Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[CH2:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23].OS(O)(=O)=O.[N:30]([O-])=O.[Na+]>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[N:13]=[N:30][CH:11]=[C:10]2[CH3:12])=[O:24]
Reactant: O=N[O-]
Reactant: C=C(C)c1cc(C(=O)OC)c(Nc2ccc(Cl)cc2Cl)c(F)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(C)cnnc2c(F)c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.4 %

Procedure:
To a solution of 4-amino-2-(2,4-dichlorophenylamino)-3-fluoro-5-isopropenyl-benzoic acid methyl ester (89.9 mg, 0.243 mmol) in THF (2 mL) and conc. H2SO4 (0.050 mL, 0.94 mmol) was added a solution of NaNO2 (24.0 mg, 0.348 mmol) in water (0.5 mL) at 0° C. The reaction temperature was kept below 5° C. during the addition. The reaction mixture was warmed to room temperature, and 2 mL of water was added. After stirring in the dark for 4 days, the reaction mixture was diluted with EtOAc, and washed with water. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2) to afford the desired product (54 mg, 58%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[OH:9])([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 24.8 %

Procedure:
3-ethylphenol (5.00 g, 41 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.83 g, 45 mmol). The addition of sulfuric acid (50 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.7 g, 25%). 1H NMR (CD3COCD3): δ 8.02 (d, 1H), 6.99 (s, 1H), 6.85 (d, 1H), 2.69 (q, 2H), 1.30 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:45])([F:44])[C:25]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC(Cl)=CC=2)[CH:29]=1)([CH3:27])[CH3:26].C(OCC)C>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[C:24]([F:45])([F:44])[F:23])[O:32][N:31]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(c1cc(NC(=O)Oc2ccc(Cl)cc2)no1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline described in Example 115B (144 mg, 0.46 mmol) in anhydrous THF (5.6 mL), was added 4-chlorophenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 259A (161 mg, 0.46 mmol) and 4-(dimethylamino)pyridine (31 mg, 0.25 mmol). The mixture was stirred at rt for 15 h. To the suspension was added diethyl ether. Sonication and filtration afforded 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (134 mg, 55%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.86 (s, 1H), 7.28-7.54 (m, 5H), 6.89 (s, 1H), 3.99 (s, 6H), 1.54 (s, 6H); LC-MS (ESI) m/z 534 (M+H)+.
Reaction SMILES: [F:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:15](Br)([CH3:17])[CH3:16].[H-].[Na+].CN(C)P(N(C)C)(N(C)C)=O>C1C=CC=CC=1>[F:1][C:2]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH:15]([CH3:17])[CH3:16])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)c1ccc(Cl)cc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C(F)(c1ccc(Cl)cc1)C(C)C
Temperature: 35 °C
Reaction time: 22 h
Yield: 61.4 %

Procedure:
A mixture of ethyl α-fluoro-4-chlorophenylacetate (2.3 g), isopropyl bromide (1.10 g), sodium hydride (0.56 g of a 50% mixture in oil), dry hexamethylphosphoramide (6 ml) and dry benzene (6 ml) was heated with stirring at a temperature of 35° C. under nitrogen for a period of 22 hours. The reaction mixture was poured into ice-water and the aqueous mixture extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and solvent removed by distillation under reduced pressure. The product was chromatographed over silica gel using 15% ethylene dichloride in petroleum ether as eluant to give ethyl α-fluoro-α-isopropyl-4-chlorophenylacetate (1.42 g; 62%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br-:1].[C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N+:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:9]=1
Reactant: c1ccncc1
Reactant: BrCCCCCc1ccc(-c2ccccc2)cc1
Product: [Br-]
Product: c1ccc(-c2ccc(CCCCC[n+]3ccccc3)cc2)cc1
Temperature: 65 °C
Yield: 90 %

Procedure:
A mixture of 4-(5-bromopentyl)-1,1′-biphenyl (335 mg, 1.10 mmol) and pyridine (1 mL) was heated at 60-70° C. for 12 hrs. The resulted mixture was washed with diethyl ether and then dissolved in water (15 mL). The aqueous solution was extracted with diethyl ether (30 mL×3). Water was removed by lyophilization to afford 381 mg of the title compound. Yield: 90%. 1H NMR (300 MHz, CDCl3) δ 1.44 (m, 2H), 1.69 (m, 2H), 2.07 (m, 2H), 2.62 (t, J=7.5 Hz, 2H), 4.96 (t, J=7.5 Hz, 2H), 7.15-7.60 (m, 9H), 8.06 (t, J=6.9 Hz, 2H), 8.42 (d, J=7.8 Hz, 1H), 9.48 (d, J=6.0 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 25.6, 30.7, 31.9, 35.2, 61.8, 126.8, 127.0, 127.1, 128.4, 128.8, 128.9, 138.6, 140.8, 141.0, 145.0 ppm.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](SC)[N:10]=2)[C:3]1([CH3:20])[CH3:19].[F:21][C:22]([F:34])([CH3:33])[CH2:23][O:24][C:25]1[C:30]([CH2:31][NH2:32])=[CH:29][N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C1COCC1>[F:34][C:22]([F:21])([CH3:33])[CH2:23][O:24][C:25]1[C:30]([CH2:31][NH:32][C:11]2[N:10]=[C:9]([NH:8][C@@H:4]3[CH2:5][CH2:6][CH2:7][C@H:2]([OH:1])[C:3]3([CH3:20])[CH3:19])[C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:29][N:28]=[CH:27][N:26]=1
Reactant: CC(F)(F)COc1ncncc1CN
Reactant: CSc1ncc(C#N)c(N[C@@H]2CCC[C@H](O)C2(C)C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(F)(F)COc1ncncc1CNc1ncc(C#N)c(N[C@@H]2CCC[C@H](O)C2(C)C)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a solution of 4-(((1R,3S)-3-hydroxy-2,2-dimethylcyclohexyl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (130 mg, crude) in THF (3.0 mL) was added (4-(2,2-difluoropropoxyl)pyrimidin-5-yl)methanamine (84 mg, 0.411 mmol) and DIEA (158 mg, 1.23 mmol). The resulting mixture was stirred at 100° C. in a microwave reactor for 1 h. The solvent was evaporated and the residue was purified by standard methods to afford the title compound (33.6 mg, 0.075 mmol, 20% yield for two steps). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.69 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 4.72 (t, J=12.0 Hz, 2H), 4.57 (s, 2H), 4.05-3.91 (m, 1H), 3.45-3.42 (m, 1H), 1.82-1.72 (m, 5H), 1.70-1.50 (m, 2H), 1.50-1.30 (m, 2H), 1.03-0.91 (m, 6H). MS (ESI) m/z 448.2 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].N1C=CN=C1.[Si:12](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Si:12]([O:5][CH2:4][CH:3]([OH:6])[CH2:2][SH:1])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC(O)CS
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC(O)CS)(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a solution of 3-mercapto-1,2-propanediol (5.00 g, 46.23 mmol) and imidazole (3.78 g, 55.47 mmol) in dimethylformamide (30 mL) was added t-butyldiphenylsilyl chloride (12.71 g, 46.23 mmol) at room temperature. After stirring for 18 h the reaction was quenched by the addition of saturated sodium bicarbonate and the mixture was extracted with ether (3×). The combined ether extracts were washed with water (2×), brine, dried and concentrated to give a yellow oil. The crude material was purified by flash chromatography with a mixture of hexanes and ethyl acetate (90:10) to give the compound as a colourless oil (14.12 g) in 88% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13]([CH3:15])=[O:14])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[K+].Cl>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13]([CH3:15])=[O:14])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(S(C)=O)ccc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(S(C)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine methyl 2-methoxy-5-methylsulfinylbenzoate (2.37 g, 12.0 mmol) and a 1 M aqueous solution of potassium hydroxide (13 mL, 13 mmol). Heat to reflux. After 2 hours, cool to ambient temperature and adjust the pH to about 2 using a 1 M aqueous hydrochloric acid (14.5 mL, 14.5 mmol). Evaporate in vacuo to give a solid. Combine the solid and dichloromethane and stir. Decant the solvent and add more dichloromethane. Again decant and combine with the first decantate, dry over Na2SO4, filter, and evaporate in vacuo to to give the -title compound: mp; 114-116° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].[NH2:11][NH:12][C:13]([NH2:15])=[S:14].N1C=CC=CC=1>O=S(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:11][NH:12][C:13]([NH2:15])=[S:14])=[O:6]
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: NC(=S)NNC(=O)c1ccnc(Cl)c1
Reaction time: 2 h

Procedure:
2-chloroisonicotinic acid 8.1.A (5000 mg, 31735 μmol) was refluxed in SOCl2 overnight under nitrogen. Another 4 mL of SOCl2 was added in the morning. After 2 hr., solution cleared up. The r×n was then concentrated and added to a thiosemicarbazide (2892 mg, 31735 μmol)/pyridine solution at 0° C. After 4 hr., LC/MS showed product MS along with many side peaks. The reaction was stopped and concentrated. Water and a small amount of EtOAc were added, precipitates were generated. Filtered and washed the precipitates with water 4 times. The solids were dried. LC/MS and the NMR of the precipitates showed to be the pure product. 4.05 g of the product 8.1.B (55%) was generated as a yellow powder.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:14]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl>[C:14]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:15]=[CH:16][C:17]([C:20]([N:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]3[CH:1]=[CH:2][CH:3]=[C:4]3[CH2:13]2)=[O:21])=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)NCc1cccn1-2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccn2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
To a mixture of 0.5 g of 4,5-dihydropyrrolo[1,2-a]quinoxaline and 0.96 g of 4-biphenylcarbonyl chloride in 50 ml of methylene chloride under argon is added 7.0 ml of triethylamine followed by stirring at room temperature for 16 hours. The reaction mixture is diluted with 50 ml of chloroform and washed with water, 2N HCl, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 0.87 g of the desired product as a solid. M+H 351.2; M+Na 373.2.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH3:23])=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]([CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[CH3:23])=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Yield: 77 %

Procedure:
A solution of acryloyl chloride (0.026 mL, 0.32 mmol) in CH2Cl2 (1 mL) was added to a mixture of N4-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N1-(2-dimethylamino-ethyl)-5-methoxy-N1-methylbenzene-1,2,4-triamine (Intermediate 97, 130 mg, 0.27 mmol) and DIPEA (0.090 mL, 0.54 mmol) in CH2Cl2 (2 mL) at 0° C. The mixture was stirred at 0° C. for 2.5 h (during this time a further 0.2 eq acryloyl chloride was added). The mixture was then diluted with CH2Cl2, washed twice with sat. NaHCO3 and then with water, dried (MgSO4), and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (111 mg, 77%) as a yellow solid; 1H NMR: (CDCl3) 2.26 (6H, s), 2.23-2.33 (2H, m), 2.70 (3H, s), 2.86-2.89 (2H, m), 3.88 (3H, s), 3.91 (3H, s), 5.67 (1H, d), 6.25-6.44 (2H, m), 6.79 (1H, s), 7.20-7.37 (3H, m), 7.57 (1H, s), 8.36-8.45 (3H, m), 9.54 (1H, s), 10.11 (1H, s); m/z: ES+ MH+ 534, 536.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26]OC3C=CC=CC=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[BrH:39].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][Br:39])[CH:20]=2)[O:7][C@@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(phenoxymethyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (10.00 g, 18.22 mmol) in acetic acid (31 mL) was added HBr in acetic acid (45.55 mL, 2.5 mL/mmol) and the reaction mixture was stirred at r.t. for 18 h. After the completion of reaction as confirmed by TLC, the reaction mixture was neutralized by the addition of saturated K2CO3 at 0° C. and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) successively. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3:7 Ethyl acetate:Pet. Ether) to afford the title compound (7.9 g, 81%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.Br[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])=[CH:12][CH:11]=1.BrC1C=C2C(=CC=1)CN(C(NC1C=C[C:44]([C:47](=[O:52])NCCC)=CC=1)=O)C2>>[OH:52][CH2:47][CH2:44][N:1]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH:3]=[N:2]1
Reactant: OB(O)c1cc[nH]n1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: O=C(Nc1ccc(Br)cc1)N1Cc2ccccc2C1
Product: O=C(Nc1ccc(-c2cnn(CCO)c2)cc1)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 280, substituting 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol for 1H-pyrazol-3-ylboronic acid and N-(4-bromophenyl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.76 (q, J=5.8 Hz, 2H), 4.14 (t, J=5.6 Hz, 2H), 4.77 (s, 4H), 4.90 (t, J=5.4 Hz, 1H), 7.25-7.41 (m, 4H), 7.41-7.51 (m, 2H), 7.51-7.60 (m, 2H), 7.80 (s, 1H), 8.04 (s, 1H), 8.32 (s, 1H); MS (ESI(+)) m/e 349 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[N:14]([C:17]1[CH:22]=[CH:21][C:20]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:19][CH:18]=1)=[C:15]=[O:16]>CN(C)C1C=CN=CC=1.O1CCCC1.C(N(CC)CC)C.CO>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:4]=1[NH:5][C:15]([NH:14][C:17]1[CH:18]=[CH:19][C:20]([B:23]2[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: CC1(C)OB(c2ccc(N=C=O)cc2)OC1(C)C
Reactant: COc1cc(C(F)(F)F)ccc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(F)(F)F)ccc1NC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reaction time: 4 h
Yield: 20.6 %

Procedure:
To a solution of 1 g of 2-methoxy-4-(trifluoromethyl)aniline and 128 mg of 4-dimethylaminopyridine in 150 mL of tetrahydrofuran and 1.5 mL of triethylamine are added, at 20° C., 1.28 g of 2-(4-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. After 4 hours, the reaction is evaporated to dryness under reduced pressure. The residue is taken up in a mixture of ethyl acetate and water. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The residual yellow oil is purified on a prepacked Biotage KP-Sil column of 60 Å SiO2 32-63 μm (eluent: 8/2 cyclohexane/ethyl acetate). A pale yellow powder is obtained, which is taken up in methanol. An insoluble white material is formed, which is separated out by filtration, and the filtrate is then evaporated to dryness under reduced pressure to give 0.47 g of a pale yellow powder of 1-(2-methoxy-4-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.CCOCC>[NH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([B:15]([OH:17])[OH:16])=[CH:13][CH:14]=1)(=[O:8])=[O:7]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(B(O)O)cc1

Procedure:
A solution of 4-t-butylaminosulfonylbenzene boronic acid (500 mg) in TFA (5 mL) was stirred at r.t. for 15 h. The mixture was diluted with ether and the solid material was filtered to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N:16](CC)C(C)C)(C)C.N[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[NH2:16])[N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccccc1
Solvent: CC(C)O
Product: Nc1cccc2nc(Cl)nc(-c3ccccc3)c12

Procedure:
A solution of 2,4-dichloro-quinazoline (15 g), N,N-diisopropyl-ethylamine (24.9 ml) and aniline (7.5 ml) in isopropanol (75 ml) is heated to reflux for 45 min. The cold reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is crystallized from diethylether-toluene (1:1) to give 2-chloro-4-phenyl-amino-quinazoline, m.p. 194-196° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11]O>OS(O)(=O)=O>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cn1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)nc1
Temperature: 60 °C

Procedure:
To a solution of 10 g 6-Amino-nicotinic acid in 100 mL MeOH, 0.8 mL concentrated H2SO4 were added and the mixture was heated to 60° C. for 12 h. Then the reaction mixture was concentrated under reduced pressure. After addition of 50 mL ice water the mixture was brought to pH 8 by addition of K2CO3. The aqueous phase was extracted with ethyl acetate (3×100 ml) and the combined organic layers were dried over MgSO4. Removal of the solvent yielded 5.5 g of the desired product which was subjected to the following reaction without further purification.
Reaction SMILES: [CH2:1]([C@:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38]([Cl:41])(=[O:40])=[O:39].[Cl-].[NH4+]>O1CCCC1>[ClH:41].[CH2:1]([C@:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][N:24]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2]
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)C1=O
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n2)C1=O
Product: Cl
Reaction time: 3 h

Procedure:
To a solution of (3R)-3-ethyl-2-oxo-1-(2-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)pyrrolidine-3-carbonitrile (100 mg) obtained in Example 220 in tetrahydrofuran (3.0 mL) were added successively dropwise triethylamine (71 μL) and methanesulfonyl chloride (24 μL) in an ice bath, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), to a solution of the obtained purified product (120 mg) in ethanol (3 mL) was added 1 M hydrochloric acid (0.25 mL), and the mixture was stirred at room temperature for 5 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized (ethanol/diisopropyl ether) to give the title compound (91 mg).