tert-butyl N-[(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate

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

Procedure: To a mixture of 5-ethenyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylic acid (105 mg, 0.387 mmol) and BOP (257 mg, 0.581 mmol) in DMF (5.2 mL) was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (145 mg, 0.581 mmol) followed by diisopropylethyl amine (0.169 mL, 0.968 mmol). The mixture was allowed to stir at room temperature for 18 h. After the reaction was complete, water was added and the aqueous layer extracted with ethyl acetate (×3). The organic layers were combined, dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography giving the title compound as an orange solid. LRMS (APCI) calc'd for (C24H27F2N5O3S) [M+H]+, 504.2. found 504.1. the aqueous layer extracted with ethyl acetate (×3) dried with magnesium sulfate filtered concentrated under reduced pressure The residue was purified by flash chromatography

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

Procedure: To a mixture of 4-(imidazo[1,2-b]pyridazin-3-yl)-5-methylthiophene-2-carboxylic acid (0.06 g, 0.24 mmol) and BOP (0.16 g, 0.36 mmol) was added tert-butyl[(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (0.06 g, 0.26 mmol) followed by diisopropylethylamine (0.09 mL, 0.49 mmol). The mixture was allowed stir at room temperature overnight. The resulting solution was diluted with water and extracted three times with dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered, concentrated and to the resulting residue was added dichloromethane and trifluoroacetic acid (1 mL, 53 mmol). The compound was purified by prep HPLC. The compound was neutralized by taking the fractions and adding an aqueous saturated sodium bicarbonate solution and extracting three times with ethyl acetate. The combined organics were dried with magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.62 (d, 1H); 8.28 (s, 1H); 8.21 (d, 1H); 7.99 (s, 1H); 7.90 (d, 1H); 7.29 (dd, 1H); 4.55 (m, 1H); 3.08 (m, 1H); 2.47 (s, 3H); 2.11 (m, 1H); 1.85 (m, 1H); 1.71 (m, TH); 1.59 (m, 2H); 1.45 (m, 1H). LRMS (APCI) calc'd for (C18H19F2N5OS) [M+H]+, 392.1. found 392.1. extracted three times with dichloromethane The combined organic layers were dried with magnesium sulfate filtered concentrated and to the resulting residue The compound was purified by prep HPLC adding an aqueous saturated sodium bicarbonate solution extracting three times with ethyl acetate The combined organics were dried with magnesium sulfate filtered concentrated

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

Procedure: A solution of tert-butyl [(1R,6R)-2-azido-3,3-difluorocyclohexyl]carbamate 28 (0.94 g, 3.40 mmol) in methanol (20 mL) was degassed with nitrogen and treated with 10% Pd/C (72 mg). The resulting heterogenous solution was exposed to a hydrogen atmosphere and stirred vigorously for 16 hours. The reaction was filtered, washing with methanol, and evaporated in vacuo to give 0.78 g (91%) of tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate 29 as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 6.67 (1H, d, J=8.3 Hz), 3.55 (1H, bs), 3.07 (1H, bs), 2.03 (1H, m), 1.62 (3H, m), 1.45 (1H, m), 1.36 (12H, m). The reaction was filtered washing with methanol evaporated in vacuo

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

Procedure: 4-[6-(Difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophene-2-carboxylic acid (0.768 g, 2.36 mmol) and BOP (3.13 g, 7.08 mmol) were dissolved in DMF (15.7 mL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (0.650 g, 2.60 mmol) and diisopropylethyl amine (619, 3.54 mmol) and the reaction stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate twice and brine once. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc/Hex) to give the title compound (0.900 g, 1.61 mmol). LRMS (APCI) calc'd for (C24H27F4N5O4S) [M+H]+, 558.2; found 558.0. the reaction stirred at room temperature for 16 h washed with saturated sodium bicarbonate twice The organic layer was dried with sodium sulfate filtered concentrated under reduced pressure The residue was purified by column chromatography (0-100% EtOAc/Hex)

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

Procedure: 5-Methyl-4-[6-(trimethoxymethyl)pyrazolo [1,5-a]pyrimidin-3-yl]thiophene-2-carboxylic acid (41.0 mg, 0.113 mmol) and BOP (59.9 mg, 0.135 mmol) were dissolved in DMF (752 μL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (31.1 mg, 0.124 mmol) and diisopropylethyl amine (59.1 μL, 0.338 mmol) and the reaction stirred at room temperature for 2 h. The reaction was then concentrated under reduced pressure and purified by column chromatography (0-60% EtOAc/DCM) to afford the title compound (quantitative yield). LRMS (APCI) calc'd for (C27H35F2N5O6S) [M+H]+, 596.2; found 596.1. the reaction stirred at room temperature for 2 h The reaction was then concentrated under reduced pressure purified by column chromatography (0-60% EtOAc/DCM)

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

Procedure: 4-Bromo-5-ethylthiophene-2-carboxylic acid (1.00 g, 4.25 mmol) and BOP (5.64 g, 12.8 mmol) were dissolved in DMF (42.5 mL) and stirred at room temperature for 5 min. To the reaction solution was added tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (1.07 g, 4.25 mmol) and diisopropylethyl amine (1.11 mL, 6.38 mmol) and the reaction stirred at room temperature for 64 h. The reaction mixture was diluted with ethyl acetate and washed with water 3×. The organic layer was collected, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-50% EtOAc/Hex) to give the title compound (1.56 g, 3.34 mmol). LRMS (APCI) calc'd for (C18H25BrF2N2O3S) [M+H]+, 467.1; found 466.9. 1H NMR (CDCl3, 500 MHz) δ 7.32 (s, 1H), 6.28 (s, 1H), 4.90 (s, 1H), 4.54 (s, 1H), 4.29 (s, 1H), 2.81 (q, J=7.5, 2H), 2.22 (m, 1H), 1.88 (m, 1H), 1.81 (m, 1H), 1.69 (m, 1H), 1.59 (m, 1H), 1.46 (s, 9H), 1.41 (m, 1H), 1.28 (t, J=7.3, 3H) the reaction stirred at room temperature for 64 h washed with water 3× The organic layer was collected dried with sodium sulfate filtered concentrated under reduced pressure The residue was purified by column chromatography (0-50% EtOAc/Hex)

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

Procedure: A solution of tert-butyl [(1R,6R)-2-azido-3,3-difluorocyclohexyl]carbamate 36 (0.94 g, 3.40 mmol) in methanol (20 mL) was degassed with nitrogen and treated with 10% PdJC (72 mg). The resulting heterogenous solution was exposed to a hydrogen atmosphere and stirred vigorously for 16 hours. The reaction was filtered, washing with methanol, and evaporated in vacuo to give 0.78 g (91%) of tert-butyl [(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate 37 as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 6.67 (1H, d, J=8.3 Hz), 3.55 (1H, bs), 3.07 (1H, bs), 2.03 (1H, m), 1.62 (3H, m), 1.45 (1H, m), 1.36 (12H, m). treated with 10% PdJC (72 mg) The reaction was filtered washing with methanol evaporated in vacuo