methyl pyrrolidine-2-carboxylate;hydrochloride

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 600 ml of technical-grade methanol are introduced into a multinecked flask equipped with dropping funnel and internal thermometer, with ice/sodium chloride cooling. 2.4 mol of thionyl chloride are added dropwise in such a way that the temperature of the reaction solution does not exceed -5° C. Then, 2.18 mol of proline are added in portions in the course of approximately 10 minutes. The mixture is stirred for approximately 4 hours at 40° C. and subsequently for three days at room temperature, and the solution is greatly concentrated, the residue is taken up several times in methanol to remove excess thionyl chloride, and the mixture is reconcentrated. After drying the product for several hours in a lukewarm water bath in an evacuated flask, the target compound is obtained in quantitative yield. Some of the oily crude product crystallises after being left to stand over several days. equipped does not exceed -5° C the solution is greatly concentrated to remove excess thionyl chloride After drying the product for several hours in a lukewarm water bath in an evacuated flask the target compound is obtained in quantitative yield Some of the oily crude product crystallises after being left to stand over several days

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 methyl pyrrolidine-2-carboxylate hydrochloride (79397-50-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=396.5 [MH+].

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 600 ml of technical-grade methanol are introduced into a multinecked flask equipped with dropping funnel and internal thermometer, with ice/sodium chloride cooling. 2.4 mol of thionyl chloride are added dropwise in such a way that the temperature of the reaction solution does not exceed -5° C. Then, 2.18 mol of proline are added in portions in the course of approximately 10 minutes. The mixture is stirred for approximately 4 hours at 40° C. and subsequently for three days at room temperature, and the solution is greatly concentrated, the residue is taken up several times in methanol to remove excess thionyl chloride, and the mixture is reconcentrated. After drying the product for several hours in a lukewarm water bath in an evacuated flask, the target compound is obtained in quantitative yield. Some of the oily crude product crystallises after being left to stand over several days. equipped does not exceed -5° C the solution is greatly concentrated to remove excess thionyl chloride After drying the product for several hours in a lukewarm water bath in an evacuated flask the target compound is obtained in quantitative yield Some of the oily crude product crystallises after being left to stand over several days

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 600 ml of technical-grade methanol are introduced into a multinecked flask equipped with dropping funnel and internal thermometer, with ice/sodium chloride cooling. 2.4 mol of thionyl chloride are added dropwise in such a way that the temperature of the reaction solution does not exceed -5° C. Then, 2.18 mol of proline are added in portions in the course of approximately 10 minutes. The mixture is stirred for approximately 4 hours at 40° C. and subsequently for three days at room temperature, and the solution is greatly concentrated, the residue is taken up several times in methanol to remove excess thionyl chloride, and the mixture is reconcentrated. After drying the product for several hours in a lukewarm water bath in an evacuated flask, the target compound is obtained in quantitative yield. Some of the oily crude product crystallises after being left to stand over several days. equipped does not exceed -5° C the solution is greatly concentrated to remove excess thionyl chloride After drying the product for several hours in a lukewarm water bath in an evacuated flask the target compound is obtained in quantitative yield Some of the oily crude product crystallises after being left to stand over several days

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 500 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 5 ml of 1,2-dichloroethane and 5 ml of tetrahydrofuran. 314 mg of methylpyrrolidine-2-carboxylate hydrochloride are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 566 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC). After cooling to 25° C. stirred at 25° C. for a further 12 h extracted three times with dichloromethane the combined organic phases are dried over sodium sulfate After filtration the filtrate is evaporated to dryness purified by chromatography (reversed phase HPLC)

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 methyl pyrrolidine-2-carboxylate hydrochloride (79397-50-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=396.5 [MH+].