N-[(4-methoxyphenyl)methyl]aniline

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

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

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

Procedure: A solution of potassium t-butoxide in THF (4.73 mL, 4.73 mmol) was added dropwise to a solution of N-(4-methoxybenzyl)aniline (0.92 g, 4.3 mmol) in THF (10 mL) at 0° C. The solution was warmed to RT for 15 minutes, recooled to 0° C. and a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.0 g, 4.30 mmol) from Example 1, step 1b, in THF (10 mL) was added in rapidly. The solution was stirred at 0° C. for 30 minutes and then at RT for 30 minutes. The reaction solution was concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 10% ethyl acetate/heptane to provide 0.75 g (48%) of 6-chloro-N-(4-methoxybenzyl)-N-phenyl imidazo[1,2-b]pyridazin-8-amine. recooled to 0° C. at RT for 30 minutes The reaction solution was concentrated in vacuo The resulting residue was purified by flash chromatography eluting with 10% ethyl acetate/heptane

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

Procedure: A solution of potassium t-butoxide in THF (4.73 mL, 4.73 mmol) was added dropwise to a solution of N-(4-methoxybenzyl)aniline (0.92 g, 4.3 mmol) in THF (10 mL) at 0° C. The solution was warmed to RT for 15 minutes, recooled to 0° C. and a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.0 g, 4.30 mmol) from Example 1, step 1b, in THF (10 mL) was added in rapidly. The solution was stirred at 0° C. for 30 minutes and then at RT for 30 minutes. The reaction solution was concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 10% ethyl acetate/heptane to provide 0.75 g (48%) of 6-chloro-N-(4-methoxybenzyl)-N-phenyl imidazo[1,2-b]pyridazin-8-amine. recooled to 0° C. at RT for 30 minutes The reaction solution was concentrated in vacuo The resulting residue was purified by flash chromatography eluting with 10% ethyl acetate/heptane

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

Procedure: A solution of potassium t-butoxide in THF (4.73 mL, 4.73 mmol) was added dropwise to a solution of N-(4-methoxybenzyl)aniline (0.92 g, 4.3 mmol) in THF (10 mL) at 0° C. The solution was warmed to RT for 15 minutes, recooled to 0° C. and a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.0 g, 4.30 mmol) from Example 1, step 1b, in THF (10 mL) was added in rapidly. The solution was stirred at 0° C. for 30 minutes and then at RT for 30 minutes. The reaction solution was concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 10% ethyl acetate/heptane to provide 0.75 g (48%) of 6-chloro-N-(4-methoxybenzyl)-N-phenyl imidazo[1,2-b]pyridazin-8-amine. recooled to 0° C. at RT for 30 minutes The reaction solution was concentrated in vacuo The resulting residue was purified by flash chromatography eluting with 10% ethyl acetate/heptane

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

Procedure: N-(4-Methoxybenzyl)aniline (215 mg, 1 mmol) was dissolved in dry DMF (4 mL), placed under a nitrogen atmosphere, and cooled to 0° C. in an ice bath. Potassium t-butoxide (1 mL, 1 mmol, 1M THF solution) was added and the mixture was allowed to stir for 10 min at 0° C. and room temperature for 30 min. The resulting mixture was cool to 0° C. Solid 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (310 mg, 1 mmol) from Example XXIV, step 1a was added. The mixture was allowed to stir for 30 min at 0° C. and overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL), washed sequentially with 10% LiCl, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the resulting material was purified by silica gel chromatography (ethyl acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to provide 0.27 g of 3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine. The resulting mixture was cool to 0° C to stir for 30 min at 0° C. and overnight at room temperature washed sequentially with 10% LiCl, water and brine dried over anhydrous magnesium sulfate The solvent was removed in vacuo the resulting material was purified by silica gel chromatography (ethyl acetate/heptane, 25 min gradient: 5-50% ethyl acetate)

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

Procedure: A solution of N-(4-methoxybenzyl)aniline (6.42 g, 30.10 mmol) in THF (10 mL) was stirred at 25° C., and potassium tert-butoxide (1M in THF, 90.30 mL, 90.30 mmol) was added. After 30 minutes, 8-bromo-6-chloroimidazo[1,2-b]pyridazine (7.00 g, 30.10 mmol, Example 1 from WO 2007/038314) was added, and the reaction solution stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2×200 mL). The organic layer was washed with saturated aqueous NaHCO3 (100 mL) and saturated aqueous at NaCl (100 mL). The organic phase was dried Na2SO4, filtered and concentrated in vacuo. The residue was purified via ISCO (5% EtOAC/DCM; 120 g column) to give 6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (9.09 g, 83% yield) as a tan solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=3.918 minutes [M+H]=365.07. The reaction was quenched with water (50 mL) extracted with ethyl acetate (2×200 mL) The organic layer was washed with saturated aqueous NaHCO3 (100 mL) and saturated aqueous at NaCl (100 mL) filtered concentrated in vacuo The residue was purified via ISCO (5% EtOAC/DCM; 120 g column)

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