(2S)-butan-2-amine

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

Procedure: A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (50 mg, 0.11 mmol), (S)-butan-2-amine (9 mg, 0.12 mmol), and HATU (45 mg, 0.12 mmol). Then added acetonitrile (1 mL) followed by N,N-diisopropylethylamine (0.09 mL, 0.55 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 0-50% EtOAc) to afford 40 mg (71%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-sec-butyl)-amide as a white solid. [M+Na]+=519. then quenched with water The mixture was extracted with ethyl acetate (3×) dried over Na2SO4 concentrated The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 0-50% EtOAc)

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

Procedure: A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (50 mg, 0.11 mmol), (S)-butan-2-amine (9 mg, 0.12 mmol), and HATU (45 mg, 0.12 mmol). Then added acetonitrile (1 mL) followed by N,N-diisopropylethylamine (0.09 mL, 0.55 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 0-50% EtOAc) to afford 40 mg (71%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-sec-butyl)-amide as a white solid. [M+Na]+=519. then quenched with water The mixture was extracted with ethyl acetate (3×) dried over Na2SO4 concentrated The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 0-50% EtOAc)

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

Procedure: N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.900 g, 2.47 mmol), S-(+)-sec-butylamine (0.235 g, 3.21 mmol), N-methylmorpholine (0.270 g, 2.67 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(sec-butyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.300 9, 27.8% yield). After completion of the reaction the solvent was distilled off under reduced pressure the precipitated crystals were isolated by filtration The crystals were washed with hexane dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add (S)-sec-butyl amine (1.18 mL, 11.8 mmol) to a suspension of 2-chloro-6-methoxy-isonicotinic acid ethyl ester (1.69 g, 7.86 mmol), palladium acetate (0.088 g, 0.4 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.250 g, 0.4 mmol), and cesium carbonate (3.8 g, 11.8 mmol) in toluene (20 mL) at room temperature and stir 15 h at 80° C. Cool to room temperature, filter through a filtering agent, concentrate and purify (silica gel chromatography, eluting with 5:95 ethyl acetate:hexanes to give the title compound (1.85 g, 93%). Cool to room temperature filter through a filtering agent concentrate purify (silica gel chromatography eluting with 5:95 ethyl acetate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Degas with nitrogen a suspension containing 2-chloro-isonicotinic acid methyl ester (2.15 g, 12.5 mmol), palladium acetate (281 mg, 1.25 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (780 mg, 1.25 mmol), cesium carbonate (4.95 g, 15 mmol), and (S)-sec-butylamine (1.5 mL, 15 mmol) in toluene (30 mL) and heat in a sealed tube at 90° C. overnight. Cool to room temperature and filter the solids through a filtering agent. Wash with ethyl acetate (30 mL), concentrate and purify (silica gel chromatography, eluting with 15:85 to 30:70 ethyl acetate:hexanes) to give the title compound. Degas with nitrogen a suspension Cool to room temperature filter the solids through a filtering agent Wash with ethyl acetate (30 mL) concentrate purify (silica gel chromatography, eluting with 15:85 to 30:70 ethyl acetate:hexanes)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Degas with nitrogen a suspension containing 2-chloro-isonicotinic acid methyl ester (2.15 g, 12.5 mmol), palladium acetate (281 mg, 1.25 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (780 mg, 1.25 mmol), cesium carbonate (4.95 g, 15 mmol), and (S)-sec-butylamine (1.5 mL, 15 mmol) in toluene (30 mL) and heat in a sealed tube at 90° C. overnight. Cool to room temperature and filter the solids through a filtering agent. Wash with ethyl acetate (30 mL), concentrate and purify (silica gel chromatography, eluting with 15:85 to 30:70 ethyl acetate:hexanes) to give the title compound. Degas with nitrogen a suspension Cool to room temperature filter the solids through a filtering agent Wash with ethyl acetate (30 mL) concentrate purify (silica gel chromatography, eluting with 15:85 to 30:70 ethyl acetate:hexanes)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add 2-chloro-6-propylsulfanyl-isonicotinic acid methyl ester (1.35 g, 5.49 mmol) palladium acetate (0.123 g, 0.549 mmol, 0.1 eq.), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.342 g, 0.549 mmol, 0.1 eq.), cesium carbonate (2.68 g, 8.24 mmol, 1.5 eq.) and toluene (20 mL) into a sealed vessel flushed with nitrogen. Slowly add (S)-sec-butylamine (0.824 mL, 8.24 mmol) and heat and stir the reaction mixture at 90° C. for 18 h. Cool the reaction mixture to room temperature, dilute with ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with the 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (55%). flushed with nitrogen Cool the reaction mixture to room temperature filter through a filtering agent Concentrate the filtrate purify (silica gel chromatography eluting with the 5:95 to 10:90 ethyl acetate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add 2-chloro-6-propylsulfanyl-isonicotinic acid methyl ester (1.35 g, 5.49 mmol) palladium acetate (0.123 g, 0.549 mmol, 0.1 eq.), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.342 g, 0.549 mmol, 0.1 eq.), cesium carbonate (2.68 g, 8.24 mmol, 1.5 eq.) and toluene (20 mL) into a sealed vessel flushed with nitrogen. Slowly add (S)-sec-butylamine (0.824 mL, 8.24 mmol) and heat and stir the reaction mixture at 90° C. for 18 h. Cool the reaction mixture to room temperature, dilute with ether and filter through a filtering agent. Concentrate the filtrate and purify (silica gel chromatography, eluting with the 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (55%). flushed with nitrogen Cool the reaction mixture to room temperature filter through a filtering agent Concentrate the filtrate purify (silica gel chromatography eluting with the 5:95 to 10:90 ethyl acetate

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add toluene (20 mL), 2-chloro-6-dimethylsulfamoyl-isonicotinic acid methyl ester (2.49 g, 8.93 mmol), palladium acetate (0.201 g, 0.893 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.556 g, 0.893 mmol) and cesium carbonate (4.36 g, 13.4 mmol) to a sealed vessel flushed with nitrogen. Slowly add (S)-sec-butylamine (1.36 mL, 13.4 mmol) to the mixture. Heat and stir the sealed vessel at 90° C. overnight. Cool to room temperature, filter through a pad of filtering agent, concentrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title compound (1.43 g, 51%). flushed with nitrogen Heat Cool to room temperature filter through a pad of filtering agent concentrate purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add toluene (20 mL), 2-chloro-6-dimethylsulfamoyl-isonicotinic acid methyl ester (2.49 g, 8.93 mmol), palladium acetate (0.201 g, 0.893 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.556 g, 0.893 mmol) and cesium carbonate (4.36 g, 13.4 mmol) to a sealed vessel flushed with nitrogen. Slowly add (S)-sec-butylamine (1.36 mL, 13.4 mmol) to the mixture. Heat and stir the sealed vessel at 90° C. overnight. Cool to room temperature, filter through a pad of filtering agent, concentrate and purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes) to give the title compound (1.43 g, 51%). flushed with nitrogen Heat Cool to room temperature filter through a pad of filtering agent concentrate purify (silica gel chromatography, eluting with 20:80 to 30:70 ethyl acetate:hexanes)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add 2-chloro-6-cyclopropanesulfonyl-isonicotinic acid tert-butyl ester (0.190 g, 0.607 mmol), palladium acetate (0.020 g, 0.091 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.057 g, 0.091 mmol), cesium carbonate (0.297 g, 0.911 mmol), and (S)-sec-butylamine (0.063 mL, 0.911 mmol) in toluene (5 mL) to a sealed tube flushed with nitrogen. Heat and stir the reaction mixture at 90° C. for 18 h. Cool and filter the mixture through a pad of filtering agent, concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give the title compound (0.120 g, 59%). flushed with nitrogen Heat Cool filter the mixture through a pad of filtering agent concentrate purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add 2-chloro-6-cyclopropanesulfonyl-isonicotinic acid tert-butyl ester (0.190 g, 0.607 mmol), palladium acetate (0.020 g, 0.091 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.057 g, 0.091 mmol), cesium carbonate (0.297 g, 0.911 mmol), and (S)-sec-butylamine (0.063 mL, 0.911 mmol) in toluene (5 mL) to a sealed tube flushed with nitrogen. Heat and stir the reaction mixture at 90° C. for 18 h. Cool and filter the mixture through a pad of filtering agent, concentrate and purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes) to give the title compound (0.120 g, 59%). flushed with nitrogen Heat Cool filter the mixture through a pad of filtering agent concentrate purify (silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes)