2-phenylmethoxyacetohydrazide

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

Procedure: To a mixture of 71, (2.7 g, 15 mmol) and trimethyl orthoformate (5 mL) was added p-TSA, (anhydrous, 255 mg, 1.5 mmol). The mixture was refluxed for 3 h and the excess trimethyl orthoformate evaporated under reduced pressure. The crude product was purified over a column of silica gel, eluting with 30% acetone-petroleum ether to give 72 as a colorless liquid (1.4 g), in 49% yield (two steps). 1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 7.39-7.31 (m, 5H), 4.77 (s, 2H), 4.64 (s, 2H). The mixture was refluxed for 3 h the excess trimethyl orthoformate evaporated under reduced pressure The crude product was purified over a column of silica gel eluting with 30% acetone-petroleum ether

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

Procedure: A mixture of 70 (2.75 g, 15.3 mmol) in methanol (50 mL) and hydrazine hydrate (65% in water, 2.3 g, 30 mmol) was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with benzene. The solvent was evaporated and the crude product was further dried under high vacuum (6 h) to give 71 (2.75 g), as a light yellow waxy material, which was used in the next step without further purification. was heated under reflux for 3 h The reaction mixture was concentrated under reduced pressure the residue was diluted with benzene The solvent was evaporated the crude product was further dried under high vacuum (6 h)

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

Procedure: A mixture of 70 (2.75 g, 15.3 mmol) in methanol (50 mL) and hydrazine hydrate (65% in water, 2.3 g, 30 mmol) was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with benzene. The solvent was evaporated and the crude product was further dried under high vacuum (6 h) to give 71 (2.75 g), as a light yellow waxy material, which was used in the next step without further purification. was heated under reflux for 3 h The reaction mixture was concentrated under reduced pressure the residue was diluted with benzene The solvent was evaporated the crude product was further dried under high vacuum (6 h)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine.2HCl (307 mg, 0.96 mmol) and N-amino-2-(phenylmethoxy)acetamide (259 mg, 1.44 mmol) in anhydrous methanol (3.0 mL) in a screw-top pressure tube was added freshly prepared sodium methoxide (615 μL of a 3.12 M solution in methanol). The tube was sealed and heated in a 90° C. oil bath for 17 h. The reaction was cooled, evaporated to dryness and partitioned between ethyl acetate and satd. NH4Cl. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give an oily brown residue. Purification by flash chromatography on silica gel eluting with 5% methanol in dichloromethane (Rf=0.43) gave a pale solid (155 mg) which was re-chromatographed using 30% hexanes in ethyl acetate to remove traces of color. The tube was sealed The reaction was cooled evaporated to dryness partitioned between ethyl acetate and satd The organic layer was separated washed with brine dried over MgSO4 concentrated in vacuo to give an oily brown residue Purification by flash chromatography on silica gel eluting with 5% methanol in dichloromethane (Rf=0.43)

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

Procedure: To a solution of hydrazine hydrate (10 ml) in ethanol (100 ml) at 0° C. was added a solution of (benzyloxy)acetyl chloride (6.4 ml) in THF (40 ml) by syringe pump over 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The ethanol was removed under reduced pressure and the remaining aqueous mixture extracted with dichloromethane (3×100 ml). The combined organic extracts were washed with aqueous K2CO3 (100 ml) then brine (100 ml) and dried (MgSO4). Concentration under reduced pressure gave 2-(benzyloxy)acetohydrazide as a colourless oil that crystallized on standing (5.5 g). The ethanol was removed under reduced pressure the remaining aqueous mixture extracted with dichloromethane (3×100 ml) The combined organic extracts were washed with aqueous K2CO3 (100 ml) brine (100 ml) and dried (MgSO4) Concentration under reduced pressure

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine.2HCl (307 mg, 0.96 mmol) and N-amino-2-(phenylmethoxy)acetamide (259 mg, 1.44 mmol) in anhydrous methanol (3.0 mL) in a screw-top pressure tube was added freshly prepared sodium methoxide (615 μL of a 3.12 M solution in methanol). The tube was sealed and heated in a 90° C. oil bath for 17 h. The reaction was cooled, evaporated to dryness and partitioned between ethyl acetate and satd. NH4Cl. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give an oily brown residue. Purification by flash chromatography on silica gel eluting with 5% methanol in dichloromethane (Rf=0.43) gave a pale solid (155 mg) which was re-chromatographed using 30% hexanes in ethyl acetate to remove traces of color. The tube was sealed The reaction was cooled evaporated to dryness partitioned between ethyl acetate and satd The organic layer was separated washed with brine dried over MgSO4 concentrated in vacuo to give an oily brown residue Purification by flash chromatography on silica gel eluting with 5% methanol in dichloromethane (Rf=0.43)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine.2HCl (307 mg, 0.96 mmol) and N-amino-2-(phenylmethoxy)acetamide (259 mg, 1.44 mmol) in anhydrous methanol (3.0 mL) in a screw-top pressure tube was added freshly prepared sodium methoxide (615 μL of a 3.12 M solution in methanol). The tube was sealed and heated in a 90° C. oil bath for 17 h. The reaction was cooled, evaporated to dryness and partitioned between ethyl acetate and satd. NH4Cl. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give an oily brown residue. Purification by flash chromatography on silica gel eluting with 5% methanol in dichloromethane (Rf=0.43) gave a pale solid (155 mg) which was re-chromatographed using 30% hexanes in ethyl acetate to remove traces of color. The tube was sealed The reaction was cooled evaporated to dryness partitioned between ethyl acetate and satd The organic layer was separated washed with brine dried over MgSO4 concentrated in vacuo to give an oily brown residue Purification by flash chromatography on silica gel eluting with 5% methanol in dichloromethane (Rf=0.43)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine.2HCl (307 mg, 0.96 mmol) and N-amino-2-(phenylmethoxy)acetamide (259 mg, 1.44 mmol) in anhydrous methanol (3.0 mL) in a screw-top pressure tube was added freshly prepared sodium methoxide (615 μL of a 3.12 M solution in methanol). The tube was sealed and heated in a 90° C. oil bath for 17 h. The reaction was cooled, evaporated to dryness and partitioned between ethyl acetate and satd. NH4Cl. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give an oily brown residue. Purification by flash chromatography on silica gel eluting with 5% methanol in dichloromethane (Rf=0.43) gave a pale solid (155 mg) which was re-chromatographed using 30% hexanes in ethyl acetate to remove traces of color. The tube was sealed The reaction was cooled evaporated to dryness partitioned between ethyl acetate and satd The organic layer was separated washed with brine dried over MgSO4 concentrated in vacuo to give an oily brown residue Purification by flash chromatography on silica gel eluting with 5% methanol in dichloromethane (Rf=0.43)

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

Procedure: To a mixture of 71, (2.7 g, 15 mmol) and trimethyl orthoformate (5 mL) was added p-TSA, (anhydrous, 255 mg, 1.5 mmol). The mixture was refluxed for 3 h and the excess trimethyl orthoformate evaporated under reduced pressure. The crude product was purified over a column of silica gel, eluting with 30% acetone-petroleum ether to give 72 as a colorless liquid (1.4 g), in 49% yield (two steps). 1H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 7.39-7.31 (m, 5H), 4.77 (s, 2H), 4.64 (s, 2H). The mixture was refluxed for 3 h the excess trimethyl orthoformate evaporated under reduced pressure The crude product was purified over a column of silica gel eluting with 30% acetone-petroleum ether

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

Procedure: A mixture of 70 (2.75 g, 15.3 mmol) in methanol (50 mL) and hydrazine hydrate (65% in water, 2.3 g, 30 mmol) was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with benzene. The solvent was evaporated and the crude product was further dried under high vacuum (6 h) to give 71 (2.75 g), as a light yellow waxy material, which was used in the next step without further purification. was heated under reflux for 3 h The reaction mixture was concentrated under reduced pressure the residue was diluted with benzene The solvent was evaporated the crude product was further dried under high vacuum (6 h)