4-chloro-1-oxidopyridin-1-ium

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-chloropiridine-N-oxide (5.00 g, 38.6 mmol) and trimethylsilyl cyanide (4.84 g, 46.3 mmol) in dichloromethane (60 ml) cooled to 0° C. was added dropwise N,N-dimethylcarbamoyl chloride (3.8 ml, 40.5 mmol). The mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was cooled to 0° C. and a 30% aqueous solution of K2CO3 (100 ml) was added. The crude product was extracted with dichloromethane (100 ml×2), the organic extracts dried (MgSO4) and evaporated to give 4-chloro-2-pyridinecarbonitrile (5.35 g, 100%). 1H-NMR (CDCl3) δ: 8.63 (1 H, d, J=4.8 Hz), 7.72 (1 H, d, J=2.6 Hz), 7.55 (1 H, dd, J=1.8, 5.1 Hz). to warm to ambient temperature The mixture was cooled to 0° C. The crude product was extracted with dichloromethane (100 ml×2) the organic extracts dried (MgSO4) evaporated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Imidazo[1,2-a]pyridine-2-ylmethanol (3.01 g, 20.3 mmol) was partially dissolved in 5:1 dioxane/DMF (30 mL) and the resulting slurry was added slowly to a stirring suspension of NaH (60% in mineral oil, 0.812 g, 16.9 mmol) in dioxane (29 mL). The resulting mixture was heated to 60° C. for 15 min. 4-Chloropyridine-N-oxide (1.5 g, 11.5 mmol) was added and the reaction mixture was heated for 1 h at 110° C. Upon cooling, the mixture was diluted with methylene chloride and a 20% NH4OH in MeOH solution. The resulting suspension was filtered through a silica gel plug using CH2Cl2 (200 mL) and 20% 4:1 MeOH/NH4OH in CH2Cl2 (500 mL). The filtrate was collected and concentrated under reduced pressure. Flash chromatography (120 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100 over 60 min) provided the title compound (1.5 g, 30%) as an orange-brown solid: 1H NMR (300 MHz, CD3OD) δ 8.42 (m, 1H), 8.24-8.22 (m, 2H), 7.97 (d, J=0.5 Hz, 1H), 7.54 (dd, J=9.1, 0.7 Hz, 1H) 7.37-7.32 (m, 1H), 7.27-7.25 (m, 2H), 6.94 (m, 1H), 5.37 (s, 2H). the reaction mixture was heated for 1 h at 110° C Upon cooling The resulting suspension was filtered through a silica gel plug The filtrate was collected concentrated under reduced pressure

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloropyridine-N-oxide (500 mg, 3.85 mmol), 2-methoxy-4-chlorophenylboronic acid (862 mg, 4.63 mmol) and K2CO3 (1.59 g, 11.55 mmol) were suspended in DMSO (5 mL) and PdCl2(dppf) (314 mg, 0.385 mmol) was added. The reaction mixture was placed under vacuum for 20 min and flushed with N2. This process was repeated, and the reaction mixture was heated at 120° C. for 3 h. The reaction mixture was cooled to 25° C. and partitioned between methylene chloride and 5% lithium chloride. The aqueous phase was removed, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (ISCO 40 g column, methylene chloride/MeOH 100:0 to 90:10) provided the title compound (673 mg, 74%) as a tan solid: 1H NMR (300 MHz, CD3OD) δ 8.21 (dd, J=5.4, 1.8 Hz, 2H), 7.47 (dd, J=5.6, 1.6 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.06 (dd, J=8.3, 2.4 Hz, 1H), 7.00 (d, J=1.7 Hz, 1H), 3.87 (s, 3H); ESI MS m/z 235 [M+H]. flushed with N2 The reaction mixture was cooled to 25° C. partitioned between methylene chloride and 5% lithium chloride The aqueous phase was removed the organic phase was washed with brine dried over Na2SO4 filtered concentrated to dryness under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cyclohexylmethanol (1.1 mL, 9.3 mmol) in DMF (8 mL) was added NaH (60% weight dispersion in mineral oil, 0.37 g, 9.3 mmol) in one portion. After the bubbles disappeared, 4-chloropyridine N-oxide (1.0 g, 7.7 mmol) was added. The reaction was stirred at room temperature under Ar until complete. The reaction was quenched with water and the aqueous mixture was extracted with CH2Cl2. The combined organic extracts were washed with H2O and 5% aqueous LiCl and dried over Na2SO4. After filtration and concentration, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give a yellow solid. The yellow solid was suspended in Ac2O (5 mL) and heated at 140° C. for 4 h. The reaction mixture was cooled, diluted with CH3OH/H2O (10 mL, 1:1) and stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give the title compound (0.92 g, 58%) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.21 (d, J=7.2 Hz, 1H), 5.83 (dd, J=7.2, 2.4 Hz, 1H), 5.64 (d, J=2.4 Hz, 1H), 3.72 (d, J=6.0 Hz, 2H), 1.84-1.68 (m, 6H), 1.30-1.01 (m, 5H). The reaction was quenched with water the aqueous mixture was extracted with CH2Cl2 The combined organic extracts were washed with H2O and 5% aqueous LiCl dried over Na2SO4 After filtration and concentration the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give a yellow solid heated at 140° C. for 4 h The reaction mixture was cooled stirred at room temperature for 1 h The mixture was concentrated the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cyclohexylmethanol (1.1 mL, 9.3 mmol) in DMF (8 mL) was added NaH (60% weight dispersion in mineral oil, 0.37 g, 9.3 mmol) in one portion. After the bubbles disappeared, 4-chloropyridine N-oxide (1.0 g, 7.7 mmol) was added. The reaction was stirred at room temperature under Ar until complete. The reaction was quenched with water and the aqueous mixture was extracted with CH2Cl2. The combined organic extracts were washed with H2O and 5% aqueous LiCl and dried over Na2SO4. After filtration and concentration, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give a yellow solid. The yellow solid was suspended in Ac2O (5 mL) and heated at 140° C. for 4 h. The reaction mixture was cooled, diluted with CH3OH/H2O (10 mL, 1:1) and stirred at room temperature for 1 h. The mixture was concentrated, and the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give the title compound (0.92 g, 58%) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.21 (d, J=7.2 Hz, 1H), 5.83 (dd, J=7.2, 2.4 Hz, 1H), 5.64 (d, J=2.4 Hz, 1H), 3.72 (d, J=6.0 Hz, 2H), 1.84-1.68 (m, 6H), 1.30-1.01 (m, 5H). The reaction was quenched with water the aqueous mixture was extracted with CH2Cl2 The combined organic extracts were washed with H2O and 5% aqueous LiCl dried over Na2SO4 After filtration and concentration the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give a yellow solid heated at 140° C. for 4 h The reaction mixture was cooled stirred at room temperature for 1 h The mixture was concentrated the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloropyridine-N-oxide (305 mg, 2.35 mmol), 4-fluoro-2-methoxyphenylboronic acid (1.0 g, 8.8 mmol) were reacted according to the procedure of Example 39 (step a) to provide the title compound (450 mg, 87%) as a purple solid: 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J=7.2 Hz, 2H), 7.45 (d, J=7.2 Hz, 2H), 7.31 (d, J=6.5 Hz, 1H), 6.80-6.71 (m, 2H), 3.85 (s, 3H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloropyridine-N-oxide (305 mg, 2.35 mmol), 4-fluoro-2-methoxyphenylboronic acid (1.0 g, 8.8 mmol) were reacted according to the procedure of Example 39 (step a) to provide the title compound (450 mg, 87%) as a purple solid: 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J=7.2 Hz, 2H), 7.45 (d, J=7.2 Hz, 2H), 7.31 (d, J=6.5 Hz, 1H), 6.80-6.71 (m, 2H), 3.85 (s, 3H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) and 4-chloropyridine-N-oxide (2.03 g, 15.7 mmol) were reacted according to Example 34 (step a) to provide the title compound (1.76 g, 50%) as a tan solid: 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.12 (d, J=7.7 Hz, 2H), 7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloropyridine-N-oxide (1.5 g, 12 mmol), 2,4-dichlorophenylboronic acid (5.4 g, 29 mmol) were reacted according to the procedure of Example 39 (step a) to provide the title compound (1.40 g, 50%) as a grey solid: 1H NMR (500 MHz, CD3OD) δ 8.26 (d, J=6.9 Hz, 2H), 7.53 (d, J=2.0 Hz, 1H), 7.37-7.35 (m, 3H), 7.29 (d, J=8.3 Hz, 1H).

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloropyridine-N-oxide (3.0 g, 23 mmol), 4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol), K2CO3 (4.8 g, 35 mmol) and PdCl2(dppf) (470 mg, 0.57 mmol) were stirred in DMSO (40 mL) under vacuum for 30 min. The flask was flushed with nitrogen and the mixture was heated to 80° C. for 10 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated and the residue was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.90 g, 34%) as a tan solid: ESI MS m/z 240 [M+H]+. The flask was flushed with nitrogen Upon cooling the mixture was diluted with methylene chloride washed with 5% lithium chloride solution (5×) dried concentrated the residue was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride