tert-butyl 3-(iodomethyl)azetidine-1-carboxylate

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

Procedure: N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (152 mg, 286 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (85.1 mg, 286 μmol) and cesium carbonate (280 mg, 859 μmol) in dimethylformamide (3 mL) were heated in a microwave at 150° C. for 30 min. The mixture was partitioned between ethyl acetate and water, washed with water, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate that was used directly without purification. MS (M+H)+=702. The mixture was partitioned between ethyl acetate and water washed with water dried concentrated in vacuo Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

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

Procedure: 2-(6-Fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (225 mg, 547 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (162 mg, 547 μmol) and cesium carbonate (534 mg, 1.64 mmol) in dimethylformamide (4 mL) were heated in a microwave at 150° C. for 30 min. The mixture was partitioned between ethyl acetate and water. Then the organic phase was washed with water 3 times, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((6-fluoro-3-(7-formyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (202 mg, 64%). The mixture was partitioned between ethyl acetate and water Then the organic phase was washed with water 3 times dried concentrated in vacuo Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

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

Procedure: 2-(6-Fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (225 mg, 547 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (162 mg, 547 μmol) and cesium carbonate (534 mg, 1.64 mmol) in dimethylformamide (4 mL) were heated in a microwave at 150° C. for 30 min. The mixture was partitioned between ethyl acetate and water. Then the organic phase was washed with water 3 times, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((6-fluoro-3-(7-formyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (202 mg, 64%). The mixture was partitioned between ethyl acetate and water Then the organic phase was washed with water 3 times dried concentrated in vacuo Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

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

Procedure: N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (56.0 mg, 188 μmol) and cesium carbonate (184 mg, 565 μmol) in dimethylformamide (2 mL) were heated in a microwave at 150° C. for 30 min. The mixture was cooled, partitioned between ethyl acetate and water, and the organic phase washed with water 3 times then dried and concentrated. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (108 mg, 82%). MS (M+H)+=700; 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.34 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.00 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.35 (dd, J=9.0, 2.1 Hz, 1H), 6.24-6.81 (m, 1H), 5.72 (s, 3H), 5.30 (s, 2H), 4.66 (d, J=7.5 Hz, 2H), 3.89 (dd, J=8.9, 5.2 Hz, 2H), 3.58 (dd, J=8.8, 7.6 Hz, 2H), 3.21-3.33 (m, 1H), 1.61 (s, 9H), 1.45 (s, 9H), 0.88-1.00 (m, 2H), −0.08-−0.01 (m, 9H). The mixture was cooled partitioned between ethyl acetate and water the organic phase washed with water 3 times then dried concentrated Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

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

Procedure: N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (56.0 mg, 188 μmol) and cesium carbonate (184 mg, 565 μmol) in dimethylformamide (2 mL) were heated in a microwave at 150° C. for 30 min. The mixture was cooled, partitioned between ethyl acetate and water, and the organic phase washed with water 3 times then dried and concentrated. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (108 mg, 82%). MS (M+H)+=700; 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.34 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.00 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.35 (dd, J=9.0, 2.1 Hz, 1H), 6.24-6.81 (m, 1H), 5.72 (s, 3H), 5.30 (s, 2H), 4.66 (d, J=7.5 Hz, 2H), 3.89 (dd, J=8.9, 5.2 Hz, 2H), 3.58 (dd, J=8.8, 7.6 Hz, 2H), 3.21-3.33 (m, 1H), 1.61 (s, 9H), 1.45 (s, 9H), 0.88-1.00 (m, 2H), −0.08-−0.01 (m, 9H). The mixture was cooled partitioned between ethyl acetate and water the organic phase washed with water 3 times then dried concentrated Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

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

Procedure: N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (152 mg, 286 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (85.1 mg, 286 μmol) and cesium carbonate (280 mg, 859 μmol) in dimethylformamide (3 mL) were heated in a microwave at 150° C. for 30 min. The mixture was partitioned between ethyl acetate and water, washed with water, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate that was used directly without purification. MS (M+H)+=702. The mixture was partitioned between ethyl acetate and water washed with water dried concentrated in vacuo Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

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

Procedure: 2-(6-Fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (225 mg, 547 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (162 mg, 547 μmol) and cesium carbonate (534 mg, 1.64 mmol) in dimethylformamide (4 mL) were heated in a microwave at 150° C. for 30 min. The mixture was partitioned between ethyl acetate and water. Then the organic phase was washed with water 3 times, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((6-fluoro-3-(7-formyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (202 mg, 64%). The mixture was partitioned between ethyl acetate and water Then the organic phase was washed with water 3 times dried concentrated in vacuo Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

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

Procedure: N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (56.0 mg, 188 μmol) and cesium carbonate (184 mg, 565 μmol) in dimethylformamide (2 mL) were heated in a microwave at 150° C. for 30 min. The mixture was cooled, partitioned between ethyl acetate and water, and the organic phase washed with water 3 times then dried and concentrated. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (108 mg, 82%). MS (M+H)+=700; 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.34 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.00 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.35 (dd, J=9.0, 2.1 Hz, 1H), 6.24-6.81 (m, 1H), 5.72 (s, 3H), 5.30 (s, 2H), 4.66 (d, J=7.5 Hz, 2H), 3.89 (dd, J=8.9, 5.2 Hz, 2H), 3.58 (dd, J=8.8, 7.6 Hz, 2H), 3.21-3.33 (m, 1H), 1.61 (s, 9H), 1.45 (s, 9H), 0.88-1.00 (m, 2H), −0.08-−0.01 (m, 9H). The mixture was cooled partitioned between ethyl acetate and water the organic phase washed with water 3 times then dried concentrated Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1.94 g of tert-butyl 3-[(tosyloxy)methyl]azetidin-1-carboxylate in 15.5 ml acetone were added 837 mg of lithium iodide and the reaction mixture was stirred for 16 hours at 35° C. After cooling, it was diluted with 200 ml ethyl acetate and the organic phase washed twice with 30 ml portions of water and once with 20 ml saturated sodium chloride solution. After drying over sodium sulphate and filtration, this was concentrated in vacuo. In this manner, 1.6 g of tert-butyl-3-(iodomethyl)azetidin-1-carboxylate were obtained, which was further reacted without purification. After cooling the organic phase washed twice with 30 ml portions of water and once with 20 ml saturated sodium chloride solution After drying over sodium sulphate and filtration this was concentrated in vacuo

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

Procedure: N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (152 mg, 286 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (85.1 mg, 286 μmol) and cesium carbonate (280 mg, 859 μmol) in dimethylformamide (3 mL) were heated in a microwave at 150° C. for 30 min. The mixture was partitioned between ethyl acetate and water, washed with water, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate that was used directly without purification. MS (M+H)+=702. The mixture was partitioned between ethyl acetate and water washed with water dried concentrated in vacuo Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

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

Procedure: 2-(6-Fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (225 mg, 547 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (162 mg, 547 μmol) and cesium carbonate (534 mg, 1.64 mmol) in dimethylformamide (4 mL) were heated in a microwave at 150° C. for 30 min. The mixture was partitioned between ethyl acetate and water. Then the organic phase was washed with water 3 times, dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((6-fluoro-3-(7-formyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (202 mg, 64%). The mixture was partitioned between ethyl acetate and water Then the organic phase was washed with water 3 times dried concentrated in vacuo Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)

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

Procedure: N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (56.0 mg, 188 μmol) and cesium carbonate (184 mg, 565 μmol) in dimethylformamide (2 mL) were heated in a microwave at 150° C. for 30 min. The mixture was cooled, partitioned between ethyl acetate and water, and the organic phase washed with water 3 times then dried and concentrated. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-5-(difluoromethoxy)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (108 mg, 82%). MS (M+H)+=700; 1H NMR (CDCl3) δ: 9.18 (s, 1H), 8.34 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.00 (s, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.35 (dd, J=9.0, 2.1 Hz, 1H), 6.24-6.81 (m, 1H), 5.72 (s, 3H), 5.30 (s, 2H), 4.66 (d, J=7.5 Hz, 2H), 3.89 (dd, J=8.9, 5.2 Hz, 2H), 3.58 (dd, J=8.8, 7.6 Hz, 2H), 3.21-3.33 (m, 1H), 1.61 (s, 9H), 1.45 (s, 9H), 0.88-1.00 (m, 2H), −0.08-−0.01 (m, 9H). The mixture was cooled partitioned between ethyl acetate and water the organic phase washed with water 3 times then dried concentrated Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes)