Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:14])[CH3:13]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C(=O)O)ccc1C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
A mixture of 3-amino-4-methylbenzoic acid (13) (27.23 g, 180.2 mmol) and acetic acid (190 mL) is heated to 60° C., and acetic anhydride (120 mL, 1300 mmol) is introduced to the reaction mixture over about 0.25 hours. The reaction mixture is then heated to reflux and stirred for about 30 minutes. The mixture is then cooled to room temperature, and the solid obtained is filtered, washed with water (100 mL), and dried to provide 3-(Acetylamino)-4-methylbenzoic Acid (14) as a light pink colored solid (26.37 g, 76% Yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:5][CH:6]=[N:7][C:8]=2[N:9]([CH2:13][CH2:14][CH3:15])[C:10](=[O:12])[N:11]=1.[H-].[Na+].Cl[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([O:20][CH2:19][N:5]1[C:4]2[C:3]([S:2][CH3:1])=[N:11][C:10](=[O:12])[N:9]([CH2:13][CH2:14][CH3:15])[C:8]=2[N:7]=[CH:6]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCn1c(=O)nc(SC)c2[nH]cnc21
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)nc(SC)c2c1ncn2COCc1ccccc1

Procedure:
After 224 mg (1.0 mmol) of Compound b obtained in Reference Example 2 was dissolved in 2 ml of N,N'-dimethylformamide, 48.0 mg (1.2 mmol) of 60% sodium hydride was added to the mixture under ice cooling. 15 minutes after, 209 μl (1.5 mmol) of benzyl chloromethyl ether was added to the mixture. The mixture was stirred for an hour, poured onto 10 ml of water, and extracted 3 times with 5 ml of chloroform. After washing with a saturated aqueous sodium chloride solution, the extracts were dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated with ether to give 223 mg (yield, 65%) of Compound f as a white powder.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[O:10][C:9](=[O:17])[CH:8]=[C:7]2[CH3:18])[CH:2]=C.O.I([O-])(=O)(=O)=[O:21].[K+]>CO.[Os](=O)(=O)(=O)=O>[OH:21][CH:2]1[O:14][C:13]2=[C:12]([O:15][CH3:16])[C:11]3[O:10][C:9](=[O:17])[CH:8]=[C:7]([CH3:18])[C:6]=3[CH:5]=[C:4]2[CH2:1]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1cc2c(C)cc(=O)oc2c(OC)c1O
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1c2c(cc3c(C)cc(=O)oc13)CC(O)O2
Reaction time: 3.5 h

Procedure:
A solution of 2.0 g (8.12 mmols) of 6-allyl-7-hydroxy-8-methoxy-4-methylcoumarin in 20 ml of methanol was treated (mechanical stirring) with 10 ml of water, 5.0 g potassium periodate, and 1.0 ml of a 10% aqueous solution of osmium tetroxide (10 mg/ml). After 3.5 hrs, the mixture was partitioned between water/methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic extracts were dried and evaporated to yield 2-hydroxy-9-methoxy-5-methyl-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one. The compound was dissolved in 40 ml of 98% formic acid and heated under reflux for 1.0 hr. The solution was cooled and evaporated to dryness. The residue was chromatographed over silica, eluting with ethyl acetate/benzene, 1:4, to afford pure 9-methoxy-5-methyl-7H-furo[3,2-g][1]benzopyran-7-one, m.p. 167°-168° (ethanol).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)(=[O:3])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25]>C(OCC)(=O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:24](=[O:26])[CH3:25])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(=O)c2cccc(N)c2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)Nc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(C)=O)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-acetylamino-2-(3-aminobenzoyl)-6-chloroindole (Example 135) and acetyl chloride. m.p.: 225-228° C. (ethyl acetate/hexane) 1H-NMR (DMSO-d6) δ: 10.59 (1H, br s), 9.75 (1H, br s), 9.45 (1H, br s), 7.96 (1H, d, J=8.8 Hz), 7.93-7.82 (2H, m), 7.58-7.40 (3H, m), 7.04 (1H, d, J=8.8 Hz), 2.17 (3H, s), 2.10 (3H, s)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH2:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[CH3:32]>>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:36]3[CH2:37][CH2:38][N:33]([CH2:31][CH3:32])[CH2:34][CH2:35]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: CCN1CCNCC1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: CCN1CCN(CCCCCCOc2c(OC)ccc3c(Nc4c(Cl)cncc4Cl)cc(=O)[nH]c23)CC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 1-ethylpiperazine following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 12.00-11.60 (br, 2H), 10.46 (s, 1H), 9.21 (s, 1H), 8.81 (s, 2H), 8.01 (d, 1H), 7.16 (d, 1H), 4.95 (s, 1H), 4.01 (t, 2H), 3.95 (s, 3H), 3.84-3.35 (br m, 8H), 3.35-3.10 (br m, 4H), 1.84-1.70 (m, 4H), 1.52-1.32 (m, 4H), 1.27 (t, 3H); MS (ESI): 548.5.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(O)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.8 %

Procedure:
To a solution of 2-hydroxy-5-(methoxycarbonyl)benzoic acid (4.0 g, 20.4 mmol) in DMF (40 mL) was added KHCO3 (2.04 g, 20.4 mmol) and benzyl bromide (3.49 g, 20.4 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 20 h. The reaction mixture was diluted with water, extracted with EtOAc (2×) and the combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. The crude material was purified by flash chromatography (gradient from 0% to 30% EtOAc/hexanes) to provide the title compound (5.3 g, 92%) as an off-white solid. 1H NMR (CDCl3) δ 11.21 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.11 (dd, J=8.8, 2.4 Hz, 1H), 7.47-7.37 (m, 5H), 7.01 (d, J=8.8 Hz, 1H), 5.42 (s, 2H), 3.89 (s, 3H); MS(ESI−) m/z 285.2 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=O.[NH2:16][CH:17]1[CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18]1>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([NH:16][CH:17]1[CH2:23][CH2:22][NH:21][C:19](=[O:20])[CH2:18]1)=[O:9]
Reactant: COc1cccc(C=CC(=O)O)c1OC
Reactant: NC1CCNC(=O)C1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cccc(C=CC(=O)NC2CCNC(=O)C2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
To a solution of 2,3-dimethoxycinnamic acid (5.0 g) in tetrahydrofuran (50 ml) was added N,N'-carbonyldiimidazole (4.28 g) and the mixture was stirred at room temperature for 30 minutes. To this was added 3-amino-δ-valerolactam (3.02 g), followed by stirring overnight. The reaction solution was diluted with chloroform and washed with a saturated soldium bicarbonate solution and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column to obtain the titled compound (2.91 g, 39.8%).
Reaction SMILES: Cl[C:2]1[C:3]([NH:29][C:30]2[CH:34]=[C:33]([CH3:35])[NH:32][N:31]=2)=[N:4][C:5]([NH:8]C2C=C(C)C(C3CCN(C4CCSCC4)CC3)=CC=2C)=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:35][C:33]1[NH:32][N:31]=[C:30]([NH:29][C:3]2[CH:2]=[CH:7][N:6]=[C:5]([NH2:8])[N:4]=2)[CH:34]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(C5CCSCC5)CC4)cc3C)ncc2Cl)n[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Nc2ccnc(N)n2)n[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-chloro-N2-(2,5-dimethyl-4-(1-(tetrahydro-2H-thiopyran-4-yl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (18 mg, 0.035 mmol) in CH2Cl2 (1 mL) was added m-CPBA (16 mg, 0.71 mmol) at 0° C. The mixture was then warmed up to room temperature and stirred for 30 min; saturated aqueous NaHCO3 solution (3 mL) was then added and the crude product extracted with CH2Cl2 (3×3 mL). The combined organic layers were concentrated and purified by preparative thin layer chromatography (silica gel, 12% MeOH/CH2Cl2 with NH3) to provide 5-chloro-N2-(2,5-dimethyl-4-(1-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl))piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine. ESMS m/z 544.2 (M+H+).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[C:11]2=[S:30])=[CH:6][CH:5]=1.[CH3:32][NH2:33]>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([N:12]2[C:13](=[O:17])[C:14]([CH3:15])([CH3:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:33][CH3:32])=[O:31])=[CH:5][CH:6]=3)[C:11]2=[S:30])=[CH:19][C:20]=1[C:26]([F:29])([F:28])[F:27])#[N:25]
Reactant: CN
Reactant: COC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Product: CNC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Reaction time: 15 h
Yield: 51 %

Procedure:
A mixture of 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5 -dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]benzoic acid methyl ester (49c) (0.02 g, 0.0435 mmol) and methylamine (2 ml distilled from its 40% aqueous solution) was kept at −20° C. for 15 hours. After evaporation of the methylamine, the mixture was chromatographed (dichloromethane:acetone, 80:20) to yield 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]-N-methylbenzamide (49d) [RD153](0.01 g, 0.0224, 51%), the structure of which is illustrated in Formula 20. The ester 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin -1-yl]benzoic acid methyl ester (49c) (0.08 g, 0.0179 mmol, 41%) was also recovered.
Reaction SMILES: [CH:1]([O:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[CH:20]([Si:22]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH2:21]>C1(C)C=CC=CC=1>[CH:1]([O:4][CH:5]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:6](=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:21][CH2:20][Si:22]([O:23][CH2:24][CH3:25])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])([CH3:3])[CH3:2]
Reactant: CC(C)OC(C(=O)c1ccccc1)c1ccccc1
Reactant: C=C[Si](OCC)(OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1C(=O)C(OC(C)C)c1ccccc1)(OCC)OCC
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
10.2 g (40 mmol) of benzoin isopropyl ether, 9.2 ml (44 mmol) of vinyltriethoxysilane and 735 mg (0.8 mmol) of RuH2 (CO) (PPh3)3 were dissolved in 60 ml of anhydrous toluene and degassed by passing in argon for 1/2 hour. The mixture was then stirred with exclusion of light and under argon, at reflux, for 7 hours and left to stand overnight at room temperature, a further 370 mg (0.4 mmol) of RuH2 (CO) (PPh3)3 and 1 ml (5 mmol) of vinyltriethoxysilane were added, and heating at reflux was carried out for a further 6.5 hours. After the toluene had been distilled off, the mixture was chromatographed on silica gel (initially heptane/CH2Cl2 9:1, then CH2 Cl2, then CH2Cl2 /ethyl acetate, finally ethyl acetate) and purified by bulb-tube distillation. 9.8 g (55%) of a pale yellowish oil were obtained. 1H-NMR (CDCl3): 0.61-0.95 ppm (2H, mc, Et-H2); 1.21 ppm (6H, d, isopropyl-CH3, 3JH,H =6.0 Hz); 1.22 ppm (9H, t, ethoxy-CH3, 3JH,H =7.0 Hz); 2.61 ppm (2H, mc, Et-H1); 3.71 ppm (1H, hept, isopropyl-H); 3.79 ppm (6H, q, ethoxy-CH2); 5.55 ppm (1H, s, benzoin-H); 7.13-7.38 ppm (8H, m, Ph-H); 7.48 ppm (1H, dd, Ph-H6, 3JH5,H6 =7.6 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:6]([C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C@H:5]([CH:15]=[O:16])[CH2:4][O:3]1.[CH3:18][CH2:19][Mg+].[Br-]>CCOCC>[CH2:18]([CH:15]([C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:17])[N:6]1[C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[OH:16])[CH3:19]
Reactant: CCCCCCC(=O)N1[C@H](C=O)COC1(C)C
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CCCCCCC(=O)N1[C@H](C(O)CC)COC1(C)C
Reaction time: 1.5 h

Procedure:
A solution of 9a (108 mg, 0.44 mmol) in ether (1 mL) is added dropwise to a cold (5°) solution of EtMgBr (3M in ether, 0.36 mL). The cold bath is removed, a crystal of iodine is added to the mixture and stirring is continued for 1.5 h at room temperature. The resulting mixture is diluted with EtOAc and washed with saturated aqueous NH4Cl solution. The aqueous phase is reextracted and the combined organic solution dried and evaporated to yield crude 10a: NMR δ0.88 (m, 1.05 (m, 1.30 (m, 1.45 (m, 2H), 1.57 (s, 3H), 1.50-1.75 (m, 5H), 2.10-2.60 (m, 2H), 3.50-4.50 (m, 4H); MS (EI) m/z 271 (M).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])[CH2:4][CH:3]=1.[O:15]([C:22]1[N:27]=[C:26]([CH2:28]Br)[CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[CH3:1][C:2]1[CH2:7][CH2:6][N:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O:11][CH2:28][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:27]=2)=[O:10])[CH2:4][CH:3]=1
Reactant: CC1=CCN(C(C(=O)O)C(C)C)CC1
Reactant: BrCc1cccc(Oc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1=CCN(C(C(=O)OCc2cccc(Oc3ccccc3)n2)C(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The resulting 2-(4-methyl-1,2,5,6-tetrahydro-1-pyridyl)-3-methylbutanoic acid (7.0 mmol) is combined with (6-phenoxy-2-pyridyl)methyl bromide (7.0 mmol) and potassium carbonate (14.0 mmol) in 15 ml dimethylformamide, and the mixture is stirred at RT, under nitrogen, for 20 hours. The solution is brought up in ether, washed with water (3X) and brine, and dried over sodium sulfate to give (6-phenoxy-2-pyridyl)methyl 2-(4-methyl-1,2,5,6-tetrahydro-1-pyridyl)-3-methylbutanoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:19]4/[C:20](=[O:28])[NH:21][C:22]5[C:27]/4=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1.[CH3:29]C1C=C2C(=CC=1)NC(=O)C2>>[CH3:29][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:28])/[C:19]/2=[CH:18]/[C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: Cc1ccc2c(c1)CC(=O)N2
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Product: Cc1ccc2c(c1)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Yield: 26 %

Procedure:
According to procedure for the synthesis of (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one, except substituting 5-methyloxindole (9 mg, 0.06 mmol) to give the title compound as an orange solid (5.9 mg, 26%). 1H NMR (400 MHz, d6-DMSO) δ 13.58 (br s, 1H), 10.53 (br s, 1H), 8.57 (br s, 2H), 8.36 (d, J=8.0 Hz, 1H), 7.93-7.46 (m, 8H), 7.06 (d, J=8.0 Hz, 1H), 6.79 (d, J=5.8 Hz, 1H), 2.16 (s, 3H); MS ESI 379.2 [M+H]+, calcd for [C24H18N4O+H]+ 379.15.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:10]([CH2:17][CH:18]([OH:21])[CH2:19][OH:20])[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:10]([CH2:17][CH:18]2[CH2:19][O:20][C:29](=[O:31])[O:21]2)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(N(CC(O)CO)C(=O)C(C)(C)C)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Br)c(N(CC2COC(=O)O2)C(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
A solution of N-[3-bromo-6-(methyloxy)-2-pyridinyl]-N-(2,3-dihydroxypropyl)-2,2-dimethylpropanamide (7.628 g, 21.130 mmol) in DCM (100 ml) and pyridine (3.407 ml, 42.26 mmol) at −78° C. under argon was treated with a solution of triphosgene (6.27 g, 21.130 mmol) in DCM (20 ml) over 5 min and the reaction was then allowed warm to rt and stirred at rt for 30 min. The reaction was then carefully treated with saturated sodium bicarbonate solution (200 ml), extracted with DCM (3×200 ml). The organic extracts were dried (MgSO4), and evaporated and chromatographed (0-50% ethyl acetate:Hexane) to give the product as a white solid (5.722 g, 70%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:6]=1.[H-].[Na+].I[CH2:18][CH3:19]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([N:7]([CH2:18][CH3:19])[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH:6]=1
Reactant: CC(C)(C)OC(=O)Nn1cnc(Br)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)n1cnc(Br)c1
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
tert-Butyl (4-bromo-1H-imidazol-1-yl)carbamate (1.16 g, 4.43 mmol) was dissolved in N,N-dimethylformamide (DMF, 12 mL) and treated with sodium hydride (0.310 g, 7.75 mmol, 60% dispersion in oil). After 45 minutes, the mixture was cooled on an ice bath and was treated with iodoethane (0.828 g, 5.31 mmol). The ice bath was removed after five minutes of stirring and the reaction was stirred for an additional 90 minutes. The reaction mixture was diluted with aqueous potassium carbonate (50 mL, 5% w/w) and the product was extracted with ethyl acetate. The organics were washed with 5% aqueous potassium carbonate and brine and dried over sodium sulfate. The organic layer was concentrated and the residue was purified using silica gel chromatography (0-10% methanol/dichloromethane) to afford the title compound (1.023 g, 3.53 mmol, 80%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=1.5 Hz, 1H), 6.93 (d, J=1.5 Hz, 1H), 3.71 (q, J=7.2 Hz, 2H), 1.44 (s, 9H), 1.16 (t, J=7.2 Hz, 3H); ESIMS m/z 290 ([M+H]+).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([O:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCOc1cccc2ccccc12
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCOc2cccc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(1-naphthyloxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-(1-naphthyloxy)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:25][CH3:26].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:33][CH:34](OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:35]>CN(C=O)C>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:35][CH2:34][Cl:33])=[C:3]([O:25][CH3:26])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cl)cc1
Reactant: COc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the DMF solution (10 mL) of tert-butyl 4-(7-hydroxy-6-methoxyquinazolin-4-yl)piperazinecarboxylate (1.8 g, 5 mmol), Cs2CO3 (3.3 g, 10 mmol) added 1-chloroethyl-tosylate (1.8 mL, 10 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated and the crude residue was purified by RP-HPLC (reverse-phase high performance liquid chromatography) to afford the intermediate tert-butyl-4-[6-methoxy-7-(2-chloroethoxy)quinazolin-4-yl]piperazinecarboxylate as the desired product (850 mg, 40%). MS (ES) 423 (M+H)
Reaction SMILES: [CH3:1][N:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[NH:3]1.C([Li])CCC.[O:20]1[CH2:22][CH2:21]1>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[NH:3][N:2]([CH2:1][CH2:22][CH2:21][OH:20])[N:7]=1
Reactant: C1CO1
Reactant: CN1N=C(Cl)C=C(N2CCOCC2)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OCCCN1N=C(Cl)C=C(N2CCOCC2)N1
Temperature: -78 °C

Procedure:
2-Methyl-4-chloro-6-morpholino-triazine (50 mmol) is dissolved in tetrahydrofuran (200 mL). The reaction is chilled to −78° C. under an inert atmosphere. A solution of n-butyllithium in hexanes (24 mL, 2.5M, 60 mmol) is added, and the reaction mixture is stirred for thirty minutes. A solution of oxirane dissolved in tetrahydrofuran (40 mL, 41.5M, 60 mmol) is added, and the reaction is allowed to warm to room temperature while stirring overnight. The solvent is removed under reduced pressure, and the crude material is dissolved in methylene chloride (200 mL) and washed with saturated ammonium chloride (2×50 mL), dried with sodium sulfate, and evaporated to dryness. The compound is purified by column chromatography to give 3-(4-chloro-6-morpholin-4-yl-triazin-2-yl)-propan-1-ol.