Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].[P:9]([Cl:14])(Cl)(Cl)(Cl)[Cl:10].Cl.C(O)=[O:17]>C(Cl)(Cl)(Cl)Cl>[Cl:10][P:9]([Cl:14])([NH:8][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:7])=[O:17]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=CO
Reactant: NC(=O)c1ccco1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NP(=O)(Cl)Cl)c1ccco1
Reaction time: 0.75 h

Procedure:
A mixture of 11.1 g (0.1 mole) of furamide, 20.8 g (0.1 mole) of phosphorus pentachloride and 150 ml of AR carbon tetrachloride was heated at 70° for 30 min. or until the HCl gas evolution had ceased. Cooled to 30° and 4.7 g (0.1 mole) of 97% formic acid was added dropwise. Stirring was continued for 45 min., before filtering. The product was washed with AR carbon tetrachloride and air-dried to give 17.8 g, m.p. softens 83°, melts 93°-112°.
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:6][N:7]=1.S(Cl)([Cl:13])=O>>[ClH:13].[Cl:13][CH2:2][C:3]1[N:4]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:6][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCCn1ccnc1CO
Product: CCCn1ccnc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 2-hydroxymethyl-1-propylimidazole (8.0 g) was added thionyl chloride (50 ml) at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from methanol-ethyl acetate, to give 2-chloromethyl-1-propylimidazole hydrochloride (4.3 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:34](=[O:35])[C:33]4[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=4)[CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)N1CCN(c2ncn(Cc3ccc(Cl)cc3)c(=O)n2)CC1
Yield: 63.1 %

Procedure:
To an N,N-dimethylformamide solution (1 mL) of 1-(4-chlorobenzyl)-4-(piperazin-1-yl)-1,3,5-triazin-2(1H)-one (31 mg, 0.10 mmol) synthesized in Reference Synthesis Example 9, triethylamine (28 μL, 0.20 mmol) and 4-fluorobenzoyl chloride (18 μL, 0.15 mmol) were added at room temperature and the resultant mixture was stirred at room temperature for 4 hours. After the completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction with ethyl acetate from the resultant reaction solution was performed. The organic layer was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/4→0/1 (v/v)) to obtain the title compound (27 mg, yield: 63%).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[NH:8][CH:9]=[CH:10][CH:11]=1)=O.[N+]([O-])(O)=O.[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:21])[F:20].[OH-].[Na+]>C(O)C(C)C>[F:17][C:18]([F:33])([O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[N:32]=[C:5]([C:7]3[NH:8][CH:9]=[CH:10][CH:11]=3)[CH:4]=[CH:3][N:31]=2)[CH:26]=[CH:27][CH:28]=1)[CH:19]([F:20])[F:21]
Reactant: CN(C)C=CC(=O)c1ccc[nH]1
Reactant: N=C(N)Nc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)CO
Product: FC(F)C(F)(F)Oc1cccc(Nc2nccc(-c3ccc[nH]3)n2)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a solution of 100 mg (0.61 mmol) of 3-dimethylamino-(1H-pyrrol-2-yl)2-propen-1-one [described in EP-A-0 233 461]in 4 ml of isobutanol are added 185 mg (0.60 mmol) of 3-(1,1,2,2-tetrafluoroethoxy)phenylguanidine nitrate. Following the addition of 32.5 mg (0.81 mmol) of sodium hydroxide, the reaction mixture is stirred for 3 hours at 110° C. The suspension is concentrated under reduced pressure, the residue is dissolved in 4 ml of methylene chloride/tetrahydrofuran (1:1 ), and the solution is extracted with 2.4 ml of water. The organic phase is dried over sodium sulfate and concentrated on a rotovap. Recrystallisation from diethyl ether/tetrahydrofuran gives N-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]-(1H-pyrrol-2-yl)-2-pyrimidine-amine; FAB-MS:353 (M+ +1 ), m.p. 142-143, Rf =0.83 (methylene chloride:methanol=9:1).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([O-:3])=O.C[Si](C)(C)[O:17][C:18]#[C:19][CH3:20].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:5]([C:4]1[CH:20]=[C:19]([CH2:18][OH:17])[O:3][N:1]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC#CO[Si](C)(C)C
Reactant: CCCCCCCCCCC[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Product: CCCCCCCCCCc1cc(CO)on1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
To a solution of 1-nitroundecane (38.0 g) and O-trimethylsilylpropynol (24.1 g) in dry benzene (300 ml) was added dropwise a solution of freshly distilled phenylisocyanate (44.9 g) and triethylamine (22.4 g) in dry benzene (50 ml) at 40° C., with stirring. The reaction mixture was heated at 60° C. for 3 hrs, cooled, and filtered. To the filtrate was added 1.0M tetrabutylammonium fluoride (40 ml). After 30 mins, the solution was evaporated, and the residue was flash chromatographed (silica gel, 1% methanol-dichloromethane) to give 15.5 g (34%) of product, mp 55°-56° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[CH:43][C:38]3[NH:39][C:40](=[O:42])[NH:41][C:37]=3[CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:44]=[CH:43][C:38]3[NH:39][C:40](=[O:42])[NH:41][C:37]=3[CH:36]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]c(=O)[nH]c4c3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (63.3 mg, 0.243 mmol), DMSO(2 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 35 mg (40%). LCMS E-S (M+H)=472.4 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.4 Hz, 6 H), 2.13 (s, 3 H), 2.22 (s, 3 H), 4.41 (d, J=4.8 Hz, 2 H), 5.30 (quin, J=6.6 Hz, 1 H), 5.91 (s, 1 H), 7.07 (d, J=8.3 Hz, 1 H), 7.86 (s, 1 H), 7.92 (dd, J=8.3, 1.8 Hz, 1 H), 8.10 (s, 1 H), 8.30-8.41 (m, 1 H), 8.98 (t, J=4.8 Hz, 1 H), 10.82 (s, 1 H), 10.89 (s, 1 H). 11.58 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][NH:26][C:25]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:26]2[CH2:27][C:28](=[O:29])[N:24]([CH3:23])[C:25]2=[O:30])=[CH:17][CH:16]=1
Reactant: CC(C)Cn1nnc2c(Br)c(-c3ccc(CCl)cc3)ccc21
Reactant: CN1C(=O)CNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)Cn1nnc2c(Br)c(-c3ccc(CN4CC(=O)N(C)C4=O)cc3)ccc21
Temperature: 50 °C

Procedure:
4-Bromo-5-[4-(chloromethyl)phenyl]-1-(2-methylpropyl)-1H-benzotriazole (170 mg, 0.449 mmol), 3-methylimidazolidine-2,4-dione (102 mg, 0.898 mmol) and potassium carbonate (186 mg, 1.347 mmol) were combined in acetonitrile (3 ml) and heated at 50° C. for 16 hours. The mixture was cooled to ambient temperature, diluted with dichloromethane and filtered. The filtrate was washed with aqueous saturated ammonium chloride and brine. The organic extract was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography (acetone/dichloromethane gradient), providing the titled compound as white solid: 1H NMR (500 MHz, d6-DMSO): 1H NMR δ 8.00 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.48 (d, J=7.9 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 4.60-4.57 (m, 4H), 3.97 (s, 2H), 2.90 (s, 3H), 2.34-2.27 (m, 1H), 0.93-0.88 (m, 6H) ppm. LRMS m/z (M+H) 455.9 and 457.9 found, 456.1 and 458.1 required.
Reaction SMILES: [OH:1][NH2:2].[F:3][C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[O:6][C:7]1[C:21]([O:22][C:23]2[CH:24]=N[C:26]([C:29]#[N:30])=[CH:27][CH:28]=2)=[CH:20][C:10]2[NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:9]=2[CH:8]=1.[CH2:35](O)C>>[F:3][C:4]1[CH:34]=[CH:33][CH:32]=[CH:31][C:5]=1[O:6][C:7]1[C:21]([O:22][C:23]2[CH:24]=[CH:35][C:26]([C:29](=[NH:30])[NH:2][OH:1])=[CH:27][CH:28]=2)=[CH:20][C:10]2[NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:9]=2[CH:8]=1
Reactant: CCO
Reactant: N#Cc1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2F)cn1
Reactant: NO
Product: N=C(NO)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 ml of hydroxyamine (50% aqueous solution) was added to an ethanol (0.5 ml) solution of 6.0 mg of 5-(2-fluoro-phenoxy)-2-pyrazin-2-yl-6-(6-cyano-pyridin-3-yloxy)-1H-benzimidazole obtained in Example 252, and the reaction liquid was stirred at room temperature for 3 hours. Then, the solvent was evaporated away under reduced pressure to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.O.[NH2:13][NH2:14]>C(O)C>[ClH:1].[CH3:11][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:13][NH2:14])[C:3]=2[S:10][CH:9]=1
Reactant: Cc1csc2c(Cl)ncnc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1csc2c(NN)ncnc12
Product: Cl
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A suspension of 4-chloro-7-methylthieno[3,2-d]pyrimidine (4, 3.1 g, 17 mmol) and hydrazine monohydrate (3.5 mL, 72 mmol) in ethanol (34 mL) was heated at reflux for 1 hour. After cooling to room temperature, the solid product was collected by vacuum filtration to give (7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazine hydrochloride (3.2 g, 88% yield) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][CH2:11][CH2:12][SH:13])[CH:6]=[CH:7][C:8]=1[Cl:9].[OH-].[K+].Br[CH2:17][C:18]([OH:20])=O.C(OC(=O)C)(=O)C>>[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[CH2:11][CH2:12][S:13][CH2:17][C:18]2=[O:20])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: SCCNc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: O=C1CSCCN1c1ccc(Cl)c(Cl)c1
Temperature: 35 °C
Reaction time: 0.29 h
Yield: 56.7 %

Procedure:
A 3-necked 3 L round bottomed flask equipped with overhead stirrer, temperature probe, and nitrogen inlet was charged with 100 grams (0.387 mol) of 2-(3,4-dichloro-phenylamino)-ethanethiol hydrochloride and 1 L of 2B-ethanol. To the resulting suspension was charged 76 grams (1.35 mol, 3.5 equivalents) of potassium hydroxide. The addition resulted in a temperature increase to approximately 35° C. This suspension was stirred at room temperature for 15-20 minutes, then cooled to 5-10° C. and treated with a solution of 59.1 grams (0.425 mol, 1.1 equivalents) of bromoacetic acid in 152 mL of 2B-ethanol. After stirring at room temperature for approximately 3 hours, the reaction mixture was concentrated under vacuum to a volume of approximately 225 mL. To this suspension was added 864 mL (9.15 mol, 23.6 equivalents) of acetic anhydride with no external cooling which resulted in a temperature increase to approximately 100° C. The flask was fitted with a condenser and receiving flask, and heated to 105-110° C. at which point distillate began to be collected. With continued heating, the internal temperature rose to 115° C., the reaction flask was refitted with a reflux condenser and the reaction mixture held at reflux for 1 hour. After allowing to cool to room temperature, the reaction mixture was poured into a 3-necked 5 L round bottomed flask containing 1700 mL of water and 864 mL of methylene chloride and stirred for 10-20 minutes at 20-25° C. The layers were separated and the organic layer was washed with 1 L of water then treated with 2 L of 10% aqueous sodium hydroxide which brought the pH to 9-10. The layers were separated, the organic layer was dried over magnesium sulfate, and concentrated atmospherically to a volume of approximately 200 mL. Displacement of the methylene chloride by isopropyl ether was accomplished by continuing to charge isopropyl ether and concentrating until an internal temperature of 68° C. was attained. The solution was then cooled to room temperature. Solids began to precipitate at 45° C. The resulting slurry was stirred at room temperature for two hours. The solids were collected by filtration, washed with isopropyl ether and vacuum dried at 45-50° C. to yield 57.5 grams (56.7% yield) of the title compound as a white solid, mp 81-83° C. 1H NMR (CDCl3) δ7.44 (d, J=8.7 Hz, 1H), 7.38 (d, J=2.5 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 3.93 (t, J=11.5 Hz, 2H), 3.43 (s, 2H), 3.01 (t, J=11.5 Hz, 2H). 13C NMR (CDCl3) δ168.10, 143.04, 134.201, 132.25, 132.09, 129.42, 126.83, 53.32, 31.81, 27.86. HRMS (FAB) calcd for C10H9Cl2NOS: 261.9860; found: 261.9839.
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:14]([CH3:15])[C:13](=[O:16])[N:12]([C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C@:10]1([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH:14]([CH3:15])[C:13](=[O:16])[N:12]([C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:11]1
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
Tert-butyl (3S)-3-{[tert-butyl(dimethyl) silyloxy]methyl}-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (3.72 g, 8.31 mmol) was dissolved in tetrahydrofuran (70 mL), and tetrabutylammonium fluoride (12.5 mL, 1.0 mol/l solution in tetrahydrofuran, 12.5 mmol) was added dropwise in an ice bath. The mixture was stirred at the same temperature for 1 hour. After concentrating the mixture, saturated aqueous solution of ammonium chloride (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (100 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (elusion by hexane:ethyl acetate=3:1→1:2) to obtain 1.87 g (67%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:10].[Cl-].[NH4+]>CCOCC>[NH2:10][C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: Brc1ccccc1
Reactant: COC(=O)CC#N
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COC(=O)C=C(N)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
47 g of bromobenzene in 90 ml of ether were added dropwise to 7.2 g of magnesium in 20 ml of ether under reflux, and the stirred mixture was refluxed for 1 hour. Thereafter, 9.9 g of methyl cyanoacetate were added dropwise while cooling with ice, and stirring was carried out for 1 hour at room temperature, for 5 hours under reflux and again for 15 hours at room temperature. 300 ml of ammonium chloride were carefully added to the reaction mixture and the aqueous phase was extracted twice with ether and the combined organic phases were washed three times with water, dried over sodium sulfate and evaporated down. The residue was distilled under greatly reduced pressure. 13 g of methyl β-amino-cinnamate were obtained (110-112° C., 10.15 mbar).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([F:18])[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:11][C:12]1[CH:13]=[C:14]([C:2]2[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CN(C)c1ccnc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CN(C)c1ccnc(-c2cc(F)cc(F)c2)c1
Temperature: 90 °C
Yield: 47.4 %

Procedure:
A mixture of 2-iodo-4-dimethylaminopyridine (2.68 g, 10.8 mmol), 3,5-difluorophenylboronic acid (2.56 g, 16.2 mmol) and K2CO3 (6.7 g, 48.6 mmol) in toluene (60 ml) and water (10 ml) were degased with nitrogen for 15 minutes. Pd(PPh3)4 (800 mg, 0.66 mmol) was added and the resulting mixture was heated to 90° C. for 48 hours under nitrogen. After being cooled to room temperature, the aqueous phase was separated and extracted with EtOAc (3×100 ml). The combined organic fractions were washed with brine, dried over MgSO4, filtered and evaporated to afford a brown oil. The following oil was dissolved in Et2O and extracted with 10% HCl solution (3×50 ml). The combined aqueous fractions were washed with Et2O (2×100 ml) and neutralized with concentrated NaOH solution. The resulting mixture was extracted with EtOAc (4×100 ml), the combined organic fractions were washed with brine (50 ml), dried over MgSO4, filtered and evaporated to dryness. The obtained residue was then purified by column chromatography (SiO2, EtOAc) to afford 1.2 g (46%) of the titled compound as a colorless oil, which solidify upon standing. The crude compound was purified by column chromatography (SiO2, CHCl3 then CHCl3/MeOH, 97/3) to afford 1 g (40%) of the titled compound as a colorless oil, which solidify upon standing.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21]N.C(Cl)Cl.C[N:27]1CCCC1=O>CO>[NH2:27][CH:19]([CH2:20][CH3:21])[CH2:18][NH:17][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2ccc(Cl)cc21
Reactant: NCCCCN
Reactant: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: CCC(N)CNc1ccc2c(=O)c(C(=O)O)cn(C)c2c1
Temperature: 130 °C

Procedure:
To a solution of 7-chloro-1-methyl-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (1.0 g, prepared according to H. Agui and T. Nakagome, J. Heterocycl. Chem., (1979), 16(7), 1353–60) in 1-methyl-2-pyrrolidinone (10 mL), was added 1,4-diaminobutane (1.84 g). The mixture was heated at 130° C. for 17 hours. The reaction mixture was cooled and poured into DCM (20 mL). The precipitate obtained was dispersed in MeOH and filtered to give the title compound (860 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[N:45](COCC[Si](C)(C)C)[C:25]4[N:26]=[CH:27][N:28]=[C:29]([O:30][C:31]5[CH:36]=[CH:35][C:34]([NH:37][C:38]([NH:40][CH:41]6[CH2:43][CH2:42]6)=[O:39])=[C:33]([Cl:44])[CH:32]=5)[C:24]=4[CH:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[Cl:44][C:33]1[CH:32]=[C:31]([O:30][C:29]2[C:24]3[CH:23]=[C:22]([C:19]4[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:17][CH:18]=4)[NH:45][C:25]=3[N:26]=[CH:27][N:28]=2)[CH:36]=[CH:35][C:34]=1[NH:37][C:38]([NH:40][CH:41]1[CH2:42][CH2:43]1)=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3cc4c(Oc5ccc(NC(=O)NC6CC6)c(Cl)c5)ncnc4n3COCC[Si](C)(C)C)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ncnc3[nH]c(-c4ccc(OCC5CCNCC5)cc4)cc23)cc1Cl)NC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
After dissolving 37 mg of 4-(4-(4-(3-chloro-4-(3-cyclopropylureido)phenoxy)-7-(2-trimethysilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenoxymethyl)piperidine-1-carboxylic acid tert-butyl ester in 1 ml of trifluoroacetic acid, the mixture was stirred at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, saturated sodium bicarnobate water was added to alkalinity and liquid separation and extraction were performed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to dryness to obtain the 25 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:11]2=[N:10]1.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:21](=[O:25])[C:22]([CH3:24])=[CH2:23])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[C:15]3[O:20][CH2:19][O:18][C:16]3=[CH:17][C:11]2=[N:10]1
Reactant: Nc1ccc(O)c(-n2nc3cc4c(cc3n2)OCO4)c1
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc(O)c(-n2nc3cc4c(cc3n2)OCO4)c1

Procedure:
According to the procedure of Example 2, a sample of 2-(2-hydroxy-5-aminophenyl)-5,6-methylenedioxybenzotriazole is treated with methacryloyl chloride in the presence of triethylamine to yield 2-(2-hydroxy-5-methacrylamidophenyl)-5,6-methylenedioxybenzotriazole. The corresponding chloro, methoxy and methylenedioxy compounds of the acrylamidophenyl series may be produced according to the general synthetic routes disclosed above for the corresponding methacrylamidophenyl compounds.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].[CH2:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].Br[CH:19](C)C(Cl)=O.N1CCCC1>O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:12]([CH:11]([N:13]3[CH2:16][CH2:17][CH2:15][CH2:14]3)[CH3:19])=[N:1][C:2]=2[CH:6]=1
Reactant: CC(Br)C(=O)Cl
Reactant: CCN(CC)CC
Reactant: NC(=O)c1sc(Br)cc1N
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: CC(c1nc2cc(Br)sc2c(=O)[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (221 mg) produced in Example 1, step D, triethylamine (0.15 mL) and tetrahydrofuran (5.0 mL) was added 2-bromopropanoylchloride (0.11 mL) with stirring at room temperature. After 10 min, pyrrolidine (0.42 mL) was added, and the mixture was stirred at 70° C. for 1 hr. The reaction system was concentrated under reduced pressure, 2M aqueous sodium hydroxide solution (1.0 mL) was added to the residue, and the mixture was stirred with heating at 120° C. for 2 hr. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (276 mg) as a pale-yellow solid.