N-ethyl-N-methylethanamine

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Racemic benzyl 2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (34 g, 63 mmol) is chirally purified by SFC (Column: Chiralpak IC (5μ), 2×250 mm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% diethylmethyl amine) in CO2; flow: 65 mL/min at UV 260 nm). The second eluting isomer is the title compound (14 g, 42%, >98% ee): [α]D20=−30 (C=1.0, methanol), ES/MS (m/e) 478 (M+H).

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to a solution of 2-anilino-4-(1-ethyl-2-methylimidazol-5-yl)pyrimidine (Example 28; 150 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled to 0° C. and the mixture stirred for 10 minutes at 0° C. then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the resultant solid placed under high vacuum (<2 mmHg) for 1 hr. The resulting solid was placed under nitrogen and a solution of 2-(2-aminoethyl)ethanol (114 mg, 1.00 mmol) and diethylmethylamine in MeOH (3 ml) was cautiously added. The solution was stirred for 30 minutes and the volatiles were evaporated. Water (20 ml) was added and the precipitated solid was collected by filtration and washed with water (2×10 ml). The residue was dissolved in MeOH (5 ml) and loaded on to an Isolute amine column, eluted with MeOH (30 ml) and the fractions containing product were evaporated to give the title compound (190 mg, 79%) as a beige solid. NMR 1.18 (t, 3H), 2.39 (s, 3H), 2.89 (t, 2H), 3.15 (m, 7H), 4.38 (q, 2H), 7.21 (d, 1H), 7.71 (m, 3H), 7.89 (d, 2H), 8.41 (d, 1H), 9.82 (s, 1H); m/z 447. then heated at 90° C. for 90 minutes The volatiles were removed by evaporation the resultant solid placed under high vacuum (<2 mmHg) for 1 hr The solution was stirred for 30 minutes the volatiles were evaporated Water (20 ml) was added the precipitated solid was collected by filtration washed with water (2×10 ml) The residue was dissolved in MeOH (5 ml) eluted with MeOH (30 ml) the fractions containing product were evaporated

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

Procedure: Chlorosulphonic acid (150 μl, 2.16 mmol) was added dropwise to a solution of 2-anilino-4-(1-ethyl-2-methylimidazol-5-yl)pyrimidine (Example 28; 150 mg, 0.54 mmol) in thionyl chloride (3 ml) cooled to 0° C. and the mixture stirred for 10 minutes at 0° C. then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the resultant solid placed under high vacuum (<2 mmHg) for 1 hr. The resulting solid was placed under nitrogen and a solution of 2-(2-aminoethyl)ethanol (114 mg, 1.00 mmol) and diethylmethylamine in MeOH (3 ml) was cautiously added. The solution was stirred for 30 minutes and the volatiles were evaporated. Water (20 ml) was added and the precipitated solid was collected by filtration and washed with water (2×10 ml). The residue was dissolved in MeOH (5 ml) and loaded on to an Isolute amine column, eluted with MeOH (30 ml) and the fractions containing product were evaporated to give the title compound (190 mg, 79%) as a beige solid. NMR 1.18 (t, 3H), 2.39 (s, 3H), 2.89 (t, 2H), 3.15 (m, 7H), 4.38 (q, 2H), 7.21 (d, 1H), 7.71 (m, 3H), 7.89 (d, 2H), 8.41 (d, 1H), 9.82 (s, 1H); m/z 447. then heated at 90° C. for 90 minutes The volatiles were removed by evaporation the resultant solid placed under high vacuum (<2 mmHg) for 1 hr The solution was stirred for 30 minutes the volatiles were evaporated Water (20 ml) was added the precipitated solid was collected by filtration washed with water (2×10 ml) The residue was dissolved in MeOH (5 ml) eluted with MeOH (30 ml) the fractions containing product were evaporated

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

Procedure: Surprisingly, diisopropylethylamine in methylene chloride gave a 59:41 mixture of starting material:2-iodo product (Run #14), and only a trace of the 2-iodo product was observed in toluene under similar conditions. The low solubility of the hydrohalide salts of TMEDA, Et3N and Et2MeN in the above solvents may be responsible for their usefulness as opposed to the poor results with diisopropylethylamine. Precipitation of these hydrohalide salts may remove sufficient acid from the reaction so that the equilibrium is displaced toward product allowing the reaction to proceed to completion. a 59:41 mixture of starting material

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

Procedure: Equimolar amounts of diethylmethylamine and trifluoromethanesulfonic acid were weighed in a glove box under argon atmosphere. The weighed diethylmethylamine and trifluoromethanesulfonic acid were mixed and stirred while being cooled by liquid nitrogen, thus obtaining a target ionic conductor. while being cooled by liquid nitrogen thus obtaining a target ionic conductor

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 30.0 g quantity of N,N diethyl-N-methvlamine (reagent, product of Tokyo Kasei Co., Ltd.) was dissolved in 120 g of toluene, followed by nitrogen replacement. Over a period of 1 hour, 31.2 g of chloromethyl methyl ether (reagent, product of Tokyo Kasei Co., Ltd.) was added dropwise to the solution at 5° C. The mixture was stirred at 5° C. for 1 hour, heated to a gradually elevated temperature and stirred at room temperature for 10 hours to complete the reaction. The reaction mixture was filtered, and the solids obtained were washed with 150 g of toluene and 150 g of acetone and then dried in a vacuum, giving 53.7 g of the desired product (white solid). heated to a gradually elevated temperature stirred at room temperature for 10 hours the reaction The reaction mixture was filtered the solids obtained were washed with 150 g of toluene and 150 g of acetone dried in a vacuum

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

Procedure: Racemic benzyl 2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (34 g, 63 mmol) is chirally purified by SFC (Column: Chiralpak IC (5 j), 2×250 mm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% diethylmethyl amine) in CO2; flow: 65 mL/min at UV 260 nm). The second eluting isomer is the title compound (14 g, 42%, >98% ee): [α]D20=−30 (C=1.0, methanol), ES/MS (m/e) 478 (M+H).

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

Procedure: Racemic benzyl 2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (34 g, 63 mmol) is chirally purified by SFC (Column: Chiralpak IC (5μ), 2×250 mm; eluent: 40% methanol/acetonitrile (8/2) with 0.2% diethylmethyl amine) in CO2; flow: 65 mL/min at UV 260 nm). The second eluting isomer is the title compound (14 g, 42%, >98% ee): [α]D20=−30 (C=1.0, methanol), ES/MS (m/e) 478 (M+H).

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

Procedure: Equimolar amounts of diethylmethylamine and trifluoromethanesulfonic acid were weighed in a glove box under argon atmosphere. The weighed diethylmethylamine and trifluoromethanesulfonic acid were mixed and stirred while being cooled by liquid nitrogen, thus obtaining a target ionic conductor. while being cooled by liquid nitrogen thus obtaining a target ionic conductor

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

Procedure: Chlorosulphonic acid (70 μl, 1.0 mmol) was added dropwise to solution of 2-anilino-4-(2-formyl-1-isopropylimidazol-5-yl)pyrimidine (Example 10; 75 mg, 0.24 mmol) in thionyl chloride (2 ml) cooled at 0° C. and the mixture was stirred at 0° C. for 10 minutes then heated at 90° C. for 90 minutes. The volatiles were removed by evaporation and the residue was dried under high vacuum (<2 mmHg) for 1 hour. The resulting solid was placed under nitrogen and a solution of 2-methoxyethylamine (100 μl, 0.5 mmol) and diethylmethylamine (0.5 ml, 7.5 mmol) in MeOH (1.5 ml) added. The mixture was stirred for 30 minutes and the volatiles were evaporated in vacuo. The residue was purified by chromatography eluting with DCM/MeOH (98:2) to give the title compound (26 mg, 24%) as glassy solid. NMR: 1.53 (d, 6H) 2.86 (q, 2H) 3.17 (s, 3H) 3.28 (t, 2H) 5.65 (m, H) 7.3 (t, 1H) 7.50 (t, 1H) 7.71 (d, 2H) 7.83 (s, 1H) 7.89 (d, 2H) 8.68 (d, 1H) 9.81 (s, 1H) 10.11 (s, 1H). then heated at 90° C. for 90 minutes The volatiles were removed by evaporation the residue was dried under high vacuum (<2 mmHg) for 1 hour The mixture was stirred for 30 minutes the volatiles were evaporated in vacuo The residue was purified by chromatography eluting with DCM/MeOH (98:2)