1-iodo-2,3-dimethylbenzene

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

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

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

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

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

Procedure: 5-{[6-(1,3-Thiazol-4-yl)pyridin-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one (66 mg, 0.18 mmol) was dissolved in degassed N,N-dimethylformamide (1 mL) and copper (I) iodide (35 mg, 0.22 mmol, 1.2 equiv), 1-iodo-2,3-dimethylbenzene (51 mg, 0.22 mmol, 1.2 equiv), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (78 mg, 0.549 mmol, 3 equiv) and potassium phosphate (0.27 g, 1.3 mmol, 7 equiv) were added. The vessel was sealed and placed into an oil bath preheated at 105° C. for 40 minutes. The mixture cooled to ambient temperature, diluted with water (5 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed three times with water and once with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 96:4; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.87 (1H, s), 8.69 (1H, s), 8.31 (1H, d, J=8.2 Hz), 8.16 (2H, m), 7.77 (1H, d, J=8.2 Hz), 7.57 (4H, m), 7.28 (1H, m), 7.22 (1H, d, J=3.9 Hz), 5.90 (2H, s), 2.37 (3H, s), 2.21 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 465.1499 [(M+H)+; calculated for C26H21N6OS: 465.1492]. The vessel was sealed placed into an oil bath extracted with ethyl acetate (3×30 mL) The combined organic extracts were washed three times with water once with brine, dried with sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel gradient chromatography (100:0 to 96:4; chloroform:methanol)

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

Procedure: 5-{[6-(1,3-Thiazol-4-yl)pyridin-3-yl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one (66 mg, 0.18 mmol) was dissolved in degassed N,N-dimethylformamide (1 mL) and copper (I) iodide (35 mg, 0.22 mmol, 1.2 equiv), 1-iodo-2,3-dimethylbenzene (51 mg, 0.22 mmol, 1.2 equiv), (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (78 mg, 0.549 mmol, 3 equiv) and potassium phosphate (0.27 g, 1.3 mmol, 7 equiv) were added. The vessel was sealed and placed into an oil bath preheated at 105° C. for 40 minutes. The mixture cooled to ambient temperature, diluted with water (5 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed three times with water and once with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 96:4; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.87 (1H, s), 8.69 (1H, s), 8.31 (1H, d, J=8.2 Hz), 8.16 (2H, m), 7.77 (1H, d, J=8.2 Hz), 7.57 (4H, m), 7.28 (1H, m), 7.22 (1H, d, J=3.9 Hz), 5.90 (2H, s), 2.37 (3H, s), 2.21 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 465.1499 [(M+H)+; calculated for C26H21N6OS: 465.1492]. The vessel was sealed placed into an oil bath extracted with ethyl acetate (3×30 mL) The combined organic extracts were washed three times with water once with brine, dried with sodium sulfate filtered concentrated in vacuo The residue was purified by silica gel gradient chromatography (100:0 to 96:4; chloroform:methanol)

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

Procedure: 5-[4-(1H-Pyrazol-1-yl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one (75 mg, 0.22 mmol) was dissolved in degassed N,N-dimethylformamide and treated with 1-iodo-2,3-dimethylbenzene (0.15 g, 0.66 mmol, 3 equiv), tribasic potassium phosphate (0.28 g, 1.31 mmol, 6 equiv), copper(I) iodide (42 mg, 0.22 mmol, 1 equiv) and (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (93 mg, 0.66 mmol, 3 equiv). The mixture was placed into an oil bath preheated at 110° C. for 30 minutes, cooled to ambient temperature, poured into sodium bicarbonate (25 mL, saturated aqueous) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (60:40 to 0:100; hexanes:ethyl acetate), providing the titled compound. 1H-NMR (400 MHz, CDCl3) δ 8.33-8.30 (1H, m), 7.90 (1H, d, J=2.6 Hz), 7.73-7.69 (3H, m), 7.58-7.52 (3H, m), 7.43 (2H, d, J=8.7 Hz), 7.31-7.27 (1H, m), 7.24-7.22 (2H, m), 6.47 (1H, dd, J=2.5, 1.8 Hz), 5.88 (2H, s), 2.37 (3H, s), 2.21 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 447.1931 [(M+H)+; calculated for C27H22N6O: 447.1928]. The mixture was placed into an oil bath extracted with ethyl acetate (3×50 mL) The combined organic extracts were dried with sodium sulfate filtered concentrated in vacuo The residue was purified via silica gel gradient chromatography (60:40 to 0:100; hexanes:ethyl acetate)

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

Procedure: 5-[4-(1H-Pyrazol-1-yl)benzyl]-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one (75 mg, 0.22 mmol) was dissolved in degassed N,N-dimethylformamide and treated with 1-iodo-2,3-dimethylbenzene (0.15 g, 0.66 mmol, 3 equiv), tribasic potassium phosphate (0.28 g, 1.31 mmol, 6 equiv), copper(I) iodide (42 mg, 0.22 mmol, 1 equiv) and (±)-trans-N,N′-dimethylcyclohexane-1,2-diamine (93 mg, 0.66 mmol, 3 equiv). The mixture was placed into an oil bath preheated at 110° C. for 30 minutes, cooled to ambient temperature, poured into sodium bicarbonate (25 mL, saturated aqueous) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel gradient chromatography (60:40 to 0:100; hexanes:ethyl acetate), providing the titled compound. 1H-NMR (400 MHz, CDCl3) δ 8.33-8.30 (1H, m), 7.90 (1H, d, J=2.6 Hz), 7.73-7.69 (3H, m), 7.58-7.52 (3H, m), 7.43 (2H, d, J=8.7 Hz), 7.31-7.27 (1H, m), 7.24-7.22 (2H, m), 6.47 (1H, dd, J=2.5, 1.8 Hz), 5.88 (2H, s), 2.37 (3H, s), 2.21 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 447.1931 [(M+H)+; calculated for C27H22N6O: 447.1928]. The mixture was placed into an oil bath extracted with ethyl acetate (3×50 mL) The combined organic extracts were dried with sodium sulfate filtered concentrated in vacuo The residue was purified via silica gel gradient chromatography (60:40 to 0:100; hexanes:ethyl acetate)

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

Procedure: A mixture of 1-iodo-2,3-dimethylbenzene (5.00 g), copper(I) iodide (82.1 mg), triphenylphosphine (283 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (446 mg), propargyl alcohol (1.40 ml), diisopropylethylamine (15.0 ml) and tetrahydrofuran (100 ml) was stirred at room temperature for 19 hr. The reaction mixture was added to brine, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-70:30) to give the object product (1.91 g) as a brown oil. the mixture was extracted with ethyl acetate washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-70:30)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of 3-[2-(4-hydroxy-phenyl)-2-methyl-morpholin-4-yl]-propionic acid tert-butyl ester (1.07 g; 3.33 mmol), and 3-iodo-o-xylene (0.97 g; 4.16 mmol) in DMSO (20 mL) was added picolinic acid (82 mg; 0.67 mmol), CuI (63.4 mg; 0.33 mmol) and powdered (1.41 g; 6.66 mmol). The resulting mixture was heated for 24 h, at 90° C. After cooling to room temperature, brine was added and the mixture extracted with CH2Cl2. The combined layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 3-{2-[4-(2,3-dimethyl-phenoxy)-phenyl]-2-methyl-morpholin-4-yl}-propionic acid tert-butyl ester (1.32 g). After cooling to room temperature the mixture extracted with CH2Cl2 The combined layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of 2-(4-hydroxy-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (10.23 g; 36.6 mmol), and 1-iodo-2,3-dimethyl-benzene (10.62 g; 45.8 mmol) in DMSO (50 mL), was added picolinic acid (0.90 g; 7.3 mmol), CuI (0.70 g; 3.7 mmol) and K3PO4 (15.55 g; 73.3 mmol). The resulting mixture was heated overnight, at 90° C. After cooling to RT, brine was added and the mixture extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to afford 2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester. After cooling to RT the mixture extracted with CH2Cl2 The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, CH2Cl2)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a degassed solution of 2-(4-hydroxy-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (10.23 g; 36.6 mmol), and 1-iodo-2,3-dimethyl-benzene (10.62 g; 45.8 mmol) in DMSO (50 mL), was added picolinic acid (0.90 g; 7.3 mmol), CuI (0.70 g; 3.7 mmol) and K3PO4 (15.55 g; 73.3 mmol). The resulting mixture was heated overnight, at 90° C. After cooling to RT, brine was added and the mixture extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, CH2Cl2) to afford 2-[4-(2,3-dimethyl-phenoxy)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester. After cooling to RT the mixture extracted with CH2Cl2 The combined organic layers were dried (Na2SO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, CH2Cl2)