[(2S)-1-ethylpyrrolidin-2-yl]methanamine

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

Procedure: Ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-(dimethylamino)acrylate (Intermediate 37, 0.500 g, 1.10 mmol) was taken up THF (40 mL) and cooled to 0° C. for 10 min and then (S)-(1-ethylpyrrolidin-2-yl)methanamine (0.153 mL, 1.10 mmol) was added and stirred at room temperature for 2 min. The reaction mixture was quenched with sat NH4Cl diluted with EtOAc and separated, dried, and solvent removed. The residue was purified by a 0-5% gradient on the ISCO of DCM/Methanol to give (S)-ethyl 2-(2,6-difluoro-5-iodonicotinoyl)-3-((1-ethylpyrrolidin-2-yl)methylamino)acrylate (0.360 g, 67%) as a red oil. The reaction mixture was quenched with sat NH4Cl diluted with EtOAc separated dried solvent removed The residue was purified by a 0-5% gradient on the ISCO of DCM/Methanol

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

Procedure: 95 g of 2-methoxy-4-amino-5-ethylsulphonylbenzoic acid dissolved in 370 ml of acetone, in the presence of 37 g of trielthylamine, is treated with 40 g of ethyl chloroformate with 57 g of (S)-(−)-1-ethyl-2-aminomethylpyrrolidine. 115 g of (S)-(−)-N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-amino-5-ethylsulphonylbenzamide is obtained (yield=84%).

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

Procedure: 95 g of 2-methoxy-4-amino-5-ethylsulphonylbenzoic acid dissolved in 370 ml of acetone, in the presence of 37 g of trielthylamine, is treated with 40 g of ethyl chloroformate with 57 g of (S)-(−)-1-ethyl-2-aminomethylpyrrolidine. 115 g of (S)-(−)-N-(1-ethyl-2-pyrrolidinylmethyl)-2-methoxy-4-amino-5-ethylsulphonylbenzamide is obtained (yield=84%).

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

Procedure: Bis (2-methoxyethoxy)aluminium dihydride (203.4 g, 0.70 mol, approx. 70% solution in toluene) and toluene (80 ml, dried over molecular sieves A) were added to a three-necked round-bottomed flask. The temperature in the flask was increased to 40° C. and then (S)-1-ethyl-2-pyrrolidinecarboxamide (21.0 g, 0.147 mol, 95% purity on GC) was added spoonwise during 45 min. In order to maintain the temperature at approx. 40° C., cooling was necessary during the addition. The temperature was decreased below 10° C. 55 min after completed addition. Water (500 ml) was added during 15 min and the pH was adjusted to 1 by adding 115 ml concentrated HCl and 100 ml H2O. After extraction, the phases were separated and 200 ml CH2Cl2 were added to the water phase. The pH was subsequently adjusted to 13-14 by adding NaOH (40%, 50 ml). The organic phase was separated and the water phase was extracted with further portions of CH2Cl2 (200+100 ml). The combined organic phases were dried, filtered and concentrated under vacuo to afford 24.8 g crude title product (83%) in an optical purity of >99%. were added to a three-necked round-bottomed flask In order to maintain the temperature at approx. 40° C. cooling was necessary during the addition was decreased below 10° C 55 min addition After extraction the phases were separated 200 ml CH2Cl2 were added to the water phase by adding NaOH (40%, 50 ml) The organic phase was separated the water phase was extracted with further portions of CH2Cl2 (200+100 ml) The combined organic phases were dried filtered concentrated under vacuo

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

Procedure: Bis (2-methoxyethoxy)aluminium dihydride (203.4 g, 0.70 mol, approx. 70% solution in toluene) and toluene (80 ml, dried over molecular sieves A) were added to a three-necked round-bottomed flask. The temperature in the flask was increased to 40° C. and then (S)-1-ethyl-2-pyrrolidinecarboxamide (21.0 g, 0.147 mol, 95% purity on GC) was added spoonwise during 45 min. In order to maintain the temperature at approx. 40° C., cooling was necessary during the addition. The temperature was decreased below 10° C. 55 min after completed addition. Water (500 ml) was added during 15 min and the pH was adjusted to 1 by adding 115 ml concentrated HCl and 100 ml H2O. After extraction, the phases were separated and 200 ml CH2Cl2 were added to the water phase. The pH was subsequently adjusted to 13-14 by adding NaOH (40%, 50 ml). The organic phase was separated and the water phase was extracted with further portions of CH2Cl2 (200+100 ml). The combined organic phases were dried, filtered and concentrated under vacuo to afford 24.8 g crude title product (83%) in an optical purity of >99%. were added to a three-necked round-bottomed flask In order to maintain the temperature at approx. 40° C. cooling was necessary during the addition was decreased below 10° C 55 min addition After extraction the phases were separated 200 ml CH2Cl2 were added to the water phase by adding NaOH (40%, 50 ml) The organic phase was separated the water phase was extracted with further portions of CH2Cl2 (200+100 ml) The combined organic phases were dried filtered concentrated under vacuo

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

Procedure: By using N-(t-butoxycarbonyl)glycine (1.0 g) and N-methylbenzylamine (736 μl) as a starting material, the title compound (740 mg) was obtained in the same manners as those of Reference Example 88, (1) and Reference Example 78, (3).

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

Procedure: By using N-(t-butoxycarbonyl)glycine (1.0 g) and N-methylbenzylamine (736 μl) as a starting material, the title compound (740 mg) was obtained in the same manners as those of Reference Example 88, (1) and Reference Example 78, (3).

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

Procedure: By using N-(t-butoxycarbonyl)glycine (1.0 g) and 3-picolylamine (577 μl) as starting materials, the title compound (892 mg) was obtained in the same manners as those of Reference Example 88, (1) and Reference Example 78, (3).

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

Procedure: By using N-(t-butoxycarbonyl)glycine (1.0 g) and 3-picolylamine (577 μl) as starting materials, the title compound (892 mg) was obtained in the same manners as those of Reference Example 88, (1) and Reference Example 78, (3).

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

Procedure: By using 3-(t-butoxycarbonylaminomethyl)pyrrolidine (1.0 g) and methanesulfonyl chloride (0.48 ml) as starting materials, the title compound (0.78 g) was obtained in the same manners as those of Reference Example 58, (1) and Reference Example 39, (2).

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

Procedure: By using 3-(t-butoxycarbonylaminomethyl)pyrrolidine (1.0 g) and methanesulfonyl chloride (0.48 ml) as starting materials, the title compound (0.78 g) was obtained in the same manners as those of Reference Example 58, (1) and Reference Example 39, (2).

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

Procedure: By using (S)-(−)-3-(t-butoxycarbonylamino)pyrrolidine (2.0 g) and methanesulfonyl chloride (1 ml) as starting materials, the title compound (1.03 g) was obtained in the same manners as those of Reference Example 58, (1) and Reference Example 39, (2).