4-amino-2-methylbutan-2-ol

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 1-fluoro-2-nitrobenzene (1.9 mL, 18 mmol), 4-amino-2-methyl-2-butanol (1.6 g, 15 mmol) and triethylamine (6.4 mL, 46 mmol) in THF (30 mL) was refluxed for 8 h. Then the reaction was quenched by addition of water (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5/1-2/1) to afford 2.8 g (82%) of the title compound. Then the reaction was quenched by addition of water (50 mL) extracted with ethyl acetate (50 mL×2) The combined organic layers were washed with brine (50 mL) dried over sodium sulfate filtered concentrated The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5/1-2/1)

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

Procedure: The 3-bromo-6-fluoroimidazo[1,2-b]pyridazine was reacted with 4-amino-2-methylbutan-2-ol using the same reaction conditions as described in example 5.6.42, Part A to obtain 82% product. the same reaction conditions

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

Procedure: The 3-bromo-6-fluoroimidazo[1,2-b]pyridazine was reacted with 4-amino-2-methylbutan-2-ol using the same reaction conditions as described in example 5.6.42, Part A to obtain 82% product. the same reaction conditions

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

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To methyl 4-bromo-2-(bromomethyl)benzoate (0.220 g, 0.714 mmol) suspended in MeOH (6.0 mL) were added 4-amino-2-methylbutan-2-ol (0.077 g, 0.750 mmol) and Et3N (0.156 mL, 1.107 mmol). The mixture was heated to reflux (85° C.) for 24 hours, then cooled to RT, and concentrated in vacuo to give the title compound, which was used without further purification. The mixture was heated cooled to RT concentrated in vacuo

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To methyl 4-bromo-2-(bromomethyl)benzoate (0.220 g, 0.714 mmol) suspended in MeOH (6.0 mL) were added 4-amino-2-methylbutan-2-ol (0.077 g, 0.750 mmol) and Et3N (0.156 mL, 1.107 mmol). The mixture was heated to reflux (85° C.) for 24 hours, then cooled to RT, and concentrated in vacuo to give the title compound, which was used without further purification. The mixture was heated cooled to RT concentrated in vacuo

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

Procedure: (R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), 4-amino-2-methylbutan-2-ol (12.92 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). This was stirred overnight and was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention time=34.1 min) to give (R/S)-2-hydroxy-N-(3-hydroxy-3-methylbutyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10.5 mg, 0.019 mmol, 26.9% yield): LCMS=517 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.23 (2 H, m), 7.65-7.77 (4 H, m), 7.54-7.66 (3 H, m), 5.10 (1 H, s), 3.32-3.42 (2 H, m), 1.62-1.78 (2 H, m), 1.22 (6 H, s). HPLC Peak RT=9.2 min (Analytical Method A). was then purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 15 mL/min, 220 nM, product retention time=34.1 min)

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

Procedure: A solution of 1-fluoro-2-nitrobenzene (1.9 mL, 18 mmol), 4-amino-2-methyl-2-butanol (1.6 g, 15 mmol) and triethylamine (6.4 mL, 46 mmol) in THF (30 mL) was refluxed for 8 h. Then the reaction was quenched by addition of water (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL) and dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5/1-2/1) to afford 2.8 g (82%) of the title compound. Then the reaction was quenched by addition of water (50 mL) extracted with ethyl acetate (50 mL×2) The combined organic layers were washed with brine (50 mL) dried over sodium sulfate filtered concentrated The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (5/1-2/1)

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

Procedure: The 3-bromo-6-fluoroimidazo[1,2-b]pyridazine was reacted with 4-amino-2-methylbutan-2-ol using the same reaction conditions as described in example 5.6.42, Part A to obtain 82% product. the same reaction conditions

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