3-Chloro-4-methylpyridazine

The product of step c) (12.2 g, 0.112 mol) in phosphorus oxychloride (125 ML) was heated at 90°C for 3 h. The mixture was cooled to room temperature and concentrated almost to dryness. The residue was poured into ice/water, made basic by careful addition of 4N NAOH and extracted with ether. The aqueous phase was re-extracted with DCM. The organic phases were combined, washed with water, dried over sodium sulphate, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel in 2: 1 ethyl acetate- isohexane to give an orange solid (11.2 g, 78percent). LH NMR (400 MHz, CDCIs) 8 8.97 (1 H, d, J = 4. 9 HZ), 7.35 (1 H, d, J = 4. 9 HZ), 2.44 (3 H, s) ppm.The product of step c) (12.2 g, 0.112 mol) in phosphorus oxychloride (125 ML) was heated at 90°C for 3 h. The mixture was cooled to room temperature and concentrated almost to dryness. The residue was poured into ice/water, made basic by careful addition of 4N NAOH and extracted with ether. The aqueous phase was re-extracted with DCM. The organic phases were combined, washed with water, dried over sodium sulphate, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel in 2: 1 ethyl acetate- isohexane to give an orange solid (11.2 g, 78percent). LH NMR (400 MHz, CDCIs) 8 8.97 (1 H, d, J = 4. 9 HZ), 7.35 (1 H, d, J = 4. 9 HZ), 2.44 (3 H, s) ppm.General procedure: [1, 1?-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (3.95 mg, 4.83 jtmol) was added to the solution of 3-bromopyridine (15.27 mg, 96.64 tmol), compound WX023-1 (50.00 mg, 96.64 tmol) and potassium carbonate (40.07 mg, 289.92 tmol) in dioxane (3.00 mE) and water (1.00 mE) at room temperature. The reaction mixture was heated to 70-80 C. and stirred for 12 hours under nitrogen atmosphere. After the reaction, the mixture was cooled to room temperature and water (3 mE) and ethyl acetate (3 mE) were added thereto, followed by filtration. The filtrate was extracted with ethyl acetate (10 mLx3). The organic phases were combined, washed with saturated brine (10 mE) and dried over anhydrous sodium sulfate, followed by filtration. The filtrate was concentrated under reduced pressure. The obtained residue was isolated by preparative HPLC to obtain the target product WX025.The product of step c) (12.2 g, 0.112 mol) in phosphorus oxychloride (125 ML) was heated at 90°C for 3 h. The mixture was cooled to room temperature and concentrated almost to dryness. The residue was poured into ice/water, made basic by careful addition of 4N NAOH and extracted with ether. The aqueous phase was re-extracted with DCM. The organic phases were combined, washed with water, dried over sodium sulphate, filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel in 2: 1 ethyl acetate- isohexane to give an orange solid (11.2 g, 78percent). LH NMR (400 MHz, CDCIs) 8 8.97 (1 H, d, J = 4. 9 HZ), 7.35 (1 H, d, J = 4. 9 HZ), 2.44 (3 H, s) ppm.General procedure: Under argon 237.8 mg (1.79 mmol) 3-Chloro-4-methylpyridazine were dissolved under starring and sonication (40 min) in 5.0 mL dry tetrahydrofurane (THF) at 0 °C. Under argon this solution was added to a mixture of 2.4 mL (2.39 mmol) (2, 2, 6, 6-Tetramethyl-l-piperidyl)magnesium chloride lithium chloride complex (1.0 M in THF/Toluene) dissolved in 3.0 mL dry THF at -70 °C. The reaction mixture was stirred 15 min at -70 °C and then 250.0 mg (1.49 mmol) of 3, 3-Dimethyl-l-(lH-l, 2, 4-taazol-l-yl)butan-2-one (for preparation see: G. Holmwood, Ger. Offen., 2937595, 1981) dissolved in 3.0 mL dry THF were added. After stirring 60 min at -70 °C and subsequently stirring at room temperature for 2.5 h, the reaction mixture was quenched by adding 5.0 mL of saturated aqueous NH4CI solution at 0 °C. After stirring for 15 min the mixture was diluted with ethylacetate and saturated aqueous NH4CI solution. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and dried over MgSO i. The residue was purified by column chromatography over silica gel using dichloromethane/ethyl acetate (Gradient: 60/40 to 0/100). 66.7 mg (0.23 mmol, 15 percent) of the title compound were obtained.A mixture of A mixture of (4-acetylphenyl)boronic acid (561 mg, 3.42 mmol), A mixture of INT-14-1-A (30 mg, 0.089 mmol), General procedure: Under nitrogen atmophere, sodium hydride (60percent suspension in mineral oil, 32 mg, 0.804 mmol) is added to example 4a (120 mg, 0.402 mmol) and 4-fluoro-3- methylbenzonitrile (109 mg, 0.804 mmol) in dry 1 , 4-dioxane (2 mL) cooled to 0°C andstirring is continued for 3h at rt. Volatiles are evaporated under reduced pressure to furnish a residue that is purified by preparative HPLC (stationary phase: Sunfire 018 0DB 5 pm 19 x 100 mm. Mobile phase: ACN/ H20 + CF3000H 0.05percent). Fractions containing the title compound are combined, acetonitrile is evaporated under reduced pressure, the aqueous layer is basified with sat. NaHCO3 and extracted with DCM.The organic layer is dried using a phase separator cartridge and the resultingsolution is evaporated under reduced pressure to furnish the title compound (105 mg, 63percent).

Molecular Weight:128.56
XLogP3:1.2
Hydrogen Bond Acceptor Count:2
Exact Mass:128.0141259
Monoisotopic Mass:128.0141259
Topological Polar Surface Area:25.8
Heavy Atom Count:8
Complexity:76.8
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes