Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:14]([N:17]=[N+]=[N-])[CH2:15][S:16][C@H:11]12)=[O:8].[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:14]([NH2:17])[CH:15]([S:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[S:16][C@H:11]12)=[O:8]
Reactant: Sc1ccccc1
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: ClCCCl
Product: NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1Sc1ccccc1

Procedure:
To a solution of 0.675 g. of p-nitrobenzyl 7β-(2-thienylacetamido)-3-azido-3-cephem-4-carboxylate in 33 ml. of 1,2-dichloroethane were added 5 equivalents (0.74 g.) of thiophenol and the solution was heated at the reflux temperature for 90 min. The reaction mixture was evaporated to dryness and the reaction product residue was chromatographed over 8 g. of silica (Merck, toluene) using 500 ml. of toluene vs. 500 ml. of 50% ethyl acetate:toluene. The early fractions (23-26) contained a mixture of starting material and the title compound. The middle fractions (31-36) contained 0.035 g. of the title compound while the later fractions (45-59) contained 0.236 g. of the 3-amino ester.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:16])=[C:6](N)[C:7]([O:13][CH3:14])=[CH:8][C:9]=1OCC)(=[O:3])[CH3:2].[CH3:17][C:18](C1C=CC(OC)=CC=1F)=[O:19].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:16][C:5]1[CH:6]=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:4]=1[C:1]1([CH3:2])[O:3][CH2:17][CH2:18][O:19]1
Reactant: CCOc1cc(OC)c(N)c(F)c1C(C)=O
Reactant: COc1ccc(C(C)=O)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCCO
Product: COc1ccc(C2(C)OCCO2)c(F)c1

Procedure:
Starting material 3-acetyl-2-fluoro-6-methoxyphenetyl-amine, was prepared in following manner: A mixture of 2-Fluoro-4-methoxyacetophenone (5 g) (Fluorochem), ethylene glycol (4 ml), and p-toluensulfonic acid (50 mg) in toluene was refluxed 10 hours to give 5.7 g of 2-(2-fluoro-4-methoxyphenyl)-2-methyl-1,3-dioxolane. This was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-benzaldehyde according to Example 362 of WO 93/03022. This compound was converted to 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)-cinnamic acid ethylester according to the methods described in Example 353 of WO 93/03022. 2-Fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid ethylester was then treated with KOH in dioxane and water to yield 2-fluoro-6-methoxy-3-(2-methyl-1,3-dioxol-2-yl)cinnamic acid. Hydrolysis with aqueous HCl in dioxane gave 3-acetyl-2-fluoro-6-methoxycinnamic acid. N-(3-Acetyl-2-fluoro-6-methoxyphenetyl)-N'-(5-chloropyrid-2-yl)-urea was then prepared in a manner analogous to the method in Example 7. 1H NMR (250 MHz, CDCl3) δ 9.18 (br s, 1H), 8.97 (br s, 1H), 7.85 (d, 1H), 7.83 (t, 1H), 7.51 (dd, 1H), 6.83 (d, 1H), 6.70 (d, 1H), 3.82 (s, 3H), 3.57 (g, 2H), 3.08-2.92 (m, 2H), 2.51 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].C(OCC)C>C(O)C>[Cl:1][C:2]1[C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:11]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)CC)c(OCCOC)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCCOC
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To 11.3 g (0.03 mole) of the ethyl 2-chloro-3-(2-methoxyethoxy)-4-ethylsulfonylbenzoate in 100 ml of 96% ethanol was added dropwise 16 ml (1.2 eq) of 10% sodium hydroxide. After stirring at room temperature for 4 hours, 100 ml of diethyl ether was added and the organic phase was extracted with 50 ml of 5% NaOH. The aqueous phase was acidified with 10% HCl and extracted two times with 50 ml chloroform. The organic phase was dried with MgSO4 and concentrated under vacuum to yield 8.8 grams of 2-chloro-3-(2-methoxyethoxy)4-ethylsulfonylbenzoic acid as a viscous oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1)=O.[CH3:25][N:26]([CH3:31])[CH2:27][CH:28]([NH2:30])[CH3:29]>>[CH3:25][N:26]([CH3:31])[CH2:27][CH:28]([NH:30][C:3]([C:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([N:17]=2)=[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:14]2=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1)=[O:2])[CH3:29]
Reactant: COC(=O)c1cccc2nc3ccc4c(OC)cccc4c3nc12
Reactant: CC(N)CN(C)C
Product: COc1cccc2c1ccc1nc3cccc(C(=O)NC(C)CN(C)C)c3nc12
Temperature: 110 °C

Procedure:
A mixture of 4-methoxy-benzo[a]phenazine-11-carboxylic acid methyl ester (IV.1) (350 mg) and 1-dimethylamino-2-propylamine (2 mL)(commercially available) was heated to 110° C. under N2 for 4 hours. The reaction mixture was then cooled and the excess amine was removed in vacuo. The residue was then purified using flash chromatography (silica, ethyl acetate and then 25% methanol in ethyl acetate) to yield the title compound as a yellow solid (164 mg).
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4].C([OH:24])C>C(O)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([OH:24])(=[O:21])[CH2:2][CH:3]([CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][CH2:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])[CH3:4]
Reactant: CCO
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phytanol (19.5 g) was dissolved in acetic acid (250 ml) and cooled in an ice bath. Chromium trioxide (21.0 g) dissolved in a minimum amount of water was added to the above solution and stirred at room temperature for 18 hours. Ethanol (50 ml) was slowly added to the reaction mixture and stirred for a further 3 hours. Most of solvent was removed and water (250 ml) was added. This solution was extracted with ether (2×200 ml) and the combined ether extract was dried (MgSO4), decolourized with activated charcoal and filtered through a thin flash silica bed. The solvent was removed and the crude product chromatographed on flash silica (1-4% methanol in dichloromethane) to give phytanoic acid as a pale yellow liquid. Yield 7.03 g, 34%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]=1[C:15]([OH:17])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[O:26]=[C:25]1[CH:24]([N:23]2[C:15](=[O:17])[C:7]3[C:8](=[CH:12][CH:13]=[CH:14][C:6]=3[O:5][C:4]3[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=3[O:2][CH3:1])[C:9]2=[O:11])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NC1CCC(=O)NC1=O
Reactant: COc1ccccc1Oc1cccc(C(=O)O)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccccc1Oc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 88 %

Procedure:
A mixture of 3-(2-methoxy-phenoxy)-phthalic acid (0.51 g, 1.8 mmol) and rac-α-aminoglutarimide hydrochloride (0.29 g, 1.8 mmol) in pyridine (10 mL) was heated to reflux for 16 h. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with dilute aqueous HCl (2×100 mL) and water (100 mL), and was evaporated. The residue was chromatographed using a CH2Cl2-methanol gradient, eluting the title compound at 95:5 CH2Cl2-methanol, 0.59 g, in 88% yield; mp 223-225° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 6.06 (99.46%); 1H NMR (DMSO-d6) δ 2.06-2.11 (m, 1H), 2.53-2.64 (m, 2H), 2.83-2.90 (m, 1H), 3.75 (s, 1H), 5.15 (dd, J=12.4 Hz, J=5.3 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 7.06 (t, J=7.3 Hz, 1H), 7.21-7.37 (m, 3H), 7.54 (d, J=7.2 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.9, 31.0, 48.9, 55.7, 113.7, 116.5, 116.7, 120.7, 121.5, 122.3, 127.2, 133.3, 137.0, 141.3, 151.2, 154.7, 165.0, 166.6, 170.0, 172.8; Anal. Calcd for C20H16N2O6: C, 63.16; H, 4.24; N, 7.37. Found: C, 63.00; H, 4.24; N, 7.29.
Reaction SMILES: CC1(C)[O:20][C:5]2=[CH:6][C:7]3[N:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]([C:14]([OH:16])=[O:15])=[N:11][C:12]=3[CH:13]=[C:4]2[O:3]1>Cl>[OH:3][C:4]1[CH:13]=[C:12]2[C:7](=[CH:6][C:5]=1[OH:20])[N:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]([C:14]([OH:16])=[O:15])=[N:11]2
Reactant: CC1(C)Oc2cc3nc(C(=O)O)c(C(=O)O)nc3cc2O1
Agent: Cl
Product: O=C(O)c1nc2cc(O)c(O)cc2nc1C(=O)O
Temperature: 75 °C

Procedure:
Compound from Example 3E (145 mg, 0.5 mmole) was slurried in 10 ml of concentrated HCl and heated at 75° C. for 1 hour with stirring. On initial heating, the compound dissolved, then a precipitate eventually formed. The slurry was evaporated to dryness in vacuo. The residue was initially soluble in water but formed a yellowbrown precipitate within a few minutes. The water was evaporated again and the residue was dried in vacuo for 3 hours to give the title compound as a brown solid, 125 mg, m.p.>300° C.
Reaction SMILES: [C@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH2:25][CH:26]=[CH:27][P:28](=[O:35])([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])[CH:22]=[CH:23][CH:24]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]>C(O)C.[Pd]>[C@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH2:25][CH2:26][CH2:27][P:28](=[O:35])([O:29][CH2:30][CH3:31])[O:32][CH2:33][CH3:34])[CH:22]=[CH:23][CH:24]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: CCOP(=O)(C=CCc1cccc(-c2ccccc2O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)c1)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CCCc1cccc(-c2ccccc2O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)c1)OCC
Yield: 112.6 %

Procedure:
Diethyl 3-(3-(2-α-D-mannopyranosyloxyphenyl)phenyl)prop-1-enylphosphonate (0.46 g, 0.80 mmol) was dissolved in ethanol (25 ml) and hydrogenated (40 psi H2, 10% Pd/C) for 3 hours. The suspension was filtered through celite and the filtrate concentrated under reduced pressure to afford diethyl 3-(3-(2-α-D-mannopyranosyloxyphenyl)phenyl)propylphosphonate (0.46 g, quantitative).
Reaction SMILES: N[C:2]12[CH:17]([OH:18])[CH2:16][CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=31)[C:8]1[C:3]2=[CH:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+]>C(O)(=O)C.O>[CH:17]([C:2]12[CH2:16][CH:9]([C:8]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=31)[C:10]1[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: NC12c3ccccc3C(CC1O)c1ccccc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=CC12CC(c3ccccc31)c1ccccc12
Reaction time: 5 h
Yield: 100.5 %

Procedure:
To a solution of 9-amino-12-hydroxy-9,10-dihydro-9,10-ethanoanthracene (3.0 g) in acetic acid (240 ml) was added a solution of sodium nitrite (6.7 g) in water (120 ml) at 2°-5° C., and the resulting mixture was stirred at the same temperature for 1 hour and at 95°-105° C. for 5 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene layer was washed with water, dried over sodium sulfate and evaporated to dryness to give crude crystals of 9-formyl-9,10-dihydro-9,10-methanoanthracene (2.8 g), which were recrystallized to give colorless crystals (2.45 g). M.P. 99°-100° C. Further, purification by recrystallization gave analytically pure 9-formyl-9,10-dihyfro-9,10-methanoanthracene, M.P. 102.5° C.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][N:21]([C:24]([CH:26]3[CH2:28][CH2:27]3)=[O:25])[CH2:22][CH3:23])=[CH:18][C:17]([CH3:29])=[CH:16][N:15]=2)[CH:7]=1)C.[Li+].[OH-].CO>C1COCC1>[CH:26]1([C:24]([N:21]([CH2:20][C:19]2[C:14]([C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:30])=[O:3])[CH:11]=[CH:10][C:9]=3[O:12][CH3:13])=[N:15][CH:16]=[C:17]([CH3:29])[CH:18]=2)[CH2:22][CH3:23])=[O:25])[CH2:27][CH2:28]1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)C2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1cc(C)cnc1-c1cc(CC(=O)O)ccc1OC)C(=O)C1CC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To (3-{3-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-5-methyl-pyridin-2-yl}-4-methoxy-phenyl)-acetic acid ethyl ester (0.154 g, 0.38 mmol) in THF (1.5 mL) was added 1N aqueous LiOH (1.14 mL, 1.14 mmol), and enough MeOH to clarify the solution. The reaction was stirred at 40° C. for 30 minutes, until no starting material was seen by analytical tlc. The mixture was concentrated, diluted with H2O, and washed twice with EtOAc. After filtering through a 25 μM nylon filter, the aqueous layer was acidified to pH 3 with 1N aqueous HCl, and the volume was reduced by half and then saturated with NH4Cl. The mixture was extracted five times with CH2Cl2, and then the aqueous layer was concentrated to leave residual salts and a trace of liquid, which was further extracted with CH2Cl2 until only a small amount of the desired product remained in the salts. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH:14]1[CH2:16][CH2:15]1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc3c(c(N)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1

Procedure:
5-Amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1-methylpiperazine were reacted and worked up in the same way as in Example 1 to give 5-amino-1-cyclopropyl-6-fluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. m.p. 216°-218° C.
Reaction SMILES: C([O:8][C:9](=[O:39])[CH2:10][C@@H:11]([N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[CH:23]1)[C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CCO.CCOC(C)=O>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:29]=[CH:28][C:27]([C:24]2[CH:25]=[CH:26][N:22]([C@@H:11]([C:12]([NH:14][C@@H:15]([CH2:20][OH:21])[C:16]([OH:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:39])=[O:8])[CH:23]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(O)[C@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 1.83 h
Yield: 74.9 %

Procedure:
According to the procedure described in Example 1(a), a mixture of 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid benzyl ester (137 mg, 0.26 mmol) in EtOH (2.5 mL) and EtOAc (2.5 mL) was hydrogenolyzed after 110 minutes to give a white solid, which was triturated with CH2Cl2/hex to provide 85 mg(75%) of 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-[2-hydroxy-1(S)-(hydroxymethyl)-2-methylpropyl]succinamic acid as a white solid, mp 150-2° C. 1H NMR (acetone-d6): δ 7.67-7.61 (m, 6H), 7.46-7.39 (m, 3H), 7.33 (t, 1H, J=7.4 Hz), 7.09 (bd, 1H, J=8.5 Hz), 6.97 (t, 1H, J=2.4 Hz), 6.53 (t, 1H, J=2.2 Hz), 5.28 (t, 1H, J=7.2 Hz), 3.81-3.67 (m, 3H), 3.35 (dd, 1H, J=7.4, 16.9 Hz), 3.02 (dd, 1H, J=7.4, 16.9 Hz), 1.24 (s, 3H), 1.12 (s, 3H). Anal. Calculated for C25H28N2O5: C, 68.79; H, 6.47; N, 6.42. Found: C, 68.54; H, 6.50; N, 6.39.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]([O:16][CH3:17])=[O:15]>CO>[Br:3][C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[C:14]([O:16][CH3:17])=[O:15])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
Potassium hydroxide (2.87 g, 51 mmol) was added to a solution of 2-bromo-1,4-benzenedicarboxylic acid, dimethyl ester (14 g, 51 mmol) in methanol (50 mL) at 25° C. The reaction mixture was stirred at 25° C. for 24 h and then at 50° C. for 3 h. The solvent was concentrated under reduced pressure and the residue was diluted with water (100 mL) and extracted with ethyl acetate (2×200 mL). The water layer was acidified to pH 2 with 2N hydrochloric acid solution and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting solid was boiled in toluene (100 mL) and the insolubles were removed by filtration. The filtrate was concentrated to dryness under reduced pressure and the resulting solid was flash chromatographed (silica gel, 50% ethyl acetate in petroleum ether with 1% acetic acid) to give 3-bromo-4-(methoxycarbonyl)benzoic acid (3.28 g, 24% yield) as a colorless solid.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:19]>>[CH2:18]([O:20][C:21]1[C:22]([NH:27][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([S:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:7])=[O:8])[CH:10]=2)=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:19]
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCC2)c1
Reactant: CCOc1cccnc1N
Product: CCOc1cccnc1NC(=O)c1cccc(S(=O)(=O)N2CCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(pyrrolidin-1-ylsulfonyl)benzoic acid and 3-ethoxypyridine-2-amine as the starting materials.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH2:15]([NH2:18])[CH2:16][NH2:17].Cl>O>[NH2:17][CH2:16][CH2:15][NH:18][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: S=C=Nc1ccccc1
Reactant: NCCN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: NCCNC(=S)Nc1ccccc1

Procedure:
A solution of phenyl isothiocyanate (500 mg) in abs. THF (6 ml) was added dropwise over 20 minutes under argon to a solution of ethylenediamine (5.56 g) in abs. THF (6 ml). Afterwards, the reaction mixture was added to water, acidified with 10% HCl and extracted with ethyl acetate. The aqueous phase was then basified with potassium carbonate and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. Subsequently, co-evaporation with toluene was effected twice. 650 mg of the desired product remained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([CH3:21])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.C([Li])CCC.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[CH:27]1([NH:33][C:34]([C:11]2[N:12]([CH3:21])[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C=NC1CCCCC1
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C(=O)NC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole (50 mg, 0.15 mmol) from Example 32, Step C (lower Rf isomer) in THF (2.5 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.120 mL, 0.18 mmol). The reaction was stirred for 1 hr and then cyclohexyl isocyanate (0.040 mL, 0.30 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (2×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=O)[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([NH:34][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:24])(=[O:32])=[O:33])=[O:17])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: Cc1oc(C(=O)O)cc1CNc1ccc(-c2ccccc2)cc1
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(CNc2ccc(-c3ccccc3)cc2)c(C)o1

Procedure:
Compound (162) was prepared from compound (160) and 2-methyl-benzenesulphonamide by adapting the procedure of Example 38(f). LC/MS System D; Rt=10.39 mins, m/z (ES+)=461 (M+H for C26H24N2O4S).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH:14]=[CH:13][CH2:12][C:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:10](=[O:28])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:31][CH2:30][C:29]([OH:33])=[O:32]
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1cccc(Cl)c1)c1ccccc1
Reactant: C=CC(=O)OC
Solvent: CO
Solvent: COCCOC
Product: O=C(O)CCC(CC=Cc1cccc(Cl)c1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 20 h

Procedure:
Triton B (1.5 ml., 40% in MeOH) is added to a stirred solution of 1-(p-chlorophenyl)-4-phenyl-7-(m-chlorophenyl)-1,6-heptadien-3-one (22.8 g., 0.056 mole) in glyme (175 ml.), followed by addition of methyl acrylate (5.76 g., 0.067 mole) in glyme (25 ml.). After stirring for 20 hours, the solvent is removed in vacuo and water (600 ml.) and dilute hydrochloric acid (25 ml.) are added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (Na2SO4). After removal of the solvent the residue is heated on a steam bath with a solution of 20% sodium hydroxide (25 ml.) in methanol (300 ml.) for 48 hours. The methanol is removed in vacuo and the residue is dissolved in water (1200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (30 ml.), and the sticky yellow solid which precipitates is collected and air-dried, yield 4.5 g., m.p. 65°-105°C. Recrystallization from benzene-petroleum ether (30°-60°C.) followed by several recrystallizations from n-butyl chloride gives material with m.p. 150°-151°C.