3-methoxyazetidine;hydrochloride

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-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-methoxyazetidine hydrochloride and isolated as white solid (11.0 mg, 60%). MS (m/e): 387.4 (MH+).

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

Procedure: As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 3-methoxyazetidine hydrochloride instead of methylamine, to the title compound (75 mg, 61%) which was obtained as a light yellow oil. MS: m/e=380.3 [M+H]+.

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

Procedure: As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 3-methoxyazetidine hydrochloride instead of methylamine, to the title compound (75 mg, 61%) which was obtained as a light yellow oil. MS: m/e=380.3 [M+H]+.

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

Procedure: A 100-mL round bottomed flask was equipped with a reflux condenser was charged with 3-methoxyazetidine hydrochloride (1.0 g, 8.09 mmol), 5-bromo-2-nitropyridine (1.97 g, 9.71 mmol), Pd2(dba)3 (370.1 mg, 0.404 mmol), Xantphos (467.6 mg, 0.809 mmol), Cs2CO3 (7.9 g, 24.3 mmol), and dioxane (50 mL). After bubbling nitrogen through the reaction mixture for 20 minutes, it was heated at 100° C. under N2 protection for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 323a as a yellow solid (1.63 g, 96%). MS-ESI: [M+H]+ 210.2 A 100-mL round bottomed flask was equipped with a reflux condenser After bubbling nitrogen through the reaction mixture for 20 minutes It was cooled to room temperature filtered The filtrate was concentrated under reduced pressure the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol

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

Procedure: A 100-mL round bottomed flask was equipped with a reflux condenser was charged with 3-methoxyazetidine hydrochloride (1.0 g, 8.09 mmol), 5-bromo-2-nitropyridine (1.97 g, 9.71 mmol), Pd2(dba)3 (370.1 mg, 0.404 mmol), Xantphos (467.6 mg, 0.809 mmol), Cs2CO3 (7.9 g, 24.3 mmol), and dioxane (50 mL). After bubbling nitrogen through the reaction mixture for 20 minutes, it was heated at 100° C. under N2 protection for 3 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 323a as a yellow solid (1.63 g, 96%). MS-ESI: [M+H]+ 210.2 A 100-mL round bottomed flask was equipped with a reflux condenser After bubbling nitrogen through the reaction mixture for 20 minutes It was cooled to room temperature filtered The filtrate was concentrated under reduced pressure the residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol

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

Procedure: 5-Bromo-2-fluoropyridine (1.7 g) was mixed with N,N-dimethylacetamide (5 ml), and 3-methoxyazetidine hydrochloride (335 mg) and potassium carbonate (1.5 g) were added thereto, followed by stirring at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 5-bromo-2-(3-methoxyazetidin-1-yl)pyridine (581 mg). were added The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were then added The organic layer was dried over Na2SO4 concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography (hexane/EtOAc)

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

Procedure: The title compound was prepared from the product of Example 50A and commercially available 3-methoxyazetidine hydrochloride by the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.29 (d, J=6.4 Hz, 3H), 3.19 (s, 3H), 3.71-3.77 (m, 1H), 3.80-3.87 (m, 1H), 4.02-4.09 (m, 1H), 4.14-4.22 (m, 2H), 4.88-5.01 (m, 2H). 5.14-5.22 (m, 1H), 7.78 (d, J=9.1 Hz, 1H), 8.02 (dd, J=8.0, 8.0 Hz, 1H), 11.82 (br s, 1H). MS (ESI+) m/z 493 (M+H)+. Anal. calcd. for C20H17ClF4N2O4S: C, 48.74; H, 3.48; N, 5.68.

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

Procedure: From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-methoxy-azetidine hydrochloride in DMF. [α]D20=+42.5° (c=0.44, CHCl3), ES-MS m/e (%): 457 (M+H+, 100).

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

Procedure: {2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (200 mg, 0.328 mmol, Intermediate 65), 3-methoxyazetidine hydrochloride (427 mg, 3.28 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The reaction vessel was then cooled to room temperature and the contents were transferred to a separatory funnel with EtOAc dilution, and extracted once with saturated, aqueous NH4Cl solution, then extracted three times with deionized water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C34H29ClF3N7O2, 659.2. m/z found, 660.3 [M+H]+. 1H NMR (600 MHz, CD3OD) δ ppm 8.78 (d, J=2.1 Hz, 1H), 8.11 (dd, J=2.5, 0.4 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.2, 2.1 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.77-7.73 (m, 2H), 7.67 (d, J=1.4 Hz, 1H), 7.62-7.59 (m, 2H), 7.59-7.56 (m, 1H), 7.17 (d, J=8.7 Hz, 2H), 6.49-6.46 (m, 1H), 6.37 (s, 1H), 4.34-4.29 (m, 4H), 4.19-4.13 (m, 1H), 4.02-3.97 (m, 2H), 3.48 (s, 3H), 3.22 (s, 3H). sealed maintained at that temperature overnight The reaction vessel was then cooled to room temperature extracted once with saturated, aqueous NH4Cl solution extracted three times with deionized water The organic phase was separated dried over MgSO4 filtered concentrated under reduced pressure The crude material was purified via reverse phase chromatography

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

Procedure: {2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (200 mg, 0.328 mmol, Intermediate 65), 3-methoxyazetidine hydrochloride (427 mg, 3.28 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The reaction vessel was then cooled to room temperature and the contents were transferred to a separatory funnel with EtOAc dilution, and extracted once with saturated, aqueous NH4Cl solution, then extracted three times with deionized water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C34H29ClF3N7O2, 659.2. m/z found, 660.3 [M+H]+. 1H NMR (600 MHz, CD3OD) δ ppm 8.78 (d, J=2.1 Hz, 1H), 8.11 (dd, J=2.5, 0.4 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.2, 2.1 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.77-7.73 (m, 2H), 7.67 (d, J=1.4 Hz, 1H), 7.62-7.59 (m, 2H), 7.59-7.56 (m, 1H), 7.17 (d, J=8.7 Hz, 2H), 6.49-6.46 (m, 1H), 6.37 (s, 1H), 4.34-4.29 (m, 4H), 4.19-4.13 (m, 1H), 4.02-3.97 (m, 2H), 3.48 (s, 3H), 3.22 (s, 3H). sealed maintained at that temperature overnight The reaction vessel was then cooled to room temperature extracted once with saturated, aqueous NH4Cl solution extracted three times with deionized water The organic phase was separated dried over MgSO4 filtered concentrated under reduced pressure The crude material was purified via reverse phase chromatography

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

Procedure: From 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)isonicotinamide with cesium carbonate and 3-methoxy-azetidine hydrochloride. ES-MS m/e (%): 457 (M+H+, 100).

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

Procedure: From 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)isonicotinamide with cesium carbonate and 3-methoxy-azetidine hydrochloride. ES-MS m/e (%): 457 (M+H+, 100).