2-(4-fluorophenyl)-2-methylpropan-1-amine

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

Procedure: To a 0° C. solution of 2-(4-fluorophenyl)-2-methylpropan-1-amine (16.8 g, 101 mmol, 1.0 equiv) and DIPEA (35 mL, 200 mmol, 2.0 equiv) in dry DCM (350 mL) was slowly added 3,5-dichlorothiadiazole (15.5 g, 101 mmol, 1.0 equiv). The reaction was allowed to stir at room temperature until starting material was consumed as judged by HPLC/MS. The reaction was diluted with water and EtOAc. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a yellow-orange oil (27 g, 94%). m/z=284.1 [M+H]+. To a 0° C. was consumed The reaction was diluted with water and EtOAc The layers were separated the organic layer was washed with brine dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of 4-fluorophenylacetonitrile (50 g, 370 mmol, 1.0 equiv) and iodomethane (70 mL, 1.11 mol, 3 equiv) in THF (370 mL) was added KOt-Bu (124 g, 1.1 mol, 3 equiv) as a solid in portions such that the reaction mixture did not exceed 50° C. The reaction mixture was stirred overnight and then quenched by the addition of brine. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-(4-fluorophenyl)-2-methylpropanenitrile as a yellow oil (57 g, 94%), which was used without further purification in the next step. To a solution of the nitrile in dry THF (800 mL) was added a solution of LAH (210 mL, 2 M in ether, 420 mmol, 1.2 equiv). After mixture was heated to reflux overnight, the reaction was allowed to cool to room temperature followed by a Fieser and Fieser work-up. Filtration of the resulting solids provided the title compound as an orange oil (57 g, 92%). m/z=168.1 [M+H]+. was used without further purification in the next step After mixture was heated to reflux overnight Filtration of the resulting solids

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

Procedure: To a 0° C. solution of 2-(4-fluorophenyl)-2-methylpropan-1-amine (16.8 g, 101 mmol, 1.0 equiv) and DIPEA (35 mL, 200 mmol, 2.0 equiv) in dry DCM (350 mL) was slowly added 3,5-dichlorothiadiazole (15.5 g, 101 mmol, 1.0 equiv). The reaction was allowed to stir at room temperature until starting material was consumed as judged by HPLC/MS. The reaction was diluted with water and EtOAc. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a yellow-orange oil (27 g, 94%). m/z=284.1 [M+H]+. To a 0° C. was consumed The reaction was diluted with water and EtOAc The layers were separated the organic layer was washed with brine dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of 4-fluorophenylacetonitrile (50 g, 370 mmol, 1.0 equiv) and iodomethane (70 mL, 1.11 mol, 3 equiv) in THF (370 mL) was added KOt-Bu (124 g, 1.1 mol, 3 equiv) as a solid in portions such that the reaction mixture did not exceed 50° C. The reaction mixture was stirred overnight and then quenched by the addition of brine. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-(4-fluorophenyl)-2-methylpropanenitrile as a yellow oil (57 g, 94%), which was used without further purification in the next step. To a solution of the nitrile in dry THF (800 mL) was added a solution of LAH (210 mL, 2 M in ether, 420 mmol, 1.2 equiv). After mixture was heated to reflux overnight, the reaction was allowed to cool to room temperature followed by a Fieser and Fieser work-up. Filtration of the resulting solids provided the title compound as an orange oil (57 g, 92%). m/z=168.1 [M+H]+. was used without further purification in the next step After mixture was heated to reflux overnight Filtration of the resulting solids

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

Procedure: To a solution of 4-fluorophenylacetonitrile (50 g, 370 mmol, 1.0 equiv) and iodomethane (70 mL, 1.1 mol, 3 equiv) in THF (370 mL) was added KOt-Bu (124 g, 1.1 mol, 3 equiv) as a solid in portions such that the reaction mixture did not exceed 50° C. The reaction mixture was stirred overnight and then quenched by the addition of brine. The mixture was diluted with EtOAc and washed twice with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-(4-fluorophenyl)-2-methylpropanenitrile as a yellow oil (57 g, 94%), which was used without further purification in the next step. To a solution of the nitrile in dry THF (800 mL) was added a solution of lithium aluminum hydride (210 mL, 2 M in ether, 420 mmol, 1.2 equiv). After the mixture was heated at reflux overnight, the reaction was allowed to cool to room temperature, and a Fieser and Fieser work-up (300 uL water/mmol, 1.0 mL 3N NaOH/mmol, 300 uL water/mmol) was performed. Filtration of the resulting solids provided the title compound as an orange oil (57 g, 92%). was used without further purification in the next step After the mixture was heated at reflux overnight Filtration of the resulting solids

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

Procedure: Using a similar procedure as was used for 6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)-5-methylpyridazin-3-amine in example 14, 3,6-dichloropyridazine-4-carboxamide (2.6 g, 13 mmol, 1.0 equiv), (2-(4-fluorophenyl)-2-methylpropan-1-amine (2.5 g, 15 mmol, 1.1 equiv), and diisopropylethylamine (2.8 mL, 16 mmol, 1.2 equiv) in CH3CN (54 mL) was heated at 60-90° C. for 48 hours. The product was purified over silica gel with 100% EtOAc to give the desired product (3.4 g, 78%) as a yellow foamy solid. The product was purified over silica gel with 100% EtOAc

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

Procedure: Using a similar procedure as was used for 6-chloro-N-(2-(4-fluorophenyl)-2-methylpropyl)-5-methylpyridazin-3-amine in example 14, 3,6-dichloropyridazine-4-carboxamide (2.6 g, 13 mmol, 1.0 equiv), (2-(4-fluorophenyl)-2-methylpropan-1-amine (2.5 g, 15 mmol, 1.1 equiv), and diisopropylethylamine (2.8 mL, 16 mmol, 1.2 equiv) in CH3CN (54 mL) was heated at 60-90° C. for 48 hours. The product was purified over silica gel with 100% EtOAc to give the desired product (3.4 g, 78%) as a yellow foamy solid. The product was purified over silica gel with 100% EtOAc

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

Procedure: A solution of (2-(4-fluorophenyl)-2-methylpropan-1-amine (5.5 g, 33 mmol, 1.8 equiv), 3,6-dichloro-4-methylpyridazine (3.0 g, 18 mmol, 1.0 equiv) and K2CO3 (5.1 g, 37 mmol, 2.0 equiv) in isopropanol (7.5 mL) was stirred at 100° C. under a blanket of nitrogen for 18 hours. The cooled mixture was partitioned between water and EtOAc and the organic fraction was concentrated in vacuo. Purification over silica gel using a 20-35% gradient of EtOAc/hexanes gave the desired product (0.80 g, 15%) of a yellow oil which was determined by HPLC to be a 5:1 mixture of regioisomers by HPLC. The cooled mixture was partitioned between water and EtOAc the organic fraction was concentrated in vacuo Purification over silica gel using a 20-35% gradient of EtOAc/hexanes

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

Procedure: A solution of (2-(4-fluorophenyl)-2-methylpropan-1-amine (5.5 g, 33 mmol, 1.8 equiv), 3,6-dichloro-4-methylpyridazine (3.0 g, 18 mmol, 1.0 equiv) and K2CO3 (5.1 g, 37 mmol, 2.0 equiv) in isopropanol (7.5 mL) was stirred at 100° C. under a blanket of nitrogen for 18 hours. The cooled mixture was partitioned between water and EtOAc and the organic fraction was concentrated in vacuo. Purification over silica gel using a 20-35% gradient of EtOAc/hexanes gave the desired product (0.80 g, 15%) of a yellow oil which was determined by HPLC to be a 5:1 mixture of regioisomers by HPLC. The cooled mixture was partitioned between water and EtOAc the organic fraction was concentrated in vacuo Purification over silica gel using a 20-35% gradient of EtOAc/hexanes

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 25 mL round bottom flask was added methyl 6-chloropyridazine-3-carboxylate (0.50 g, 2.90 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (0.60 g, 3.6 mmol, 1.2 equiv), potassium carbonate (300 mg, 2.2 mmol, 0.75 equiv), and isopropanol (3 mL). The reaction mixture was stirred and heated at 120° C. for 12 h. The reaction was then filtered through celite, concentrated, and purified by silica gel chromatography (0-40% EtOAC/hexanes) to afford 360 mg (43%) of methyl 6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3-carboxylate as an off-white foam. The reaction was then filtered through celite, concentrated purified by silica gel chromatography (0-40% EtOAC/hexanes)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 25 mL round bottom flask was added methyl 6-chloropyridazine-3-carboxylate (0.50 g, 2.90 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (0.60 g, 3.6 mmol, 1.2 equiv), potassium carbonate (300 mg, 2.2 mmol, 0.75 equiv), and isopropanol (3 mL). The reaction mixture was stirred and heated at 120° C. for 12 h. The reaction was then filtered through celite, concentrated, and purified by silica gel chromatography (0-40% EtOAC/hexanes) to afford 360 mg (43%) of methyl 6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazine-3-carboxylate as an off-white foam. The reaction was then filtered through celite, concentrated purified by silica gel chromatography (0-40% EtOAC/hexanes)

Conditions: temp:250.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 5 mL microwave vial was added 3-chloro-6-(1H-pyrazol-1-yl)pyridazine (320 mg, 1.8 mmol, 1.0 equiv), 2-(4-fluorophenyl)-2-methylpropan-1-amine (386 mg, 2.3 mmol, 1.3 equiv), diisopropylethylamine (620 μL, 3.6 mmol, 2.0 equiv), and NMP (4 mL). The reaction was heated in a microwave reactor to 250° C. and stirred for 15 min. A portion (roughly a third) of the reaction was purified by reverse phase chromatography and then silica gel chromatography (10% MeOH/DCM) to give 61 mg of N-(2-(4-fluorophenyl)-2-methylpropyl)-6-(1H-pyrazol-1-yl)pyridazin-3-amine, m/z=312.1 [M+H]. A portion (roughly a third) of the reaction was purified by reverse phase chromatography