(9aR)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the dihydrochloride salt of (R)-octahydropyrido[1,2-a]pyrazine (649 mg, 3.05 mmol), diisopropylethylamine (1.17 ml, 6.72 mmol), 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine (290 mg, 1.12 mmol) and dimethylsulfoxide (1 ml) was heated in a closed vessel at 160° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulphate. The solvent was removed in vacuo to give 398 mg of the title compound as the free base. The reaction mixture was cooled to room temperature washed with water (2×15 ml) and brine (15 ml) The organic layer was dried over magnesium sulphate The solvent was removed in vacuo

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the dihydrochloride salt of (R)-octahydropyrido[1,2-a]pyrazine (649 mg, 3.05 mmol), diisopropylethylamine (1.17 ml, 6.72 mmol), 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine (290 mg, 1.12 mmol) and dimethylsulfoxide (1 ml) was heated in a closed vessel at 160° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulphate. The solvent was removed in vacuo to give 398 mg of the title compound as the free base. The reaction mixture was cooled to room temperature washed with water (2×15 ml) and brine (15 ml) The organic layer was dried over magnesium sulphate The solvent was removed in vacuo

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

Procedure: (R)-Octahydro-1,4-dioxo-2H-pyrido[1,2-a]pyrazine (0.5 g, 2.98 mmol) was added portionwise to a stirred solution of lithium aluminium hydride (1M in tetrahydrofuran; 11.9 ml, 11.9 mmol). The resulting mixture was heated under reflux for 0.5 h. The solution was then cooled to 0° C. and treated dropwise with water (1.35 ml), 1 M sodium hydroxide solution (0.45 ml), then water (1.35 ml). Tetrahydrofuran (10 ml) was added and the solution stirred for 0.5 h, before filtration. The filter cake was washed with tetrahydrofuran (2×5 ml) and the combined filtrate and washings concentrated to yield (R)-octahydro-2H-pyrido[1,2-a]pyrazine as a yellow oil (0.29 g, 2.07 mmol). The resulting mixture was heated under reflux for 0.5 h The filter cake was washed with tetrahydrofuran (2×5 ml) the combined filtrate and washings concentrated

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

Procedure: (R)-Octahydro-1,4-dioxo-2H-pyrido[1,2-a]pyrazine (0.5 g, 2.98 mmol) was added portionwise to a stirred solution of lithium aluminium hydride (1M in tetrahydrofuran; 11.9 ml, 11.9 mmol). The resulting mixture was heated under reflux for 0.5 h. The solution was then cooled to 0° C. and treated dropwise with water (1.35 ml), 1 M sodium hydroxide solution (0.45 ml), then water (1.35 ml). Tetrahydrofuran (10 ml) was added and the solution stirred for 0.5 h, before filtration. The filter cake was washed with tetrahydrofuran (2×5 ml) and the combined filtrate and washings concentrated to yield (R)-octahydro-2H-pyrido[1,2-a]pyrazine as a yellow oil (0.29 g, 2.07 mmol). The resulting mixture was heated under reflux for 0.5 h The filter cake was washed with tetrahydrofuran (2×5 ml) the combined filtrate and washings concentrated

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

Procedure: Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-octahydro-1H-pyrido[1,2-a]pyrazine (1.2 equiv) to give 197 (M+1 436.0)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the dihydrochloride salt of (R)-octahydropyrido[1,2-a]pyrazine (649 mg, 3.05 mmol), diisopropylethylamine (1.17 ml, 6.72 mmol), 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine (290 mg, 1.12 mmol) and dimethylsulfoxide (1 ml) was heated in a closed vessel at 160° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulphate. The solvent was removed in vacuo to give 398 mg of the title compound as the free base. The reaction mixture was cooled to room temperature washed with water (2×15 ml) and brine (15 ml) The organic layer was dried over magnesium sulphate The solvent was removed in vacuo

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

Procedure: Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-octahydro-1H-pyrido[1,2-a]pyrazine (1.2 equiv) to give 197 (M+1 436.0)

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

Procedure: Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-octahydro-1H-pyrido[1,2-a]pyrazine (1.2 equiv) to give 197 (M+1 436.0)

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

Procedure: Phenylmethyl (9aR)-octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate (688 mg, 2.50 mmol) was dissolved in MeOH (15 mL), degassed and placed under argon. 10% Pd/C (206 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for 2 h. The contents were then degassed, and the Pd/C was removed by filtration through Celite, washing with MeOH. The filtrate was concentrated in vacuo to provide pure (9aR)-octahydro-2H-pyrido[1,2-a]pyrazine (364 mg, 99%). LCMS: (M+H)+: 141.1. degassed 10% Pd/C (206 mg) was added the contents were thoroughly degassed for 2 h The contents were then degassed the Pd/C was removed by filtration through Celite washing with MeOH The filtrate was concentrated in vacuo

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

Procedure: Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-octahydro-1H-pyrido[1,2-a]pyrazine (1.2 equiv) to give 197 (M+1 436.0)

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of the dihydrochloride salt of (R)-octahydropyrido[1,2-a]pyrazine (649 mg, 3.05 mmol), diisopropylethylamine (1.17 ml, 6.72 mmol), 3-chloro-6-(4-trifluoromethylphenyl)-pyridazine (290 mg, 1.12 mmol) and dimethylsulfoxide (1 ml) was heated in a closed vessel at 160° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 ml) and washed with water (2×15 ml) and brine (15 ml). The organic layer was dried over magnesium sulphate. The solvent was removed in vacuo to give 398 mg of the title compound as the free base. The reaction mixture was cooled to room temperature washed with water (2×15 ml) and brine (15 ml) The organic layer was dried over magnesium sulphate The solvent was removed in vacuo

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

Procedure: (R)-Octahydro-1,4-dioxo-2H-pyrido[1,2-a]pyrazine (0.5 g, 2.98 mmol) was added portionwise to a stirred solution of lithium aluminium hydride (1M in tetrahydrofuran; 11.9 ml, 11.9 mmol). The resulting mixture was heated under reflux for 0.5 h. The solution was then cooled to 0° C. and treated dropwise with water (1.35 ml), 1 M sodium hydroxide solution (0.45 ml), then water (1.35 ml). Tetrahydrofuran (10 ml) was added and the solution stirred for 0.5 h, before filtration. The filter cake was washed with tetrahydrofuran (2×5 ml) and the combined filtrate and washings concentrated to yield (R)-octahydro-2H-pyrido[1,2-a]pyrazine as a yellow oil (0.29 g, 2.07 mmol). The resulting mixture was heated under reflux for 0.5 h The filter cake was washed with tetrahydrofuran (2×5 ml) the combined filtrate and washings concentrated