N-(4-fluoro-2-Methoxy-5-nitrophenyl)-4-(1-Methylin

in room temperature, 1000 ml of 2-pentanol was added to a 2 L reaction flask, 50 g of 3- (2-chloro-4-pyrimidinyl) -1-methyl -1H- indole, 42 g of 4-fluoro-2-methoxy-5-nitroaniline, 3.54 g p-toluenesulfonic acid, The mixture was heated to 80 ° C and reacted for 6 hours.The mixture was cooled to 25 ° C to 28 ° C, Filter, The filter cake was washed with 50 ml of 2-pentanol.After the filter cake is dry, Dried in a vacuum oven to give 80.1 g of a yellow solid, Yield: 99.0percent.3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (10.00 g, 41.15 mmol), 4-fluoro-2-methoxy-5-nitroaniline (8.42 g, 45.27 mmol) and 4-methyl-benzenesulfonic acidmonohydrate (8.60 g, 45.27 mmol) were heated at 85 °C in 1, 4-dioxane (200 mL) for 7 h.The reaction was cooled to room temperature and diluted with water (150 mL) and 40percent aqNaOH added until pH = 9. The solid was collected by filtration and washed with EtOH (40mL) to afford the yellow solid (15.70 g, 97.0 percent yield): 1H NMR (400 MHz, DMSO-d6)δ9.72 (s, 1H), 8.82 (s, 1H), 8.67 (s, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.48 (dd, J = 20.7, 9.2 Hz, 2H), 7.32 (s, 1H), 7.14 (s, 1H), 4.01 (s, 3H), 3.93 (s, 3H). MS(ESI) m/z 394.3 [M+H]+.p-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol) was added in one portion to a mixture of 3-(2-chloropyrimidin-4-yl)-1-methylindole (Intermediate 130, 24.27 g, 99.58 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 18.54 g, 99.58 mmol) in 2-pentanol (500 mL). The resulting mixture was stirred at 105°C for 2.5h. and then cooled to r.t. The resulting precipitate was collected by filtration, washed with 2-pentanol (50 mL) and dried under vacuum to give some of the desired product as a yellow solid. The filtrate was cooled and the resulting precipitate was collected by filtration and washed with 2-pentanol (10 mL). The two crops of product were combined and triturated with CHP-Toluenesulfonic acid hydrate (22.73 g, 119.5 mmol)Was added to a solution of 3- (2-chloropyrimidin-4-yl) -1-methyl-indole (Intermediate 20, 24.27 g, 99.58 mmol)And 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 22, 18.54 g, 99.58 mmol)In a mixture of 2-pentanol (500 mL).The resulting mixture was stirred at 105 ° C for 2.5 hours.Then cooled to room temperature.The resulting precipitate was collected by filtration, Washed with 2-pentanol (50 mL), dried under vacuum, Some of the desired product was obtained as a yellow solid. The filtrate was cooled, The resulting precipitate was collected by filtration, Washed with 2-pentanol (10 mL).The two batches were combined and ground with CH' CN to obtain a solid, The solid was collected by filtration, dried under vacuum, The title compound was obtained as a yellow solid (37.4 g, 95percent).4-fluoro-2-methoxy-5-nitroaniline (1.40 g, 7.52 mmol), 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (1.83 g, 7.52 mmol) was dissolved in 2-pentanol (50 mL).Then p-toluenesulfonic acid monohydrate (1.55 g, 9.0 mmol) was added.The reaction solution was stirred at 105°C for 3 hours.After the reaction is over, Cool to room temperatureFilter through a suction funnel.The solid was washed with 2-pentanol (50 mL).It was washed with a mixed solvent of dichloromethane (50 mL) and petroleum ether (50 mL).It was then dried in vacuo to give a yellow solid (2.80 g, yield: 94.6percent).The starting material 3-(2-chloro-4-pyrimidinyl)-1-methyl-1H-indole 2.5 kg (10.26 mol)2 kg (10.74 mol) of 4-fluoro-2-methoxy-5-nitroaniline was added to a 50 L ethanol reactor under stirring.After stirring evenly, the oil bath was heated at 120 ° C, and 2.34 kg (12.31 mol) of p-toluenesulfonic acid was slowly added.Then reflux overnight, the reaction is completed, the heating is stopped, the temperature is lowered to room temperature, and suction filtration is performed.The filter cake was rinsed with 5 L of isopropanol and dried to give a yellow solid 3.7 kg, yield 91.5percent.(HPLC purity >95percent).To a 250 mL three-necked flask was added 3- (2-chloropyrimidin-4-yl) -1-methylindole (2.430 g, 10 mmol)4-fluoro-2-methoxy-5-nitroaniline (2.418 g, 13 mmol)And p-toluenesulfonic acid monohydrate (2.850 g, 15 mmol)And 80 mL of 2-pentanol was added, Start stirring and heating, 80 reflux 2.5h, After completion (CHCl3:MeOH = 8:1, Rf = 0.5 ) detection reaction, TLC Turn off heating, From a bottle of three bottles with a needle through the plastic plug and slowly into the amount of ethanol, As the temperature decreases, Precipitation of yellow solid, Ice bath to continue to precipitate solid, Filtration, ethanol washing, Dried to give 3.431 g of compound 3 as a yellow solid, Yield 87percent.40 g (0.164 mol) of SM1, 30.6 g (0.164 mol) of SM2 and 62.3 g (0.328 mol) of mono-p-toluenesulfonic acid monohydrate were added to 200 ml of isobutyl alcohol and warmed to reflux for 6 h. A yellow solid precipitated and dropped to After washing at room temperature, filtration, isopropanol and vacuum drying at 50 ° C 54.8 g of a yellow solid was obtained with a yield of 85.0percent.3-(2-chloropyrimidin-4-yl)-1-methyl-indole (2g, 8.21 mmol) and 4-fluoro-2- methoxy-5-nitro-aniline (1833 mg, 9.85 mmol) were suspended in 2-pentanol. Para- toluenesulfonic acid (1873 mg, 9.85 mmol) was added and the reaction heated to 110 °C for 2 hours under microwave conditions. The reaction mixture was allowed to cool to r.t. and the resulting precipitate collected by filtration, washed with 2-pentanol, triturated with acetonitrile and dried in vacuo to a yellow solid (2453 mg, 76percent). NMR and LC-MS conform to structure and match literature reports.Intermediate 6: N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine 3. Synthesis of intermediate 006-5 The intermediates 006-2 (75 mg, 307.8 mmol) and 006-4 (57.4 g, 308.4 mmol), 975 mL of isopropyl alcohol, and p-toluenesulfonic acid (63.7 g, 369.9 mmol) were sequentially added into a 2 L four-necked flask under nitrogen atmosphere, and the reaction was heated and maintained at 105°C for 5 h. The reaction mixture was cooled to room temperature and filtered, and the filter cake was washed with 750 mL of isopropanol three times. The filter cake was washed three times with 750 mL of acetonitrile and dried to give 75 g of the intermediate 006-5 (62percent) as a yellow solid. LC-MS: 394.1.To a solution of 3-(2-chloropyrimidin-4-yl)-l -methyl- IH-indole (50 mg, 0.205 mmol), and 4-fluoro-2-methoxy-5-nitroaniline (40 mg, 0.215 mmol) in isopropyl alcohol (10 mL) was added 4-methylbenzenesulfonic acid (45 mg, 0.261 mmol). The resulting mixture was heated at 105 °C for 2.5 h. The mixture was cooled to RT. The precipitate was collected by filtration, washed with 2-pentanol (50 mL), and dried under vacuum to afford N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH-indol-3- yl)pynmidin-2-amine as a yellow solid (51 mg, 62percent). LC/MS (ESI) m/z 394.1 [M+H]4-Methylbenzenesulfonic acid hydrate (8.7 g) was added in one portion to 3-(2- chloropyrimidin-4-yl)-1-methylindole (9.3 g) and 4-fluoro-2-methoxy-5-nitroaniline (7.1 g) in nbutanol (200 mL). The resulting mixture was stirred at reflux for 1 h. The mixture was cooled to room temperature. The precipitate was collected by filtration, washed with n-butanol (50 mL), and dried under vacuum to afford N-(4-fluoro-2-methoxy-5-nitrophenyl)- 4-(1- methylindol-3- yl)pyrimidin-2-amine as a yellow solid (CompoundS, 15.5 g).To a solution of 1 (393 mg, 1 mmol) and thiomorpholine(154 mg, 1.5 mmol) in DMF (20 mL), DIPEA (194 mg, 1.5 mmol) wasadded. After stirring at 60 C for 4 h, the mixture was poured intoice water. The resulting precipitate was filtered off, washed withwater, and dried under vacuum to give the product as a yellowsolid. 66% yield. 1H NMR (400 MHz, Chloroform-d) d 9.62 (s, 1H), 8.39 (t, J 5.1 Hz, 1H), 8.25 (s, 1H), 8.17 (dd, J 6.4, 2.5 Hz, 1H), 7.59(s, 1H), 7.45e7.39 (m, 1H), 7.31 (td, J 4.2, 3.6, 1.9 Hz, 1H), 7.20 (dd, J 8.2, 5.3 Hz, 1H), 6.63 (s, 1H), 4.00 (s, 3H), 3.94 (s, 3H), 3.39e3.25(m, 4H), 2.90e2.77 (m, 4H).To a solution of 1 (393 mg, 1 mmol) and 2-(methylamino) ethanol (150 mg, 2 mmol) in DMF (20 mL), DIPEA (158 mg, 2 mmol)was added. After stirring at 60 C for 4 h, the mixture was pouredinto ice water. The resulting precipitate was filtered off, washedwith water, and dried under vacuum to give the product as a yellowsolid. 61% yield. 1H NMR (400 MHz, Chloroform-d) d 9.55 (s, 1H), 8.39 (d, J 5.3 Hz, 1H), 8.23 (s, 1H), 8.18 (dd, J 6.8, 2.2 Hz, 1H), 7.57(s, 1H), 7.48e7.37 (m, 1H), 7.31 (tt, J 7.1, 5.4 Hz, 2H), 7.20 (d, J 5.3 Hz, 1H), 6.68 (s, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.78 (q, J 5.5 Hz, 2H), 3.39 (t, J 5.2 Hz, 2H), 2.86 (s, 3H).

Molecular Weight:393.4
XLogP3:3.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:4
Exact Mass:393.12371755
Monoisotopic Mass:393.12371755
Topological Polar Surface Area:97.8
Heavy Atom Count:29
Complexity:579
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes