N-cyclopentylidenehydroxylamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-4(3H)-pyrimidinone(1.28 g, 0.0027 mol), cyclopentanone oxime(027 g, 0.0027 mol), potassium carbonate(0.38 g, 0.027 mol) and tetrahydrofuran(11 ml) was heated under reflux for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and washed with brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-3 (1.23 g, yield 84.7%) as a white amorphous solid, m.p.76-78° C. was heated under reflux for 3 hours extracted with ethyl acetate washed with brine The organic phase was dried over anhydrous sodium sulfate concentrated The residue was purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-3 (1.23 g, yield 84.7%) as a white amorphous solid, m.p.76-78° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2.0 g of hydroxyiminocyclopentane in 30 ml of tetrahydrofuran was added 28 ml of 15% n-hexane solution of n-butyllithium at room temperature. After the mixture was stirred for 30 minutes at the same temperature, a solution of 6.0 g of ethyl 2-(4-iodomethylphenyl)propionate in 20 ml of tetrahydrofuran was added and stirring was continued for further 10 minutes at room temperature. The reaction mixture was poured into a mixture of 80 ml of ice-water and 20 ml of concentrated hydrochloric acid, extracted with ether, the solvent removed by distillation to afford a residue, to which 1.0 g of sodium hydroxide and 40 ml of methanol were added and the mixture was allowed to stand at room temperature overnight. To the reaction mixture was added 30 ml of water, methanol was removed by distillation, and the residual aqueous layer was shaken with ether and then acidified with hydrochloric acid. Extraction of the acidified layer with ether and decoloration of the product through a silica gel column afforded 2.8 g of the desired compound, which by recrystallization from a mixture of ether and n-hexane yielded colorless crystals, m.p. 146°-148° C. stirring was continued for further 10 minutes at room temperature extracted with ether the solvent removed by distillation to afford a residue to stand at room temperature overnight was removed by distillation the residual aqueous layer was shaken with ether Extraction of the acidified layer with ether and decoloration of the product through a silica gel column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2.0 g of hydroxyiminocyclopentane in 30 ml of tetrahydrofuran was added 28 ml of 15% n-hexane solution of n-butyllithium at room temperature. After the mixture was stirred for 30 minutes at the same temperature, a solution of 6.0 g of ethyl 2-(4-iodomethylphenyl)propionate in 20 ml of tetrahydrofuran was added and stirring was continued for further 10 minutes at room temperature. The reaction mixture was poured into a mixture of 80 ml of ice-water and 20 ml of concentrated hydrochloric acid, extracted with ether, the solvent removed by distillation to afford a residue, to which 1.0 g of sodium hydroxide and 40 ml of methanol were added and the mixture was allowed to stand at room temperature overnight. To the reaction mixture was added 30 ml of water, methanol was removed by distillation, and the residual aqueous layer was shaken with ether and then acidified with hydrochloric acid. Extraction of the acidified layer with ether and decoloration of the product through a silica gel column afforded 2.8 g of the desired compound, which by recrystallization from a mixture of ether and n-hexane yielded colorless crystals, m.p. 146°-148° C. stirring was continued for further 10 minutes at room temperature extracted with ether the solvent removed by distillation to afford a residue to stand at room temperature overnight was removed by distillation the residual aqueous layer was shaken with ether Extraction of the acidified layer with ether and decoloration of the product through a silica gel column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-4(3H)-pyrimidinone(1.28 g, 0.0027 mol), cyclopentanone oxime(027 g, 0.0027 mol), potassium carbonate(0.38 g, 0.027 mol) and tetrahydrofuran(11 ml) was heated under reflux for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and washed with brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-3 (1.23 g, yield 84.7%) as a white amorphous solid, m.p.76-78° C. was heated under reflux for 3 hours extracted with ethyl acetate washed with brine The organic phase was dried over anhydrous sodium sulfate concentrated The residue was purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-3 (1.23 g, yield 84.7%) as a white amorphous solid, m.p.76-78° C.

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cyclopentane (1 ml), t-butyl nitrite (1 mmol), N-hydroxyphthalimide (0.2 mmol), and acetic acid (1 ml) were placed in a flask and were stirred at 80° C. in an atmosphere of argon gas (1 atm=0.101 MPa) for 20 hours. The resulting reaction mixture was analyzed to find that cyclopentanone oxime, nitrocyclopentane, cyclopentanone, and cyclopentyl acetate were formed in yields of 4%, 2%, 3%, and less than 1%, respectively. The resulting reaction mixture

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The core molecule was synthesized following method A. Potassium t-butoxide (12 g, 110 mmol) was added in portions to a cooled (0° C.) solution of cyclopentanone oxime (9.9 g, 100 mmol) in DMF (150 mL). The cooled reaction mixture was stirred for 20 minutes and then 1-fluoro-4-nitrobenzene (14 g, 100 mmol) was added in portions. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to remove the DMF and then treated with water (300 mL). The precipitate was collected by filtration and washed with water to provide cyclopentanone O-(4-nitro-phenyl)-oxime (17 g). Cyclopentanone O-(4-nitro-phenyl)-oxime (14 g, 62 mmol) was dissolved in glacial acetic acid (40 mL) and 1.9 N hydrochloric acid (40 mL) was added. The reaction mixture was stirred at room temperature for 50 minutes and then concentrated. The solid was mixed with water (250 mL) and allowed to stand for 1 hour. The crude mixture was extracted with ethyl acetate and the combined organic phases were dried (Na2SO4) and concentrated. The crude material was dissolved in toluene (350 mL) and p-toluenesulfonic acid (2.0 g, 10 mmol) was added. The reaction mixture was heated to reflux for 4 hours and water was removed with a Dean-Stark trap. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na2SO4) and concentrated to give 5-nitro-2,3-dihydro-1H-cyclopenta[b]benzofuran (10 g). A mixture of give 5-nitro-2,3-dihydro-1H-cyclopenta[b]benzofuran (5.4 g, 27 mmol) and Raney nickel (˜5 g wet weight) in ethanol (50 mL) was hydrogenated at 50 PSI on a Parr shaker for 2 hours. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was purified by column chromatography to provide 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (4.0 g). Mp 86.5-88.5° C. The core molecule was synthesized The cooled reaction mixture The reaction mixture was stirred at ˜10° C. for 30 minutes stirred for an additional 4 hours The reaction mixture was concentrated under reduced pressure to remove the DMF treated with water (300 mL) The precipitate was collected by filtration washed with water

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2.0 g of hydroxyiminocyclopentane in 30 ml of tetrahydrofuran was added 28 ml of 15% n-hexane solution of n-butyllithium at room temperature. After the mixture was stirred for 30 minutes at the same temperature, a solution of 6.0 g of ethyl 2-(4-iodomethylphenyl)propionate in 20 ml of tetrahydrofuran was added and stirring was continued for further 10 minutes at room temperature. The reaction mixture was poured into a mixture of 80 ml of ice-water and 20 ml of concentrated hydrochloric acid, extracted with ether, the solvent removed by distillation to afford a residue, to which 1.0 g of sodium hydroxide and 40 ml of methanol were added and the mixture was allowed to stand at room temperature overnight. To the reaction mixture was added 30 ml of water, methanol was removed by distillation, and the residual aqueous layer was shaken with ether and then acidified with hydrochloric acid. Extraction of the acidified layer with ether and decoloration of the product through a silica gel column afforded 2.8 g of the desired compound, which by recrystallization from a mixture of ether and n-hexane yielded colorless crystals, m.p. 146°-148° C. stirring was continued for further 10 minutes at room temperature extracted with ether the solvent removed by distillation to afford a residue to stand at room temperature overnight was removed by distillation the residual aqueous layer was shaken with ether Extraction of the acidified layer with ether and decoloration of the product through a silica gel column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-4(3H)-pyrimidinone(1.28 g, 0.0027 mol), cyclopentanone oxime(027 g, 0.0027 mol), potassium carbonate(0.38 g, 0.027 mol) and tetrahydrofuran(11 ml) was heated under reflux for 3 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and washed with brine. The organic phase was dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-3 (1.23 g, yield 84.7%) as a white amorphous solid, m.p.76-78° C. was heated under reflux for 3 hours extracted with ethyl acetate washed with brine The organic phase was dried over anhydrous sodium sulfate concentrated The residue was purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound II-3 (1.23 g, yield 84.7%) as a white amorphous solid, m.p.76-78° C.