ethyl 3-azabicyclo[3.1.0]hexane-6-carboxylate

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1.523 g of ethyl(3-azabicyclo[3.1.0]hex-6-yl)carboxylate in N,N-dimethylformamide (30 ml) were added 2.30 g of sodium hydrogencarbonate and 1.39 g of 8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and the resulting mixture was heated to 80° C. for 2 hours. After adding water and ethyl acetate, the organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Then the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.574 g of the title compound as pale yellow crystals. the organic layer was washed with water dried over magnesium sulfate concentrated under reduced pressure Then the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol)

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

Procedure: In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with ethyl 3-azabicyclo[3.1.0]hexane-6-carboxylate (179236-79-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=422.5 [MH+].

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

Procedure: In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with ethyl 3-azabicyclo[3.1.0]hexane-6-carboxylate (179236-79-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=422.5 [MH+].

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of cyclobutanone (157 mg, 2.19 mmol) in acetic acid (0.11 mL, 1.56 mmol) was added to a stirred solution of ethyl 3-aza bicyclo[3.1.0]hexane-6-carboxylate (243 mg, 1.56 mmol, obtained in the above step) in dichloromethane, cooled at 0° C. Solid sodium triacetoxy borohydride (727 mg, 3.43 mmol) was added portion wise over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 16 hours. The reaction mixture was cooled to 0° C. and basified with saturated sodium bicarbonate solution (pH: 7.5). The two layers were separated, the organic layer was washed with brine, dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to obtain ethyl 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylate (219 mg). The reaction mixture was gradually warmed to room temperature The two layers were separated the organic layer was washed with brine dried over anhydrous sodium sulfate the volatiles were removed under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1.523 g of ethyl(3-azabicyclo[3.1.0]hex-6-yl)carboxylate in N,N-dimethylformamide (30 ml) were added 2.30 g of sodium hydrogencarbonate and 1.39 g of 8-chloromethyl-10H-pyrazino[2,3-b][1,4]benzothiazine and the resulting mixture was heated to 80° C. for 2 hours. After adding water and ethyl acetate, the organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Then the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.574 g of the title compound as pale yellow crystals. the organic layer was washed with water dried over magnesium sulfate concentrated under reduced pressure Then the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol)

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

Procedure: In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with ethyl 3-azabicyclo[3.1.0]hexane-6-carboxylate (179236-79-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=422.5 [MH+].