3,3-difluorocyclobutan-1-amine

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: To a vial charged with 2-((2-chloro-5-cyano-3-(4-oxopiperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 13) (30 mg, 0.053 mmol) and 3,3-difluorocyclobutanamine (6.79 mg, 0.063 mmol) in methanol (132 μl) and tetrahydrofuran (132 μl) was added trimethyl orthoformate (58.4 μl, 0.528 mmol). The reaction mixture was stirred at room temperature. Sodium cyanoborohydride (6.64 mg, 0.106 mmol) was added and the reaction mixture was stirred at room temperature 6 h. The reaction mixture was diluted with water and methanol and filtered. The solid was taken up in DMF and partitioned between water and ethyl acetate. The aqueous layer was washed with ethyl acetate (3×). The combined organics were washed with 10% lithium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was taken forward as is. the reaction mixture was stirred at room temperature 6 h filtered partitioned between water and ethyl acetate The aqueous layer was washed with ethyl acetate (3×) The combined organics were washed with 10% lithium chloride solution dried over anhydrous sodium sulfate filtered concentrated in vacuo

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

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

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a vial containing 2-[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]ethanol (600 mg, 2.51 mmol) and 3,3-difluorocyclobutylamine (540 mg, 3.76 mmol) in acetonitrile (12.5 mL) was added DIPEA (2.21 mL, 12.5 mmol) at room temperature, and the mixture was stirred at 100° C. in an oil bath for 6.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified via silica gel chromatography using a gradient of EtOAc/heptane (20-40%) to afford the title compound (722.5 mg, 93%) as light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J=5.5 Hz, 1 H), 4.82 (br s, 1 H), 4.38-4.26 (m, 1 H), 3.56-3.47 (m, 2 H), 3.03-2.87 (m, 2 H), 2.83-2.65 (m, 4 H), 2.42 (s, 3 H). m/z (APCI+) for C11H14ClF2N3OS 310.1 (M+H)+. The reaction mixture was concentrated under reduced pressure the residue was purified via silica gel chromatography

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

Procedure: A mixture of 3,3-difluoro-cyclobutylamine×HCl (49 mg, 0.34 mmol), DIPEA (0.26 ml, 1.5 mmol), N-(trans-4-trifluoromethyl-cyclohexyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (125 mg, 0.34 mmol, prepared according to WO2010/100249) and MeCN (5 mL) is stirred for 16 h at reflux. Then the mixture is concentrated, diluted with EtOAc, washed with water, concentrated, dried and directly used in the next step. at reflux Then the mixture is concentrated diluted with EtOAc washed with water concentrated dried

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

Procedure: To a vial charged with 2-((2-chloro-5-cyano-3-(4-oxopiperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 13) (30 mg, 0.053 mmol) and 3,3-difluorocyclobutanamine (6.79 mg, 0.063 mmol) in methanol (132 μl) and tetrahydrofuran (132 μl) was added trimethyl orthoformate (58.4 μl, 0.528 mmol). The reaction mixture was stirred at room temperature. Sodium cyanoborohydride (6.64 mg, 0.106 mmol) was added and the reaction mixture was stirred at room temperature 6 h. The reaction mixture was diluted with water and methanol and filtered. The solid was taken up in DMF and partitioned between water and ethyl acetate. The aqueous layer was washed with ethyl acetate (3×). The combined organics were washed with 10% lithium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was taken forward as is. the reaction mixture was stirred at room temperature 6 h filtered partitioned between water and ethyl acetate The aqueous layer was washed with ethyl acetate (3×) The combined organics were washed with 10% lithium chloride solution dried over anhydrous sodium sulfate filtered concentrated in vacuo

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