3-Bromo-5-nitropyridine

General procedure: To a solution of sodium phenoxide prepared from substituted phenol (1 mmol) and NaH (60% in mineral oil, 0.04 g, 1 mmol) in DMSO (10 mL), was added an appropriate 3-nitropyridine (1 mmol). The reaction mixture was stirred at room temperature for 1-24 h until the starting compound was completely consumed (TLC), then poured into water and acidified to pH 2-3 with hydrochloric acid. A precipitate was filtered off, washed with water and dried in air.General procedure: To a solution of sodium phenoxide prepared from substituted phenol (1 mmol) and NaH (60% in mineral oil, 0.04 g, 1 mmol) in DMSO (10 mL), was added an appropriate 3-nitropyridine (1 mmol). The reaction mixture was stirred at room temperature for 1-24 h until the starting compound was completely consumed (TLC), then poured into water and acidified to pH 2-3 with hydrochloric acid. A precipitate was filtered off, washed with water and dried in air.General procedure: To a solution of appropriate 3-nitropyridine (1 mmol) in DMF or NMP (5 mL) was added an appropriate thiol (1.5 mmol), K2CO3 (0.138 g, 1 mmol) and the reaction mixture was stirred at 70 C until the starting compound was completely consumed (TLC), then poured into water, acidified to pH 2-3 with concentrated hydrochloric acid and extracted with chloroform. Organic phase was washed several times with water, dried over anhydrous Na2SO4 and evaporated. The residue was purified by flash-chromatography on silica gel with chloroform as eluent.General procedure: An appropriate 2-hydrazinopyridine (10 mmol) was added to a solution of silver nitrate (5.1 g, 30 mmol) in distilled water (100 mL). The suspension was heated to 80 C with vigorous stirring to prevent excessive foaming. After the evolution of nitrogen ceased, the reaction mixture was heated additionally for 1-2h until the starting compound was completely consumed (TLC). A precipitate of metallic silver was filtered off and washed with chloroform. The filtrate was extracted with chloroform, combined extracts were washed with brine, dried over anhydrous Na2SO4 and evaporated. Traces of colored impurities, if present, can be removed from chloroform solution by shaking with activated charcoal.A solution of 5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2, 3-dihydropyridazin-3-one (1 g, 2.54 mmol, 1.00 equiv), [Pd(allyl)Cl]2 (92.96 mg, 0.10 equiv), Rockphos (119.03 mg, 0.10 equiv), Cs2CO3 (2.48 g, 7.61 mmol, 3.00 equiv), Under nitrogen, a solution of 5-[1-(hydroxymethyl)-2, 3-dihydro-1H-isoindol-2-yl]-4-(trifluoromethyl)-2-[[2-(trimethylsilyl)ethoxy]methyl]-2, 3-dihydropyridazin-3-one (500 mg, 1.13 mmol, 1.00 equiv), (Pd(allyl)Cl)2 (41 mg), Rockphos (53 mg), Cs2CO3 (1.1 g, 3.38 mmol, 2.98 equiv) and A mixture of 2-methyl- 1, 2, 5 -thiadiazolidine l, l-dioxide (900 mg, 6.61 mmol), 3- bromo-5-nitro-pyridine (1.61 g, 7.93 mmol), Cul (378 mg, 1.98 mmol), CS2CO3 (3.23 g, 9.91 mmol) and DMEDA (350 mg, 3.97 mmol) in anhydrous dioxane (80 mL) was degassed and purged with N2 for 3 times. Then the resulting reaction mixture was heated at 100 C for 16 hours under N2 atmosphere. The reaction mixture turned into brown suspension from blue. LCMS showed the purity of the desired product is 91% (Rt = 0.693 min; MS Calcd: 258.0; MS Found: 258.8 [M+H]+). The reaction mixture was filtered and the solid was washed with EtOAc (50 mL x3) and the filtrate was concentrated. The residue was purified by Combi Flash (1% to 5% EtOAc in DCM) to give 2-methyl-5-(5-nitropyridin-3-yl)-l, 2, 5-thiadiazolidine 1, 1- dioxide (1.57 g, yield: 92%) as a yellow solid. (2110) NMR (400 MHz, CDCb) d 2.91 (3H, s), 3.62 (2H, t, J= 6.4 Hz), 3.96 (2H, t , J= 6.4 Hz), 8.27 (1H, t, J= 2A Hz), 8.84 (1H, d, J= 2.4 Hz), 9.19 (1H, d, J= 2.0 Hz).To a pre-heated round bottom flask Pd2(dba)3 (125 mg, 0.13 mmol), Xantphos (155 mg, 0.26 mmol) and potassium carbonate (740 mg, 5.36 mmol) was added and flushed with argon for 10 min. DMF (4 niL) was added to the mixture and flushed for another 5 min, which was followed by addition of 67 (500 mg, 2.68 mmol) and 68 (545 mg, 2.68 mmol) and then refluxed for 24 h. The reaction mixture was then partitioned between ethyl acetate and water, dried over anhydrous Na2S04, filtered, concentrated and purified by column chromatography using silica gel (15 % EtOAc/DCM) to give 69 (250 mg, 30%) as light yellow solid. lH NMR (600 MHz, DMSO-ifc) delta (ppm) 8.72 (s, 1H), 8.69 (s, 1H), 7.94 (s, 1H), 3.46 (t, / = 5 Hz, 4H), 3.35 (t, / = 5H, 4H), 1.41 (s, 9H).

Molecular Weight:202.99
XLogP3:1.4
Hydrogen Bond Acceptor Count:3
Exact Mass:201.93779
Monoisotopic Mass:201.93779
Topological Polar Surface Area:58.7
Heavy Atom Count:10
Complexity:136
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes