(1R,2R)-2-aminocyclopentan-1-ol;hydrochloride

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

Procedure: To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.040 g, 0.20 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added trans-2-aminocyclopentanol hydrochloride (56 mg, 0.41 mmol) and triethylamine (0.14 ml, 1.02 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 262 (M+H)+; 1H NMR (MeOH) 4.79 (m, 1H), 4.17-4.40 (m, 3H), 3.18 (m, 1H), 2.48 (m, 4H); 2.00-2.30 (m, 4H), 1.80 (m, 2H), 1.66 (2H, m). concentrated under reduced pressure purified by flash chromatography with 3% methanol

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

Procedure: To a solution of trans-2-aminocyclopentanol hydrochloride (385 mg, 2.82 mmol) in 1,2-dichloroethane was added benzaldehyde (748 mg, 7.04 mmol) and triethylamine (0.51 mL, 3.7 mmol). The mixture was heated to reflux for 2 hours, cooled to room temperature, and sodium triacetoxyborohydride was added. The reaction mixture was heated at reflux for an additional 18 hours, cooled to room temperature, then taken up in dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and with water, then dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) afforded the title compound as a golden oil. Yield: 734 mg, 2.61 mmol, 93%. LCMS m/z 282.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.35-7.39 (m, 4H), 7.32 (br dd, J=7.8, 7.2 Hz, 4H), 7.21-7.26 (m, 2H), 4.05-4.12 (m, 1H), 3.79 (d, J=13.9 Hz, 2H), 3.52 (d, J=13.9 Hz, 2H), 2.90-2.99 (m, 1H), 1.74-1.95 (m, 2H), 1.52-1.71 (m, 3H), 1.39-1.49 (m, 1H). The mixture was heated to reflux for 2 hours The reaction mixture was heated at reflux for an additional 18 hours cooled to room temperature The organic layer was washed with saturated aqueous sodium bicarbonate solution and with water dried over magnesium sulfate filtered concentrated in vacuo Purification via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane)

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

Procedure: To a solution of trans-2-aminocyclopentanol hydrochloride (385 mg, 2.82 mmol) in 1,2-dichloroethane was added benzaldehyde (748 mg, 7.04 mmol) and triethylamine (0.51 mL, 3.7 mmol). The mixture was heated to reflux for 2 hours, cooled to room temperature, and sodium triacetoxyborohydride was added. The reaction mixture was heated at reflux for an additional 18 hours, cooled to room temperature, then taken up in dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and with water, then dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) afforded the title compound as a golden oil. Yield: 734 mg, 2.61 mmol, 93%. LCMS m/z 282.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.35-7.39 (m, 4H), 7.32 (br dd, J=7.8, 7.2 Hz, 4H), 7.21-7.26 (m, 2H), 4.05-4.12 (m, 1H), 3.79 (d, J=13.9 Hz, 2H), 3.52 (d, J=13.9 Hz, 2H), 2.90-2.99 (m, 1H), 1.74-1.95 (m, 2H), 1.52-1.71 (m, 3H), 1.39-1.49 (m, 1H). The mixture was heated to reflux for 2 hours The reaction mixture was heated at reflux for an additional 18 hours cooled to room temperature The organic layer was washed with saturated aqueous sodium bicarbonate solution and with water dried over magnesium sulfate filtered concentrated in vacuo Purification via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane)

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

Procedure: A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-formylbenzoate (0.11 g), trans-2-aminocyclopentanol hydrochloride (0.04 g), triethylamine (0.04 mL) and anhydrous magnesium sulfate (0.07 g) in THF (2.20 mL) was stirred at room temperature for 5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.20 mL) and THF (2.20 mL), sodium triacetoxyborohydride (0.13 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.06 g). The insoluble substance was removed by filtration the filtrate was concentrated under reduced pressure The residue was diluted with methanol (2.20 mL) and THF (2.20 mL), sodium triacetoxyborohydride (0.13 g) was added The reaction mixture was diluted with ethyl acetate the mixture was washed with water and saturated brine The organic layer was dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:137.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound 7A (about 1 mole) was combined with (R,R)-2-amino-1-cyclopentanol hydrochloride (Compound 8A, about 1.2 moles) and sodium bicarbonate (about 3 moles). To this reaction mixture was added N,N-dimethylacetamide (“DMA”), and the reaction mixture was agitated at about 135-140° C. for about 15-17 hours until complete consumption of the starting material was indicated. Compound 9A is an intermediate that is formed, but not isolated, from the reaction mixture. The reaction mixture was then cooled to about 45-50° C., and tetrabutylammonium hydroxide (about 0.05 moles of about a 40% solution in water) was charged therein, followed by methanol. The reaction mixture was refluxed at about 80-85° C. for about 8-9 hours until complete deprotection of the acetate group was indicated. The reaction mixture was cooled to about 40-45° C. and concentrated under vacuum. The pH of the reaction mixture was adjusted to about 5-6 with dilute acetic acid, and the reaction mixture was heated to about 55-65° C., and seeded with a small amount of Compound 13A. The reaction mixture was then cooled to about 30-35° C. over a period of about 2 hours, and water was added over a period of about 1 hour. The reaction mixture was further cooled to about 0-5° C. over a period of about 1 hour, and agitated at that temperature for about 4 hours. The Compound 13A product was isolated by filtration, washed with water and dried to provide about an 85-90% yield. that is formed not isolated, from the reaction mixture The reaction mixture was then cooled to about 45-50° C. The reaction mixture was refluxed at about 80-85° C. for about 8-9 hours until complete deprotection of the acetate group The reaction mixture was cooled to about 40-45° C. concentrated under vacuum the reaction mixture was heated to about 55-65° C. The reaction mixture was then cooled to about 30-35° C. over a period of about 2 hours water was added over a period of about 1 hour The reaction mixture was further cooled to about 0-5° C. over a period of about 1 hour agitated at that temperature for about 4 hours

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

Procedure: To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.040 g, 0.20 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added trans-2-aminocyclopentanol hydrochloride (56 mg, 0.41 mmol) and triethylamine (0.14 ml, 1.02 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 262 (M+H)+; 1H NMR (MeOH) 4.79 (m, 1H), 4.17-4.40 (m, 3H), 3.18 (m, 1H), 2.48 (m, 4H); 2.00-2.30 (m, 4H), 1.80 (m, 2H), 1.66 (2H, m). concentrated under reduced pressure purified by flash chromatography with 3% methanol

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

Procedure: As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using trans-2-aminocyclopentanol hydrochloride instead of isopropylamine, to the title compound (100 mg, 78%), which was obtained as a white solid. MS: m/e=395.1 [M+H]+.

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

Procedure: Compound 7A (about 1 mole) was combined with (R,R)-2-amino-1-cyclopentanol hydrochloride (Compound 8A, about 1.2 moles) and sodium bicarbonate (about 3 moles). To this reaction mixture was added N,N-dimethylacetamide (“DMA”), and the reaction mixture was agitated at about 135–140° C. for about 15–17 hours until complete consumption of the starting material was indicated. Compound 9A is an intermediate that is formed, but not isolated, from the reaction mixture. The reaction mixture was then cooled to about 45–50° C., and tetrabutylammonium hydroxide (about 0.05 moles of about a 40% solution in water) was charged therein, followed by methanol. The reaction mixture was refluxed at about 80–85° C. for about 8–9 hours until complete deprotection of the acetate group was indicated. The reaction mixture was cooled to about 40–45° C. and concentrated under vacuum. The pH of the reaction mixture was adjusted to about 5–6 with dilute acetic acid, and the reaction mixture was heated to about 55–65° C., and seeded with a small amount of Compound 13A. The reaction mixture was then cooled to about 30–35° C. over a period of about 2 hours, and water was added over a period of about 1 hour. The reaction mixture was further cooled to about 0–5° C. over a period of about 1 hour, and agitated at that temperature for about 4 hours. The Compound 13A product was isolated by filtration, washed with water and dried to provide about an 85–90% yield. that is formed not isolated, from the reaction mixture The reaction mixture was then cooled to about 45–50° C. The reaction mixture was refluxed at about 80–85° C. for about 8–9 hours until complete deprotection of the acetate group The reaction mixture was cooled to about 40–45° C. concentrated under vacuum the reaction mixture was heated to about 55–65° C. The reaction mixture was then cooled to about 30–35° C. over a period of about 2 hours water was added over a period of about 1 hour The reaction mixture was further cooled to about 0–5° C. over a period of about 1 hour agitated at that temperature for about 4 hours

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

Procedure: To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.040 g, 0.20 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added trans-2-aminocyclopentanol hydrochloride (56 mg, 0.41 mmol) and triethylamine (0.14 ml, 1.02 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 262 (M+H)+; 1H NMR (MeOH) 4.79 (m, 1H), 4.17-4.40 (m, 3H), 3.18 (m, 1H), 2.48 (m, 4H); 2.00-2.30 (m, 4H), 1.80 (m, 2H), 1.66 (2H, m). concentrated under reduced pressure purified by flash chromatography with 3% methanol

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

Procedure: To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.040 g, 0.20 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added trans-2-aminocyclopentanol hydrochloride (56 mg, 0.41 mmol) and triethylamine (0.14 mL, 1.02 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 262 (M+H)+; 1H NMR (MeOH) 4.79 (m, 1H), 4.17-4.40 (m, 3H), 3.18 (m, 1H), 2.48 (m, 4H); 2.00-2.30 (m, 4H), 1.80 (m, 2H), 1.66 (2H, m). concentrated under reduced pressure purified by flash chromatography with 3% methanol

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

Procedure: 3-Methyluracil (12.6 mg, 0.1 mmol) was dissolved in 0.5 mL of DMF, and then BOP (71 mg, 0.16 mmol) was added. The mixture was stirred at room temperature for two minutes, then (1R,2R)-(−)-2-hydroxycyclopentylamine hydrochloride salt (22 mg, 0.16 mmol) was added, followed by DBU (51 uL, 3.4 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was purified by a semi-preparative HPLC to give pure product (16 mg, yield 76%). MS (ESI) m/z 210.1 [M+H]+. The mixture was stirred at room temperature overnight The reaction mixture was purified by a semi-preparative HPLC

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

Procedure: To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.040 g, 0.20 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added trans-2-aminocyclopentanol hydrochloride (56 mg, 0.41 mmol) and triethylamine (0.14 ml, 1.02 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 262 (M+H)+; 1H NMR (MeOH) 4.79 (m, 1H), 4.17-4.40 (m, 3H), 3.18 (m, 1H), 2.48 (m, 4H); 2.00-2.30 (m, 4H), 1.80 (m, 2H), 1.66 (2H, m). concentrated under reduced pressure purified by flash chromatography with 3% methanol