1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole

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

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

Procedure: decahydroisoquinoline (B); octahydroindole (C); octahydrocyclopenta[b]pyrrole (D); 2-azaspiro[4.5]decane (E); 2-azaspiro[4.4]-nonane (F); spiro[(bicyclo[2.2.1]heptane)-2,3'-pyrrolidine] (G); spiro[(bicyclo[2.2.2]octane)-2,3'-pyrrolidine] (H); 2-azatricyclo[4.3.0.16,9 ]decane (I); decahydrocyclohepta[b]pyrrole (J); hexahydrocyclopropa[b]pyrrole (K); octahydroisoindole (L); octahydrocyclopenta[c]pyrrole (M); 2,3,3a,4,5,7a-hexahydroindole (N); 1,2,3,3a,4,6ahexahydrocyclopenta[b]pyrrole (O); pyrrolidine (P); indoline (Q) and thiazolidine (R), all of which can be optionally substituted.

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

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

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

Procedure: This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)thio)propanoic acid 14, using octahydrocyclopenta[c]pyrrole in place of morpholine. 1H-NMR (300 MHz, DMSO-d6+D2O, ppm): δ 9.54 (s, 1H), 8.92 (d, J=3 Hz, 1H), 8.25 (s, 1H), 8.11 (d, J=9 Hz, 1H), 7.73 (m, 2H), 7.58 (m, 2H), 7.49 (m, 2H), 7.45 (m, 2H), 7.02 (s, 1H), 6.80 (d, J=9 Hz, 1H), 4.60 (s, 2H), 3.84 (s, 2H), 3.05 (d, J=6 Hz, 2H), 2.77 (m, 2H), 2.56 (m, 3H), 1.80 (m, 2H), 1.52 (m, 3H). MS (ES, m/z): 703 [M+H]+. This compound was prepared

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

Procedure: This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)thio)propanoic acid 14, using octahydrocyclopenta[c]pyrrole in place of morpholine. 1H-NMR (300 MHz, DMSO-d6+D2O, ppm): δ 9.54 (s, 1H), 8.92 (d, J=3 Hz, 1H), 8.25 (s, 1H), 8.11 (d, J=9 Hz, 1H), 7.73 (m, 2H), 7.58 (m, 2H), 7.49 (m, 2H), 7.45 (m, 2H), 7.02 (s, 1H), 6.80 (d, J=9 Hz, 1H), 4.60 (s, 2H), 3.84 (s, 2H), 3.05 (d, J=6 Hz, 2H), 2.77 (m, 2H), 2.56 (m, 3H), 1.80 (m, 2H), 1.52 (m, 3H). MS (ES, m/z): 703 [M+H]+. This compound was prepared

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

Procedure: To a 3-L 3-neck flask jacketed at 20° C. and stirred at 300 rpm was added 500 mL of dH2O and 20 mL of a 25 wt % octahydrocyclopenta[c]pyrrole solution in water. The pH was adjusted to approximately 7.6 with concentrated H3PO4 to give a colorless, homogeneous solution, to which 2.0 mL of A. niger catalase suspension (Novozyme; “Catalyzyme 101”) and 5.0 g of monoamine oxidase powder of the polypeptide of SEQ ID NO: 16 (prepared by the method of Example 3) were added to give a pale yellow solution. The head space of the vessel was swept with dry air at approximately 0.2 L/min. The pH of the reaction was maintained at 7.5 via feedback controlled addition of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water in 20-100 μL portions. The dimer of (3aR,6aS) octahydrocyclopenta[c]pyrrole to precipitated from the reaction and the reaction mixture became a white slurry. After 380 mL of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water had been added, the product was separated from the reaction mixture via steam distillation (still head temperature ˜98° C.). The receiver pot contained a suspension of the dimer of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole in water. 1.1-1.2 equivalent of concentrated HCl was added to the receiver pot break the dimer and give a homogeneous solution of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole hydrochloride in water. This solution was used directly to make (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carbonitrile in Example 27. To a 3-L 3-neck flask jacketed at 20° C. to give a colorless, homogeneous solution were added to give a pale yellow solution with dry air at approximately 0.2 L/min The pH of the reaction was maintained at 7.5 via feedback addition of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water in 20-100 μL portions The dimer of (3aR,6aS) octahydrocyclopenta[c]pyrrole to precipitated from the reaction After 380 mL of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water had been added the product was separated from the reaction mixture via steam distillation (still head temperature ˜98° C.) a suspension of the dimer of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole in water

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

Procedure: To a 3-L 3-neck flask jacketed at 20° C. and stirred at 300 rpm was added 500 mL of dH2O and 20 mL of a 25 wt % octahydrocyclopenta[c]pyrrole solution in water. The pH was adjusted to approximately 7.6 with concentrated H3PO4 to give a colorless, homogeneous solution, to which 2.0 mL of A. niger catalase suspension (Novozyme; “Catalyzyme 101”) and 5.0 g of monoamine oxidase powder of the polypeptide of SEQ ID NO: 16 (prepared by the method of Example 3) were added to give a pale yellow solution. The head space of the vessel was swept with dry air at approximately 0.2 L/min. The pH of the reaction was maintained at 7.5 via feedback controlled addition of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water in 20-100 μL portions. The dimer of (3aR,6aS) octahydrocyclopenta[c]pyrrole to precipitated from the reaction and the reaction mixture became a white slurry. After 380 mL of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water had been added, the product was separated from the reaction mixture via steam distillation (still head temperature ˜98° C.). The receiver pot contained a suspension of the dimer of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole in water. 1.1-1.2 equivalent of concentrated HCl was added to the receiver pot break the dimer and give a homogeneous solution of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole hydrochloride in water. This solution was used directly to make (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carbonitrile in Example 27. To a 3-L 3-neck flask jacketed at 20° C. to give a colorless, homogeneous solution were added to give a pale yellow solution with dry air at approximately 0.2 L/min The pH of the reaction was maintained at 7.5 via feedback addition of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water in 20-100 μL portions The dimer of (3aR,6aS) octahydrocyclopenta[c]pyrrole to precipitated from the reaction After 380 mL of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water had been added the product was separated from the reaction mixture via steam distillation (still head temperature ˜98° C.) a suspension of the dimer of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole in water

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

Procedure: decahydroisoquinoline (B); octahydroindole (C); octahydrocyclopenta[b]pyrrole (D); 2-azaspiro[4.5]decane (E); 2-azaspiro[4.4]-nonane (F); spiro[(bicyclo[2.2.1]heptane)-2,3'-pyrrolidine] (G); spiro[(bicyclo[2.2.2]octane)-2,3'-pyrrolidine] (H); 2-azatricyclo[4.3.0.16,9 ]decane (I); decahydrocyclohepta[b]pyrrole (J); hexahydrocyclopropa[b]pyrrole (K); octahydroisoindole (L); octahydrocyclopenta[c]pyrrole (M); 2,3,3a,4,5,7a-hexahydroindole (N); 1,2,3,3a,4,6ahexahydrocyclopenta[b]pyrrole (O); pyrrolidine (P); indoline (Q) and thiazolidine (R), all of which can be optionally substituted.

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

Procedure: decahydroisoquinoline (B); octahydroindole (C); octahydrocyclopenta[b]pyrrole (D); 2-azaspiro[4.5]decane (E); 2-azaspiro[4.4]-nonane (F); spiro[(bicyclo[2.2.1]heptane)-2,3'-pyrrolidine] (G); spiro[(bicyclo[2.2.2]octane)-2,3'-pyrrolidine] (H); 2-azatricyclo[4.3.0.16,9 ]decane (I); decahydrocyclohepta[b]pyrrole (J); hexahydrocyclopropa[b]pyrrole (K); octahydroisoindole (L); octahydrocyclopenta[c]pyrrole (M); 2,3,3a,4,5,7a-hexahydroindole (N); 1,2,3,3a,4,6ahexahydrocyclopenta[b]pyrrole (O); pyrrolidine (P); indoline (Q) and thiazolidine (R), all of which can be optionally substituted.

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

Procedure: To a 3-L 3-neck flask jacketed at 20° C. and stirred at 300 rpm was added 500 mL of dH2O and 20 mL of a 25 wt % octahydrocyclopenta[c]pyrrole solution in water. The pH was adjusted to approximately 7.6 with concentrated H3PO4 to give a colorless, homogeneous solution, to which 2.0 mL of A. niger catalase suspension (Novozyme; “Catalyzyme 101”) and 5.0 g of monoamine oxidase powder of the polypeptide of SEQ ID NO: 16 (prepared by the method of Example 3) were added to give a pale yellow solution. The head space of the vessel was swept with dry air at approximately 0.2 L/min. The pH of the reaction was maintained at 7.5 via feedback controlled addition of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water in 20-100 μL portions. The dimer of (3aR,6aS) octahydrocyclopenta[c]pyrrole to precipitated from the reaction and the reaction mixture became a white slurry. After 380 mL of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water had been added, the product was separated from the reaction mixture via steam distillation (still head temperature ˜98° C.). The receiver pot contained a suspension of the dimer of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole in water. 1.1-1.2 equivalent of concentrated HCl was added to the receiver pot break the dimer and give a homogeneous solution of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole hydrochloride in water. This solution was used directly to make (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carbonitrile in Example 27. To a 3-L 3-neck flask jacketed at 20° C. to give a colorless, homogeneous solution were added to give a pale yellow solution with dry air at approximately 0.2 L/min The pH of the reaction was maintained at 7.5 via feedback addition of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water in 20-100 μL portions The dimer of (3aR,6aS) octahydrocyclopenta[c]pyrrole to precipitated from the reaction After 380 mL of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water had been added the product was separated from the reaction mixture via steam distillation (still head temperature ˜98° C.) a suspension of the dimer of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole in water

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

Procedure: To a 3-L 3-neck flask jacketed at 20° C. and stirred at 300 rpm was added 500 mL of dH2O and 20 mL of a 25 wt % octahydrocyclopenta[c]pyrrole solution in water. The pH was adjusted to approximately 7.6 with concentrated H3PO4 to give a colorless, homogeneous solution, to which 2.0 mL of A. niger catalase suspension (Novozyme; “Catalyzyme 101”) and 5.0 g of monoamine oxidase powder of the polypeptide of SEQ ID NO: 16 (prepared by the method of Example 3) were added to give a pale yellow solution. The head space of the vessel was swept with dry air at approximately 0.2 L/min. The pH of the reaction was maintained at 7.5 via feedback controlled addition of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water in 20-100 μL portions. The dimer of (3aR,6aS) octahydrocyclopenta[c]pyrrole to precipitated from the reaction and the reaction mixture became a white slurry. After 380 mL of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water had been added, the product was separated from the reaction mixture via steam distillation (still head temperature ˜98° C.). The receiver pot contained a suspension of the dimer of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole in water. 1.1-1.2 equivalent of concentrated HCl was added to the receiver pot break the dimer and give a homogeneous solution of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole hydrochloride in water. This solution was used directly to make (1S,3aR,6aS)-octahydrocyclopenta[c]pyrrole-1-carbonitrile in Example 27. To a 3-L 3-neck flask jacketed at 20° C. to give a colorless, homogeneous solution were added to give a pale yellow solution with dry air at approximately 0.2 L/min The pH of the reaction was maintained at 7.5 via feedback addition of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water in 20-100 μL portions The dimer of (3aR,6aS) octahydrocyclopenta[c]pyrrole to precipitated from the reaction After 380 mL of the 25 wt % octahydrocyclopenta[c]pyrrole solution in water had been added the product was separated from the reaction mixture via steam distillation (still head temperature ˜98° C.) a suspension of the dimer of (3aS,6aR)-1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole in water