3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine

Step 5: 3-chloro-6-(1-methyl-1/-/-pyrazol-4-yl)pyridazineWater (253 mL) and THF (842 mL) were put in the reaction balloon. The reagents were added one by one to the stirred reaction mixture: potassium phosphate monohydrate 86, 2 g (374 mmol) and BTEAC 2, 25g (9, 88 mmol). Then 3-chloro-6-iodopyhdazine, 45 g (187, 2 mmol) and 1-methyl-4-(4, 4, 5, 5-tetramethyl-[1 , 3, 2]dioxaborolan-2-yl)-1 H-pyrazole, 46, 73g(224, 6 mmol) were added and finally triphenylphosphine, 1 , 96g (7, 49 mmol) and palladiumdiacetate, 420 mg (1 , 87 mmol) were added. The reaction mixture was heated at 65°C for 16h . The reaction mixture was allowed to cool to 60: 6-(l-methyI-li/-pyrazol-4-yl)-[l , 2, 4] triazolo [4, 3-6] pyridazine-3-thiol; Step 1: 3-Chloro-6-(l-methyl-lHTo a solution of 3, 6-dichloropyridazine (500 mg, 3.4 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (560 mg, 2.7 mmol), K2CO3 (1.1 g, 8.1 mmol) in 1, 4-dioxane/H2O (2.5:1, 5 mL) was added PdCl2(dppf)2. After stirred at 90 °C for 5 h, the reaction mixture was was extracted with CH2Cl2 (40 mL), and the organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2) afforded 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (494 mg, 75 percent). 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (1a) A flask was charged with 3, 6-dichloropyridazine (AJdrich, 23.91 g, 160.5 mmol), l-Methyl-4-(4, 4, 5, 5-tetramethyl-[l, 3, 2idioxaborolan-2-yl)-lH-pyrazole (20 g, 96 mmol), 2.0 M NaPreparation 1A flask was charged with 3, 6-dichloropyridzine (Aldrich, 297 mg, 2.0 mmol), l-Methyl-4-(4, 4, 5, 5-tetramethyl-[l, 3, 2]dioxaborolan-2-yl)-lH-pyrazole (499 mg, 2.4 mmol), 2 M NaA solution of 3, 6-dichloropyridazine (4.57 g, 0.003 1 mol), (1-methyl-1H-pyrazol-4- yl)boronic acid pinacol ester (3.82 g, 0.0 184 mol) and a solution ofNa2CO3 2M (18.3 mL) in dioxane (18.4 mL) was stirred for 1 minute. PdC12(PPh3)2 (1.29 g, 0.0018 mol) was added and the solution was heated at 80°C for 15 hours. The mixture was cooled to room temperature and poured into water. K2C03 was added and the mixture wasfiltered through a short pad of Celite®. The organic layer was dried (Mg504), filtered and evaporated to dryness. The Celite® was washed with CH2C12, the filtrate was dried (Mg504) and evaporated. The residue was crystallized from CH2C12. The precipitate was filtered and dried to give 1.5 g of a first batch of intermediate 5 (42percent). The filtrate was purified by chromatography over silica gel (30 g of SiOHl5-40jim, mobile phase : gradient from CH2C12 100percent to CH2C12 95percent/CH3OH 5percent). The pure fractions were collected and evaporated until dryness to give 1.58 g of a second batch of intermediate 5 (44percent)3 -Chloro-6-(l -methyl- lH-p razol-4-yl)pyridazine To a 100 mL flask is added 3-chloro-6-(lH-pyrazol-4-yl) pyridazine (1.7 g, 9.4 mmol) , potassium ierf-butoxide (1.23 g, 10.4 mmol), 18-crown-6 (250 mg, 0.94 mmol), and ether (40 mL). The reaction mixture is stirred at room temperature for 20 min and then cooled to 0 °C, followed by addition of iodomethane dropwise (1.56 g, 10.9 mmol). The mixture is allowed to warm up to room temperature and stirred overnight. Then ice-water (30 mL) is added and the mixture is extracted with dichloromethane (3 X 50 mL). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to give the titled compound as a brown solid (1.7 g, 93percent yield). ( MS: [M+l] 195)o a 250 ml flask of the three-port adding dioxane (67 ml) and water (27 ml) as the solvent, then adding 3, 6- [...] (2.68g, 18mmol), potassium carbonate (6.0g, 43 . 5mmol), 1-methylpyrazole-4-boronic acid pinacone ester (2.99g, 14 . 4mmol), [ 1, 1 '-bis (diphenylphosphino) ferrocene] palladium dichloride (0.7g, 0 . 96mmol), after the replacement of nitrogen, raising the temperature to 80 °C. Reaction 10 after two hours, concentrating the reaction liquid, column chromatography separation, to obtain strawcoloured solid 3-chloro-6 - (1-methyl -1H-pyrazol-4-yl) pyridazine (HJ-8) 1.96g, yield 70percent

Molecular Weight:194.62
XLogP3:0.8
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:194.0359239
Monoisotopic Mass:194.0359239
Topological Polar Surface Area:43.6
Heavy Atom Count:13
Complexity:178
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes