(2-fluorophenyl)methylhydrazine;hydrochloride

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

Procedure: This compound was generated exploiting General Procedure A-I from 1-(1-methyl-1H-pyrazol-3-yl)ethanone (1.67 g, 13.45 mmol) in the initial Claisen condensation, and using (2-fluorobenzyl)hydrazine hydrochloride (2.38 g, 13.45 mmol) in the pyrazole formation step (72%, two steps). The ester was then carried on to the corresponding amidine, again, as outlined in General Procedure A-I. The amidine (213 mg, 0.714 mmol) was cyclized via treatment with sodium 3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate (446 mg, 2.86 mmol) in ethanol (5.0 mL)—stirring at 90° C. for 14 hour. The solvent was removed in vacuo, and purification by silica gel chromatography (0-10% methanol in DCM) provided a mixture of the desired compound and a side-product. The mixture was then subjected to reverse-phase preparative HPLC which afforded Compound 92 (20 mg, 7.6% yield) as a white solid. Claisen condensation The solvent was removed in vacuo, and purification by silica gel chromatography (0-10% methanol in DCM) provided

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold solution of 1-(5-fluoropyridin-2-yl)ethanone (1 equiv.) in toluene (9.6 ml) at 0° C., was added 1M LiHMDS in toluene (1 equiv.). The mixture was stirred at 0° C. for 5 min. To this mixture, was added a solution of isoxazole-3-carbonyl chloride (1 equiv.) in toluene (4.8 ml). The mixture was removed from the ice bath and stirred at 25° C. for 5 min. To this mixture, were added 6 N HCl (1 equiv.), followed by (2-fluorobenzyl)hydrazine hydrochloride (1 equiv.) and ethanol (5 ml). The mixture was heated to 100° C. for 2 h. The mixture was cooled to 25° C. and concentrated under vacuum to give a thick red oil. The oil was purified by column chromatography (0 to 35% ethyl acetate in hexanes) to give 3-(1-(2-fluorobenzyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-5-yl)isoxazole (13% yield) as a clear film and its regioisomer 3-(1-(2-fluorobenzyl)-5-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl)isoxazole (14% yield) as a white solid. The mixture was removed from the ice bath stirred at 25° C. for 5 min The mixture was heated to 100° C. for 2 h The mixture was cooled to 25° C. concentrated under vacuum to give a thick red oil The oil was purified by column chromatography (0 to 35% ethyl acetate in hexanes)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold solution of 1-(5-fluoropyridin-2-yl)ethanone (1 equiv.) in toluene (9.6 ml) at 0° C., was added 1M LiHMDS in toluene (1 equiv.). The mixture was stirred at 0° C. for 5 min. To this mixture, was added a solution of isoxazole-3-carbonyl chloride (1 equiv.) in toluene (4.8 ml). The mixture was removed from the ice bath and stirred at 25° C. for 5 min. To this mixture, were added 6 N HCl (1 equiv.), followed by (2-fluorobenzyl)hydrazine hydrochloride (1 equiv.) and ethanol (5 ml). The mixture was heated to 100° C. for 2 h. The mixture was cooled to 25° C. and concentrated under vacuum to give a thick red oil. The oil was purified by column chromatography (0 to 35% ethyl acetate in hexanes) to give 3-(1-(2-fluorobenzyl)-3-(5-fluoropyridin-2-yl)-1H-pyrazol-5-yl)isoxazole (13% yield) as a clear film and its regioisomer 3-(1-(2-fluorobenzyl)-5-(5-fluoropyridin-2-yl)-1H-pyrazol-3-yl)isoxazole (14% yield) as a white solid. The mixture was removed from the ice bath stirred at 25° C. for 5 min The mixture was heated to 100° C. for 2 h The mixture was cooled to 25° C. concentrated under vacuum to give a thick red oil The oil was purified by column chromatography (0 to 35% ethyl acetate in hexanes)