(8aS)-1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine

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

Procedure: To crude 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoyl chloride (4 mmol) in anhydrous dichloromethane (100 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine (0.505 g, 4 mmol) in dichloromethane (10 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.933 g, 8.8 mmol) was added. The mixture was stirred at room temperature overnight. Then dichloromethane was removed by concentration in vacuo, and 2-fluoroaniline (4.44 g, 40 mmol) in dichloromethane (30 mL) was added. The mixture was stirred at room temperature for 4 days. At that time, sodium carbonate (0.42 g, 4 mmol) and methanol (20 mL) were added, the mixture was stirred for 30 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then methanol/ethyl acetate=1:15) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.20-1.38 (m, 1H), 1.60-2.20 (m, 7H), 2.80-3.40 (m, 4H), 4.40-4.60 (m, 1H), 7.20 (m, 4H), 7.60 (m, 1H), 7.88 (m, 1H), 10.60 (br s, 1H); MS (ESI) m/z 456 (M+H)+. was added The mixture was stirred at room temperature for 4 days the mixture was stirred for 30 minutes filtered concentrated The residue was purified by chromatography on silica gel (ethyl acetate

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

Procedure: To 3-(chlorosulfonyl)benzoyl chloride (0.474 g, 1.981 mmol) in anhydrous dichloromethane (40 mL) was added 1-(bis(4-fluorophenyl)methyl)piperazine (0.571 g, 1.981 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.64 g, 6 mmol) was added. The mixture was stirred at room temperature overnight. Then (S)-octahydropyrrolo[1,2-a]pyrazine (0.250 g, 1.981 mmol) was added. The mixture was stirred at reflux for 20 minutes and then at room temperature for 3 days. Methanol (5 mL) was added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=20:1) to give the titled compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (m, 1H), 1.55 (m, 2H), 1.71 (m, 1H), 1.95 (m, 4H), 2.08 (m, 1H), 2.28 (m, 3H), 2.39 (m, 3H), 2.85 (m, 1H), 2.92 (m, 1H), 3.57 (m, 2H), 3.74 (m, 2H), 4.45 (s, 1H), 7.13 (m, 4H), 7.45 (m, 4H), 7.66 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H); MS (ESI) m/z 581 (M+H)+. The mixture was stirred at reflux for 20 minutes at room temperature for 3 days the mixture was stirred for 20 minutes filtered concentrated The residue was purified by chromatography on silica gel (ethyl acetate/methanol=20:1)

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

Procedure: To 3-(chlorosulfonyl)benzoyl chloride (0.521 g, 2.18 mmol) in anhydrous dichloromethane (10 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine (0.250 g, 1.98 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. The mixture was stirred at room temperature for 5 hours. Then 2-fluoroaniline (1.54 g, 13.87 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (dichloromethane, then methanol/dichloromethane=1:10) to give the titled compound. The mixture was stirred at room temperature overnight concentrated The residue was purified by chromatography on silica gel (dichloromethane

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

Procedure: To 3-(chlorosulfonyl)benzoyl chloride (0.474 g, 1.98 mmol) in anhydrous dichloromethane (10 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine (0.250 g, 1.98 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.420 g, 3.96 mmol) was added. The mixture was stirred at room temperature for 5 hours. Then 2,6-difluoroaniline (2.56 g, 19.81 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (dichloromethane, then methanol/dichloromethane=1:10) to give the title compound. The mixture was stirred at room temperature overnight concentrated The residue was purified by chromatography on silica gel (dichloromethane

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

Procedure: To 3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid (0.9 g, 3.05 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.27 g, 3.35 mmol) in N,N-dimethylacetamide (6.4 mL) and 2-methyltetrahydrofuran (15 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine (0.55 g, 4.33 mmol) in 2-methyltetrahydrofuran (4 mL). The reaction was stirred at ambient temperature overnight and then diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (10 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL). The combined organic layers were washed with 6% NaHCO3/6% NaCl (10 mL), saturated NaCl (2×10 mL, 2×20 mL) and 1:1 saturated NaCl/water (2×20 mL), and then concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound. The organic solution was washed with 6% NaHCO3/6% NaCl (10 mL) the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL) The combined organic layers were washed with 6% NaHCO3/6% NaCl (10 mL), saturated NaCl (2×10 mL, 2×20 mL) and 1:1 saturated NaCl/water (2×20 mL) concentrated The residue was concentrated from ethanol (2×10 mL)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared starting from 100 mg (0.188 mmoles) of 1-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]cyclopropanecarboxamide (D2), 70 mg (0.554 mmol) of (8aS)-octahydropyrrolo[1,2-a]pyrazine, 52.2 mg (0.377 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 150° C. overnight and then added to a saturated NH4Cl solution and back extracted with dichloromethane; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 1:1, to ethyl acetate 100%, affording 72 mg of the title compound as pale yellow solid. The title compound was prepared back extracted with dichloromethane the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 1:1, to ethyl acetate 100%

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

Procedure: To crude 2-chloro-5-(chlorosulfonyl)-4-fluorobenzoyl chloride (4 mmol) in anhydrous dichloromethane (100 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine (0.505 g, 4 mmol) in dichloromethane (10 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.933 g, 8.8 mmol) was added. The mixture was stirred at room temperature overnight. Then dichloromethane was removed by concentration in vacuo, and 2-fluoroaniline (4.44 g, 40 mmol) in dichloromethane (30 mL) was added. The mixture was stirred at room temperature for 4 days. At that time, sodium carbonate (0.42 g, 4 mmol) and methanol (20 mL) were added, the mixture was stirred for 30 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then methanol/ethyl acetate=1:15) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.20-1.38 (m, 1H), 1.60-2.20 (m, 7H), 2.80-3.40 (m, 4H), 4.40-4.60 (m, 1H), 7.20 (m, 4H), 7.60 (m, 1H), 7.88 (m, 1H), 10.60 (br s, 1H); MS (ESI) m/z 456 (M+H)+. was added The mixture was stirred at room temperature for 4 days the mixture was stirred for 30 minutes filtered concentrated The residue was purified by chromatography on silica gel (ethyl acetate

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

Procedure: To 3-(chlorosulfonyl)benzoyl chloride (0.474 g, 1.981 mmol) in anhydrous dichloromethane (40 mL) was added 1-(bis(4-fluorophenyl)methyl)piperazine (0.571 g, 1.981 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.64 g, 6 mmol) was added. The mixture was stirred at room temperature overnight. Then (S)-octahydropyrrolo[1,2-a]pyrazine (0.250 g, 1.981 mmol) was added. The mixture was stirred at reflux for 20 minutes and then at room temperature for 3 days. Methanol (5 mL) was added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=20:1) to give the titled compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (m, 1H), 1.55 (m, 2H), 1.71 (m, 1H), 1.95 (m, 4H), 2.08 (m, 1H), 2.28 (m, 3H), 2.39 (m, 3H), 2.85 (m, 1H), 2.92 (m, 1H), 3.57 (m, 2H), 3.74 (m, 2H), 4.45 (s, 1H), 7.13 (m, 4H), 7.45 (m, 4H), 7.66 (s, 1H), 7.70 (m, 2H), 7.80 (m, 1H); MS (ESI) m/z 581 (M+H)+. The mixture was stirred at reflux for 20 minutes at room temperature for 3 days the mixture was stirred for 20 minutes filtered concentrated The residue was purified by chromatography on silica gel (ethyl acetate/methanol=20:1)

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

Procedure: To 3-(chlorosulfonyl)benzoyl chloride (0.521 g, 2.18 mmol) in anhydrous dichloromethane (10 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine (0.250 g, 1.98 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. The mixture was stirred at room temperature for 5 hours. Then 2-fluoroaniline (1.54 g, 13.87 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (dichloromethane, then methanol/dichloromethane=1:10) to give the titled compound. The mixture was stirred at room temperature overnight concentrated The residue was purified by chromatography on silica gel (dichloromethane

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

Procedure: To 3-(chlorosulfonyl)benzoyl chloride (0.474 g, 1.98 mmol) in anhydrous dichloromethane (10 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine (0.250 g, 1.98 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.420 g, 3.96 mmol) was added. The mixture was stirred at room temperature for 5 hours. Then 2,6-difluoroaniline (2.56 g, 19.81 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (dichloromethane, then methanol/dichloromethane=1:10) to give the title compound. The mixture was stirred at room temperature overnight concentrated The residue was purified by chromatography on silica gel (dichloromethane

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

Procedure: To 3-{[(3-fluorophenyl)amino]sulfonyl}benzoic acid (0.9 g, 3.05 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.27 g, 3.35 mmol) in N,N-dimethylacetamide (6.4 mL) and 2-methyltetrahydrofuran (15 mL) was added (S)-octahydropyrrolo[1,2-a]pyrazine (0.55 g, 4.33 mmol) in 2-methyltetrahydrofuran (4 mL). The reaction was stirred at ambient temperature overnight and then diluted with 2-methyltetrahydrofuran (15 mL). The organic solution was washed with 6% NaHCO3/6% NaCl (10 mL), and the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL). The combined organic layers were washed with 6% NaHCO3/6% NaCl (10 mL), saturated NaCl (2×10 mL, 2×20 mL) and 1:1 saturated NaCl/water (2×20 mL), and then concentrated. The residue was concentrated from ethanol (2×10 mL) to give the title compound. The organic solution was washed with 6% NaHCO3/6% NaCl (10 mL) the aqueous layer was extracted with 2-methyltetrahydrofuran (15 mL) The combined organic layers were washed with 6% NaHCO3/6% NaCl (10 mL), saturated NaCl (2×10 mL, 2×20 mL) and 1:1 saturated NaCl/water (2×20 mL) concentrated The residue was concentrated from ethanol (2×10 mL)

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

Procedure: At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (479 mg, 2.5 mmol) was added to a solution of 3-(3,4-dimethoxybenzoyl)propionic acid (596 mg, 2.5 mmol) and 3-hydroxy-3H-dihydrobenzo[d][1,2,3]triazin-4-one (408 mg, 2.5 mmol) in a mixture of dichloromethane (10 ml) and N,N-dimethylformamide (10 ml). The reaction mixture was stirred for 25 min at 0° C. A solution of the crude dihydrochloride salt of (S)-octahydro-pyrrolo[1,2-a]pyrazine in N,N-dimethylformamide (4 ml) and ethyldiisopropylamine (3.0 ml, 17.5 mmol) were added successively. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (200 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by HPLC on a C18-reversed phase column, using a mixture of 1% trifluoroacetic acid in water and acetonitrile as eluent, to give 148 mg of the title compound. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature washed with a saturated aqueous solution of sodium hydrogen carbonate The aqueous phase was extracted with ethyl acetate (2×100 ml) The combined organic layers were dried over magnesium sulphate The solvent was removed in vacuo The crude product was purified by HPLC on a C18-reversed phase column a mixture of 1% trifluoroacetic acid in water and acetonitrile as eluent