Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BrH:13].N([O-])=O.[Na+]>C(#N)C.O.[Cu]Br>[Br:13][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1NCCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 7-amino-3,4-dihydro-1(2H)-isoquinolinone, (for a synthesis see Girard, Yves; Atkinson, Joseph G.; Belanger, Patrice C.; Fuentes, Jose J.; Rokach, Joshua; Rooney, C. Stanley; Remy, David C.; Hunt, Cecilia A J. Org. Chem. (1983), 48(19), 3220) (0.773 g, 4.772 mmol) in acetonitrile (10 ml) at 0° C. was added 48% aqueous hydrobromic acid (10 ml, precooled to 0° C.). The mixture was stirred at 0° C. for 0.5 h before addition of a solution of sodium nitrite (0.379 g, 5.49 mmol) in water (2 ml) over 0.4 h. The reaction was then stirred at 0° C. for 0.5 h and then copper(I) bromide (0.822 g, 5.726 mmol) was added portionwise over 10 min. The reaction mixture was then warmed to room temperature, stirred at room temperature for 0.5 h and then at 70° C. for 1 h. The reaction mixture was then cooled to 0° C., water (60 ml) was added and the mixture stirred at 0° C. for 1 h before filtering and drying in vacuo. The residue was dissolved in 10% methanol/dichloromethane, dried with magnesium sulphate and evaporated to give the desired product (0.679 g, 63%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[N:23]=[CH:24][N:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)[C:21]=2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([NH:50][C:51]2([C:54]([F:57])([F:56])[F:55])[CH2:53][CH2:52]2)=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[C:21]4[CH:20]=[CH:19][N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([NH:50][C:51]3([C:54]([F:57])([F:56])[F:55])[CH2:52][CH2:53]3)=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: O=C(NC1(C(F)(F)F)CC1)c1cnc(Cl)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)NC6(C(F)(F)F)CC6)cn5)C4)c3)ncnc21
Temperature: 125 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
N,N-Diisopropylethylamine (0.71 mL, 4.1 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (0.70 g, 1.4 mmol) and 5-chloro-N-[1-(trifluoromethyl)cyclopropyl]pyrazine-2-carboxamide (0.36 g, 1.4 mmol) in NMP (5.0 mL). The reaction mixture was stirred at 125° C. for 2 h. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-80%) to afford the desired product (0.90 g). LCMS (M+H)+: m/z=639.2.
Reaction SMILES: Cl.Cl.[I:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[N:6]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:5]=1.C(=O)(O)[O-].[Na+].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.O1CCOCC1>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:14]3[CH2:19][CH2:18][N:17]([C:33]([O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[CH2:16][CH2:15]3)[N:5]=[C:4]([I:3])[C:12]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncnc2c1c(I)nn2C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.1 %

Procedure:
To a mixture of 3-iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (13.86 g, 0.0333 mol) and sodium bicarbonate (8.4 g, 0.0999 mol) in water (140 mL) was added benzylchloroformate (6.48 g, 0.0383 mol) in dioxane (120 mL) at room temperature. The mixture was stirred at room temperature under an atmosphere of nitrogen for 18 hours. The yellow solid was filtered and washed with ethyl ether to yield benzyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (12 g, 0.025 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.5 min. MS: MH+ 479.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([C:23](OCC)=[O:24])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([CH2:23][OH:24])[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)n(-c2cccnc2F)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1cccc(Br)c1)c1cc(CO)nn1-c1cccnc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A solution of ethyl 5-[(3-bromophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylate (467 mg) in tetrahydrofuran (5 mL) was cooled to −78° C., and a 1.5 mol/L solution (2.7 mL) of diisobutylaluminum hydride in toluene was added dropwise. The reaction mixture was stirred at 0° C. for 2 hr, treated with 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow oil (yield 371 mg, yield 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=4)=[C:11]3[C:10]([CH3:27])=[N:9]2)=[CH:5][CH:4]=1.CO.[NH4+].[Cl-].Cl>[Zn].C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=4)=[C:11]3[C:10]([CH3:27])=[N:9]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc([N+](=O)[O-])cc4)ccnc32)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4)ccnc32)cc1
Yield: 93.7 %

Procedure:
To a 100 mL round-bottomed flask with stir bar containing 1-(4-methoxybenzyl)-3-methyl-4-(4-nitrophenoxy)-1H-pyrazolo[3,4-b]pyridine (0.185 g, 0.474 mmol) was added MeOH (10 mL) and THF (10 mL) followed by zinc (0.155 g, 2.37 mmol). Next, saturated NH4Cl (0.5 mL) was added with stirring. Concentrated HCl (0.5 mL) was added until all solids dissolved (except for some zinc powder) and the pH had dropped to 2. The reaction was stirred for 18 hours at room temperature. The reaction was concentrated and partitioned between EtOAc (100 mL) and 1:1 saturated NaHCO3/water (100 mL). The aqueous phase washed with EtOAc (75 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The product (160 mg, 82%) was obtained as a yellow gum. LRMS (esi pos) m/e 361 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](OCC)(OCC)(OCC)[CH3:13]>>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:12]([CH3:13])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1ccc(I)cc1
Product: Cc1nnc(-c2ccc(I)cc2)o1
Temperature: 130 °C

Procedure:
Triethyl orthoacetate (10 ml) was added to 4-iodo-benzoic acid hydrazide (Intermediate 14) (0.55 g, 2.1 mmol) and heated under nitrogen at 130° C. for 3 hours. The triethyl orthoacetate was removed in vacuo and the residue partitioned between ethyl acetate (30 ml) and water (30 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over magnesium sulfate filtered and the solvent removed in vacuo. The residue was purified by silica SPE cartridge (10 g) eluting with 20:1 cyclohexane/ethyl acetate v:v to 5:1 cyclohexane/ethyl acetate v:v. The desired product was obtained as a white solid (0.31 g, 1.1 mmol).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[S:51]([CH3:54])(=[O:53])=[O:52]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[C:31](=[N:33][N:34]([CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[S:51]([CH3:54])(=[O:53])=[O:52])[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CS(=O)(=O)c1ccccc1CBr
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn(Cc3ccccc3S(C)(=O)=O)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-(methylsulfonyl)benzene and isolated as white solid. MS (m/e): 443.3 (MH+).
Reaction SMILES: C(N(CC)CC)(C)C.[Si:9]([O:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([CH3:29])=[CH:22][C:23]([CH3:28])([CH3:27])[NH:24]2)=[CH:19][CH:18]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].I[CH:31]([CH3:40])[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C(OCC)C>[C:36]([O:35][C:33]([CH2:32][CH2:31][CH2:40][N:24]1[C:25]2[C:20](=[CH:19][CH:18]=[C:17]([O:16][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:26]=2)[C:21]([CH3:29])=[CH:22][C:23]1([CH3:28])[CH3:27])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC1=CC(C)(C)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reactant: CC(I)CC(=O)OC(C)(C)C
Agent: CCN(CC)C(C)C
Solvent: CCOCC
Product: CC1=CC(C)(C)N(CCCC(=O)OC(C)(C)C)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reaction time: 96 h
Yield: 27 %

Procedure:
N-Isopropyl-N,N-diethylamine (8.17 g, 63.4 mmol) was added to a mixture of compound 3 (9.60 g, 31.7 mmol) and t-butyl 3-iodobutyrate [a) V. Chaleix, V. Sol, Y.-M. Huang, M. Guilloton, R. Granet, J. C. Blais, P. Krausz, Eur. J. Org. Chem. 2003, 1486-1493; b) M. P. Glenn, P. Kahnberg, G. M. Boyle, K. A. Hansford, D. Hans, A. C. Martyn, P. G. Parsons, D. P. Fairlie J. Med. Chem. 2004, 47, 2984-2994] (10.7 g, 34.9 mmol) in a screw-cup bottle, and the reaction mixture was stirred at +110° C. (bath temp.) for 4 days. After cooling, the reaction mixture was diluted with diethyl ether, passed through a plug of silica gel (eluting with ether), and the solvents were evaporated in vacuo. The residue was dissolved in a hexane/ether (3/1) mixture, washed with sat. aq. NaHCO3, and the solution was passed again through a plug of silica gel (eluting with hexane/ether (3/1) mixture). According to TLC (hexane/ether=10/1), two spots were detected in the eluate: that of compound 3 (Rf=0.48) and compound 4 (Rf=0.43). After evaporation of solvents in vacuo, the oily residue was distilled in the Kugelrohr distillation apparatus. Compound 4 (4.16 g, 27% yield) was collected at 180° C. (0.6 Torr). The first fraction (4.0 g, b.p. 150° C. at 0.6 Torr) was shown to be compound 3 (ca. 95% pure), and the second one (2.0 g, b.p. 150-180° C. at 0.6 Torr) a mixture of compounds 3 and 4 in ca. 1/3 ratio. 1H NMR (300 MHz, CDCl3): δ=0.21 (s, 6 H, SiMe2But), 0.98 (s, 9 H, SiMe2But), 1.28 (s, 6 H, 2×Me), 1.46 (s, 9 H, CO2But), 1.86 (m, 2 H, NCH2CH2CH2CO2But), 1.95 (d, J=0.5 Hz, 3 H, Me), 2.30 (m, 2 H, NCH2CH2CH2CO2But), 3.20 (m, 2 H, NCH2CH2CH2CO2But), 5.10 (d, J=0.5 Hz, 1 H, HC═), 6.02 (dd, J=1.8 and 0.4 Hz, 1 H), 6.10 (dd, J=8.5 and 1.8 Hz, 1 H), 6.88 (dd, J=8.5 and 0.4 Hz, 1 H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>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.C(O)C.C1(C)C=CC=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[N:7][C:2]([C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: OB(O)c1ccco1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccco2)nc1
Temperature: 25 °C

Procedure:
A mixture of the product of Step 1 (205 mg, 0.5 mmol), 2-furanylboronic acid (112 mg, 2 mmol), 1M sodium carbonate solution (2.5 ml, 2.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) in 1:1 toluene:ethanol (10 ml) was stirred at reflux under an atmosphere of argon for 1.5 hours. After cooling to room temperature the reaction mixture was acidified with 2N hydrochloric acid and applied to a 10 g SCX column and eluted in methanol then 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo. The crude residue was purified by mass directed autoprep to afford the title product (E272). MS (ES+) 443 [M+H]+.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.O.[NH2:21][NH2:22]>CCO>[N+:17]([C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[NH:22][N:21]=[C:4]2[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:19])=[O:18]
Reactant: O=C(Nc1ccccc1)c1cc([N+](=O)[O-])ccc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]nc(Nc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
2-Fluoro-5-nitro-N-phenyl benzamide (100 mg, 0.38 mmol) was suspended in EtOH (10 mL) and the mixture heated to 50° C. To the resulting solution was added hydrazine monohydrate (0.1 mL, 1.9 mmol). The mixture was heated at reflux for 30 minutes, at which time LC-MS showed complete conversion to the aryl hydrazine (ES+m/e=273). The mixture was allowed to cool to room temperature, concentrated and the residue partitioned between EtOAc and saturated ammonium chloride solution. The layers were separated and the organic phase was dried over sodium sulfate and concentrated to a yellow foam. The residue was dissolved in phosphorous oxychloride (5 mL) and the mixture heated at 90° C. for 30 minutes, then allowed to cool to room temperature and stirred overnight. The reaction mixture was concentrated and the residue partitioned between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated to afford the title compound as a red solid (80 mg, 83%); 1H NMR (400 MHz, DMSO) 6.88 (1H, t), 7.31 (2H, t), 7.51 (1H, d), 7.74 (2H, t), 8.17 (1H, dd), 9.24 (1H, s), 9.42 (1H, s), 12.74 (1H, s); MS (ES+) m/e=255.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](O)=[O:22]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:21]([C:20]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:18]([Cl:17])[CH:19]=2)[OH:22])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(Cl)c(Cl)c1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 3,4-dichlorobenzoic acid
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7](O)[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[Br:29][CH2:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: Cc1ncsc1C(C)O
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ncsc1CCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
A solution of 1 g (7 mmol) of 4-methyl-5-thiazolylethanol in 15 mL of dichloromethane is cooled to 0° C. under argon. In a first stage, 1.8 g (7 mmol) of triphenylphosphine are added. Next, 1.30 g (7 mmol) of N-bromosuccinimide are added portionwise over 5 minutes. After stirring for 2 hours at 0° C., the solvent is evaporated off under vacuum. The residue obtained is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 900 mg of 5-(2-bromoethyl)-4-methylthiazole, the characteristics of which are as follows:
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([CH:9](Br)Br)=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:13]1(=[O:20])[CH:18]=[CH:17][C:16](=[O:19])[CH:15]=[CH:14]1.[I-].[Na+]>CN(C=O)C>[CH:5]1[C:4]2[C:3](=[CH:2][C:18]3[C:13](=[O:20])[C:14]4[C:15]([C:16](=[O:19])[C:17]=3[CH:9]=2)=[CH:9][C:4]2[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:2]=4)[CH:8]=[CH:7][CH:6]=1
Reactant: BrC(Br)c1ccccc1C(Br)Br
Reactant: O=C1C=CC(=O)C=C1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2cc3ccccc3cc2C(=O)c2cc3ccccc3cc21
Temperature: 120 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a clear solution of α,α,α′,α′-tetrabromo-o-xylene (30.5 g, 0.073 mol) in DMF (100 mL) was added benzoquinone (3.125 g, 0.03 mol) and sodium iodide (27.25 g, 0.18 mol). The resulting brown suspension was heated and stirred at 120° C. overnight. After cooling to RT, the yellow solids were filtered via vacuum filtration. The yellow solids were washed with water, saturated sodium bisulfite solution and dried to yield the product (8.1 g, 91%). 1H NMR (500 MHz, CDCl3): δ 8.96 (s, 4H), 8.14 (m, 4H), 7.72 (m, 4H). 13C NMR (125.68 MHz, CDCl3): δ 183.2, 135.47, 130.80, 130.30, 129.98, 129.66. m/z: 308 [M+].
Reaction SMILES: [Br-].[C:2]1([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][O:10][C:9]2=[N+:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[C:31]2[CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[C:31]2[CH2:39][CH:40]2[CH2:41][CH2:42][N:43]([CH2:11][CH2:12][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([N:13]([CH3:15])[CH3:14])=[O:10])[CH2:44][CH2:45]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(Cn2c(CC3CCNCC3)nc3ccccc32)cc1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C(CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A mixture of 5.55 parts of N-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide, 4.85 parts of 1-[(4-fluorophenyl)methyl]-2-(4-piperidinylmethyl)-1H-benzimidazole, 2 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.8 parts (20%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 151.4° C. (150).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]2[N:23]=[CH:22][O:21][N:20]=2)[C:3]=1[S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:43](OC)(OC)[O:44][CH3:45]>>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([N:1]=[CH:43][O:44][CH3:45])=[C:3]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:25])=[O:26])[C:4]([C:19]2[N:23]=[CH:22][O:21][N:20]=2)=[N:5]1
Reactant: Nc1c(S(=O)(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC=Nc1c(S(=O)(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 23 %

Procedure:
To 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1,2,4-oxadiazol-3-yl)-4-trifluoromethylsulfonylpyrazole (1.00 g, 2.02 mmol) and 10 ml of trimethyl orthoformate was added p-toluenesulfonic acid monohydrate (0.05 g) with stirring at room temperature. The mixture was stirred with heating at reflux for 59 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in 50 ml of toluene and then concentrated under reduced pressure. After this procedure was repeated once again, the resulting concentrated residue was purified by subjecting to silica gel column chromatography [eluent: mixed solvent of ethyl acetate and chloroform (volume ratio=1:20)]. The resulting crystal was washed with hexane and filtered to obtain 124 mg (0.46 mmol) of the title compound as a colorless crystal. Yield 23.0%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH:29]([CH3:35])[CH2:30][CH2:31][CH2:32][C:33]#[CH:34]>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.[Cu](I)I.C(N(CC)CC)C>[CH2:15]([O:14][C:11]1[CH:10]=[N:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]#[C:33][CH2:32][CH2:31][CH2:30][CH:29]([O:28][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][O:22]3)[CH3:35])=[CH:3][CH:4]=2)=[N:13][CH:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#CCCCC(C)OC1CCCCO1
Reactant: Brc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(CCCC#Cc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1)OC1CCCCO1
Temperature: 90 °C

Procedure:
In a reactor equipped with a stirrer and a thermometer, 2-(4-bromophenyl)-5-benzyloxypyrimidine, 6-tetrahydropyranyloxy-1-heptyne, dichlorobis(triphenylphosphine)palladium, copper iodide, triphenylphosophine and triethylamine are charged and heated up to 90° C. to carry out a reaction for 8 hours. After extraction with toluene and washing with water, the mixture is evaporated under reduced pressure. A resulting residue is purified by silica gel column chromatography to obtain 5-benzyloxy-2-[4-(6-tetrahydropyranyloxy-1-heptynyl)phenyl]pyrimidine.