tert-butyl 4-aminobutanoate;hydrochloride

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

Procedure: 1.3 ml of N-ethylmorpholine and 3.08 g of L-pyroglutamic acid 2,4,5-trichlorophenyl ester were added to a solution of 1.95 g (10 mmols) of 4-aminobutyric acid tert. butyl ester hydrochloride in 20 ml of dimethylformamide. The solution was left overnight at room temperature. It was concentrated, the residue was dissolved in a mixture of ethyle acetate and water, and the ethyl acetate solution was shaken with sodium bicarbonate solution, KHSO4 -solution and NaCl-solution, dried with Na2SO4 and concentrated. The residue was triturated with petroleum ether. It was concentrated the residue was dissolved in a mixture of ethyle acetate and water dried with Na2SO4 concentrated The residue was triturated with petroleum ether

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

Procedure: A solution of 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (45 mg, 0.15 mmol, 4-amino-butyric acid tert-butyl ester HCl salt (115 mg, 0.59 mmol), and triethylamine (81 μL, 0.58 mmol) in 1,2-dichloroethane (1.5 mL) was treated with sodium triacetoxyborohydride (65 mg, 0.29 mmol). After stirring at room temperature over night, the mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate. The organic phase was dried over MgSO4, filtered and concentrated and residue was purified by silica gel column eluted with ethyl acetate in hexane from 0 to 100% to give colorless oil (33 mg, yield: 50%). ESI-MS: 454.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ=7.65-7.70 (m, 3H), 7.38-7.40 (dd, 1H), 7.10-7.14 (m, 2H), 4.22-4.28 (m, 1H), 3.90 (s, 2H), 2.67 (t, 2H), 2.28 (t, 4H), 1.89 (d, 2H), 1.81 (t, 2H), 1.40 (m, 1H), 1.42 (s, 9H), 1.30 (m, 4H), 0.9 (s, 9H). washed with aqueous sodium bicarbonate The organic phase was dried over MgSO4 filtered concentrated residue was purified by silica gel column eluted with ethyl acetate in hexane from 0 to 100%

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

Procedure: A solution of 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (45 mg, 0.15 mmol, 4-amino-butyric acid tert-butyl ester HCl salt (115 mg, 0.59 mmol), and triethylamine (81 μL, 0.58 mmol) in 1,2-dichloroethane (1.5 mL) was treated with sodium triacetoxyborohydride (65 mg, 0.29 mmol). After stirring at room temperature over night, the mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate. The organic phase was dried over MgSO4, filtered and concentrated and residue was purified by silica gel column eluted with ethyl acetate in hexane from 0 to 100% to give colorless oil (33 mg, yield: 50%). ESI-MS: 454.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ=7.65-7.70 (m, 3H), 7.38-7.40 (dd, 1H), 7.10-7.14 (m, 2H), 4.22-4.28 (m, 1H), 3.90 (s, 2H), 2.67 (t, 2H), 2.28 (t, 4H), 1.89 (d, 2H), 1.81 (t, 2H), 1.40 (m, 1H), 1.42 (s, 9H), 1.30 (m, 4H), 0.9 (s, 9H). washed with aqueous sodium bicarbonate The organic phase was dried over MgSO4 filtered concentrated residue was purified by silica gel column eluted with ethyl acetate in hexane from 0 to 100%

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of tert-butyl 4-aminobutanoate hydrochloride (Bachem F-3755, 8.54 g, 28.9 mmol), sodium bicarbonate (6.0 g, 72.2 mmol) and 5,6-dichloronicotinonitrile (Bionet GC-0755, 5.0 g, 28.9 mmol) was prepared in dioxane under nitrogen, and then heated at 50° C. for 16 hours. The reaction mixture was filtered to remove inorganic solids and filtrate was concentrated under reduced pressure. After purification by flash chromatography (silica, pet ether/EtOAc), the title compound was obtained as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.40 (1H, d), 8.05 (1H, d), 7.58 (1H, t), 3.42 (2H, m), 2.21 (2H, t), 1.76 (2H, m), 1.37 (9H, s). The reaction mixture was filtered to remove inorganic solids and filtrate was concentrated under reduced pressure After purification by flash chromatography (silica, pet ether/EtOAc)

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

Procedure: A solution of 6-(4-tert-butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (45 mg, 0.15 mmol, 4-amino-butyric acid tert-butyl ester HCl salt (115 mg, 0.59 mmol), and triethylamine (81 μL, 0.58 mmol) in 1,2-dichloroethane (1.5 mL) was treated with sodium triacetoxyborohydride (65 mg, 0.29 mmol). After stirring at room temperature over night, the mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate. The organic phase was dried over MgSO4, filtered and concentrated and residue was purified by silica gel column eluted with ethyl acetate in hexane from 0 to 100% to give colorless oil (33 mg, yield: 50%). ESI-MS: 454.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ=7.65-7.70 (m, 3H), 7.38-7.40 (dd, 1H), 7.10-7.14 (m, 2H), 4.22-4.28 (m, 1H), 3.90 (s, 2H), 2.67 (t, 2H), 2.28 (t, 4H), 1.89 (d, 2H), 1.81 (t, 2H), 1.40 (m, 1H), 1.42 (s, 9H), 1.30 (m, 4H), 0.9 (s, 9H). washed with aqueous sodium bicarbonate The organic phase was dried over MgSO4 filtered concentrated residue was purified by silica gel column eluted with ethyl acetate in hexane from 0 to 100%

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

Procedure: To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (30 mg, 0.089 mmol), tert-butyl 4-aminobutanoate hydrochloride (20.88 mg, 0.107 mmol), and TEA (0.037 mL, 0.267 mmol) in DMF (1 mL) was added HATU (40.6 mg, 0.107 mmol). The reaction was stirred at room temperature overnight. The mixture was added 1M HCl (1 mL) and purified by HPLC to give the title compound. LCMS m/z=479.3 [M+H]+. purified by HPLC

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

Procedure: A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), tert-butyl 4-aminobutanoate hydrochloride (8.55 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC. LCMS m/z=519.7 [M+H]+. purified by HPLC

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 3 g (14.74 mmol) of 2-chloro-3,5-dinitropyridine in dioxane is admixed with 3.46 g (17.69 mmol) of tert-butyl 4-aminobutanoate hydrochloride and then with 4.21 ml (22.11 mmol) of triethylamine. The reaction mixture is stirred at 60° C. for 3 hours.

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

Procedure: A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with tert-butyl 4-aminobutanoate hydrochloride (Bachem, 244.6 mg; 1.25 mmol) and polymer supported carbonate (150 mg) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid (85 mg, 70%). was filtered the solvent removed in vacuo The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc

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

Procedure: A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with tert-butyl 4-aminobutanoate hydrochloride (Bachem, 244.6 mg; 1.25 mmol) and polymer supported carbonate (150 mg) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid (85 mg, 70%). was filtered the solvent removed in vacuo The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc

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

Procedure: N-[2-(cyanomethyl)-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide (Intermediate 6) (160 mg; 0.48 mmol; 1 eq) is dissolved in DMF (8 ml). Tert-butyl 4-aminobutanoate hydrochloride (94.8 mg; 0.48 mmol; 1 eq) and triethylamine (148 μl; 1.07 mmol; 2.20 eq) are added. After less than 1 min, the mixture becomes homogeneous. After 30 min the reaction is complete. DMF is removed under reduced pressure. The resulting crude oil is dissolved in DCM and washed twice with NH4Cl sat. solution and twice with NaHCO3 sat. solution. The organic layer is dried over Na2SO4, filtered and concentrated. The resulting crude product is purified by preparative HPLC. The purified fractions are neutralized with NaHCO3 sat. solution and the desired compound is extracted with DCM. After less than 1 min DMF is removed under reduced pressure The resulting crude oil is dissolved in DCM washed twice with NH4Cl sat. solution and twice with NaHCO3 sat. solution The organic layer is dried over Na2SO4 filtered concentrated The resulting crude product is purified by preparative HPLC the desired compound is extracted with DCM

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 3 g (14.74 mmol) of 2-chloro-3,5-dinitropyridine in dioxane is admixed with 3.46 g (17.69 mmol) of tert-butyl 4-aminobutanoate hydrochloride and then with 4.21 ml (22.11 mmol) of triethylamine. The reaction mixture is stirred at 60° C. for 3 hours.