Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][C:6](=[CH:8][CH2:9][CH2:10][O:11]CC2C=CC=CC=2)[CH2:5][CH2:4][O:3]1>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1([CH3:19])[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:5][CH2:4][O:3]1
Reactant: CC1(C)CC(=CCCOCc2ccccc2)CCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CC(CCCO)CCO1
Reaction time: 16 h
Yield: 54.8 %

Procedure:
A solution of 2,2-dimethyl-4-{3-[(phenylmethyl)oxy]propylidene}tetrahydro-2H-pyran (5.98 g, 22.97 mmol) in ethyl acetate (70 ml) was hydrogenated over 10% palladium on activated carbon (0.733 g, 0.689 mmol) at atmospheric pressure and room temperature. After 16 hours, the mixture was filtered under vacuum through Celite, washed through with EtOAc (2×50 mL) and the filtrate was evaporated to dryness to give a yellowish mobile oil. 1H NMR showed that most of the benzyl group had been hydrogenated but the double bond was still present. The residue was dissolved in ethyl acetate (70 ml) and was hydrogenated over 10% palladium on activated carbon (1.1 g) at atmospheric pressure and room temperature. After 16 hours, the mixture was filtered under vacuum through Celite, washed through with EtOAc (2×50 mL) and the filtrate was evaporated to dryness to give a yellowish mobile oil. The residue was purified by chromatography on silica (100 g) using a cyclohexane:ethyl acetate 0->50% gradient over 40 mins on a Flashmaster II. The desired fractions (analysed with a permanganate dip) were combined and concentrated under vacuum to give the title compound as a pale yellow oil (2.17 g).
Reaction SMILES: [C:1]([C:9]1[C:10](OCC)=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([NH2:31])([CH2:29][CH3:30])[CH3:28]>>[C:1]([C:9]1[C:10]([NH:31][CH:27]([CH2:29][CH3:30])[CH3:28])=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C)N
Reactant: CCOc1c(C(=O)c2ccccc2)cnc2c1cnn2Cc1ccco1
Product: CCC(C)Nc1c(C(=O)c2ccccc2)cnc2c1cnn2Cc1ccco1

Procedure:
34.7 g. of 5-benzoyl-4-ethoxy-1-(2-furanyl)methyl-1H-pyrazolo[3,4-b]pyridine (0.1 mol.) is refluxed for 10 hours with 50 ml. of sec. butylamine. The excess amine is removed in vacuo and the residue recrystallized from methanol to obtain 5-benzoyl-4-sec.butylamino-1-(2-furanyl)methyl-1H-pyrazolo[3,4-b]pyridine, yield 31 g. (83%), m.p. 112°-114° (methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:11][CH2:10]1.C(O[Na])(C)(C)C.O>CS(C)=O>[CH:9]1([S:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: BrC1CC1
Reactant: Fc1ccc(S)cc1
Agent: CC(C)(C)O[Na]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc(SC2CC2)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
To a stirred solution of 4-fluorobenzenethiol (134 g, 1.05 mol) in DMSO (3 L) under nitrogen atmosphere were added cyclopropyl bromide (140 g, 1.15 mol) and t-BuONa (138.7 g, 1.44 mol). Then the reaction mixture was heated to 80° C. and stirred for 2 days. TLC (petroleum ether) indicated the reaction was complete. After cooled to room temperature, the mixture was poured into water (2 L), extracted with diethyl ether (1.5 L×3). The combined organic phases were washed with water (1 L), then brine (1 L), dried over Na2SO4 and concentrated in vacuum to give cyclopropyl(4-fluorophenyl)sulfane (129 g, 73.1%) as a colorless oil. To a mixture of cyclopropyl(4-fluorophenyl)sulfane (129 g, 0.77 mol) and acetic acid (1.9 L) was added 30% H2O2 (1.2 L), and the mixture was heated to reflux and stirred overnight. TLC (petroleum ether:ethyl acetate=4:1) indicated the reaction was complete. After cooled to room temperature, the mixture was poured into water (1 L), then Na2S2O3 (200 g) was added to consume excess H2O2, then Na2CO3 was added to adjust pH =7. The mixture was extracted with ethyl acetate (1.5 L×2). The combined organic layers were washed with water (1 L), dried over Na2SO4 and concentrated in vacuum to give 69 g of crude product, which was purified by column chromatography (25% ethyl acetate in petroleum ether) to give the title compound (42 g, 27.3%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[C:12]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][CH:15]=[C:14]([C:2]2[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=2)[CH:13]=1
Reactant: COc1cc(Cl)cnc1OC
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(-c2cccc(-c3ccccc3)c2)cnc1OC
Temperature: 150 °C
Yield: 34.2 %

Procedure:
To a mixture of 5-chloro-2,3-dimethoxypyridine (200 mg, 1.15 mmol), biphenyl-3-ylboronic acid (207 mg, 1.045 mmol), PdCl2(dppf).CH2Cl2 (43 mg, 0.052 mmol), under nitrogen, was added. THF (2.5 mL) followed by 1 M aqueous Na2CO3 solution (1.57 mL). The reaction mixture was heated at 150° C. (microwave irradiation) for 40 min, cooled to room temperature and partitioned between water and EtOAc. Layers were separated and the aqueous solution was extracted with EtOAc (2×). Combined organic solutions were dried over Na2SO4 and concentrated. Purification by flash chromatography (24 g silica gel, 1% to 20% EtOAc in hexanes) afforded 104 mg (34%) of 5-(biphenyl-3-yl)-2,3-dimethoxypyridine as a light yellow viscous liquid. LC/MS (M+H)+ 292.2.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:13]=1[C:24]([F:27])([F:26])[F:25])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.[Cl-].[Na+].O>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH2:29][CH2:28][C@@H:9]([OH:8])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][C:13]=2[C:24]([F:26])([F:27])[F:25])[CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(-c2ccccc2)cc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
(2R)-2-(tert-Butyldimethylsilyloxy)-4-(3-pyridyl)-1-(3-trifluoromethylbiphenyl-4-yloxy)butane (0.8 g, ~67% pure) was dissolved in tetrahydrofuran (10 ml) and tetrabutylammonium fluoride (0.84 g) was added. The reaction was stirred at ambient temperature for 1 hour and was then poured into brine and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. The residue obtained was purified by reverse phase HPLC to give the title compound as a white solid (0.13 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[CH:19](=[O:23])[CH:20]([CH3:22])[CH3:21]>C1COCC1>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CC(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 99.7 %

Procedure:
To a solution of 1-iodo-2-nitrobenzene (1.12 g, 4.5 mmol) in anhydrous THF (15 mL) cooled to minus 40° C. under nitrogen atmosphere, a solution of phenylmagnesium chloride (2 M in THF, 2.4 mL, 4.8 mmol) was added dropwise at a rate that the temperature would not exceed minus 35° C. Upon completion of the addition the mixture was stirred for five minutes at minus 40° C., followed by addition of isobutyraldehyde (0.545 mL, 6.0 mmol). The mixture was gradually warmed up to room temperature, quenched with saturated ammonium chloride (6 mL), poured into water (80 mL), and extracted with ethyl acetate three times (100 mL). Combined organic phase was washed with brine (80 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield racemic (RS)-1-(2-nitrophenyl)-2-methyl-propanol (0.876 g, 99%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.84 (dd, 1 H, J=1.2 and 8.2 Hz, Ph-H), 7.73 (dd, 1 H, J=1.4 and 7.9 Hz, Ph-H), 7.61 (m, 1 H, Ph-H), 7.39 (m, 1 H, Ph-H), 5.03 (dd, 1 H, J=4.5 and 5.8 Hz, Ph-CH), 2.42 (d, 1 H, J=4.5 Hz, OH), 2.02 (m, 1 H, CH), 0.95 (d, 3 H, J=6.7 Hz, CH3), 0.89 (d, 3 H, J=6.8 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 148.48 (C), 138.91 (C), 132.95 (CH), 128.85 (CH), 127.95 (CH), 124.21 (CH), 73.79 (CH), 34.30 (CH), 19.66 (CH3), 17.01 (CH3).
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[O:24][CH3:25])=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[ClH:34].[CH3:25][O:24][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)=[CH:16][C:11]=1[NH:10][C:9]([NH2:26])=[NH:8]
Reactant: COc1ccc(-c2cc(C)ccn2)cc1N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2cc(C)ccn2)cc1NC(=N)N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(2-methoxy-5-(4-methylpyridin-2-yl)phenyl)guanidine (200 mg) in dichloromethane (2 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 4 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the resultant precipitate was collected by filtration and dried under reduced pressure to give (2-methoxy-5-(4-methylpyridin-2-yl)phenyl)guanidine dihydrochloride (127 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CCN=C=NCCCN(C)C.Cl.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:8]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
To a stirred solution of 5-chloro-4-(4-chloro-3-(trifluoromethyl)phenoxy)-2-fluorobenzoic acid (Preparation 32, 219 mg, 0.58 mmol) in DCM (3 mL) were added EDCl (167 mg, 0.87 mmol) and DMAP (106 mg, 0.87 mmol) and the reaction stirred at room temperature for 30 minutes. Methanesulfonamide (83 mg, 0.87 mmol) was added and the stirring continued at room temperature for 16 hours. DCM (25 mL) and 2M aq. HCl (5 mL) were added and the two layers separated. The organic extract was washed with 2M aq. HCl (5 mL) and brine (10 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc:heptane:AcOH (50:50:0.5), followed by recrystallisation from hot IPA to yield the title compound (89 mg, 34%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2cnc3cc(C(F)(F)F)ccc32)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-n2cnc3cc(C(F)(F)F)ccc32)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To an ice cooled solution of 1-(3-methoxyphenyl)-5-trifluoromethylbenzimidazole (79a)(0.50 g, 1.71 mmol) under nitrogen in dry methylene chloride (20 ml) was added boron tribromide (2.6 ml of an 1M solution in methylene chloride). The ice bath was removed and the reaction mixture was stirred for two days at room temperature, Dilution with water and extractive workup with ether was followed by chromatography. Yield: 0.29 g, 1.04 mmol, 61%. mp 168°-170° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11](O)(=[O:16])[CH2:12][C:13]([OH:15])=[O:14].N1C=CC=CC=1.NC1C=CC=CC=1>C(O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:11](=[O:16])[C:12]([C:13]([OH:15])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1ccc(O)c(C=O)c1
Solvent: O
Solvent: Nc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2oc(=O)c(C(=O)O)cc2c1
Temperature: 40 °C

Procedure:
2 g of 5-methylsalicylaldehyde (14.7 mmol), 3.06 g of malonic acid (29.4 mmol), 1.3 g of pyridine and 0.08 g of aniline are dissolved in a minimum amount of ethanol. The mixture is heated at 40° C. on a water bath for 6 h. Next, it is diluted with water, acidified and then extracted with ether. The solvent is removed by distillation under reduced pressure. The residue obtained is recrystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17].[C:21](Cl)(=[O:26])[CH2:22][C:23](Cl)=[O:24].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:16]([C:15]1[CH:14]=[C:13]([N:12]2[C:23](=[O:24])[CH2:22][C:21](=[O:26])[NH:1][C:2]3[C:11]4[C:6]([CH:5]=[CH:4][C:3]2=3)=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:20]=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1cccc(Nc2ccc3ccccc3c2N)c1
Reactant: O=C(Cl)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 27.4 %

Procedure:
To an ice-cold solution of 3-(1-amino-2-naphthylamino)benzonitrile (968 mg, 3.73 mmol) in toluene (10 mL) was added malonyl chloride (436 μL, 4.48 mmol). The mixture was stirred at 80° C. for 20 minutes, then at 110° C. for 10 minutes. After the reaction mixture was cooled to room temperature, the solution part of the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution, and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. While The precipitated solid in the reaction mixture was dissolved in chloroform, was washed with a saturated aqueous sodium bicarbonate solution, and saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residues were combined, and Each product purified by silica gel column chromatography (hexane/ethyl acetate=1/4), and the residue was recrystallized from ethyl acetate to give the titled compound as a pale yellow crystal (335 mg, yield 27%). mp: 220-222° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([CH:15]([C:24]([NH2:26])=[O:25])[C:16]2[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH2:31]([O:33][C:34](=[O:41])[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:32].[Na].[Na].C(OC(=O)CC(OCC)=O)C.[I-].[K+]>C(Cl)(Cl)Cl.C(O)C>[CH2:31]([O:33][C:34](=[O:41])[CH:35]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([CH:15]([CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:14])[C:24]([NH2:26])=[O:25])=[CH:17][CH:18]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:32]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(CCl)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(C(C(N)=O)C(C)c2ccccc2N2CCCCC2)cc1)C(=O)OCC

Procedure:
A solution of 3.7 gm (10 m mol) of 4-[(1-(2-piperidinophenyl)-ethyl)-aminocarbonylmethyl]-benzyl chloride [m.p.: 123°-125° C.; prepared from the alcohol described in Example 25 by means of thionyl chloride in chloroform] in 35 ml of absolute ethanol was added dropwise to a solution of sodium malonic acid diethyl ester [prepared from 0.7 gm (30 m mol) of sodium in 25 ml of absolute ethanol and 4.8 gm (30 m mol) of malonic acid diethyl ester]. A catalytic amount of potassium iodide was added, and the mixture was refluxed for 16 hours. After evaporation in vacuo, the evaporation residue was adjusted neutral by means of hydrochloric acid and extracted with methylene chloride. The organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone=6:1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=2)[C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:27][N:28]([C:30](=[O:33])[CH2:31][CH3:32])[NH2:29].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCCl.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:10]=[C:9](/[CH:11]=[CH:12]/[CH:13]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:14]([F:17])([F:15])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][N:28]([CH3:27])[C:30](=[O:33])[CH2:31][CH3:32])=[O:5]
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: CCC(=O)N(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCC(=O)N(C)NC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br

Procedure:
To a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl) but-1-enyl) benzoic acid (200 mg, 0.41 mmol) in DCE (15 mL) was added N-methylpropionohydrazide (WO 2009110510) (50 mg, 0.49 mmol), DMAP (55 mg, 0.45 mmol), EDC.HCl (60 mg, 0.41 mmol) and DIPEA (0.20 mL, 1.1 mmol). The reaction mixture was stirred at 25° C. for 12 h, —diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh) eluting with 30% EtOAc in hexane afforded the title compound as an off white solid (86 mg, 34%).
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[NH2:31][C:32]1[N:37]=[CH:36][C:35]([C:2]2[N:6]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:4]([CH3:17])[C:3]=2[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:34][CH:33]=1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: Nc1ccc(B(O)O)cn1
Product: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(-c2ccc(N)nc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with 6-amino-pyridin-3-yl-boronic acid to give the title compound as off-white solid. MS: 499.2 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:29][CH3:30])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][C:7]1=[O:28]>CO.[Pd]>[CH3:30][O:29][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][CH2:8][C:7]1=[O:28]
Reactant: COc1ccc2c(c1)N(CCC(OC)OC)C(=O)CN2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)N(CCC(OC)OC)C(=O)CN2
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Benzyl 4-(3,3-dimethoxypropyl)-6-methoxy-3-oxo-3,4-dihydroquinoxalin-1(2H)-carboxylate (386 mg, 0.931 mmol) was dissolved in methanol (5 ml), 10% palladium on carbon (50% wet, 200 mg) was added thereto and the mixture was stirred at room temperature for 4 hours under a hydrogen gas atmosphere. After removing the catalyst by filtration using celite, the filtrate was concentrated under reduced pressure to yield 201 mg (77%) of a crude product of the title compound in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>O>[OH:17][CH:15]1[CH2:16][N:6]2[C:2](=[N:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)[NH:1][CH2:13]1
Reactant: ClCC1CO1
Reactant: Nc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1CNc2nc3ccccc3n2C1
Reaction time: 3 h

Procedure:
1.33 g. (0.01 moles) of 2-amino-benzimidazole are dissolved in 100 ml. of alcohol, and 0.4 g. (0.01 moles) of sodium hydroxide dissolved in 5 ml. of water are added to the mixture, followed by the addition of 0.92 g. (0.01 moles) of epichlorohydrine. The reaction mixture is boiled for about 3 hours. The reaction is completed when the inorganic salt ceases to separate. The separated sodium chloride is filtered off, washed with 2 × 5 ml. of alcohol, and the combined filtrate and wash is evaporated to dryness. 1.8 g. (80%) of white, crystalline 1,2,3,4-tetrahydro-3-hydroxy-pyrimido[1,2-a]benzimidazole are obtained; m.p.: 158°-160°C (heating rate: 4°C/min.).
Reaction SMILES: [Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+].[Na].[C:11](O)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[C:32](OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+:6].[Na+:6].[Na+:6].[CH2:32]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: C=Cc1ccccc1

Procedure:
About 30 parts by weight of an aqueous sodium silicate solution containing 14.7% Na2O and 29.4% SiO2 by weight, 20 parts by weight of styrenes, 0.5 parts by weight of the sodium salt of ricinoleic sulphonates and 1 part by weight of benzoic acid are thoroughly mixed and emulsified; then 0.1 part by weight of potassium persulfate, 0.01 part by weight of ferric sulfate and 0.1 part by weight of benzoyl peroxide is added to the emulsion and thoroughly mixed at ambient temperature (24° C.) and pressure. The mixture is polymerized in 1 to 24 hours thereby producing a poly(sodium silicate-styrene) copolymer emulsion.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:33]2[S:34][C:35]3[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=3[N:37]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[S:34][C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A suspension of 0.2 g (0.469 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide, 0.17 g (0.775 mmol) of 2-(piperazin-1-yl)-benzothiazole, 0.1 g of potassium carbonate and 1 ml of water in 10 ml of acetonitrile is stirred for 10 hours at ambient temperature. The reaction mixture is then poured onto water, extracted with dichloromethane and the organic phase is dried over sodium sulphate. The product is purified by column chromatography on silica gel (eluant: dichloromethane/acetone =20:1, then dichloromethane/methanol=20:1).