(4-bromo-2-fluorophenyl)hydrazine

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

Procedure: Prepare the tide compound by essentially following the procedure as described in Preparation 4 (Method 2) with 2-fluoro-4-bromophenylhydrazine (Preparation 14) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain the title compound as a tan foam in 32% yield. MS (ES): m/z 353, 355 (M+H), 351, 353(M−H); HPLC (Method A): Rt=2.34, (89%). Prepare the tide compound

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

Procedure: To a mixture of (4-bromo-2-fluorophenyl)hydrazine (3.4 g) in methanol (25 mL) was added methyl ethanimidothioate hydroiodide (3.6 g), and the mixture was stirred at room temperature for 40 min. The solvent was evaporated under reduced pressure. To a mixture of the obtained residue in toluene (20 mL) were added methyl orthoformate (15 mL) and pyridine (15 mL), and the mixture was stirred at 100° C. for 9 hr. The reaction mixture was allowed to cool to room temperature, and diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.7 g). The solvent was evaporated under reduced pressure To a mixture of the obtained residue in toluene (20 mL) were added methyl orthoformate (15 mL) and pyridine (15 mL) the mixture was stirred at 100° C. for 9 hr to cool to room temperature diluted with saturated aqueous sodium hydrogen carbonate solution the mixture was extracted with ethyl acetate The extract was washed with saturated brine the organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

Procedure: To a mixture of 4-bromo-2-fluoroaniline (5.0 g) in concentrated hydrochloric acid (25 mL) was added a mixture of sodium nitrite (1.9 g) in water (2.5 mL) at −20° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was added dropwise to a mixture of tin chloride (19 g) in concentrated hydrochloric acid (25 mL) at −20° C., and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, and washed with diethyl ether. The obtained solid was neutralized with 10% aqueous potassium carbonate solution, and ethyl acetate was added. The insoluble material was removed by filtration, the filtrate was extracted with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.4 g). was added the mixture was stirred at room temperature for 1 hr The precipitate was collected by filtration washed with diethyl ether was added The insoluble material was removed by filtration the filtrate was extracted with ethyl acetate the extract was washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure

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

Procedure: To a mixture of (4-bromo-2-fluorophenyl)hydrazine (3.4 g) in methanol (25 mL) was added methyl ethanimidothioate hydroiodide (3.6 g), and the mixture was stirred at room temperature for 40 min. The solvent was evaporated under reduced pressure. To a mixture of the obtained residue in toluene (20 mL) were added methyl orthoformate (15 mL) and pyridine (15 mL), and the mixture was stirred at 100° C. for 9 hr. The reaction mixture was allowed to cool to room temperature, and diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.7 g). The solvent was evaporated under reduced pressure To a mixture of the obtained residue in toluene (20 mL) were added methyl orthoformate (15 mL) and pyridine (15 mL) the mixture was stirred at 100° C. for 9 hr to cool to room temperature diluted with saturated aqueous sodium hydrogen carbonate solution the mixture was extracted with ethyl acetate The extract was washed with saturated brine the organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

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

Procedure: To a mixture of 4-bromo-2-fluoroaniline (5.0 g) in concentrated hydrochloric acid (25 mL) was added a mixture of sodium nitrite (1.9 g) in water (2.5 mL) at −20° C., and the mixture was stirred at 0° C. for 30 min. The reaction mixture was added dropwise to a mixture of tin chloride (19 g) in concentrated hydrochloric acid (25 mL) at −20° C., and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, and washed with diethyl ether. The obtained solid was neutralized with 10% aqueous potassium carbonate solution, and ethyl acetate was added. The insoluble material was removed by filtration, the filtrate was extracted with ethyl acetate, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.4 g). was added the mixture was stirred at room temperature for 1 hr The precipitate was collected by filtration washed with diethyl ether was added The insoluble material was removed by filtration the filtrate was extracted with ethyl acetate the extract was washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure

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

Procedure: Prepare the tide compound by essentially following the procedure as described in Preparation 4 (Method 2) with 2-fluoro-4-bromophenylhydrazine (Preparation 14) and N-(4-oxo-cyclohexyl)-isobutyramide, to obtain the title compound as a tan foam in 32% yield. MS (ES): m/z 353, 355 (M+H), 351, 353(M−H); HPLC (Method A): Rt=2.34, (89%). Prepare the tide compound