3-chloro-4-hydroxybenzonitrile

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

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under N2, a solution of 3-chloro-4-hydroxybenzonitrile (15.4 g, 0.1 mole) in dry DMF (75 ml) was added rapidly dropwise to a stirred suspension of sodium hydride (4.0 g, 0.1 mole, 60% oil dispersion) in dry DMF (25 ml). After heating at 70° C. for 2 hours, the mixture was cooled to 20° C. and a solution of methyliodide (30 ml) in dry DMF (50 ml) was added dropwise. Following an 18 hour period at room temperature, the precipitate of sodium iodide was removed by filtration and the solvent was stripped from the filtrate under reduced pressure. The crystalline residue was slurried in water and the product was collected to yield 16.8 g (quant.) of 26, m.p. 105°-108° C. A sample recrystallized from IPA--H2O melted at 107°-109° C. the mixture was cooled to 20° C. the precipitate of sodium iodide was removed by filtration the product was collected

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

Procedure: The title compound was prepared from 3-chloro-4-hydroxybenzaldehyde and hydroxyl ammonium chloride, using the same method as that described for preparation 70. The title compound was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0 to 90:10, to afford the title compound as a white solid in 76% yield. that described for preparation 70 The title compound was purified by column chromatography on silica gel eluting with pentane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-4-cyanophenol (2.15 g), 3-bromo-1-chloropropane (2.3 g), dimethylformamide (3 ml) and potassium carbonate (1.5 g) was heated at 100° C. for one hour. The inorganic salt was then filtered off and the solvent was distilled off. The residue was dissolved in chloroform, chromatographed on a column of silica gel (80 g), and eluted with a solution of petroleum ether-ethyl acetate (10:1) to give 3-(2-chloro-4-cyanophenoxy)propyl chloride as a colorless oil (3.06 g). The inorganic salt was then filtered off the solvent was distilled off The residue was dissolved in chloroform chromatographed on a column of silica gel (80 g) eluted with a solution of petroleum ether-ethyl acetate (10:1)

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

Procedure: While a solution of 2-chloro-4-cyanophenol (50 g) and epichlorohydrin (60.3 g) in ethanol (55 ml) was refluxed, a solution of potassium hydroxide (21.9 g) in ethanol (90 ml) was added dropwise over a period of 40 minutes and the reaction mixture was further refluxed for 100 minutes. After the mixture was cooled, water (50 ml) was added thereto and it was neutralized with 1N hydrochloric acid. After the solvent was distilled off, the residue was extracted with diethyl ether. The extract was dried (over magnesium sulfate) and the diethyl ether was distilled off. The residue was distilled under reduced pressure to give 27 g of 3-chloro-4-(2,3-epoxy)propylbenzonitrile as a colorless oil. After crystallization, the crystals are recrystallized from isopropyl ether-ethyl acetate to give colorless needles. m.p. 71.0°-71.8° C. the reaction mixture was further refluxed for 100 minutes After the mixture was cooled After the solvent was distilled off the residue was extracted with diethyl ether The extract was dried (over magnesium sulfate) the diethyl ether was distilled off The residue was distilled under reduced pressure

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

Procedure: While a solution of 2-chloro-4-cyanophenol (50 g) and epichlorohydrin (60.3 g) in ethanol (55 ml) was refluxed, a solution of potassium hydroxide (21.9 g) in ethanol (90 ml) was added dropwise over a period of 40 minutes and the reaction mixture was further refluxed for 100 minutes. After the mixture was cooled, water (50 ml) was added thereto and it was neutralized with 1N hydrochloric acid. After the solvent was distilled off, the residue was extracted with diethyl ether. The extract was dried (over magnesium sulfate) and the diethyl ether was distilled off. The residue was distilled under reduced pressure to give 27 g of 3-chloro-4-(2,3-epoxy)propylbenzonitrile as a colorless oil. After crystallization, the crystals are recrystallized from isopropyl ether-ethyl acetate to give colorless needles. m.p. 71.0°-71.8° C. the reaction mixture was further refluxed for 100 minutes After the mixture was cooled After the solvent was distilled off the residue was extracted with diethyl ether The extract was dried (over magnesium sulfate) the diethyl ether was distilled off The residue was distilled under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-4-cyanophenol (2.15 g), 3-bromo-1-chloropropane (2.3 g), dimethylformamide (3 ml) and potassium carbonate (1.5 g) was heated at 100° C. for one hour. After the inorganic salt was filtered off, the solvent was distilled off and the residue was dissolved in chloroform. The solution was chromatographed on a column of silica gel (80 g) and eluted with a solution of petroleum ether-ethyl acetate (10:1) to give 3.06 g of 3-(2-chloro-4-cyanophenoxy)propyl chloride as a colorless oil. After the inorganic salt was filtered off the solvent was distilled off the residue was dissolved in chloroform The solution was chromatographed on a column of silica gel (80 g) eluted with a solution of petroleum ether-ethyl acetate (10:1)

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

Procedure: (Z)-tert-butyl 5-chloro-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (75 mg, 0.18 mmol) was dissolved in anhydrous DMF (0.6 mL). 3-chloro-4-hydroxybenzonitrile (41 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) were added. After 24 h, H2O (3.5 mL) was added to the reaction and the bright yellow precipitate was filtered and dried. The crude solid was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). After 1 h, the reaction was concentrated to dryness and the residue was triturated with Et2O (3 mL) and filtered to provide (Z)-3-chloro-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzonitrile (45 mg, 57% over two steps) as a bright yellow solid. the bright yellow precipitate was filtered dried The crude solid was dissolved in dichloromethane (1 mL) After 1 h the reaction was concentrated to dryness the residue was triturated with Et2O (3 mL) filtered

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

Procedure: (Z)-tert-butyl 5-chloro-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (75 mg, 0.18 mmol) was dissolved in anhydrous DMF (0.6 mL). 3-chloro-4-hydroxybenzonitrile (41 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) were added. After 24 h, H2O (3.5 mL) was added to the reaction and the bright yellow precipitate was filtered and dried. The crude solid was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). After 1 h, the reaction was concentrated to dryness and the residue was triturated with Et2O (3 mL) and filtered to provide (Z)-3-chloro-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yloxy)benzonitrile (45 mg, 57% over two steps) as a bright yellow solid. the bright yellow precipitate was filtered dried The crude solid was dissolved in dichloromethane (1 mL) After 1 h the reaction was concentrated to dryness the residue was triturated with Et2O (3 mL) filtered

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

Procedure: The title compound was prepared from 3-chloro-4-hydroxybenzaldehyde and hydroxyl ammonium chloride, using the same method as that described for preparation 70. The title compound was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0 to 90:10, to afford the title compound as a white solid in 76% yield. that described for preparation 70 The title compound was purified by column chromatography on silica gel eluting with pentane

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under N2, a solution of 3-chloro-4-hydroxybenzonitrile (15.4 g, 0.1 mole) in dry DMF (75 ml) was added rapidly dropwise to a stirred suspension of sodium hydride (4.0 g, 0.1 mole, 60% oil dispersion) in dry DMF (25 ml). After heating at 70° C. for 2 hours, the mixture was cooled to 20° C. and a solution of methyliodide (30 ml) in dry DMF (50 ml) was added dropwise. Following an 18 hour period at room temperature, the precipitate of sodium iodide was removed by filtration and the solvent was stripped from the filtrate under reduced pressure. The crystalline residue was slurried in water and the product was collected to yield 16.8 g (quant.) of 26, m.p. 105°-108° C. A sample recrystallized from IPA--H2O melted at 107°-109° C. the mixture was cooled to 20° C. the precipitate of sodium iodide was removed by filtration the product was collected

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

Procedure: The title compound was prepared from 3-chloro-4-hydroxybenzaldehyde and hydroxyl ammonium chloride, using the same method as that described for preparation 70. The title compound was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0 to 90:10, to afford the title compound as a white solid in 76% yield. that described for preparation 70 The title compound was purified by column chromatography on silica gel eluting with pentane