Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[N+:13]([C:16]1[C:21]([CH:22]=O)=[CH:20][C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)([O-:15])=[O:14]>CO>[C:7]([C:9](=[CH:22][C:21]1[CH:20]=[C:19]([O:24][CH3:25])[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[N+:13]([O-:15])=[O:14])[C:10]([NH2:12])=[O:11])#[N:8]
Reactant: N#CCC(N)=O
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Solvent: C1CCNCC1
Solvent: CO
Product: COc1cc(C=C(C#N)C(N)=O)c([N+](=O)[O-])cc1OC

Procedure:
Piperidine (2.1 g., 0.0237 mole) and 2-cyanoacetamide (22.0 g., 0.263 mole) are added to a slurry of 6-nitroveratraldehyde (50.0 g., 0.237 mole) in methanol (500 ml.). The mixture is heated to reflux for 2 hours, and then cooled in an ice bath and filtered. The bright yellow filter cake is washed with cold isopropanol (300 ml.) and then air dried. Yield = 60.1 g. (93%); m.p. 265°-266° C.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]CCCC)[C:13]([CH3:28])=[C:12]2[CH2:29][C:30]([NH2:32])=[O:31])C.[OH-].[Na+].O.Cl>CO>[NH2:32][C:30](=[O:31])[CH2:29][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:33])[CH:10]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:13]=1[CH3:28]
Reactant: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(CC(N)=O)c2cc(OCCCC(=O)O)ccc2n1C1CCCCC1
Yield: 28 %

Procedure:
A mixture of 190 mg (0.46 mmol) of [4-[[3-(2-amino-2-oxoethyl)-1-decyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester and 2 mL of 5N NaOH in 20 mL of MeOH was heated to maintain reflux for 2.5 hours, cooled, poured into water and made strongly acidic with 5N HCl. The precipitate was filtered and recrystallized from MeOH. There was obtained 50 mg (28% yield) of [4-[[3-(2-amino-2-oxoethyl)-1-cyclohexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid. mp, 212-214° C.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:17]([CH:19]1[CH2:23][CH2:22][N:21](C(OCC2C=CC=CC=2)=O)[CH2:20]1)=O.O>O1CCCC1>[NH:21]1[CH2:22][CH2:23][CH:19]([CH2:17][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:20]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC1CCNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of ethyl diethylphosphonoacetate (15.9 g) in tetrahydrofuran (200 mL) was added sodium hydride (60% in oil, 2.88 g) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added benzyl 3-formylpyrrolidine-1-carboxylate (15.0 g) and the mixture was stirred for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was dissolved in methanol (500 ml), palladium hydroxide/carbon (2.0 g) was added, and the mixture was stirred under a hydrogen atmosphere (3 atm) at 40° C. for 4 hr. The reaction solution was allowed to cool to room temperature, the reaction system was substituted by nitrogen, filtered, and the solvent was evaporated to give the title compound (8.0 g, yield 73%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14]
Reactant: C=CC(=O)OC
Reactant: Clc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)CCn1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4.64 g (0.03 mol) of 6-chloropurine, 12.9 g (0.15 mol) of methyl acrylate, 0.3 g (0.002 mol) of finely ground potassium carbonate and 50 mL of dimethylsulfoxide was stirred at room temperature for 48 h. The solvent was removed by distillation (0.1 mm) and the residue was extracted with methanol. The insoluble salts were removed by filtration and the filtrate was concentrated in vacuo. The residue was then dissolved in methanol, and petroleum ether was added to effect crystallization. Yield 3.71 g (51%); m.p. 93.5°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:13]([F:14])=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[C:22][Si](C)(C)C)=[CH:17][CH:16]=2)[N:11]=[C:10]([C:27]([O:29][CH3:30])=[O:28])[C:9]=1[Cl:31]>CO.O>[NH2:7][C:8]1[C:13]([F:14])=[C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[CH:19][CH:20]=2)[N:11]=[C:10]([C:27]([O:29][CH3:30])=[O:28])[C:9]=1[Cl:31]
Reactant: COC(=O)c1nc(-c2ccc(C#C[Si](C)(C)C)cc2)c(F)c(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2F)cc1
Temperature: 23 °C
Yield: 97.6 %

Procedure:
Potassium carbonate (100 mg, 0.74 mmol, 1.0 equiv) was added to a stirred mixture of methyl 4-amino-3-chloro-5-fluoro-6-(4-((trimethylsilyl)ethynyl)phenyl)picolinate (280 mg, 0.74 mmol, 0.10 equiv) in methanol (3.7 mL) at 23° C. The heterogeneous pale yellow mixture was stirred at 23° C. for 30 m. The reaction mixture was diluted with water (200 mL) and extracted with dichloromethane (5×50 mL). The organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a tan powder (220 mg, 96%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[N:5][N:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[CH:7]=1)#[N:2].C([Li])CCC.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31]>O1CCCC1.ClCCl>[C:1]([C:3]1[C:4]([C:20]([F:23])([F:21])[F:22])=[N:5][N:6]([C:8]2[C:9]([Cl:19])=[CH:10][C:11]([C:15]([F:17])([F:18])[F:16])=[CH:12][C:13]=2[Cl:14])[C:7]=1[Si:30]([CH3:32])([CH3:31])[CH3:29])#[N:2]
Reactant: C[Si](C)(C)Cl
Reactant: N#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(F)(F)F
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(C#N)c(C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 0.03 h

Procedure:
A stirred solution of 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethylpyrazole (1.5 g) in dry tetrahydrofuran cooled to -78° C. was treated with a solution of n-butyl lithium (2.6 M in hexane, 1.71 ml) dropwise under nitrogen. The temperature was kept below -65° C. during the addition, and the resultant solution kept at -78° C. for 1 hour. A solution of trimethylsilyl chloride (0.56 ml) in dry tetrahydrofuran (2 ml) was then added, dropwise, during 2 minutes. The mixture was allowed to reach room temperature over 2 hours, left overnight and evaporated in vacuo to give a pale yellow solid. This was dissolved in dichloromethane, washed with water, dried over anhydrous magnesium sulphate, and evaporated in vacuo. The product was recrystallized from hexane to give 4-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-trifluoromethyl-5-trimethylsilylpyrazole as white crystals, m.p. 108°-110° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Reactant: CCCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCNc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1

Procedure:
A solution of (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (0.408 g, 1.5 mmol): butylamine (0.549 g, 7.5 mmol, 5 eqv.) and ethanol (10 mL) was stirred at reflux for 3 hours. The solution was allowed to cool to room temperature before the addition of 1.5 mL of 1.0 N NaOH. The solution was concentrated and the residues were purified by elution from a silica gel column with 5% methanol-chloroform (0.440 g, 97%). The title compound was dissolved in hot acetonitrile then cooled to produce a white powder, m.p. 116-118° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][SH:11])=[N:5][N:4]=[N:3]1.[N+:12]([C:15]1[CH:16]=[CH:17][C:18](Cl)=[N:19][CH:20]=1)([O-:14])=[O:13]>[OH-].[Na+].CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][S:11][C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:20][N:19]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCS
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
1-Methyl-5-(3-mercaptopropyl)thio-1,2,3,4-tetrazole (1.9 g) is dissolved in 1 N aqueous sodium hydroxide (30 ml), and thereto is added dropwise a solution of 5-nitro-2-chloropyridine (1.9 g) in acetone (20 ml) under ice-cooling. After the addition, the mixture is stirred at room temperature for 3 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with ether, and the ether solution is washed with diluted aqueous sodium hydroxide and saturated aqueous sodium chloride and dried over sodium sulfate. After ether is distilled off, the residue is purified by column chromatography (Kieselgel 60), followed by eluting with n-hexane-ether (4:1) to give 1-methyl-5-[3-(5-nitro-2-pyridyl)thiopropyl]thio-1,2,3,4-tetrazole (1.4 g), pale brown liquid, nD29 =1.6289.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[C:1]1([C:7]2[O:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=3)=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2nnc(-c3ccccc3)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2nnc(-c3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A mixture of methyl 4-[5-phenyl-1,3,4-oxadiazol-2-yl]benzoate (0.180 g), 1 M aqueous sodium hydroxide solution (1.3 ml), tetrahydrofuran (2 ml) and methanol (1 ml) was stirred at room temperature for 1 hr. and acidified by adding 1 M hydrochloric acid. The crystals were collected by filtration to give 4-[5-phenyl-1,3,4-oxadiazol-2-yl]benzoic acid (0.150 g, yield 88%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: >300° C.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH3:13]>C(O)C>[C:1]([CH:9]=[C:10]([NH2:13])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)CC(=O)c1cccnc1
Reactant: N
Solvent: CCO
Product: CC(N)=CC(=O)c1cccnc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
7.5 g of nicotinoyl-acetone are dissolved in 45 ml of anhydrous ethanol and, after adding 20 ml of ammonia, the mixture is then stirred for 3 days at 50° C in an autoclave. Concentrating the clear solution leaves an oil which becomes solid after a short time. After recrystallisation from toluene, 2-nicotinoyl-1-methylvinylamine (melting point 82°) is obtained in a 91% yield.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[O:20][CH3:21])=[O:5])C.[CH2:22]([N:25]=[C:26]=[O:27])[CH2:23][CH3:24]>>[CH:17]([N:16]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([O:20][CH3:21])[C:9]=3[N:8]=[CH:7][C:6]=2[C:4](=[O:5])[N:25]([CH2:22][CH2:23][CH3:24])[C:26]1=[O:27])([CH3:18])[CH3:19]
Reactant: CCCN=C=O
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC(C)C
Product: CCCn1c(=O)c2cnc3c(OC)cccc3c2n(C(C)C)c1=O
Yield: 35.1 %

Procedure:
1-Isopropyl-7-methoxy-3-propyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (23 mg) was prepared from 4-isopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (60 mg, 0.20 mmol) and n-propyl isocyanate (1.0 mmol) following general procedure C. LCMS: m/z 328 [M+1]+.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9]C[CH:7](C#N)[CH2:6]1)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[C:17]([OH:20])(=[O:19])[CH3:18]>O.C(OCC)(=O)C>[CH2:1]([C@H:5]1[CH2:6][CH2:7][CH:18]([C:17]([OH:20])=[O:19])[CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCC[C@H]1CCC(C#N)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC[C@H]1CCC(C(=O)O)C1
Reaction time: 1 h
Yield: 36.5 %

Procedure:
A mixture of 73 mg of (1RS,3S)-3-butyl-1-cyanocyclopentane (prepared in Reference Example 13), 0.6 ml of conc. sulphuric acid, 0.6 ml of acetic acid and 0.6 ml of water was stirred for 1 hr. at 110° C. To the reaction solution, 30 ml of ethyl acetate and 20 ml of water were added. The oily layer which separated was washed with water, dried over anhydrous magnesium sulphate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 30 mg of the title compound having the following physical characteristics, in a 36.5% yield.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Cl:9][C:10](Cl)=[CH:11][C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14]>CN(C)C=O.C(Cl)Cl>[Cl:9][CH:10]=[C:11]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([CH3:16])([CH3:15])[CH:13]=[CH2:14]
Reactant: C=CC(C)(C)C=C(Cl)Cl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC(C)(C)C(=CCl)Oc1ccccc1
Yield: 84.1 %

Procedure:
116 g (1 mol) of sodium phenolate and 82.5 g (0.5 mole) of 1,1-dichloro-3,3-dimethyl-1,4-pentadiene in 500 ml of dimethylformamide were heated under reflux for 8 hours. The solution was diluted with methylene chloride and extracted by shaking with dilute sodium hydroxide solution. After the methylene chloride phase had been dried over sodium sulphate, the solvent was stripped off in vacuo. The residual crude product was distilled in vacuo. 93.6 g (84% of theory) of 1-chloro-3,3-dimethyl-2-phenoxy-1,4-pentadiene of boiling point 80° to 90° C./0.5 mm Hg were obtained. ##STR26##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(Br)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Yield: 100 %

Procedure:
Following Example 121c, 264a (0.58 g, 1.25 mmol), trifluoroacetic acid (0.96 mL, 12.5 mmol) and methylene chloride (20 mL) were reacted. Work-up and concentrated to afford a quantitative yield of 264b (454 mg) as yellow oil, which was used without purification in the next step. MS (ESI+) m/z 365.2 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=3)[CH2:22][NH:21][N:20]=2)=[CH:15][CH:14]=1.C(=O)C>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][N:25]=3)[CH2:22][N:21]([C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[O:11])[N:20]=2)=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(C2CNN=C2c2ccc(Cl)cc2)nc1
Reactant: CSc1ccc(N=C=O)cc1
Agent: CC=O
Solvent: ClCCl
Product: CSc1ccc(NC(=O)N2CC(c3ccc(C(F)(F)F)cn3)C(c3ccc(Cl)cc3)=N2)cc1

Procedure:
4-(Methylthio)phenyl isocyanate (2.8 g, 17 mmol) was added to a stirring slurry of 3.8 g (3.0 mmol) of the product of Example 6 in methylene chloride (25 mi) at 21° C. causing rapid formation of a pale precipitate. TLC showed complete conversion after 19 hr and the precipitate, which was the corresponding bisaryl urea, was removed by gravity filtration. The filtrate was diluted with saturated aqueous sodium bicarbonate and the layers separated. The organic layer was dried over sodium sulfate, filtered, and evaporated to obtain a red oil which solidified on standing. This was purified by column chromatography eluting with 100:0 to 90:10 methylene chloride/ethyl acetate solvent. The product was recrystallized by dissolving in ethyl acetate and then adding hexane to obtain 0.44 g (29 percent of theory; 9 percent from the ethanone) of the title compound as fine white needles melting at 225°-226° C.;
Reaction SMILES: [CH:1]1([C:13]([O:15]C)=[O:14])[CH2:5][CH2:4][N:3]2[CH:6]=[CH:7][C:8]([C:9]([O:11]C)=[O:10])=[C:2]12.[OH-].[Na+].Cl>O>[CH:8]1([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][N:3]2[CH:4]=[CH:5][C:1]([C:13]([OH:15])=[O:14])=[C:2]12
Reactant: COC(=O)c1ccn2c1C(C(=O)OC)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccn2c1C(C(=O)O)CC2
Temperature: 0 °C
Yield: 71.7 %

Procedure:
Dimethyl 2,3-dihydro-1H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (1.26 g, 5 mmol) and sodium hydroxide (1.00 g, 25 mmol) were heated in water (10 mL) at reflux for 1 hour. The resulting solution was cooled to 0° C. and acidified with hydrochloric acid (12M) to pH 1. 2,3-Dihydro-1H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylic acid (0.70 g, 71.4% yield) was collected by filtration and dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[CH3:12][Mg]Br>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([OH:11])[CH3:12])[CH:8]=2)[CH:3]=[N:2]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a solution of 1H-indazole-6-carbaldehyde (200 mg, 1.37 mmol) in THF (7 mL) at −78° C. was added methyl magnesium bromide (1.4 mL, 4.11 mmol) dropwise under argon. The solution was warmed to rt and quenched with saturated ammonium chloride (2 mL). The mixture was extracted into ethyl acetate (3×10 mL), dried over MgSO4 and concentrated. The yellow oil was purified by silica gel chromatography (EtOAc/Hex 4:1) to yield the title compound as a clear oil (135 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.76 (s, 1H), 7.50-7.47 (m, 2H), 5.05 (q, 1H, J=7.4 Hz), 1.57 (d, 3H, J=7.2 Hz); MS ESI [M+H]+, calcd for [C9H10N2O+H]+ 163.1; found m/z 163.0.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].Cl.[Cl:7][C:8]1[CH:17]=[C:12]([C:13]([NH:15][OH:16])=[O:14])[C:11](O)=[CH:10][CH:9]=1.[OH-].[NH4+]>O.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:5][CH:1]3[CH2:2][CH:3]([CH3:4])[O:16][N:15]3[C:13](=[O:14])[C:12]=2[CH:17]=1
Reactant: C/C=C/C=O
Reactant: O=C(NO)c1cc(Cl)ccc1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CC2Oc3ccc(Cl)cc3C(=O)N2O1
Temperature: 90 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
360 ml. of tetrahydrofuran is combined with 90 gm. of crotonaldehyde and placed in an ice bath. 100 gm. of hydrogen chloride are passed into the mixture at 20°-30° C. 158 gm. of 5-chlorosalicylhydroxamic acid is added in one portion and the mixture stirred at 25°-30° C. for about two hours until the solid dissolves. The mixture is cooled in a water bath and 400 ml. of concentrated ammonium hydroxide diluted with 400 ml. of water is added with stirring. The temperature of the mixture is allowed to rise to about 50° C. during the alkali addition and the mixture is then heated on a steam bath to about 90° C. and a vacuum applied to remove as much tetrahydrofuarn as possible. A solid precipitates while heating. 400 ml. of water are added and the entire mixture is cooled to about 10° C. in an ice bath. The solid is filtered and washed with water and pulled dry. The cake is recrystallized from 800 ml. boiling isopropanol refrigerated overnight. The crystals are filtered, washed with cold isopropanol and dried at about 100° C. 136 gm. 7-chloro-2-methyl-3,3a-dihydro-2H, 9H-isoxazolo (3,2-b) (1,3) benzoxazin-9-one (m.p. 144°-148° C.) for a yield of 67% is obtained.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH:11]([CH3:13])[O:10][C@H:9](O)[C:8]2=[O:15])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][C:49]=1[N:50]1[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]1)[CH:45]=O>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[O:10]/[C:9](=[CH:45]\[C:44]3[CH:47]=[CH:48][C:49]([N:50]4[CH:54]=[C:53]([CH3:55])[N:52]=[CH:51]4)=[C:42]([F:41])[CH:43]=3)/[C:8]2=[O:15])=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccc(F)cc2)C(=O)[C@@H](O)O1
Reactant: Cc1cn(-c2ccc(C=O)cc2F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Product: Cc1cn(-c2ccc(/C=C3\O[C@@H](C)CN(Cc4ccc(F)cc4)C3=O)cc2F)cn1

Procedure:
9.06 mg of the title compound was obtained from (S)-4-(4-fluorobenzyl)-2-hydroxy-6-methylmorpholin-3-one, thionyl chloride, triphenylphosphine, and 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde in the same manner as in Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:31][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.O.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:31][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Temperature: 50 °C
Yield: 97.2 %

Procedure:
Methyl 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate (5.83 g, 12.8 mmol) was dissolved in 25 mL of THF and 25 mL of water and treated with LiOH (1.35 g, mono-hydrate). The whole was heated at 50° C. for 3 h, cooled to room temperature and acidified. The resulting precipitate was filtered and washed with water. The filter cake was dried to a constant weight under vacuum to give 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (5.47 g, yield 97%). ESI-MS: 440.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][CH3:11].[Li+].CC([N-]C(C)C)C.[I:20]I>C1COCC1.C(OCC)(=O)C>[F:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]([O:10][CH3:11])=[C:2]([F:1])[C:7]=1[I:20]
Reactant: II
Reactant: COc1c(C)cc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(C)cc(F)c(I)c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1,5-difluoro-2-methoxy-3-methylbenzene (0.65 g, 4.1 mmol) in THF (1 mL) was added to LDA (4.3 mmol) in THF (10 mL) at −55° C. and the solution stirred for 45 minutes. Solid iodine (1.15 g, 4.5 mmol) was added and the solution allowed to warm to ambient temperature. The solution was diluted with ethyl acetate and washed with sodium bicarbonate (saturated solution 15 mL) and sodium thiosulfate (saturated solution, 15 mL), dried (sodium sulfate) and concentrated. The residue was purified by chromatography (hexanes) to give 1,3-difluoro-2-iodo-4-methoxy-5-methylbenzene: 1H NMR (300 MHz, CDCl3): δ 6.72 (dd, 1H), 3.84 (d, 3H,), 2.26 (s, 3H).