tert-butyl (2S)-2-benzylpiperazine-1-carboxylate

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

Procedure: The title compound was prepared according to the procedure described for Example 1, Step A except using 2(S)-benzyl-1-tert-butoxycarbonylpiperazine (0.292 g, 1.06 mmol), 2,3-dimethylbenzoic acid (0.159 g, 1.06 mmol), HOBT (0.157 g, 1.02 mmol), EDC.HCl (0.213 g, 1.11 mmol) and triethylamine to adjust the pH to 7. The title compound was obtained as a thick oil. 1HNMR (DMSO-d6, 300 MHz) δ 7.15 (2H, m), 6.06 (1H,m), 4.42 (1H,m), 3.6-4.2 (2H, m), 2.7-3.24 (4H, m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.6 (15H, m), 0.72-1.00 (3H, m). The title compound was prepared

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

Procedure: The title compound was prepared according to the procedure described in Example 1, Step C, except using 1-tert-butoxycarbonyl-2(S),4-dibenzylpiperazine (4.78 g, 11.3 mmol) and 10% palladium on carbon (1.04 g). The title compound was obtained as an oil. 1HNMR (300 MHz, CD3OD) δ 7.25 (5H, m), 4.35 (1H, m), 4.00 (1H, d, J=12 Hz), 2.7-3.3 (7H, m), 1.25 (9H, s). The title compound was prepared

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,6-dichloropyrazine 114 (0.1 g, 0.67 mmol.) and (S)-1-Boc-2-benzylpiperazine 107 (0.37 g, 1.34 mmol) in dioxane (2 mL) and trifluoromethylbenzene (2 mL) was added diisopropylethylamine (0.26 g, 2.0 mmol). The reaction mixture was heated in a microwave reactor at 180° C. for 20 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with saturated ammonium chloride solution, water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield the desired 2-[(S)-4-Boc-3-benzylpiperazinyl]-6-chloropyrazine 115 (0.234 g, 0.6 mmol). The organic layer was washed with saturated ammonium chloride solution, water and brine The organic layer was dried over sodium sulfate The organic solvent was evaporated under reduced pressure The crude product was purified by flash column chromatography

Conditions: temp:210.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-amino-3,5-dibromopyrazine 106 (0.2 g, 0.79 mmol.) and (S)-1-Boc-2-benzylpiperazine 107 (0.44 g, 1.59 mmol) in dioxane (2 mL) and trifluoromethylbenzene (2 mL) was added diisopropylethylamine (0.31 g, 2.4 mmol). The reaction mixture was heated in a microwave reactor at 210° C. for 20 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 2-amino-5-bromo-3-[(S)-4-Boc-3-benzylpiperazinyl]pyrazine 108 (0.24 g, 0.536 mmol). The organic layer was washed with water and brine The organic layer was dried over sodium sulfate The organic solvent was evaporated under reduced pressure The crude product was purified by RP-HPLC

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

Procedure: The title compound was prepared according to the procedure described for Example 1, Step A except using 2(S)-benzyl-1-tert-butoxycarbonylpiperazine (0.292 g, 1.06 mmol), 2,3-dimethylbenzoic acid (0.159 g, 1.06 mmol), HOBT (0.157 g, 1.02 mmol), EDC.HCl (0.213 g, 1.11 mmol) and triethylamine to adjust the pH to 7. The title compound was obtained as a thick oil. 1HNMR (DMSO-d6, 300 MHz) δ 7.15 (2H, m), 6.06 (1H,m), 4.42 (1H,m), 3.6-4.2 (2H, m), 2.7-3.24 (4H, m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.6 (15H, m), 0.72-1.00 (3H, m). The title compound was prepared

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

Procedure: The title compound was prepared according to the procedure described in Example 1, Step C, except using 1-tert-butoxycarbonyl-2(S),4-dibenzylpiperazine (4.78 g, 11.3 mmol) and 10% palladium on carbon (1.04 g). The title compound was obtained as an oil. 1HNMR (300 MHz, CD3OD) δ 7.25 (5H, m), 4.35 (1H, m), 4.00 (1H, d, J=12 Hz), 2.7-3.3 (7H, m), 1.25 (9H, s). The title compound was prepared

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

Procedure: The title compound was prepared according to the procedure described in Example 1, Step C, except using 1-tert-butoxycarbonyl-2(S),4-dibenzylpiperazine (4.78 g, 11.3 mmol) and 10% palladium on carbon (1.04 g). The title compound was obtained as an oil. 1HNMR (300 MHz, CD3OD) δ 7.25 (5H, m), 4.35 (1H, m), 4.00 (1H, d, J=12 Hz), 2.7-3.3 (7H, m), 1.25 (9H, s). The title compound was prepared

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

Procedure: The title compound was prepared according to the procedure described for Example 1, Step A except using 2(S)-benzyl-1-tert-butoxycarbonylpiperazine (0.292 g, 1.06 mmol), 2,3-dimethyl-benzoic acid (0.159 g, 1.06 mmol), HOBT (0.157 g, 1.02 mmol), EDC.HCl (0.213 g, 1.11 mmol) and triethylamine to adjust the pH to 7. The title compound was obtained as a thick oil (0.416 g). NMR (DMSO-d6, 300 MHz) δ 7.15 (2H, m), 6.06 (1H,m), 4.42 (1H,m), 3.6-4.2 (2H, m), 2.7-3.24 (4H, m), 2.24 (3H, s), 2.03-2.20 (3H, 4s), 1.10-1.6 (15H, m), 0.72-1.00 (3H, m). The title compound was prepared

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

Procedure: The title compound was prepared according to the procedure described in Example 2, Step C, except using 1-tert-butoxycarbonyl-2(S),4-dibenzylpiperazine (4.78 g, 11.3 mmol) and 10% palladium on carbon (1.04 g). The title compound was obtained as an oil. NMR (300 MHz, CD3OD) δ 7.25 (5H, m), 4.35 (1H, m), 4.00 (1H, d, J=12 Hz), 2.7-3.3 (7H, m), 1.25 (9H, s). The title compound was prepared

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

Procedure: The title compound was prepared by the method outlined for Example 1 using (3R)-3-(5-Bromo-2-methoxyphenoxy)-1-methylpyrrolidine as the aryl halide and 2(S)-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component. The title compound was isolated as an orange oil. LC/MS (Method B) 0.87 min, [M+1]+ 382. The title compound was prepared by the method

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

Procedure: The title compound was prepared by the method outlined for Example 1 using (3S)-3-(5-Bromo-2-methoxyphenoxy)-1-methylpyrrolidine as the aryl halide and 2(S)-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component. The title compound was isolated as an orange oil. 1H NMR (MeOH-d4) 7.33-7.30 (m, 2H), 7.26-7.22 (m, 3H), 6.83 (d, J=9.2, 1H), 6.44 (m, 2H), 4.81 (m, 1H), 3.73 (s, 3H), 3.36-3.28 (m, 2H), 3.04 (m, 2H), 2.93-2.66 (m, 8H), 2.52-2.46 (m, 1H), 2.36 (s, 3H), 2.19 (m, 1H), 1.95 (m, 1H). The title compound was prepared by the method

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

Procedure: The title compound was prepared by the method outlined for Example 1 using 4-(5-bromo-2-methoxy-phenoxy)-1-methyl-piperidine as the aryl halide and 2(S)-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component. The title compound was isolated as an orange oil. 1H NMR (MeOH-d4) 7.33-7.29 (m, 2H), 7.25-7.22 (m, 3H), 6.85 (d, J=8.8, 1H), 6.55 (d, J=2.8, 1H), 6.50 (dd, J=8.8, 2.8, 1H), 4.24 (m, 1H), 3.74 (s, 3H), 3.35-3.27 (m, 2H), 3.05-3.00 (m, 2H), 2.91-2.85 (m, 1H), 2.74-2.65 (m, 5H), 2.36 (m, 3H), 2.28 (s, 3H), 1.90 (m, 2H), 1.78 (m, 2H). LC/MS (Method B) 0.97 min, [M+1]+ 396. The title compound was prepared by the method