3-broMo-1H-pyrazol-5-aMine

This intermediate, 3, 4-dibromo-5-nitro-1H-pyrazole (69 g) was reduced by refluxing with Stannous chloride, dihydrate (135 g) in Ethyl acetate (600 mL) and Ethanol (300 mL) at 110° C. for 45 minutes. The yellow homogenous reaction solution was cooled to room temperature and slowly poured over a vigorously stirring solution of sodium bicarbonate (33 g) in water (200 mL) and ethyl acetate (800 mL). To the resultant slurry was added Celite (30 g), and this slurry was filtered through a bed of Celite. The filter cake was washed with additional ethyl acetate (600 mL). The organic solution was then washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product as an orange oil. The crude product was then purified by flash column chromatography (Biotage, Quad 25; Eluent: 6percent EtOH in methylene chloride). This afforded the title compound as a light beige solid (13.2 g, 32percent). 1.0 g of compound II was dissolved in 15 mL of acetic acid, and 0.61 g of To a solution of To a solution of Na (7.10 g, 309 mmol) in EtOH (125 mL) was added A mixture of methyl 2-hydroxy-4-oxo-4-(pyridin-2-yl)but-2-enoate [1224740-13-9] (730 mg, 3.52 mmol) and 3-bromo-lH-pyrazol-5-amine [950739-21-6] (628 mg, 3.88 mmol) in MeOH (17 mL) was stirred under reflux for 18 h. The reaction mixture was cooled to rt and the precipitate was filtered off, rinsed with MeOH and dried. The residue (546 mg) was purified via achiral SFC (Stationary phase: Lux Cellulose-2 5 pm 250*30mm, mobile phase: 60% C02, 40% MeOH) to afford intermediate 1171 (147 mg, 13%) as a yellow solid.To the solution of 40 mg of 4-amino-7 -(tert-butyl)-7H-pyrrolo[2, 3-d]pyrimidine-5-carboxylic acid obtained in step 5 of ReferenceExample 7 was suspended in 2 mL of DMF, and 33 mgof 3-bromo-lH-pyrazol-5-amine, 89 f.LL of diisopropylethylamine, and 78 mg ofHATU were added thereto, followedby stirring at room temperature overnight. 2 mL of anaqueous sodium hydroxide solution (1 mol/L) was added tothe reaction mixture, and the mixture was stirred at roomtemperature for 1 hour. Thereafter, the reaction mixture waspartitioned between ethyl acetate and water. The organiclayer was washed with water and a saturated aqueoussodium chloride solution, and dried over sodium sulfate.After concentration, the residue was purified by silica gelchromatography (ethyl acetate/methanol= I/O-'> 10/1 ), thereby obtaining 6.5 mg of the title compound as a whitesolid.Step 17A: Ethyl 2-bromo-7-methylpyrazolo[1.5-a]pyrimidine-6-carboxylate (0758) A solution of 3-bromo-lH-pyrazol-5-amine (4.2 g, 26 mmol, 1.0 eq) and ethyl (3Z)-3-[(dimethylamino)methylidene]-4-oxopentanoate (4.9 g, 26 mmol, 1.0 eq) in ethanol (300 mL) was prepared and heated to reflux for 2 hrs. The reaction mixture was concentrated. Silica gel column was loaded using methylene chloride and run using an increasing gradient of MeOH (0-5%) in methylene chloride over 20 min to provide ethyl 2-bromo-7-methylpyrazolo[l, 5-a]pyrimidine-6-carboxylate 17a (6.0 g, 21 mmol, 81%) as a white solid.General procedure: 1H-Pyrazol-5-amine 1 (1 equiv.), 3-oxopropanenitrile 2 (1 equiv.), benzaldehyde 3 (1 equiv.), and Et3N (2 equiv.) were stirred in DMF (1 M) at 90 C for 16 h. The volatiles were removed under reduced pressure (or positive N2 (g) pressure). Sodium nitrite (3 equiv.) and acetic acid (134 equiv.) were added to the crude material, and the reaction mixture was stirred for 10 min. The volatiles were removed under reduced pressure (or positive N2 (g) pressure), and the crude reaction mixture was subjected to silica gel column chromatography with ethyl acetate in hexanes.1-(1, 3-dimethyl-1H-pyrazol-4-yl)-4, 4, 4-trifluoro-3-hydroxybut-2-en-1-one (Preparation 5, 1.7 g) and A mixture of 3-amino-5-bromopyrazole C-8 (3.24 g, 20 mmol) and diketone C-2 (5.52 g, 20 mmol) in Acetic acid (20 mL) was heated to 80 C. After 1 h, the reaction mixture was cooled to rt, and diluted with IPA. A yellow ppt formed in the mixture, which was collected by filtration. Upon standing, additional ppt was formed in the mother liquor. The combined crops were collected and dried under vacuum to afford 3.89 g of compound C-9 as a yellow solid (9.67 mmol, 48% yield). [0369] 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.99 (s, 3H) 4.05 (s, 3H) 6.85 (s, 1H) 7.00 (d, J=8.47 Hz, 1H) 7.57 (s, 1H) 7.62 (dd, J=8.45, 2.16 Hz, 1H) 7.80 (d, J=2.14 Hz, 1H) [0370] MS (M+H+) 402.2