1-bromo-4-phenylbutan-2-one

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Following the procedure in Example 7 Step E, 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (740 mg, 2.163 mmol), 1-bromo-4-phenylbutan-2-one (687.6 mg, 3.028 mmol) and triethylamine (0.5014 mL, 3.676 mmol) afforded 5-bromo-3-(4-fluorophenoxy)-N-(4-phenethylthiazol-2-yl)pyridin-2-amine (1040 mg, 102.2% yield) as a white solid after drying. 1H NMR (CDCl3) δ 8.71 (bs, 1H), 8.13 (d, 1H), 7.28 (m, 2H), 7.20 (m, 3H), 7.13 (m, 2H), 7.06 (m, 3H), 6.43 (s, 1H), 3.05-2.92 (m, 4H), Mass spectrum (apci) m/z=470.2, 472.2 (M+H).

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

Procedure: Prepared according to the method of Example 7 Step E from 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea and 1-bromo-4-phenylbutan-2-one. 1H NMR (d6-DMSO) δ 8.26 (m, 1H), 7.45 (m, 3H), 7.31-7.11 (m, 81H), 6.74 (s, 1H), 2.92 (m, 4H). Mass spectrum (apci) m/z=452.3 (M+H). Prepared

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.863 g, 1 eq.) was suspended in dimethylacetamide (DMA) (15 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (360 mg, 2.2 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and 1-bromo-4-phenylbutan-2-one (1.1 g, 1.2 eq.) was added. The reaction was stirred at room temperature for 2 hours. The reaction was poured onto 100 mL water and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with water (2×100 mL), brine (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product, 5-(2-oxo-4-phenylbutyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.56 g) was used without purification. LCMS: 358 [M+H]. The reaction was warmed to room temperature The reaction was cooled to 0° C. The reaction was stirred at room temperature for 2 hours extracted with dichloromethane (2×100 mL) washed with water (2×100 mL), brine (2×100 mL) dried over sodium sulfate filtered concentrated under reduced pressure The crude product, 5-(2-oxo-4-phenylbutyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.56 g) was used without purification

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

Procedure: Following the procedure in Example 7 Step E, 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (740 mg, 2.163 mmol), 1-bromo-4-phenylbutan-2-one (687.6 mg, 3.028 mmol) and triethylamine (0.5014 mL, 3.676 mmol) afforded 5-bromo-3-(4-fluorophenoxy)-N-(4-phenethylthiazol-2-yl)pyridin-2-amine (1040 mg, 102.2% yield) as a white solid after drying. 1H NMR (CDCl3) δ 8.71 (bs, 1H), 8.13 (d, 1H), 7.28 (m, 2H), 7.20 (m, 3H), 7.13 (m, 2H), 7.06 (m, 3H), 6.43 (s, 1H), 3.05-2.92 (m, 4H). Mass spectrum (apci) m/z=470.2, 472.2 (M+H).

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

Procedure: Prepared according to the method of Example 7 Step E from 1-(5-bromo-3-phenoxypyridin-2-yl)thiourea and 1-bromo-4-phenylbutan-2-one. 1H NMR (d6-DMSO) δ 8.26 (m, 1H), 7.45 (m, 3H), 7.31-7.11 (m, 8H), 6.74 (s, 1H), 2.92 (m, 4H). Mass spectrum (apci) m/z 452.3 (M+H). Prepared

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with ethyl 2-(5-bromo-2-thioureidopyridin-4-yl)acetate (2.200 g, 6.914 mmol), 1-bromo-4-phenylbutan-2-one (1.884 g, 8.297 mmol), DIEA (1.806 mL, 10.37 mmol) and ethanol (100 mL). The mixture was heated stirred at 70° C. for 2 hours, then cooled. The reaction was concentrated, and the residue was partitioned between chloroform and dilute sodium bicarbonate solution. The organic phase was washed with dilute sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The solid residue was recrystallized from hexane/ethyl acetate to give the desired product (1.815 g, 58.81% yield) as a yellow solid. The mixture was heated cooled The reaction was concentrated the residue was partitioned between chloroform and dilute sodium bicarbonate solution The organic phase was washed with dilute sodium bicarbonate solution dried over magnesium sulfate filtered evaporated The solid residue was recrystallized from hexane/ethyl acetate

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with 1-(4-(benzyloxy)-5-bromopyridin-2-yl)thiourea (2.34 g, 6.92 mmol), 1-bromo-4-phenylbutan-2-one (1.65 g, 7.26 mmol), and triethylamine (1.93 ml, 13.8 mmol). Ethanol (100 mL) was added and the reaction was stirred at 75° C. for 8 hours. The reaction was cooled and filtered, and the collected solids were washed with water to give the desired product (2.54 g, 77.9% yield) as a white solid. The reaction was cooled filtered the collected solids were washed with water

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with 1-(4-(benzyloxy)-5-bromopyridin-2-yl)thiourea (2.34 g, 6.92 mmol), 1-bromo-4-phenylbutan-2-one (1.65 g, 7.26 mmol), and triethylamine (1.93 ml, 13.8 mmol). Ethanol (100 mL) was added and the reaction was stirred at 75° C. for 8 hours. The reaction was cooled and filtered, and the collected solids were washed with water to give the desired product (2.54 g, 77.9% yield) as a white solid. The reaction was cooled filtered the collected solids were washed with water

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(4-(4-methoxybenzylthio)-5-bromopyridin-2-yl)thiourea (3.0 g, 7.8 mmol) and 1-bromo-4-phenylbutan-2-one (1.77 g, 7.8 mmol) were diluted in EtOH (120 mL). Triethylamine (2.2 ml, 15.6 mmol) was added, and the solution was heated at 75° C. for 3 hours. The solution was cooled and concentrated to half the amount of solvent. The solid was filtered and rinsed with cold EtOH to provide the desired product (2.44 g, 61% yield) as a tan solid. The solution was cooled concentrated to half the amount of solvent The solid was filtered rinsed with cold EtOH

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was charged with ethyl 3-(5-bromo-2-thioureidopyridin-4-yloxy)-4-chlorobenzoate (0.200 g, 0.464 mmol), 1-bromo-4-phenylbutan-2-one (0.105 g, 0.464 mmol) and triethylamine (0.0470 g, 0.464 mmol). Ethanol (5 mL) was added and the reaction was heated at 70° C. for 6 hours, and then concentrated to provide ethyl the desired product (0.250 g, 95 yield) as white solid. LC/MS (apci) M+2H: 560 (100%). concentrated