1-Ethylpyrazole-4-boronic acid pinacol ester

To a solution of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.0 g, 5.2 mmol) in DMF (10 mL) were added cesium carbonate (2.5 g, 7.7 mmol) and iodoethane (1.2 mL, 15 mmol) . The mixture was stirred at rt for 12 h and diluted with water (30 mL) . The resulting mixture was extracted with DCM (30 mL × 3) . The combinded orgainc layers were dried over anhydrous Na(107a) Step 8 NaH 60percent dispersion in mineral oil (50.0 mg, 1.24 mmol) was suspended in DMF (2 mL) followed by the addition of a solution of 4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2- yl)-1H-pyrazole (200 mg, 1.03 mmol) in DMF (550 pL). The resulting mixture was stirred at r.t. for ihour. lodomethane (132 pL, 1.6Smmol) was added dropwise and stirring was continued for 2 days. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine. Dried Mg504, filtered and concentrated in vacuo. The product was purified by flash chromatography (dry packing) on silica gel using a gradient 0 to 30percent EtOAc in hexanes and afforded the title compound (62.7 mg, 0.28 mmol, 27percent) as a yellow oil.b) l-Ethyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole To a degassed (NTo a degassed (NExample 22: 3-(l-Azetidin-3-yl-lH-pyrazol-4-yl)-6-(6-methyl-[l, 2, 4]triazolo[4, 3- b]pyridazin-3-ylsulfanyl)-quinoline (Compound 62); [0396] To 3-{4-[6-(6-methyl-[l, 2, 4]triazolo[4, 3-b]pyridazin-3-ylsulfanyl)-quinolin-3-yl]- pyrazol-l-yl}-azetidine- 1-carboxylic acid tert-butyl ester (65 mg, 0.126 mmol) was added 6 mL of (1 :1) TFA: dichloromethane. The mixture was allowed to sit for 2 hours. The EPO General procedure: Aryl bromide (0.1 mmol, 1.0 eq.) and the corresponding boronicacid/boronic acid pinacol ester (0.2 mmol, 2.0 eq.) were placed in around-bottom flask, followed by DME (5.0 mL) and Na2CO3 aqueoussolution (2.0 M, 2.5 mL). The solution was degassed before additionof Pd(dppf)Cl2eCH2Cl2 (0.02 mmol, 0.2 eq.) in one portion. Thesolution was degassed again and heated at 95 C for 12 h. Theaqueous layer was extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by flash columnchromatography to afford the desired product.Into a stirred mixture of 7-bromo-2-(((4-fluorobenzyl)amino)methyl)imidazo[1, 2- c]quinazolin-5-amine, prepared in accordance with Example 22 and other proceedures described herein using appropriate reagents, (12mg, 0.031mmol), was added cesium carbonate (15mg, 0.046mmol), Will be 60118 (46.05g), 60180 (26.8g) dissolved in 800mLIn a mixed solvent of 1, 4-dioxane and 80 mL of water, Add potassium carbonate (33.4g)And [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.9 g), and argon gas was substituted for the air therein.After the reaction was heated to 80 C, the reaction was completed.Cool to room temperature, Add 200mL of water, Extracted with ethyl acetate, Combine the organic phase, The organic phase is washed sequentially with water.Washed with saturated saline, Dry over anhydrous sodium sulfate, filter, concentrate, The residue obtained was purified by column chromatography to yield 38.9 g.Yield: 93%, Purity: 98%.General procedure: A pressure reactor or an open round bottom flask equipped with a condenser is charged with heteroarylbromide derivative (1 eq.), boronic acid or boronic acid pinacol ester (1.1 to 1.5 eq.), a base (CS2CO3, Na2CC>3, or KF, 2 to 3 eq.) and dioxane/water solvent mixture: 4/1 or 3/1 or DMF/water solvent mixture: 4/1 or THF/water mixture: 9/1 or DME/water: 10/1). The mixture is either heated to 50 °C or reflux, degassed with N2 then Pd catalyst (Pd(Pli3)4 or Pd(dppf)Cl2-DCM adduct (0.07 to 0.2 eq.) is added or degassed with N2 or Ar at RT before addition of the catalyst or the solvent is degassed before being added in the mixture and the catalyst is added at the end. The mixture is stirred to 50 °C-l l0 °C for 15 min to 20 h. Either the reaction mixture is concentrated in vacuo and the residue is taken up in EtOAc or DCM and water or the reaction mixture is quenched with water or a saturated NaHC03 solution. The reaction mixture is then extracted with EtOAc or DCM. The combined organic layers are optionally washed with brine, dried over anhydrous Na2S04 or MgS04, filtered, concentrated in vacuo and purified by flash chromatography on silica gel or/and Biotage® SNAP KP-NH cartridge to afford the expected compound. Optionally the compounds can be triturated in ACN and filtered.General procedure: To a 1, 4-dioxane (1.0 mL) solution of N-((1S, 2R)-2-(3-bromo-6-fluoro-2-methylphenyl)-1-(5-oxo-4, 5-dihydro-1, 3, 4-oxadiazol-2-yl)propyl)-4-chloro-2-methoxybenzenesulfonamide (11 mg), 4-methoxyphenylboronic acid (5.0 mg), [1, 1?-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (4.0 mg), and a sodium carbonateaqueous solution (2 M, 100 mL) was added sequentially at room temperature, and the reaction solution wasstirred at 100 ° C for 1 hour. The reaction solution was allowed to cool to room temperature, insoluble matter was removedby CELITE filtration, and the residue was washed with hexane / ethyl acetate = 1/1 (10 mL). The combined filtrate wasconcentrated under reduced pressure, and the obtained residue was purified by reverse phase HPLC (water / acetonitrile)to give the title compound.A vial equipped with a magnetic stir bar was charged with tert-butyl 5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-6-cyano-3-iodo-1H-indazole-1-carboxylate (12.0 mg, 0.019 mmol),

Molecular Weight:222.09
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:222.1539580
Monoisotopic Mass:222.1539580
Topological Polar Surface Area:36.3
Heavy Atom Count:16
Complexity:255
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes