPLC purity (214 nm): 96%. 1H NMR (300 MHz, d6-DMSO): δ 11.43 (s, 1H), 8.25 (t, J=3.6 Hz, 1H), 7.30 (d, J=6.9 Hz, 2H), 7.41-7.18 (m, 7H), 5.95 (s, 1H), 5.83 (s, 1H), 4.27 (d, J=3.6 Hz, 2H), 3.31 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl:10][C:11]1[C:12]([CH3:18])=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:11]([Cl:10])[C:12]=1[CH3:18]
Reactant: O=Cc1ccccc1Cl
Reactant: Cc1c(N)cccc1Cl
Solvent: CCO
Product: Cc1c(Cl)cccc1N=Cc1ccccc1Cl
Reaction time: 0.25 h

Procedure:
o-Chlorobenzaldehyde (0.20 mole) is treated with 3-chloro-2-methyl aniline (0.20 mole) with vigorous stirring in a 1 l. Erlenmeyer Flask. After 15 mins., 33 cc of 95% ethanol is added and the reaction mixture is stirred vigorously for an additional 5 mins. The reaction mixture is left standing at room temperature for 10 mins., then it is placed in an ice bath for 0.5 hr. The crystals which formed are collected, washed with 95% ethanol, and air dried. Recrystallization from 85% ethanol gives N-(o-Chlorobenzylidene)-2-methyl-3-chloroaniline. m.p. 83°-85° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1
Reactant: CCOC(=O)c1cc2cc(OC)ccc2o1
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(O)ccc2o1

Procedure:
Ethyl 5-methoxybenzofuran carboxylate (22.7 mmol) was dissolved in dichlormethane (20 ml) and a 1.0 M solution of boron tribromide methyl sulphide complex in dichloromethane (68.1 mmol) was added. The mixture was heated at reflux over night The solvent was evaporated under vacuo and the residue purified by flash chromatography to obtain ethyl 5-hydroxybenzofuran carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:38][O:39][CH3:40])[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH2:18][Cl:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C1(OC)C=CC=CC=1.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].C(OC(C)C)(C)C>ClCCl>[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52].[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:38][O:39][CH3:40])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][Cl:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CCl)CS[C@H]12)c1nsc(N)n1

Procedure:
To a mixture of benzhydryl 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (1.47 g), dichloromethane (5 ml) and anisole (1.4 ml) was added trifluoroacetic acid (5 ml) under ice-cooling with stirring. After being stirred for 30 minutes at the same temperature, the mixture was poured into diisopropyl ether (100 ml). The resulting precipitate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid trifluoroacetate (syn isomer). This compound was dissolved in N,N-dimethylformamide (15 ml). To the solution was added 2-(N,N-dimethylamino)methyl-5-hydroxy-4-pyridone (1.24 g). After being 10 stirred for 5 hours at ambient temperature, the reaction mixture was poured into ethyl acetate (100 ml). The resulting precipitate was collected by filtration, washed with ethyl acetate. The precipitate was suspended in water (100 ml) and the suspension was adjusted to pH 2.0 with diluted hydrochloric acid. After removal of insoluble material by filtration, the aqueous solution was subjected to column chromatography on Diaion HP-20 [Trademark: prepared by Mitsubishi Chemical Industries]. The column was washed with water and the elution was carried out with 30% aqueous methanol. The fractions containing desired product were combined and methanol was evaporated in vacuo. The resulting aqueous layer was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4-carboxylate (syn isomer) (0.28 g) as a powder.
Reaction SMILES: [C:1]([CH2:13][C:14]([O:16]CC)=O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH2:19][C:20]([NH2:22])=[O:21]>Cl.C(O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]2[NH:22][C:20](=[O:21])[NH:19][C:14](=[O:16])[CH:13]=2)[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: NC(N)=O
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cc(=O)[nH]c(=O)[nH]2)cc1OC
Temperature: 120 °C
Yield: 27.6 %

Procedure:
To a mixture of ethyl veratroylacetate (45 g) and urea (11.7 g) were added conc. hydrochloric acid (5 drops) and ethanol (5 ml). The mixture was heated at 120° C. for 16 hours under reduced pressure. To the residue was added another conc. hydrochloric acid (5 drops) and ethanol (5 ml) and the mixture was heated again at 150° C. for 2 hours under reduced pressure. The resulting residue was washed successively with ethyl acetate, ethanol and isopropyl ether to give 6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (12.2 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:23])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.O>ClCCl>[F:11][C:12]1[CH:13]=[C:14]([C:15]([N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:10]=[CH:9][N:8]=[CH:7][C:3]2=3)=[O:16])[CH:18]=[C:19]([F:23])[C:20]=1[O:21][CH3:22]
Reactant: c1cc2c(cn1)NCCO2
Reactant: COc1c(F)cc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1c(F)cc(C(=O)N2CCOc3ccncc32)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
In a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (60 mg, 0.44 mmol) and 3,5-difluoro-4-methoxy-benzoyl chloride (120 mg, 0.572 mmol) were dissolved in dichloromethane (1 ml). Triethylamine (0.080 ml, 0.57 mmol) was added thereto and stirred at room temperature for 1 hour. After completion of the reaction by adding water to the reaction mixture, the organic layer was extracted with dichloromethane, and the combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:ethyl acetate:n-hexane=1:2:5. The fractions containing the product were collected and evaporated to obtain the target compound 28 as white solid (102 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].[CH:12](O)=O.C(OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:12]=[N:8][CH2:7][CH2:6]2
Reactant: O=CO
Reactant: COc1cccc(CCN)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)CCN=C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In tetrahydrofuran (100 ml), 3-methoxyphenethylamine (75.0 g) was dissolved. To the resulting solution, formic acid (60 ml) and acetic anhydride (108 ml) were added under ice cooling, followed by stirring overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture to separate the organic layer. The organic layer was washed with saturated aqueous NaCl solution and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was dissolved in benzene (200 ml), followed by the dropwise addition of phosphorus oxychloride (140 ml) under ice cooling. After stirring at 70° C. for 15 minutes, the reaction mixture was successively added with ice and 2N hydrochloric acid. The resulting mixture was stirred for 1 hour under ice cooling. The water layer was separated from the reaction mixture, neutralized with potassium carbonate and then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol=100:1), whereby the title compound (13.5 g, 17%) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[F:22]C1C=C(N2CCNCC2)C=CC=1.CN(CCN)C.O1CCCC1.[ClH:46]>>[ClH:46].[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: Fc1cccc(N2CCNCC2)c1
Agent: CN(C)CCN
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2cccc(F)c2)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 2.4 g (0.015 mole) of 1-(3-fluorophenyl)piperazine and 1.3 g (0.015 mole) of unsym-dimethyethylenediamine in a total volume of 200 ml of tetrahydrofuran gave a clear oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the collected solid was recrystallized from methanol-ethyl ether to give 2.7 g (50%) of the title compound as a white solid, m.p. 200°-203° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9](=[O:12])[C:8]2[CH2:7][O:6][CH:5]([CH2:13][CH3:14])[CH2:4][C:3]1=2.C(O[CH:19]=[CH:20][CH:21]=[CH2:22])(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:13]([CH:5]1[O:6][CH2:7][C:8]2[C:9](=[O:12])[C:10]3[C:11]([C:2](=[O:1])[C:3]=2[CH2:4]1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:14]
Reactant: CCC1CC2=C(CO1)C(=O)C=CC2=O
Reactant: C=CC=COC(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC1CC2=C(CO1)C(=O)c1ccccc1C2=O
Yield: 20 %

Procedure:
Following the procedure described in step 4, example 26, the starting quinone from step 3 herein (250 mg; 1.30 mmol) and 1-acetoxy-1,3-butadiene (876 μl; 7.8 mmol) were reacted in toluene (10 ml) to yield after chromatography using 2% ethyl acetate in toluene the title compound (62 mg; 20%) along with mixed fractions containing a lot of desired titled product (230 mg), M.P.: 98°-101° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[Cl:11].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Cl:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:18][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: OCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)c(Cl)c1
Temperature: 120 °C
Yield: 46.9 %

Procedure:
N,N-Dimethylacetamide (42 mL), 16.2 g of 1,2-dichloro-4-nitrobenzene, 12 g of 4-chlorobenzyl alcohol, and 8.7 g of potassium carbonate were mixed together, and the mixture was stirred with heating at 100 to 140° C. for 30 hr. This reaction solution was concentrated under the reduced pressure. The residue was dissolved in 100 mL of ethyl acetate and 100 mL of toluene, and the solution was washed with water and brine. The organic layer was concentrated under the reduced pressure, and the residue was recrystallized from ethanol to give 11.77 g of 2-chloro-1-(4-chlorobenzyloxy)-4-nitrobenzene (yield 46.9%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:25][C:26](=[O:36])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:18]([O:25][C:26](=[O:36])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:14]([C:13]2[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=3)=[N:10][O:11][C:12]=2[CH3:17])=[O:16])[CH2:30]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Reactant: Cc1onc(-c2ncc(Cl)cc2Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ncc(Cl)cc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Yield: 89.6 %

Procedure:
Combine 3-(3,5-dichloro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid (0.35 g, 0.0013 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.38 g, 0.0013 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25, 0.0013 mol), 1-hydroxy-7-azabenzo-triazole (0.18 g, 0.0013 mol), and N,N-diisopropylethyl amine (0.67 mL, 0.0039 mol) in N,N-dimethylformamide (8 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Concentrate and elute over silica gel using ethyl acetate/dichloromethane to give 0.603 g (90%) of the desired amide. MS(ES): (M+1)+ 517.2, 519.2 m/z.
Reaction SMILES: C([N:8]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=2)[C:15]2[C:10](=[C:11]([NH:27][CH:28]=[O:29])[C:12]([OH:26])=[CH:13][CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[ClH:30]>C(O)C.[C].[Pd]>[ClH:30].[OH:25][C:20]1[CH:19]=[C:18]([CH:16]2[C:15]3[C:10](=[C:11]([NH:27][CH:28]=[O:29])[C:12]([OH:26])=[CH:13][CH:14]=3)[CH2:9][NH:8][CH2:17]2)[CH:23]=[CH:22][C:21]=1[OH:24]
Reactant: O=CNc1c(O)ccc2c1CN(Cc1ccccc1)CC2c1ccc(O)c(O)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=CNc1c(O)ccc2c1CNCC2c1ccc(O)c(O)c1

Procedure:
450 mg of 2-benzyl-4-(3,4-dihydroxyphenyl)-8-formamido-7-hydroxy-1,2,3,4-tetrahydroisoquinoline was dissolved in 9 ml of ethanol, and after adding thereto 0.86 ml of 2N hydrochloric acid, 0.05 g of 10% palladium-carbon, hydrogenation reaction was performed at room temperature. The hydrogenation reaction was over, the reaction mixture was filtered, and concentrated. The residue was changed to precipitates with treatment of isopropyl alcohol and acetonitrile, and the precipitates were collected by filtration, affording 320 mg of 4-(3,4-dihydroxyphenyl)-8-formamido-7-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[Cl:13].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[C:14]1(=[O:24])[N:18]([CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[Cl:13])[C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12
Reactant: COC(=O)c1ccc(CBr)c(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 85 °C

Procedure:
A mixture of methyl 4-bromomethyl-3-chlorobenzoate 10 g, 38 mmol) and potassium phthalimide (9.85 g, 53 mmol) in dimethylformamide (65 mL) was stirred and heated to 85° C. for 2 h. The hot mixture was poured into ice water and the resulting solid was filtered, washed sequentially with water, ethanol and a small amount of ether and dried to give the title compound.
Reaction SMILES: Br[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:25]1[S:26][CH:27]=[CH:28][N:29]=1)CCC>>[S:26]1[CH:27]=[CH:28][N:29]=[C:25]1[C:2]1[O:6][C:5]([N:7]2[CH2:11][C@:10]3([CH:16]4[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]4)[CH2:12]3)[O:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(Br)o1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-c2nccs2)o1

Procedure:
The title compound was prepared by a method analogous to that described in Example 14 from (R)-3′-(5-bromofuran-2-yl)spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-(tri-n-butylstannyl)thiazole. The title compound (19 mg) was obtained as a pale solid, m/z 332 (MH+).
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][OH:4].Cl[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:33])([CH3:32])[CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:8]=1[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1.[Cl-].[NH4+]>C(OCC)(=O)C>[OH:4][CH2:3][CH2:2][O:5][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:33])([CH3:32])[CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C:8]=1[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)COC3CCCCO3)cc2)cc1
Reactant: OCCO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)COC4CCCCO4)cc3)ncnc2OCCO)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
Sodium (35.65 g) is gradually added to ethylene glycol (1.3 liter) at 23-75° C., and thereto is added N-[6-chloro-5-(4-methylphenyl)pyrimidin-4-yl]-4-[2-(2-tetrahydropyranyloxy)-1,1-dimethylethyl]benzenesulfonamide (160 g) at 4° C. The mixture is stirred at 100° C. for 16 hours, and allowed to cool to room temperature. The reaction mixture is poured into a mixture of a saturated aqueous ammonium chloride solution and ethyl acetate under ice-cooling, and the mixture is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium chloride solution, and the organic layer is dried over anhydrous sodium sulfate and activated carbon. The solid materials are removed by filtration through a Celite pad, and the filtrate is concentrated under reduced pressure. The residue is crystallized from ethyl acetate-diisopropyl ether to give N-[6-(2-hydroxyethoxy)-5-(4-methylphenyl)-pyrimidin-4-yl]-4-[2-(2-tetrahydropyranyloxy)-1,1-dimethyl-ethyl]benzenesulfonamide (80.26 g) as colorless crystals. In addition, the mother liquor is concentrated, and the resultant is recrystallized from ethyl acetate-diisopropyl ether to give the crystals of the above compound (73.1 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>>[C:15]([O:12][C:9]1[CH:8]=[CH:7][C:6]([S:3]([C:2]([F:13])([F:1])[F:14])(=[O:4])=[O:5])=[CH:11][CH:10]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(c1ccc(O)cc1)C(F)(F)F
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
Preparation according to Preparation 16 using 4-[(trifluoromethyl)sulfonyl]phenol (4.5 g, 23.2 mmol), acetic anhydride (13.4 g, 130 mmol) and pyridine (10.6 ml, 130 mmol). Crude yield: 6.8 g. MS m/z (rel. intensity, 70 eV) 268 (M+, 6), 157 (bp), 93 (84), 65 (52), 64 (43).
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]#[N:11])[CH2:4][CH2:3]1.B.O1CCCC1.Cl.[OH-].[Na+].CCOCC>C1COCC1.C(Cl)Cl>[NH2:11][CH2:10][CH2:9][CH2:8][N:5]1[CH2:4][CH2:3][C:2]([OH:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1
Reactant: N#CCCN1CCC(O)(c2ccccc2)CC1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: NCCCN1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 3-(4-hydroxy-4-phenylpiperidin-1-yl)propionitrile (3.71 g, 16.1 mmol, 1.00 equiv) in THF (15 mL) at room temperature was added borane-tetrahydrofuran complex (1.0M in THF, 56.3 mL, 56.3 mmol, 3.50 equiv) dropwise. The mixture was stirred at reflux for 4.5 hours and then cooled to room temperature. Aqueous HCl (6N, 85 mL) was added and the mixture was stirred at 50°-70° C. for 2 hours. The mixture was basified to pH 9-10 by addition of 6N aqueous NaOH and extracted with EtOAc (75 mL) and CH2Cl2 (3×75 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2Cl2 (75 mL) was added HCl in Et2O (1.0M, 38 mL, 2.3 equiv). After removal of the solvents, the residue was triturated with Et2O (185 mL). The resulting white solid war collected by filtration and washed with Et2O. Water (50 mL) was added to this solid, and the mixture was basified to pH 10-11 by addition of 1N aqueous NaOH and extracted with CH2Cl2 (150 mL+2×75 mL). The combined CH2Cl2 solutions were dried over MgSO4 and concentrated to give 3.12 g (83%) of colorless oil, which was characterized spectroscopically.