(E)-3-phenylprop-2-enamide

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), 4-dimethylamino-1-bromobenzene (201 mg, 1.00 mmol), trans-cinnamamide (178 mg, 1.21 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting bright yellow suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate-dichloromethane 1:1. The filtrate was concentrated, the residue was dissolved in 10 mL of dichloromethane and purified by flash chromatography on silica gel (2×20 cm, ethyl acetate-dichloromethane 1:4, 15 mL fractions). Fractions 10-20 provided 261 mg (98% yield) of the desired product as a bright yellow solid. evacuated The Schlenk tube was sealed with a Teflon valve to reach room temperature filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate-dichloromethane 1:1 The filtrate was concentrated the residue was dissolved in 10 mL of dichloromethane purified by flash chromatography on silica gel (2×20 cm, ethyl acetate-dichloromethane 1:4, 15 mL fractions)

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

Procedure: The amine bis-hydrochloride (from Step 4) (68.2 mg, 0.19 mmol), the lithium carboxylate prepared in Step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (72.8 mg, 0.38 mmol) and 1-hydroxybenzotriazole hydrate (30.8 mg, 0.23 mmol) are dissolved in pyridine (2 ml) and stirred at room temperature for 72 hours. The reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (40 ml) and washed with H2O (20 ml), brine (20 ml), dried (MgSO4), filtered and concentrated. The residue is dissolved in CH3OH/CH2Cl2, absorbed onto silica gel and is purified on a Biotage 12M column with SIM using 2% CH3OH (saturated with NH3) in CH2Cl2 as the eluent to afford 56.2 mg (0.096 mmol, 51%) of the desired cinnamide. 1H-NMR (DMSO) δ: 8.66, 8.48, 8.02, 7.64, 7.49, 7.40, 7.35, 6.70, 4.86, 4.22, 3.84, 3.60. The reaction mixture is concentrated The residue is dissolved in CH2Cl2 (40 ml) washed with H2O (20 ml), brine (20 ml) dried (MgSO4) filtered concentrated The residue is dissolved in CH3OH/CH2Cl2 absorbed onto silica gel is purified on a Biotage 12M column with SIM

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (2E)-3-phenylprop-2-enamide (2.00 g, 13.6 mmol) and sodium bicarbonate (4.57 g, 54.4 mmol) in tetrahydrofuran (48 mL) was cooled to 0° C. Ethyl 3-bromo-2-oxopropanoate (3.16 mL, 25.2 mmol) was added drop-wise, and the reaction mixture was heated at reflux for 4 hours, whereupon it was filtered through diatomaceous earth and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (33 mL), cooled to 0° C., and treated drop-wise with trifluoroacetic anhydride (14.8 mL, 105 mmol). The reaction mixture was stirred at room temperature for 10 hours, then cooled to 0° C. and quenched via addition of saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane) provided partially purified product; this was crystallized from heptane/ethyl acetate to afford the product as pale yellow needles. Yield: 1.52 g, 6.25 mmol, 46%. LCMS m/z 244.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.63 (d, J=16.4 Hz, 1H), 7.51-7.56 (m, 2H), 7.34-7.43 (m, 3H), 6.97 (d, J=16.5 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H). the reaction mixture was heated at reflux for 4 hours, whereupon it was filtered through diatomaceous earth concentrated in vacuo The residue was dissolved in tetrahydrofuran (33 mL) cooled to 0° C. cooled to 0° C. quenched via addition of saturated aqueous sodium bicarbonate solution The mixture was extracted three times with ethyl acetate the combined organic layers were washed with saturated aqueous sodium chloride solution dried over sodium sulfate filtered concentrated under reduced pressure Chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane) provided partially purified product this was crystallized from heptane/ethyl acetate

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

Procedure: The amine bis-hydrochloride (from Step 4) (68.2 mg, 0.19 mmol), the lithium carboxylate prepared in Step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (72.8 mg, 0.38 mmol) and 1-hydroxybenzotriazole hydrate (30.8 mg, 0.23 mmol) are dissolved in pyridine (2 ml) and stirred at room temperature for 72 hours. The reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (40 ml) and washed with H2O (20 ml), brine (20 ml), dried (MgSO4), filtered and concentrated. The residue is dissolved in CH3OH/CH2Cl2, absorbed onto silica gel and is purified on a Biotage 12M column with SIM using 2% CH3OH (saturated with NH3) in CH2Cl2 as the eluent to afford 56.2 mg (0.096 mmol, 51%) of the desired cinnamide. 1H-NMR (DMSO) δ: 8.66, 8.48, 8.02, 7.64, 7.49, 7.40, 7.35, 6.70, 4.86, 4.22, 3.84, 3.60. The reaction mixture is concentrated The residue is dissolved in CH2Cl2 (40 ml) washed with H2O (20 ml), brine (20 ml) dried (MgSO4) filtered concentrated The residue is dissolved in CH3OH/CH2Cl2 absorbed onto silica gel is purified on a Biotage 12M column with SIM

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

Procedure: The amine bis-hydrochloride (from Step 4) (68.2 mg, 0.19 mmol), the lithium carboxylate prepared in Step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (72.8 mg, 0.38 mmol) and 1-hydroxybenzotriazole hydrate (30.8 mg, 0.23 mmol) are dissolved in pyridine (2 ml) and stirred at room temperature for 72 hours. The reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (40 ml) and washed with H2O (20 ml), brine (20 ml), dried (MgSO4), filtered and concentrated. The residue is dissolved in CH3OH/CH2Cl2, absorbed onto silica gel and is purified on a Biotage 12M column with SIM using 2% CH3OH (saturated with NH3) in CH2Cl2 as the eluent to afford 56.2 mg (0.096 mmol, 51%) of the desired cinnamide. 1H-NMR (DMSO) δ: 8.66, 8.48, 8.02, 7.64, 7.49, 7.40, 7.35, 6.70, 4.86, 4.22, 3.84, 3.60. The reaction mixture is concentrated The residue is dissolved in CH2Cl2 (40 ml) washed with H2O (20 ml), brine (20 ml) dried (MgSO4) filtered concentrated The residue is dissolved in CH3OH/CH2Cl2 absorbed onto silica gel is purified on a Biotage 12M column with SIM

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), (2E)-3-phenylprop-2-enamide (15.0 mg, 0.10 mmol), tetrakis(triphenylphosphine) palladium (0) (5.0 mg, 0.004 mmol) and potassium carbonate (17.6 mg, 0.127 mmol) was added 1,4-dioxane (1.0 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 110° C. for 20 minutes. Analysis by LCMS indicated that no reaction occurred. To the mixture was added diisopropylethylamine (0.044 mL, 0.255 mmol), Combiphos catalyst POPd (Dihydrogen dichlorobis(di-tert-butylphosphinito-κP)palladate(2-)) (5.0 mg, 0.01 mmol) and tetrabutylammonium bromide (5.0 mg, 0.015 mmol) and heated with microwave radiation at 130° C. for 70 minutes. After cooling to room temperature, removed solvent under reduced pressure, dissolved residue in methanol (25 mL), and added silica gel (200 mg). Following evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethylacetate:methanol (100:0 to 80:20) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give a gold oil. Added diethyl ether (15 mL) to precipitate, and vacuum filtered to give (2Z)-3-(3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)-3-phenylprop-2-enamide (0.009 g) as a yellow solid. 1H NMR (CDCl3): δ8.80 (s, 1H), 8.48-8.46 (m, 1H), 7.40-7.28 (m, 7H), 7.17-7.15 (m, 1H), 7.02 (s, 1H), 6.89-6.86 (m, 2H), 6.44 (m, 1H), 5.34 (s, 2H), 3.83-3.79 (m, 9H), 2.60-2.57 (m, 3H). MS m/z 537 (M+1). In a sealed reaction vessel heated with microwave radiation at 130° C. for 70 minutes After cooling to room temperature removed solvent under reduced pressure dissolved residue in methanol (25 mL) added silica gel (200 mg) evaporation of the volatiles under reduced pressure subjected to a gradient elution concentrated under reduced pressure to give a gold oil Added diethyl ether (15 mL) to precipitate vacuum filtered

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (40 mg, 0.085 mmol), (2E)-3-phenylprop-2-enamide (15.0 mg, 0.10 mmol), tetrakis(triphenylphosphine) palladium (0) (5.0 mg, 0.004 mmol) and potassium carbonate (17.6 mg, 0.127 mmol) was added 1,4-dioxane (1.0 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 110° C. for 20 minutes. Analysis by LCMS indicated that no reaction occurred. To the mixture was added diisopropylethylamine (0.044 mL, 0.255 mmol), Combiphos catalyst POPd (Dihydrogen dichlorobis(di-tert-butylphosphinito-κP)palladate(2-)) (5.0 mg, 0.01 mmol) and tetrabutylammonium bromide (5.0 mg, 0.015 mmol) and heated with microwave radiation at 130° C. for 70 minutes. After cooling to room temperature, removed solvent under reduced pressure, dissolved residue in methanol (25 mL), and added silica gel (200 mg). Following evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethylacetate:methanol (100:0 to 80:20) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give a gold oil. Added diethyl ether (15 mL) to precipitate, and vacuum filtered to give (2Z)-3-(3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)-3-phenylprop-2-enamide (0.009 g) as a yellow solid. 1H NMR (CDCl3): δ8.80 (s, 1H), 8.48-8.46 (m, 1H), 7.40-7.28 (m, 7H), 7.17-7.15 (m, 1H), 7.02 (s, 1H), 6.89-6.86 (m, 2H), 6.44 (m, 1H), 5.34 (s, 2H), 3.83-3.79 (m, 9H), 2.60-2.57 (m, 3H). MS m/z 537 (M+1). In a sealed reaction vessel heated with microwave radiation at 130° C. for 70 minutes After cooling to room temperature removed solvent under reduced pressure dissolved residue in methanol (25 mL) added silica gel (200 mg) evaporation of the volatiles under reduced pressure subjected to a gradient elution concentrated under reduced pressure to give a gold oil Added diethyl ether (15 mL) to precipitate vacuum filtered

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), 4-dimethylamino-1-bromobenzene (201 mg, 1.00 mmol), trans-cinnamamide (178 mg, 1.21 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting bright yellow suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate-dichloromethane 1:1. The filtrate was concentrated, the residue was dissolved in 10 mL of dichloromethane and purified by flash chromatography on silica gel (2×20 cm, ethyl acetate-dichloromethane 1:4, 15 mL fractions). Fractions 10-20 provided 261 mg (98% yield) of the desired product as a bright yellow solid. evacuated The Schlenk tube was sealed with a Teflon valve to reach room temperature filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate-dichloromethane 1:1 The filtrate was concentrated the residue was dissolved in 10 mL of dichloromethane purified by flash chromatography on silica gel (2×20 cm, ethyl acetate-dichloromethane 1:4, 15 mL fractions)

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

Procedure: Heated at 70° for 25 min. at which time the HCl gas evolution had ceased, a mixture of 59 g (0.4 mole) of cinnamide, 83.5 g (0.4 mole) of phosphorus pentachloride and 500 ml of AR carbon tetrachloride. After cooling to 30°, added dropwise, 19 g (0.4 mole) of 97% formic acid. Chilled to 0° and filtered. Air-dried to give 107.5 g, m.p. softens 82°, melts 83°-90°. After cooling to 30° added dropwise Chilled to 0° filtered Air-dried to give 107.5 g m.p. softens 82° melts 83°-90°

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

Procedure: Acrylic acid vii is converted to the acid chloride with oxalyl chloride, and the resulting acid chloride is reacted with an aniline in the presence of base. The resulting acrylamide viii is then reacted with an appropriately substituted aryl iodide ix in the presence of a palladium catalyst and a base to give the cinnamide vi.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), 4-dimethylamino-1-bromobenzene (201 mg, 1.00 mmol), trans-cinnamamide (178 mg, 1.21 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting bright yellow suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate-dichloromethane 1:1. The filtrate was concentrated, the residue was dissolved in 10 mL of dichloromethane and purified by flash chromatography on silica gel (2×20 cm, ethyl acetate-dichloromethane 1:4, 15 mL fractions). Fractions 10-20 provided 261 mg (98% yield) of the desired product as a bright yellow solid. evacuated The Schlenk tube was sealed with a Teflon valve to reach room temperature filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate-dichloromethane 1:1 The filtrate was concentrated the residue was dissolved in 10 mL of dichloromethane purified by flash chromatography on silica gel (2×20 cm, ethyl acetate-dichloromethane 1:4, 15 mL fractions)

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

Procedure: The amine bis-hydrochloride (from Step 4) (68.2 mg, 0.19 mmol), the lithium carboxylate prepared in Step 3, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (72.8 mg, 0.38 mmol) and 1-hydroxybenzotriazole hydrate (30.8 mg, 0.23 mmol) are dissolved in pyridine (2 ml) and stirred at room temperature for 72 hours. The reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (40 ml) and washed with H2O (20 ml), brine (20 ml), dried (MgSO4), filtered and concentrated. The residue is dissolved in CH3OH/CH2Cl2, absorbed onto silica gel and is purified on a Biotage 12M column with SIM using 2% CH3OH (saturated with NH3) in CH2Cl2 as the eluent to afford 56.2 mg (0.096 mmol, 51%) of the desired cinnamide. 1H-NMR (DMSO) δ: 8.66, 8.48, 8.02, 7.64, 7.49, 7.40, 7.35, 6.70, 4.86, 4.22, 3.84, 3.60. The reaction mixture is concentrated The residue is dissolved in CH2Cl2 (40 ml) washed with H2O (20 ml), brine (20 ml) dried (MgSO4) filtered concentrated The residue is dissolved in CH3OH/CH2Cl2 absorbed onto silica gel is purified on a Biotage 12M column with SIM