(2S)-2-phenylpropan-1-amine

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

Procedure: A solution of (1-Methyl-3-phenyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (100 mg, 0.28 mmol), DIC (53 mg, 0.42 mmol) and HOBt (49 mg, 0.36 mmol) in DMF (5 ml) was stirred at rt for 10 min. (S)-(+)-2-Phenyl-propylamine (42 mg, 0.31 mmol) was added to the reaction mixture at rt and stirring was continued overnight at rt. After completion of the reaction, ice-cold water (10 mL) was added to the reaction mixture and the mixture was stirred for 20 min. The reaction mixture was extracted with diethyl ether, dried over sodium sulfate and concentrated under reduced pressure. The solid was triturated with pentane (20 ml×3) followed by hexane (15 ml) to yield the title compound as white solid. (100 mg, 75%). Mp=91-93° C. [1H-NMR (CDCl3, 300 MHz) δ 7.63-7.42 (m, 5H), 7.20-6.92 (m, 5H), 6.80 (s, 1H), 6.18-6.12 (m, 1H), 4.92 (dd, 2H), 4.1 (s, 3H), 3.81-3.68 (m, 1H), 3.40-3.33 (m, 1H), 2.98-2.90 (m, 1H), 1.41 (d, 3H); HPLC RtA=6.325 min. (98%); LCMS RtA=1.835, [M+H]+=469.1] was added to the reaction mixture at rt was added to the reaction mixture the mixture was stirred for 20 min The reaction mixture was extracted with diethyl ether dried over sodium sulfate concentrated under reduced pressure The solid was triturated with pentane (20 ml×3)

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

Procedure: A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 0.1 g), N,N-diisopropylethylamnie (0.1 mL), (S)-2-phenyl-1-propylamine (0.05 mL) and tetrahydrofuran (1 mL) was stirred at room temperature overnight. Cyclopropylamine (0.2 mL) was added followed by the addition of cyclopentylmagnesium bromide (2M in diethyl ether, 0.8 mL). The mixture was stirred for 10 min., quenched with sat. NH4Cl and extracted into ethyl acetate. The organic phase concentrated in vacuo. The residue was treated with ethanol (5 mL), wet 10% palladium on carbon (45 mg) was added followed by N,N-diisopropylethylamnie (0.1 mL) and ammonium formate (0.4 g). The mixture was stirred under nitrogen atmosphere at 70° C. for 30 min. The mixture was filtered through a pad of Celite and the filtrate concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (64 mg). The mixture was stirred for 10 min. quenched with sat. NH4Cl extracted into ethyl acetate The organic phase concentrated in vacuo The residue was treated with ethanol (5 mL), wet 10% palladium on carbon (45 mg) was added The mixture was stirred under nitrogen atmosphere at 70° C. for 30 min The mixture was filtered through a pad of Celite the filtrate concentrated in vacuo Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent)

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

Procedure: A solution of {3-[(S)-3-(Toluene-4-sulfonyloxy)-butoxy]-phenyl}-acetic acid methyl ester (0.2 g, 0.51 mmol) and (S)-2-Phenyl-propylamine (0.19, 0.77 mmol) in acetonitrile (30 ml) was treated with solid potassium carbonate (0.149, 1.02 mmol). The reaction was heated to reflux and stirred for six days. Upon cooling to room temperature, the reaction was filtered through a pad of celite, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil (0.12 g, 40%). MS m/e 356.6 (M+H)+. The reaction was heated to reflux the reaction was filtered through a pad of celite washed with EtOAc the filtrate was concentrated in vacuo The crude product was purified by column chromatograph (EtOAc:Hexane/20:80)

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

Procedure: A solution of {3-[(S)-3-(Toluene-4-sulfonyloxy)-butoxy]-phenyl}-acetic acid methyl ester (0.2 g, 0.51 mmol) and (S)-2-Phenyl-propylamine (0.19, 0.77 mmol) in acetonitrile (30 ml) was treated with solid potassium carbonate (0.149, 1.02 mmol). The reaction was heated to reflux and stirred for six days. Upon cooling to room temperature, the reaction was filtered through a pad of celite, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil (0.12 g, 40%). MS m/e 356.6 (M+H)+. The reaction was heated to reflux the reaction was filtered through a pad of celite washed with EtOAc the filtrate was concentrated in vacuo The crude product was purified by column chromatograph (EtOAc:Hexane/20:80)

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

Procedure: To a solution of (S)-(−)-2-phenyl propylamine (0.5 g, 3.7 mmol) in dry dichloromethane (100 ml) was added acetic acid (2 drops) followed by 2-chloro-3-trifluoromethylbenzaldehyde (1.1 g, 5.5 mmol) and sodium triacetoxyborohydride (1.5 g, 7.4 mmol). After the resulting mixture was stirred for 1.5 h at room temperature, water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified by silica gel column chromatograph using EtOAc:Hexane/25:75 as the eluant to give 0.55 g (45% yield) of the title compound as an oil. MS m/e327.6 (M+H)+. to quench the reaction The aqueous layer was extracted with ethyl acetate The combined organic layers was washed with brine dried over sodium sulfate concentrated in vacuo The crude mixture was purified by silica gel column chromatograph

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

Procedure: To a solution of (S)-2-phenyl propylamine (0.5 g, 3.7 mmol) in dry dichloromethane was added acetic acid followed by 2-chloro-3-trifluoromethylbenzaldehyde (1.1 g, 5.5 mmol) and sodium triacetoxyborohydride (1.5 g, 7.4 mmol). After the resulting mixture was stirred for 1.5 h at RT water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified by column chromatograph (Ethyl acetate:Hexane/25:75) to give the title compound as an oil (0.55 g, 45%). MS (ESI) 327.6 (M+H)+. was added to quench the reaction The aqueous layer was extracted with ethyl acetate The combined organic layers were washed with brine dried over sodium sulfate concentrated in vacuo The crude mixture was purified by column chromatograph (Ethyl acetate:Hexane/25:75)

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

Procedure: To a solution of (S)-2-phenyl propylamine (0.5 g, 3.7 mmol) in dry dichloromethane was added acetic acid followed by 2-chloro-3-trifluoromethylbenzaldehyde (1.1 g, 5.5 mmol) and sodium triacetoxyborohydride (1.5 g, 7.4 mmol). After the resulting mixture was stirred for 1.5 h at RT water was added to quench the reaction. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude mixture was purified by column chromatograph (Ethyl acetate:Hexane/25:75) to give the title compound as an oil (0.55 g, 45%). MS (ESI) 327.6 (M+H)+. was added to quench the reaction The aqueous layer was extracted with ethyl acetate The combined organic layers were washed with brine dried over sodium sulfate concentrated in vacuo The crude mixture was purified by column chromatograph (Ethyl acetate:Hexane/25:75)

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

Procedure: The product of Example 430F (62 mg, 0.142 mmol) in dimethyl sulfoxide (2 mL) under a nitrogen atmosphere was reacted with (S)-(−)-β-methylphenethylamine (23 mg, 0. 170 mmol), N,N-diisopropylethylamine (0.123 mL, 0.708 mmol), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (55 mg, 0.170 mmol at room temperature for 20 hours. The reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate (50 mL). The organic extract was washed sequentially with water (3×10 mL), saturated aqueous sodium hydrogencarbonate (20 mL), and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification of the residue by silica gel flash chromatography eluting with 4:96 methanol/methylene chloride afforded the title compound (67 mg, 0.121 mmol, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.19 (d, J=6.99 Hz, 3 H) 1.33 (d, J=6.99 Hz, 6 H) 2.91-3.07 (m, 1 H) 3.14-3.29 (m, 1 H) 5.50 (s, 2 H) 6.51 (d, J=8.46 Hz, 2 H) 7.12 (d, J=8.82 Hz, 2 H) 7.16-7.34 (m, 5 H) 7.63 (d, J=8.46 Hz, 1 H) 7.77 (s, 1 H) 8.50 (t, J=5.88 Hz, 1 H) 8.62 (s, 1 H) 8.82 (d, J=8.82 Hz, 1 H) 9.97 (s, 1 H); MS (ESI+) m/z 555 (M+H)+, 1109 (2M+H)+, MS (ESI−) m/z 553 (M−H)−. extracted with ethyl acetate (50 mL) The organic extract was washed sequentially with water (3×10 mL), saturated aqueous sodium hydrogencarbonate (20 mL), and brine (20 mL) dried over magnesium sulfate filtered concentrated by rotary evaporation Purification of the residue by silica gel flash chromatography eluting with 4:96 methanol/methylene chloride

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

Procedure: A solution of (1-Methyl-3-phenyl-4-trifluoromethyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)-acetic acid (100 mg, 0.28 mmol), DIC (53 mg, 0.42 mmol) and HOBt (49 mg, 0.36 mmol) in DMF (5 ml) was stirred at rt for 10 min. (S)-(+)-2-Phenyl-propylamine (42 mg, 0.31 mmol) was added to the reaction mixture at rt and stirring was continued overnight at rt. After completion of the reaction, ice-cold water (10 mL) was added to the reaction mixture and the mixture was stirred for 20 min. The reaction mixture was extracted with diethyl ether, dried over sodium sulfate and concentrated under reduced pressure. The solid was triturated with pentane (20 ml×3) followed by hexane (15 ml) to yield the title compound as white solid. (100 mg, 75%). Mp=91-93° C. [1H-NMR (CDCl3, 300 MHz) δ 7.63-7.42 (m, 5H), 7.20-6.92 (m, 5H), 6.80 (s, 1H), 6.18-6.12 (m, 1H), 4.92 (dd, 2H), 4.1 (s, 3H), 3.81-3.68 (m, 1H), 3.40-3.33 (m, 1H), 2.98-2.90 (m, 1H), 1.41 (d, 3H); HPLC RtA=6.325 min. (98%); LCMS RtA=1.835, [M+H]+=469.1] was added to the reaction mixture at rt was added to the reaction mixture the mixture was stirred for 20 min The reaction mixture was extracted with diethyl ether dried over sodium sulfate concentrated under reduced pressure The solid was triturated with pentane (20 ml×3)

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

Procedure: A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 0.1 g), N,N-diisopropylethylamnie (0.1 mL), (S)-2-phenyl-1-propylamine (0.05 mL) and tetrahydrofuran (1 mL) was stirred at room temperature overnight. Cyclopropylamine (0.2 mL) was added followed by the addition of cyclopentylmagnesium bromide (2M in diethyl ether, 0.8 mL). The mixture was stirred for 10 min., quenched with sat. NH4Cl and extracted into ethyl acetate. The organic phase concentrated in vacuo. The residue was treated with ethanol (5 mL), wet 10% palladium on carbon (45 mg) was added followed by N,N-diisopropylethylamnie (0.1 mL) and ammonium formate (0.4 g). The mixture was stirred under nitrogen atmosphere at 70° C. for 30 min. The mixture was filtered through a pad of Celite and the filtrate concentrated in vacuo. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded the title compound as a solid (64 mg). The mixture was stirred for 10 min. quenched with sat. NH4Cl extracted into ethyl acetate The organic phase concentrated in vacuo The residue was treated with ethanol (5 mL), wet 10% palladium on carbon (45 mg) was added The mixture was stirred under nitrogen atmosphere at 70° C. for 30 min The mixture was filtered through a pad of Celite the filtrate concentrated in vacuo Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent)

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

Procedure: Prepared from 2-quinoxaloyl chloride (0.47 g, 2.4 mmol), (S)-2-phenyl-1-propylamine (0.30 g, 2.2 mmol), pyridine (5 mL), and water (50 mL) yielding 0.48 g (74%) of (173):

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

Procedure: To a solution of maleic anhydride (765 mg, 7.8 mmol) in acetic acid (20 mL) at rt was added (S)-2-phenylpropylamine. The mixture was stirred overnight then was partially concentrated. Water (50 mL) was added causing precipitation of the product acid. The white solid was collected by suction filtration, washed with water, and dried to provide 1.44 g (79%) of the pure acid. 1H NMR (400 MHz, CDCl3): 7.38-7.32 (m, 2H), 7.29-7.24 (m, 1H), 7.24-7.20 (m, 2H), 6.68 (br m, 1H), 6.29 (d J=12.7, 1H), 6.18 (d, J=12.7, 1H), 3.78-3.69 (m, 1H), 3.47-3.38 (m, 1H), 3.11-3.00 (m, 1H), 1.33 (d, J=7.0, 3H). then was partially concentrated Water (50 mL) was added precipitation of the product acid The white solid was collected by suction filtration washed with water dried