Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[CH:4][CH:3]=1.C(O)(=O)C.Cl>O>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[C@@H:13]2[CH2:15][C@@H:14]2[F:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(Cl)ccc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(Cl)ccc2c1=O
Temperature: 130 °C
Yield: 88.8 %

Procedure:
A mixture of ethyl 7,8-dichloro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.114 g, 3.237 mmol), acetic acid (8 ml) and concentrated hydrochloric acid (4 ml) was heated under reflux for 2 hours in an oil bath at 130° C. After then adding water (40 ml) and cooling with ice, the crystals formed were filtered out and washed with water (5 ml×2), 5% aqueous ethanol solution (5 ml×2), and diethyl ether (5 ml×2), thereby obtaining 909 mg (89%) of the title compound as a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][N:7]=[C:6](Cl)[CH:5]=1.O1CCCC1.[Br-].[F:18][C:19]1([F:27])[CH2:24][CH2:23][CH:22]([CH2:25][Zn+])[CH2:21][CH2:20]1>C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:18][C:19]1([F:27])[CH2:24][CH2:23][CH:22]([CH2:25][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=2)[C:3]([O:2][CH3:1])=[O:11])[CH2:21][CH2:20]1
Reactant: FC1(F)CCC(C[Zn+])CC1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(CC2CCC(F)(F)CC2)c1
Temperature: 60 °C
Yield: 76.6 %

Procedure:
To methyl-2-chloroisonicotinate (1.664 g, 9.7 mmol) and bis(tri-tert-butylphosphine)palladium(0) (198 mg, 0.38 mmol) under nitrogen was added tetrahydrofuran (10 mL). To the resulting solution was added freshly prepared ((4,4-difluorocyclohexyl)methyl)zinc(II) bromide (14.55 mmol, 0.5 M in 29 mL DMA) and the resulting brown mixture heated to 60° C. for 4 h. The reaction mixture was diluted with ethyl acetate and washed with satd NaHCO3 (2 times), satd NH4Cl and brine. The organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and added onto an SCX-2 cation exchange column. The column was washed with DCM, MeOH and then eluted with NH3/MeOH. The NH3/MeOH layer was evaporated leaving methyl 2-((4,4-difluorocyclohexyl)methyl)isonicotinate (2 g, 67%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 1.30-1.46 (m, 2H), 1.58-1.79 (m, 4H), 1.87-2.14 (m, 3H), 2.82 (d, 2H), 3.96 (s, 3H), 7.65-7.73 (m, 2H), 8.70 (d, 1H). MS m/z 270 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[F-:13].[K+]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([F:13])(=[O:11])=[O:10]
Reactant: [F-]
Reactant: Cc1ccc(Br)c(S(=O)(=O)Cl)c1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Br)c(S(=O)(=O)F)c1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
32 g of 2-bromo-5-methylbenzenesulfonyl chloride are dissolved in 75 ml of dioxane, and a solution of 20.6 g of KF in 20 ml of water is added. The mixture is stirred at 45° C. for 48 h, poured into 500 ml of water and stirred subsequently for 30 min, and finally the product is filtered off with suction. 24 g of a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:27])[C:10]([NH:24][CH2:25][CH3:26])=[C:11]([C:13]3[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[CH:12]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].O1CCCC1>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]3[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[C:10]3[N:24]([CH2:25][CH3:26])[C:29](=[O:30])[NH:27][C:9]=3[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCNc1c(N)cc(-c2c(C)noc2C)cc1-c1c(C)ccc2ncccc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(=O)[nH]c2cc(-c3c(C)noc3C)cc(-c3c(C)ccc4ncccc34)c21
Temperature: 105 °C

Procedure:
4-(3,5-Dimethylisoxazol-4-yl)-N1-ethyl-6-(6-methylquinolin-5-yl)benzene-1,2-diamine (90 mg, 0.24 mmol) and 1,1′-carbonyldiimidazole (86.2 mg, 0.53 mmol) were added to tetrahydrofuran (10 ml) in a sealed vessel and heated to 105° C. overnight. The reaction mixture was the diluted in EtOAc and aqueous ammonium chloride and extracted with EtOAc (3 times). Organics were washed with ammonium chloride, water and brine and dried over sodium sulfate. Solvent was evaporated to dryness Crude material was purified by silica gel chromatography (DCM/MeOH as eluent) then by preparative HPLC to afford 5-(3,5-dimethylisoxazol-4-yl)-1-ethyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: B.O1CCCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[Br:28][C:29]1[CH:38]=[CH:37][C:32]([C:33](=[O:36])[CH2:34][Br:35])=[CH:31][CH:30]=1.Cl>C1(C)C=CC=CC=1.ClCCl.CO>[Br:35][CH2:34][C@H:33]([C:32]1[CH:37]=[CH:38][C:29]([Br:28])=[CH:30][CH:31]=1)[OH:36]
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O[C@H](CBr)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.9 %

Procedure:
A borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran, 270 ml, 270 mmol) was added to the solution of (S)—CBS ((S)-2-methyl-CBS-oxazaborolidine, 50 ml, 1.0M solution in toluene) at −30° C. over 15 minutes and the solution was stirred for 15 minutes. 4-Bromophenacyl bromide (75.0 g, 270 mmol) in dichloromethane (350 ml) was dropped over 70 minutes keeping the temperature −32 to −28° C. After one hour stirring, the solution was warmed to room temperature, and methanol (10 ml) was added slowly and then 0.5 M hydrochloric acid (300 ml) was dropped over 10 minutes. The solution was filtered after 40 minutes stirring and filtrate was extracted with dichloromethane. The combined organic layer was washed with 0.5 M hydrochloric acid, 0.1M aqueous sodium hydroxide and brine and dried over anhydrous sodium sulfate. Concentration of the organic layer yielded 2-bromo-(1S)-1-(4-bromophenyl)ethanol (77 g) as a pale brown oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.O.[F:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:18][C:19]1[C:24]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OB(O)c1cccnc1F
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Temperature: 100 °C
Yield: 52.7 %

Procedure:
A solution of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1) (6.00 g, 25.1 mmol) in dioxane (54 mL) was sequentially treated with water (7.2 mL), 2-fluoropyridin-3-ylboronic acid (Asymchem Laboratories, Inc., Morrisville, N.C.) (5.31 g, 37.7 mmol), sodium carbonate monohydrate (9.35 g, 75.4 mmol) and PdCl2(dppf) (Strem Chemicals, Inc., Newburyport, Mass.) (0.616 g, 0.754 mmol). The stirred mixture was degassed (alternating vacuum/nitrogen) and heated under nitrogen at 100° C. for 10 h. The mixture was cooled and extracted into EtOAc (500 mL) from water (400 mL). The aqueous layer was extracted with EtOAc (200 mL) and the combined organic extracts were dried (MgSO4), filtered through Celite® (diatomaceous earth), and concentrated. The crude product was dissolved in a small volume of DCM and purified by flash chromatography (50% to 75% to 100% EtOAc/hexane) to give 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.96 g, 53% yield) as an off-white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.11 (s, 1H), 8.91 (s, 1H), 8.58 (m, 1H), 8.49 (s, 1H), 7.62 (m, 1H), 5.85 (d, 1H), 4.05 (m, 1H), 3.75 (m, 1H), 2.38 (m, 1H), 2.05 (m, 2H), 1.79 (m, 1H), 1.61 (m, 2H).
Reaction SMILES: [ClH:1].[CH:2]1([NH:5][C:6](=[O:25])[CH:7]([OH:24])[CH:8]([NH:16]C(=O)OC(C)(C)C)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.COC(C)(C)C>C(Cl)Cl>[ClH:1].[NH2:16][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:7]([OH:24])[C:6]([NH:5][CH:2]1[CH2:4][CH2:3]1)=[O:25]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: NC(Cc1ccccc1)C(O)C(=O)NC1CC1
Reaction time: 8 h
Yield: 95.5 %

Procedure:
HCl (4 M in dioxane, 16 mL, 64.00 mmol) was added dropwise to a solution of tert-butyl 4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-ylcarbamate (7.5 g, 22.43 mmol) in DCM (130 mL). After stirring for 5 h additional HCl (4 M in dioxane, 5 mL, 20.00 mmol) was added and the stirring was continued overnight. The solvent was reduced in vacuo and methyl-tert-butyl-ether (200 mL) was added. The precipitate obtained was filtered, washed with methyl-tert-butyl-ether and n-pentane and dried providing the title compound (5.8 g, 96%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)=O.Cl.[H][H]>C(O)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CN(C)CCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)CCCc1ccc(N)cc1
Reaction time: 6 h

Procedure:
A solution of 3-dimethylamino-1-(4-nitrophenyl)propan-1-one (hydrochloride, 0.25 g) in glacial acetic acid (10 ml) was adjusted to pH 1 with concentrated hydrochloric acid and, under nitrogen, palladium(II) hydroxide (20% on carbon, 0.1 g) was added. The nitrogen atmosphere was replaced by hydrogen, and the suspension was shaken for 6 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous phase was adjusted to pH>12 with sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases were dried and concentrated. The product with the molecular weight of 178.28 (C11H18N2); MS (ESI): 179 ([M+H]+), was obtained in this way.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH:36]([Br:39])[CH:37]=[O:38])[CH:31]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:30]2=[O:48])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[CH:36]([Br:39])[CH:37]=[O:38])[CH:31]([NH:40][C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[C:30]2=[O:48])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CS(=O)C12
Reaction time: 0.5 h

Procedure:
A solution of 85% pure meta-chloroperbenzoic acid (4.31 g) in methylene chloride (50 cc) is added dropwise, over a period of 30 minutes, to a solution, cooled to between 0° and -5° C., of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (mixture of the diastereoisomers at the substituent in the 3-position) (14.69 g) in methylene chloride (150 cc). After 30 minutes at -5° C., the reaction mixture is poured into a mixture of a semi-saturated solution of sodium bicarbonate (100 cc) and methylene chloride (200 cc). The organic phase is washed with distilled water (150 cc) and a semi-saturated solution of sodium chloride (150 cc) and then dried over sodium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 20° C. to give crude 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8 -oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (mixture of the diastereoisomers at the substituent in the 3-position) (13.35 g) in the form of a hard, light brown foam. The crude product obtained is divided into 2 batches, which are chromatographed on a column (height: 30 cm, diameter: 5 cm) of silica gel (0.04-0.063 mm), elution being carried out under a pressure of 0.4 bar (40 kPa) with a mixture of cyclohexane and ethyl acetate (40/60 by volume), and 125 cc fractions being collected. Fractions 7 to 10 from both chromatographic separations are combined and concentrated to dryness under reduced pressure (30 mm HG; 4 kPa) at 20° C. to give 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (mixture of the diastereoisomers at the substituent in the 3-position) (2.43 g) in the form of a hard yellow foam.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH:8]=[N:9][OH:10])=[O:5].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.[CH3:38][OH:39].Cl.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]([CH:38]=[O:39])[OH:10])=[O:5]
Reactant: CO
Reactant: O=C(NCC=NO)c1cc(Cl)cc(Cl)c1Cl
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Product: O=CN(O)CCNC(=O)c1cc(Cl)cc(Cl)c1Cl
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of 2,3,5-trichloro-N-(2-hydroxyimino-ethyl)-benzamide (0.85 g, 3.0 mmol ) in MeOH (50 mL) under an argon atmosphere at 0° C. was added methyl orange (trace) followed by a saturated solution of MeOH/HCl until a persistent red color was observed. Sodium cyanoborohydride (0.23 g, 3.65 mmol) was dissolved in MeOH (5 mL) was added sequentially with saturated MeOH/HCl over 0.5 h. The reaction mixture was stirred an additional 1 h and the MeOH was removed in vacuo. The residue was basidified with 10% NaOH and extracted (4×25 mL) with dichloromethane/MeOH (9:1). The combined organic extracts were washed with brine, were dried (NaHCO3) and were concentrated. The residue was diluted with ether/MeOH (9:1) and the precipitate was collected to provide the title compound (0.27 g, 32%) as a white solid. ESMS: M+H=283.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28]C)[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[C:15]([C:21]([OH:23])=[O:22])=[N:14]2)=[CH:8][C:7]=1[CH3:24].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[OH:28])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[C:15]([C:21]([OH:23])=[O:22])=[N:14]2)=[CH:8][C:7]=1[CH3:24]
Reactant: COc1ccc(Oc2c(C)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2C)cc1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(-n2nc(C(=O)O)c(=O)[nH]c2=O)cc(C)c1Oc1ccc(O)c(Br)c1
Reaction time: 18 h
Yield: 52.6 %

Procedure:
To a solution (40 ml) of 2-[4-(3-bromo-4-methoxy-phenoxy)-3,5-dimethyl-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid (800 mg) in methylene chloride (40 ml) was added boron tribromide (5.2 ml of a 1.0 M solution). After stirring for 18 h, the reaction mixture was poured over ice and stirred at room temperature for 3 h. The reaction was extracted three times with 1N potassium hydroxide, and the aqueous layers were combined, acidified to pH 2 with hydrochloric acid, and extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried and concentrated to give fluffy yellow solid (408 mg) of the title compound. MS Calc.447; Found: 446 (M−1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12]>C(O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][C@@H:2]1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)C1CCc2ccccc2O1
Solvent: CCO
Product: O=C(O)[C@H]1CCc2ccccc2O1
Yield: 13.4 %

Procedure:
A solution of (+)-(R)-α-methylbelnzylamine (0.37 mol) in ethanol (100 ml) was added to a solution of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (0.36 mol) in ethanol (200 ml). The mixture was allowed to crystallize out. The precipitate was filtered off and dried. The residue was crystallized 4 times from ethanol. The precipitate was filtered off and dried. The residue was taken up in water, treated with HCl 10% and extracted with diethyl ether. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 8.6 g of (−)-(R)-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (mp. 85.5° C., [α]D20=−6.7° (c=100 mg/10 ml in methanol)) (interm. 1).
Reaction SMILES: C(C=O)=O.CC(C=O)=O.[CH2:10]([C:17]([CH:19]=O)=O)[C@H:11](O)[C@H:12](O)[CH2:13]O.Cl(O)(=O)(=O)=O.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>CC(=O)C(=O)C>[N:32]1[C:12]2[C:11](=[CH:10][CH:17]=[CH:19][CH:13]=2)[N:33]=[CH:26][CH:27]=1.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]
Reactant: O=CC(=O)C[C@H](O)[C@H](O)CO
Agent: CC(=O)C(C)=O
Agent: CC(=O)C=O
Agent: Nc1ccccc1N
Product: c1ccc2nccnc2c1
Reaction time: 1 h

Procedure:
The quantities of residual glyoxal, methylglyoxal, and 3-deoxyglucosone in the sample solution were determined by high-performance liquid chromatography (HPLC) following the incubation. More specifically, 40 μl of 2M perchloric acid, 40 μl of 1% o-phenylenediamine, and 100 μl of 25 μM 2,3-butanedione were added to 100 μl of the sample after the incubation; the mixture was stirred and incubated at 25° C. for 1 hour. Quinoxaline derivatives produced in the reaction of the dicarbonyl compounds and o-phenylenediamine were quantified by HPLC using a reverse-phase column according to the method of Ohmori et al. (Ohmori S. et al., J. Chromatogr. 414: 149–155,1987). Glyoxal, methylglyoxal, and 3-deoxyglucosone were used as standard samples.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([CH3:41])=[C:18]([C:37]([F:40])([F:39])[F:38])[C:19]=2[CH2:20][O:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([CH2:29][CH2:30][C:31](OCC)=[O:32])=[CH:24][C:23]=2[F:36])=[CH:11][CH:10]=1)[CH3:8]>>[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]([CH3:41])=[C:18]([C:37]([F:38])([F:40])[F:39])[C:19]=2[CH2:20][O:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([CH2:29][CH2:30][CH2:31][OH:32])=[CH:24][C:23]=2[F:36])=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(CC)cc3)sc(C)c2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2sc(C)c(C(F)(F)F)c2COc2c(F)cc(CCCO)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 223 by LAH reduction of ethyl 3-(4-[[2-(4-ethylphenyl)-5-methyl-4-(trifluoromethyl)thiophen-3-yl]methoxy]-3,5-difluorophenyl)propanoate to give the desired product as off-white oil. 1H NMR (300 MHz, CDCl3) δ: 7.47 (d, J=8.1 Hz, 2H), 7.24 (s, 2H), 6.74 (d, J=9.3 Hz, 2H), 5.02 (s, 2H), 3.66-3.72 (m, 2H), 2.68-2.74 (m, 2H), 2.60 (s, 3H), 1.81-1.88 (m, 2H), 1.27 (t, J=3.9 Hz, 3H). Mass spectrum (ESI, m/z): Calcd. for C24H23F5O2S, 283.1 [M-C9H9F2O2]. found 283.1.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:31]([C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)[C:32]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Reactant: COc1ccc(N=C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(Cl)nc32)cc1
Yield: 68.2 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 4-methoxyphenyl isocyanate (1.31 mL, 9.51 mmol) in DMA afforded crude product. Recrystallization from chloroform provided 1.85 g of the title compound as a solid, mp 238-240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: O=C(Cl)C=Cc1ccc(Cl)cc1
Yield: 100.4 %

Procedure:
3-(4-chloro-phenyl)-acryloyl chloride was prepared as follows: To a stirred suspension of 4-chloro-trans-cinnamic acid (2.51 g, 13.77 mmol) in benzene was added thionyl chloride (1.1 mL, 15.14 mmol) and a catalytic amount of DMAP. The reaction mixture was heated at reflux for 1.5 h. The volatile materials were removed under reduced pressure. The white residue was dissolved in Et2O and concentrated again under reduced pressure, to give 3-(4-chloro-phenyl)-acryloyl chloride (2.78 g, quantitative) as a white solid: 1H NMR (CDCl3) δ 7.81 (d, 1H, J=15.6 Hz), 7.54 (d, 2H, J=8.6 Hz), 7.44 (d, 2H, J=8.6 Hz), 6.65 (d, 1H, J=15.6 Hz).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:15]([OH:21])[C:16]([O:18]CC)=[O:17])[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1>[CH2:1]([O:8][C@H:9]([C@@H:15]([OH:21])[C:16]([OH:18])=[O:17])[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](OCc1ccccc1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](O)[C@@H](OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
(2R,3R)-Diethyl 2-(benzyloxy)-3-hydroxysuccinate (15 g, 50.6 mmol) was dissolved in 30% aqueous THF (250 mL) and lithium hydroxide hydrate (4.25 g, 101 mmol) was added and the reaction stirred at ambient temperature overnight. The reaction was then partitioned between aqueous citric acid and EtOAc, dried over Na2SO4, filtered and concentrated to afford (2R,3R)-2-(benzyloxy)-3-hydroxysuccinic acid (11.5 g, 47.9 mmol, 94.6% yield) as a clear colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[C:26](=[O:32])[CH:25]=[C:24]3[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([OH:20])[C:9]2[N:10]=[CH:11][N:12](S(N(C)C)(=O)=[O:15])[CH:13]=2)=[CH:4][CH:3]=1.N>Cl.O.CO>[OH2:15].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:20])([C:9]2[N:10]=[CH:11][NH:12][CH:13]=2)[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[C:26](=[O:32])[CH:25]=[C:24]3[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)n1cnc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)c1
Agent: Cl
Agent: N
Solvent: CO
Solvent: O
Product: Cn1c(=O)cc(-c2ccccc2)c2cc(C(O)(c3ccc(Cl)cc3)c3c[nH]cn3)ccc21
Temperature: 110 °C
Yield: 49.7 %

Procedure:
A mixture of (+)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (2.4 g) in hydrochloric acid (10 ml), water (30 ml) and methanol (15 ml) was stirred and heated at 110° C. for 14 hours. The mixture was cooled, basified with NH3 (aq.) and extracted with DCM. The organic layer was dried, filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2). The pure fractions were collected and evaporated. The residue (1.25 g) was crystallized from 2-propanone/DIPE, yielding 1 g (48.3%) of (±)-6-[(4-chlorophenyl)hydroxy(1H-imidazol-4-yl)methyl]-1-methyl-4-phenyl-2(1H)-quinolinone monohydrate (comp. 43).