(2S)-3-phenylpropane-1,2-diamine

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 21.2 mmoles (3.18 grams) of (S)-1,2-diamino-3-phenylpropane were dissolved in 12 ml of benzene, treated with 42.4 mmoles (3.11 ml) of acetone and a spatula tip of p-toluenesulfonic acid. The mixture was heated for 12 hours under reflux in a Soxhlet apparatus which is filled with calcined calcium sulfate as drying agent. After drawing off the solvent in a vacuum there was obtained a light yellowish oil. It was dissolved in 50 ml of methanol, cooled in an ice-salt bath to -10° C. and treated with 80.0 mmoles (3.03 grams) of NaBH4. It was allowed to come to room temperature under stirring and heated for a further 12 hours under reflux. After cooling the solvent was distilled in a vacuum and hydrolyzed with 30 ml of water. It was shaken with 150 ml of ether and the organic phase washed twice with 30 ml of water each time. After drying over sodium sulfate the ether was drawn off and the brownish oil obtained was distilled in a high vacuum at 100° C. air bath temperature. Colorless oil. The mixture was heated for 12 hours under reflux in a Soxhlet apparatus which as drying agent was obtained a light yellowish oil to come to room temperature heated for a further 12 hours under reflux After cooling the solvent was distilled in a vacuum and hydrolyzed with 30 ml of water It was shaken with 150 ml of ether the organic phase washed twice with 30 ml of water each time After drying over sodium sulfate the ether the brownish oil obtained was distilled in a high vacuum at 100° C. air bath temperature

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

Procedure: 225 mmoles (9.00 grams) of NaOH were dissolved in 45 ml of water, cooled in an ice bath and treated with 49 mmoles (7.35 grams) of (S)-1,2-diamino-3-phenylpropane dissolved in about 45 ml of benzene. Within 30 minutes with stirring there was dropped in a solution of 108 mmoles (10.3 ml) of ethyl chloroformate in 45 ml of benzene and the mixture allowed to stir for 3 hours at room temperature. The organic phase was separated off and the aqueous solution shaken twice with 20 ml of benzene. The combined phases were dried over sodium sulfate and freed from solvent. There were obtained 40.33 mmoles (11.87 grams) of colorless, crystalline solid [(S)-1,2-bis(N-ethyloxycarbonylamino)-3-phenylpropane]. This was added in small portions to an ice cooled suspension of 370 mmoles (14.0 grams) of LiAlH4 in 300 ml of tetrahydrofuran. After heating for 24 hours under reflux by ice cooling the product was carefully hydrolyzed with 1.5 moles (27 ml) of water. The hydrolysis products were filtered off and the filtrate concentrated. The residue was extracted for 12 hours with 150 ml of tetrahydrofuran in a Soxhlet apparatus. The extract was combined with the filtrate and the solvent distilled off in a vacuum. The light brownish liquid was distilled in a high vacuum at 85° C. Colorless liquid. cooled in an ice bath to stir for 3 hours at room temperature The organic phase was separated off the aqueous solution shaken twice with 20 ml of benzene The combined phases were dried over sodium sulfate

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

Procedure: 225 mmoles (9.00 grams) of NaOH were dissolved in 45 ml of water, cooled in an ice bath and treated with 49 mmoles (7.35 grams) of (S)-1,2-diamino-3-phenylpropane dissolved in about 45 ml of benzene. Within 30 minutes with stirring there was dropped in a solution of 108 mmoles (10.3 ml) of ethyl chloroformate in 45 ml of benzene and the mixture allowed to stir for 3 hours at room temperature. The organic phase was separated off and the aqueous solution shaken twice with 20 ml of benzene. The combined phases were dried over sodium sulfate and freed from solvent. There were obtained 40.33 mmoles (11.87 grams) of colorless, crystalline solid [(S)-1,2-bis(N-ethyloxycarbonylamino)-3-phenylpropane]. This was added in small portions to an ice cooled suspension of 370 mmoles (14.0 grams) of LiAlH4 in 300 ml of tetrahydrofuran. After heating for 24 hours under reflux by ice cooling the product was carefully hydrolyzed with 1.5 moles (27 ml) of water. The hydrolysis products were filtered off and the filtrate concentrated. The residue was extracted for 12 hours with 150 ml of tetrahydrofuran in a Soxhlet apparatus. The extract was combined with the filtrate and the solvent distilled off in a vacuum. The light brownish liquid was distilled in a high vacuum at 85° C. Colorless liquid. cooled in an ice bath to stir for 3 hours at room temperature The organic phase was separated off the aqueous solution shaken twice with 20 ml of benzene The combined phases were dried over sodium sulfate

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

Procedure: 8-(2-naphthyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (350 mg, 1 mmol), K3CO3 (100 mg) and (2S)-3-phenylpropane-1,2-diamine (150 mg, 1 mmol) were combined in dry DMF (ca. 5 mL) and the mixture was stirred at room temperature for 48 h. To the reaction solution was added water (ca. 10 mL) at RT and a precipitate formed. The suspension was stirred at RT for 1 h. The solid was filtered off and washed with water (3×10 ml) and dried under vacuum at 50° C. overnight; MS (m/z) 472.3 (M+H)+; C29H25N7 requir. 471.56. a precipitate formed The suspension was stirred at RT for 1 h The solid was filtered off washed with water (3×10 ml) dried under vacuum at 50° C. overnight

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

Procedure: 8-(2-naphthyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (350 mg, 1 mmol), K3CO3 (100 mg) and (2S)-3-phenylpropane-1,2-diamine (150 mg, 1 mmol) were combined in dry DMF (ca. 5 mL) and the mixture was stirred at room temperature for 48 h. To the reaction solution was added water (ca. 10 mL) at RT and a precipitate formed. The suspension was stirred at RT for 1 h. The solid was filtered off and washed with water (3×10 ml) and dried under vacuum at 50° C. overnight; MS (m/z) 472.3 (M+H)+; C29H25N7 requir. 471.56. a precipitate formed The suspension was stirred at RT for 1 h The solid was filtered off washed with water (3×10 ml) dried under vacuum at 50° C. overnight

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

Procedure: A mixture of 8-(4-fluorophenyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (1.0 g, 3.0 mmole), potassium carbonate (1.5 g) and (2S)-3-phenylpropane-1,2-diamine (540 mg, 3.6 mmole) in 50 ml of DMF was stirred at room temperature (RT) for 48 hours. The reaction solution was poured into water (200 mL), and the resulting precipitate was filtered and washed with water. The crude product was purified by flash chromatography (3%-15% MeOH/NH3 in DCM) to provide 1-(8-(4-fluorophenyl)-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-yl)amino-2(S)-amino-3-phenylpropane was obtained as white solid; MS: m/z (M+H)+ 440.1; C25H22FN7 requir. 439.5. the resulting precipitate was filtered washed with water The crude product was purified by flash chromatography (3%-15% MeOH/NH3 in DCM)

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

Procedure: A mixture of 8-(4-fluorophenyl)-5-methylthio-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidine (1.0 g, 3.0 mmole), potassium carbonate (1.5 g) and (2S)-3-phenylpropane-1,2-diamine (540 mg, 3.6 mmole) in 50 ml of DMF was stirred at room temperature (RT) for 48 hours. The reaction solution was poured into water (200 mL), and the resulting precipitate was filtered and washed with water. The crude product was purified by flash chromatography (3%-15% MeOH/NH3 in DCM) to provide 1-(8-(4-fluorophenyl)-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-yl)amino-2(S)-amino-3-phenylpropane was obtained as white solid; MS: m/z (M+H)+ 440.1; C25H22FN7 requir. 439.5. the resulting precipitate was filtered washed with water The crude product was purified by flash chromatography (3%-15% MeOH/NH3 in DCM)

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

Procedure: Following the procedure as described in Example 9, making variations as required to replace 1,2-diaminopropane with (S)-3-phenylpropane-1,2-diamine to react with 2-benzamidoisonicotinic acid, N-(4-(4-benzyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide was obtained in 34% yield: MS (ES+) m/z 357.3 (M+1).

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

Procedure: Following the procedure as described in Preparation 11, making variations as required to replace 2-aminopentanenitrile with L-phenylalanineamide to react with lithium aluminum hydride, (S)-3-phenylpropane-1,2-diamine was obtained as a colorless solid in 35% yield: MS (ES+) m/z 151.2 (M+1). as described in Preparation 11

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

Procedure: Following the procedure as described in Preparation 11, making variations as required to replace 2-aminopentanenitrile with L-phenylalanineamide to react with lithium aluminum hydride, (S)-3-phenylpropane-1,2-diamine was obtained as a colorless solid in 35% yield: MS (ES+) m/z 151.2 (M+1). as described in Preparation 11

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

Procedure: A sample of the compound from step 4a (790 mg, 4.48 mmole) was dissolved in 30 mL of THF and 6 mL of water, triphenylphosphine (5.0 g, 19.1 mmole) was added, and the reaction mixture was stfired for 24 hours at reflux. The solvent was removed, and the residue was dissolved in 2 N HCl. NaCl was added, and the solution was extracted with ethyl ether. The aqueous layer was adjusted to pH 12 with K2CO3, saturated with NaCl, then extracted with GICl3 and CHCl3 containing 15% isopropanol. The solvent was removed under vacuum to afford 439 mg of the title compound. MS m/z (M+H)+: 151, MS m/z (M+NH4)+: 168. at reflux The solvent was removed the residue was dissolved in 2 N HCl NaCl was added the solution was extracted with ethyl ether extracted with GICl3 and CHCl3 containing 15% isopropanol The solvent was removed under vacuum

Conditions: temp:190.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A neat mixture of 6-bromo-[2,4′]bipyridine (2.35 gm, 10 mmole) and (S)-2-amino-3-phenylpropylamine (3 gm, 20 mmole) was heated to 190° C. for 4 hr. The reaction was cooled to rt and purified (SiO2, CH2Cl2/MeOH/NH4OH: 100/11/8) to give the step 1 compound. (This reaction provides major products wherein the less hindered amine functionality displaces the bromide,when the nucleophile is an alkyldiamine) MS (m/z): Calcd. C19H20N4 (M+): 304, found (M+H)+: 305.2. The reaction was cooled to rt purified (SiO2, CH2Cl2/MeOH/NH4OH: 100/11/8) to give the step 1 compound (This reaction provides major products wherein the