2-ethylbutanoyl chloride

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

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

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

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

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

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

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

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

Procedure: A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in pyridine at 0° C. was treated dropwise with 2-ethylbutanoyl chloride (176 mg, 1.30 mmol). After 7 hours, 2M LiOH (5 mL) was added to the mixture and stirring was continued at room temperature for 30 minutes. Water (25 mL) was then added, and the solid formed was filtered, washed with water (3×5 mL) and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-ethylbutanamide (235 mg, 82% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.06 (s, 1H), 9.46 (s, 1H), 8.34 (d, 1H), 7.53 (s, 1H), 2.30-2.24 (m, 1H), 1.62-1.52 (m, 2H), 1.47-1.41 (m, 2H), 0.90 (t, 6H); LCMS (APCI+) m/z 328, 330 (M+H)+, Retention time=3.20 minutes (Method 2). was continued at room temperature for 30 minutes the solid formed was filtered washed with water (3×5 mL) dried

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

Procedure: tert-Butyl (R)-N-[2-[7-carbamoyl-1-(3-hydroxy-propyl)-1H-indol-5-yl]-1-methylethyl]-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate (2.00 g) was dissolved in dry pyridine (3 ml), and 2-ethylbutyryl chloride (0.54 g) prepared from 2-ethylbutyric acid and oxalyl chloride was added to the solution. After the mixture was stirred overnight at room temperature, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine subsequently, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent:hexane/ethyl acetate=2/1) to give white amorphous (R)-3-[5-[2-[N-(tert-butoxycarbonyl)-N-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-7-carbamoyl-1H-indol-1-yl]propyl 2-ethylbutyrate (1.66 g). was added to the solution the mixture was extracted with ethyl acetate The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine subsequently dried over anhydrous magnesium sulfate The solvent was removed in vacuo the residue was purified by column chromatography on silica gel (eluent:hexane/ethyl acetate=2/1)

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

Procedure: To a mixture of 4,6-diaminoquinazoline hydrochloride (1.97 g), tripropylamine (2.60 g) and dry pyridine (20 ml) in an ice-bath was added dropwise during 10 minutes 2-ethylbutyryl chloride (1.75 g). The mixture was stirred for 3 hours at the same temperature. Crushed ice was added to the reaction mixture. The mixture was stirred for 5 minutes and concentrated under reduced pressure. After the addition of water (50 ml), sodium hydrogen carbonate (3.36 g) was added in small portions to the residue to give precipitates which were separated by filtration, washed with water and dried. The crude crystals were dissolved in a mixture of chloroform and methanol under heating. After insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure to give a residue, which was suspended in ethyl acetate. After stirring under heating, the suspension was filtered to give crystalline 4-amino-6-(2-ethylbutyramido)quinazoline (1.20 g). Crushed ice was added to the reaction mixture The mixture was stirred for 5 minutes concentrated under reduced pressure After the addition of water (50 ml), sodium hydrogen carbonate (3.36 g) was added in small portions to the residue to give precipitates which were separated by filtration washed with water dried The crude crystals were dissolved in a mixture of chloroform and methanol under heating After insoluble materials were removed by filtration the filtrate was concentrated under reduced pressure to give a residue, which After stirring under heating the suspension was filtered

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 250 ml round bottom flask equipped with a stirring motor and thermometer is placed 12.17 g of potassium hydroxide pellets (0.1875 moles 86.4% pure) and 16.3 g of water (0.997 total moles of water added, including the water contained in the KOH pellets). The solution is cooled to about 5° C. and then 17.42 g (0.075 moles, 58.55% pure) of diethyl ketone hydroperoxide monomer is added slowly. A solid forms and stirring is difficult. Petroleum ether (25 ml) is added to aid the stirring. Following completion of the monomer addition, the solution is cooled to about 0° C. and 19.67 g (0.1463 moles) of 2-ethyl butanoyl chloride is slowly added. Care must be taken to prevent excessive temperature rise during acid chloride addition. After completion of the acid chloride addition, the reaction temperature is allowed to slowly rise to about +5° C. and stirring is maintained for 11/2 hours. In a 250 ml round bottom flask equipped with a stirring motor and thermometer added completion of the monomer addition the solution is cooled to about 0° C. to slowly rise to about +5° C. stirring is maintained for 11/2 hours

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