3-(iodomethyl)-3-methyloxetane

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS (m/e): 367.3 (MH+). isolated as white solid

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

Procedure: A cooled (0° C.) solution of (rac)-4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (example 83) (75 mg, 0.27 mmol) in DMF (1.4 mL) was treated with NaH (55% in oil, 18.7 mg, 0.43 mmol) and after ½ h with 3-(iodomethyl)-3-methyloxetane (209 mg, 0.59 mmol, synthesized by refluxing 3-(chloromethyl)-3-methyloxetane with 5 eq. sodium iodide in acetone overnight) in DMF (1 mL). After warming up to room temperature over 5 h, the reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with Et2O (3×). The organic phases were washed once with aq. 10% NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (20 g SiO2, Telos-cartridge, 1 to 3% 2-propanol in CH2Cl2) to give the title compound (28 mg, 29%) as brown oil. MS: 364.5 (M+H+). followed by extraction with Et2O (3×) The organic phases were washed once with aq. 10% NaCl solution The combined organic phases were dried (Na2SO4) filtered purified by flash chromatography (20 g SiO2, Telos-cartridge, 1 to 3% 2-propanol in CH2Cl2)

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

Procedure: A cooled (0° C.) solution of (rac)-4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (example 83) (75 mg, 0.27 mmol) in DMF (1.4 mL) was treated with NaH (55% in oil, 18.7 mg, 0.43 mmol) and after ½ h with 3-(iodomethyl)-3-methyloxetane (209 mg, 0.59 mmol, synthesized by refluxing 3-(chloromethyl)-3-methyloxetane with 5 eq. sodium iodide in acetone overnight) in DMF (1 mL). After warming up to room temperature over 5 h, the reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with Et2O (3×). The organic phases were washed once with aq. 10% NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (20 g SiO2, Telos-cartridge, 1 to 3% 2-propanol in CH2Cl2) to give the title compound (28 mg, 29%) as brown oil. MS: 364.5 (M+H+). followed by extraction with Et2O (3×) The organic phases were washed once with aq. 10% NaCl solution The combined organic phases were dried (Na2SO4) filtered purified by flash chromatography (20 g SiO2, Telos-cartridge, 1 to 3% 2-propanol in CH2Cl2)

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS (m/e): 367.3 (MH+). isolated as white solid

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS (m/e): 367.3 (MH+). isolated as white solid

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS (m/e): 367.3 (MH+). isolated as white solid

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS(m/e): 367.3 (MH+). isolated as white solid

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-tert-butyl (4-((5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate (103 mg, 0.19 mmol) in acetonitrile (2 mL) and THF (2 mL) was added 3-(iodomethyl)-3-methyl-oxetane (78 mg, 0.38 mmol) and potassium carbonate (130 mg, 0.94 mmol). The mixture was heated at 65° C. for 3 days. After cooling to room temperature, water (20 mL) was added and the mixture extracted with DCM (50 mL×3). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0 to 15% methanol/DCM) gave tert-butyl N-[2-(2,6-difluorophenyl)-4-[[1-methyl-5-[(4R)-4-[(3-methyloxetan-3-yl)methylamino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (130 mg, quantitative). This solid (130 mg, 0.21 mmol) was stirred with TFA (3 mL) and DCM (3 mL) at room temperature for 1 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 334 (55.7 mg, 51%). 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.18 (s, 1H), 7.56 (s, 1H), 7.55-7.41 (m, 3H), 7.26 (t, J=8.7 Hz, 2H), 4.28 (d, J=5.6 Hz, 2H), 4.12 (d, J=5.5 Hz, 2H), 3.65 (s, 3H), 3.23-3.00 (m, 4H), 2.83-2.70 (m, 1H), 2.70-2.58 (m, 2H), 1.99-1.77 (m, 3H), 1.68-1.51 (m, 3H), 1.17 (s, 3H). LCMS (ES+) m/z 532 (M+1) After cooling to room temperature the mixture extracted with DCM (50 mL×3) The organic layer was separated dried over MgSO4 concentrated under reduced pressure Purification via silica gel column chromatography (0 to 15% methanol/DCM)

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

Procedure: A cooled (0° C.) solution of (rac)-4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (example 83) (75 mg, 0.27 mmol) in DMF (1.4 mL) was treated with NaH (55% in oil, 18.7 mg, 0.43 mmol) and after ½ h with 3-(iodomethyl)-3-methyloxetane (209 mg, 0.59 mmol, synthesized by refluxing 3-(chloromethyl)-3-methyloxetane with 5 eq. sodium iodide in acetone overnight) in DMF (1 mL). After warming up to room temperature over 5 h, the reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with Et2O (3×). The organic phases were washed once with aq. 10% NaCl solution. The combined organic phases were dried (Na2SO4), filtered and purified by flash chromatography (20 g SiO2, Telos-cartridge, 1 to 3% 2-propanol in CH2Cl2) to give the title compound (28 mg, 29%) as brown oil. MS: 364.5 (M+H+). followed by extraction with Et2O (3×) The organic phases were washed once with aq. 10% NaCl solution The combined organic phases were dried (Na2SO4) filtered purified by flash chromatography (20 g SiO2, Telos-cartridge, 1 to 3% 2-propanol in CH2Cl2)

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS (m/e): 367.3 (MH+). isolated as white solid