2-[(2-Chloro-4-nitrophenoxy)methyl]pyridine

2-(Chloromethyl)pyridine hydrochloride (16.4 g, 0.1 mol) and KStep 1: 2-CHLORO-4-NITRO PHENOL 10G (57.6 MMOL, 1EQ), 2-PYCOLYL CHLORIDE hydrogen chloride 9.45g (57.6 mmol, 1 eq) cesium carbonate 41.3 (126.8 mmol, 2.2 eq) and sodium iodide 8. 64G (57.6 mmol, 1 eq) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, YIELDING 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8G, 52percent) as a red solid. 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8 g, 30. 2MMOL, 1 eq) and 8. 44g iron (151.1 mmol, 5 eq) were mixed in 100 mL acetic acid and 50 mL ethyl acetate and were stirred at rt overnight. The reaction mixture was filtered through celite pad. The filtrate was concentrated in vacuo and neutralized with sat. NA2CO3 solution. The solution was extracted with ethyl acetate and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 30percent ethyl acetate/hexane yielding 3. 2G of 3-Chloro-4- (pyridin-2-ylmethoxy)-phenylamine as a white solid (52percent). 1H-NMR (CDCL3) No. 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H), . 6.80 (d, 1H), 7.22 (m, 1 H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H) ; LCMS RT = 0.89 min; [M+H]+= 235.1.2-chloro-4-nitro phenol 1Og (57.6 mmol, leq), 2-pycolyl chloride hydrogen chloride 9.45g (57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide 8.64g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8g, 52percent) as a red solid. 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and 8.44g iron (151.1 mmol, 5 equiv) were mixed in 100 mL acetic acid and 50 mL EtOAc and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52percent) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, IH), 6.76 (d, IH), . 6.80 (d, IH), 7.22 (m, IH), 7.64 (d, IH), 7.73 (td, IH), 8.55 (m, IH); LCMS RT = 0.89 min; [M+H]+ = 235.1.2-chloro-4-nitro phenol (10 g, 57.6 mmol, 1 equiv), 2-pycolyl chloride hydrogen chloride (9.45 g, 57.6 mmol, 1 equiv), cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide (8.64 g, 57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60° C. for 5 h. The resulted suspension was filtered and washed with water (400 mL), yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 52percent) as a red solid.2-Chloro-4-nitro phenol 10 g (57.6 mmol, 1 eq), 2-(chloromethyl)pyridine hydrogen chloride 9.45 g (57.6 mmol, 1 equiv), cesium carbonate (41.3 g, 126.8 mmol, 2.2 equiv) and sodium iodide 8.64 g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60 Sodium hydride (95percent, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31. 3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2- CHLORO-L-FLUORO-4-NITRO-BENZENE (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 HOURS. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7. 52 g (28.5 mmol, 100percent) of the clean desired material as a yellow powder.Sodium hydride (95percent, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31.3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-Chloro-1-fluoro-4-nitro-benzene (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 hours. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7.52 g (28.5 mmol, 100percent) of the clean desired material as a yellow powder.A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. Example 71; 4-f [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino) [1]benzothieno[2, 3-d] pyrimidin-7-ol; Step 1. Preparation of 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine; EPO Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with HA mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4- fluoronitrobenzene and the mixture was stirred at 40 °C for a minimum of 18 hours until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50 °C, 10 mm Hg, 24 h) to the product in 85-95percent yield.Example 3 Preparation of N-[3-Chloro-4-(2-pyridinylmethoxy)]phenyl-2-cyanoacetamide In a 12-L multi-necked flask, 2-pyridyl carbinol (0.13 kg, 1.19 mole, 1.05 eq) was dissolved in acetonitrile (0.88 L) and to it was added potassium hydroxide flakes (85percent) (80 g, 1.25 eq). The resulting suspension was warmed to 35° C. A solution of 3-chloro-4-fluoronitrobenzene (0.20 kg, 1.14 mol) in acetonitrile (1.0 L) was added at 35-40° C. The mixture was held for 18 h until reaction completion. The mixture was then cooled back to 20-25° C., quenched with water (4 L) and the resulting slurry was filtered and washed with water (3.x.200 mL). The resulting product was isolated as a tan solid (251 g, 84percent yield). A mixture of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene (0.149 kg, 0.56 mole) and 2percent (w/w) of 5percent Pt/C (6.0 g, 50percent water wet) in tetrahydrofuran (0.895 L) was hydrogenated in a 2-L stainless steel Parr reactor at 25 psi, 25° C. for a minimum of 8 h. The mixture was filtered through a celite pad (50 g, 15 cm diameter) and washed with tetrahydrofuran (0.45 L). The filtrate was distilled to a volume of 0.30 L and the concentrate was transferred to a 2-L multi-neck flask and used as is in the next step. To the 2-L flask equipped with mechanical stirrer, temperature probe, claisen head and condenser was added ethylcyanoacetate (0.421 kg, 3.72 mole, 6.6 eq.). The reaction mixture was heated to (100-115° C.) while removing tetrahydrofuran and ethanol. The temperature was raised to 125° C. and the mixture was held for a minimum of 24 h until the aniline starting material was consumed and no distillate was collected. The mixture was cooled to room temperature over 1 h. At 50-60° C., solids crystallized out and ethyl acetate (0.15 L) was added. The mixture was further cooled to 0-10° C. and held for 1 h. The mixture was filtered on a 15 cm diameter Buchner funnel and washed with 50 mL of the filtrate followed by pre-cooled (0-10° C.) ethyl acetate (0.15 L). The product was dried at 60° C. for a minimum of 16 h in a vacuum oven to give the titled compound (0.12 kg, 71percent) as a brown solid. The product was purified by slurrying in cold ethyl acetate (1-1.3 volumes) for 1 hr. Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with HSynthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with HSynthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with HTo a mixture of pyridin-2-ylmethanol (6.82 g, 62.5 mmol), Aliquat 336 (8.08 g, 20.0 mmol), potassium hydroxide (3.51 g, 62.5 mmol) and water (40 mL) were added toluene (80 mL) and 1, 2- dichloro-4-nitrobenzene (10.0 g, 52.1 mmol). The mixture was heated to 602-(Chloromethyl)pyridine hydrochloride (16.4 g, 0.1 mol) and KStep 1: 2-CHLORO-4-NITRO PHENOL 10G (57.6 MMOL, 1EQ), 2-PYCOLYL CHLORIDE hydrogen chloride 9.45g (57.6 mmol, 1 eq) cesium carbonate 41.3 (126.8 mmol, 2.2 eq) and sodium iodide 8. 64G (57.6 mmol, 1 eq) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, YIELDING 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8G, 52percent) as a red solid. 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8 g, 30. 2MMOL, 1 eq) and 8. 44g iron (151.1 mmol, 5 eq) were mixed in 100 mL acetic acid and 50 mL ethyl acetate and were stirred at rt overnight. The reaction mixture was filtered through celite pad. The filtrate was concentrated in vacuo and neutralized with sat. NA2CO3 solution. The solution was extracted with ethyl acetate and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 30percent ethyl acetate/hexane yielding 3. 2G of 3-Chloro-4- (pyridin-2-ylmethoxy)-phenylamine as a white solid (52percent). 1H-NMR (CDCL3) No. 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H), . 6.80 (d, 1H), 7.22 (m, 1 H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H) ; LCMS RT = 0.89 min; [M+H]+= 235.1.2-chloro-4-nitro phenol 1Og (57.6 mmol, leq), 2-pycolyl chloride hydrogen chloride 9.45g (57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide 8.64g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8g, 52percent) as a red solid. 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and 8.44g iron (151.1 mmol, 5 equiv) were mixed in 100 mL acetic acid and 50 mL EtOAc and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52percent) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, IH), 6.76 (d, IH), . 6.80 (d, IH), 7.22 (m, IH), 7.64 (d, IH), 7.73 (td, IH), 8.55 (m, IH); LCMS RT = 0.89 min; [M+H]+ = 235.1.2-chloro-4-nitro phenol (10 g, 57.6 mmol, 1 equiv), 2-pycolyl chloride hydrogen chloride (9.45 g, 57.6 mmol, 1 equiv), cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide (8.64 g, 57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60° C. for 5 h. The resulted suspension was filtered and washed with water (400 mL), yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 52percent) as a red solid.2-Chloro-4-nitro phenol 10 g (57.6 mmol, 1 eq), 2-(chloromethyl)pyridine hydrogen chloride 9.45 g (57.6 mmol, 1 equiv), cesium carbonate (41.3 g, 126.8 mmol, 2.2 equiv) and sodium iodide 8.64 g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60 Sodium hydride (95percent, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31. 3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2- CHLORO-L-FLUORO-4-NITRO-BENZENE (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 HOURS. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7. 52 g (28.5 mmol, 100percent) of the clean desired material as a yellow powder.Sodium hydride (95percent, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31.3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-Chloro-1-fluoro-4-nitro-benzene (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 hours. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7.52 g (28.5 mmol, 100percent) of the clean desired material as a yellow powder.A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. Example 71; 4-f [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino) [1]benzothieno[2, 3-d] pyrimidin-7-ol; Step 1. Preparation of 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine; EPO Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with HA mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4- fluoronitrobenzene and the mixture was stirred at 40 °C for a minimum of 18 hours until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50 °C, 10 mm Hg, 24 h) to the product in 85-95percent yield.Example 3 Preparation of N-[3-Chloro-4-(2-pyridinylmethoxy)]phenyl-2-cyanoacetamide In a 12-L multi-necked flask, 2-pyridyl carbinol (0.13 kg, 1.19 mole, 1.05 eq) was dissolved in acetonitrile (0.88 L) and to it was added potassium hydroxide flakes (85percent) (80 g, 1.25 eq). The resulting suspension was warmed to 35° C. A solution of 3-chloro-4-fluoronitrobenzene (0.20 kg, 1.14 mol) in acetonitrile (1.0 L) was added at 35-40° C. The mixture was held for 18 h until reaction completion. The mixture was then cooled back to 20-25° C., quenched with water (4 L) and the resulting slurry was filtered and washed with water (3.x.200 mL). The resulting product was isolated as a tan solid (251 g, 84percent yield). A mixture of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene (0.149 kg, 0.56 mole) and 2percent (w/w) of 5percent Pt/C (6.0 g, 50percent water wet) in tetrahydrofuran (0.895 L) was hydrogenated in a 2-L stainless steel Parr reactor at 25 psi, 25° C. for a minimum of 8 h. The mixture was filtered through a celite pad (50 g, 15 cm diameter) and washed with tetrahydrofuran (0.45 L). The filtrate was distilled to a volume of 0.30 L and the concentrate was transferred to a 2-L multi-neck flask and used as is in the next step. To the 2-L flask equipped with mechanical stirrer, temperature probe, claisen head and condenser was added ethylcyanoacetate (0.421 kg, 3.72 mole, 6.6 eq.). The reaction mixture was heated to (100-115° C.) while removing tetrahydrofuran and ethanol. The temperature was raised to 125° C. and the mixture was held for a minimum of 24 h until the aniline starting material was consumed and no distillate was collected. The mixture was cooled to room temperature over 1 h. At 50-60° C., solids crystallized out and ethyl acetate (0.15 L) was added. The mixture was further cooled to 0-10° C. and held for 1 h. The mixture was filtered on a 15 cm diameter Buchner funnel and washed with 50 mL of the filtrate followed by pre-cooled (0-10° C.) ethyl acetate (0.15 L). The product was dried at 60° C. for a minimum of 16 h in a vacuum oven to give the titled compound (0.12 kg, 71percent) as a brown solid. The product was purified by slurrying in cold ethyl acetate (1-1.3 volumes) for 1 hr. Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with HSynthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with HSynthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with HTo a mixture of pyridin-2-ylmethanol (6.82 g, 62.5 mmol), Aliquat 336 (8.08 g, 20.0 mmol), potassium hydroxide (3.51 g, 62.5 mmol) and water (40 mL) were added toluene (80 mL) and 1, 2- dichloro-4-nitrobenzene (10.0 g, 52.1 mmol). The mixture was heated to 60

Molecular Weight:264.66
XLogP3:2.8
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:264.0301698
Monoisotopic Mass:264.0301698
Topological Polar Surface Area:67.9
Heavy Atom Count:18
Complexity:285
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes