Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[SH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH:15]1([CH2:14][N:6]2[C:5]3[CH:18]=[CH:19][C:2]([S:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:3][C:4]=3[N:8]=[C:7]2[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:17][CH2:16]1
Reactant: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CC1
Reactant: COC(=O)CS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CSc1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Yield: 129.1 %

Procedure:
To a solution of 5-bromo-1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazole (Step D, 1.40 g, 4.36 mmol) in 1,4-dioxane (9 mL) were added N,N-diisopropylethylamine (1.52 mL, 8.72 mmol), methyl mercaptoacetate (0.39 ml, 4.36 mmol), tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.218 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (252 mg, 0.436 mmol). The mixture was heated to reflux for 21 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to give a dark brown syrup. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1 as eluent) to afford the title compound (1.95 g, quant.) as an orange syrup.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[F:12].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br-:1].[F:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1ccc(F)c(CBr)c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]

Procedure:
20 g (85.5 mmol) of the compound from Example 26A are dissolved in 250 ml of anhydrous toluene, and 22.4 g (85.5 mmol) of triphenylphosphine are added. The solution is heated under reflux for 16 h, resulting in the formation of a precipitate. The mixture is allowed to cool, and the precipitate is filtered off. After washing with diethyl ether, the precipitate is dried under reduced pressure. This gives 39 g (92% of theory) of the desired product.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:19][N:20]([CH3:17])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNCCc1ccccn1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: C=O
Product: CN(CCc1ccccn1)CON(Cc1ccccc1)Cc1ccccc1

Procedure:
The procedure of Example I is repeated using 21.33 g of dibenzylhydroxylamine, 9.73 g of aqueous formaldehyde (37%) solution and 13.62 g of 2-[2-(N-methylamino)ethyl]pyridine, to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[N:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN1CCCC1=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)=[CH:3][CH:4]=4)=[N:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1)c1cccc(C(F)(F)F)c1
Yield: 24.5 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.484 mmol), 3-(trifluoromethyl)benzoic acid (110 mg, 0.581 mmol), oxalyl chloride (84 μL, 0.969 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (5 mL) and N-methylpyrrolidone (5 mL) as starting materials and in the same manner as in Example 412, the title compound (57 mg, 24%) was obtained as a white powder.
Reaction SMILES: C([N:8]1[C:12]2([CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[O:23]([C:21]1[CH:22]=[C:17]([N:14]2[CH2:15][CH2:16][C:12]3([NH:8][CH2:9][CH2:10][CH2:11]3)[CH2:13]2)[CH:18]=[N:19][CH:20]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CN2CCCC23CCN(c2cncc(Oc4ccccc4)c2)C3)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: c1ccc(Oc2cncc(N3CCC4(CCCN4)C3)c2)cc1
Yield: 92.7 %

Procedure:
To a solution of 1-benzyl-7-(5-phenoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (690 mg, 1.79 mmol) in ethanol (25 mL) in a pressure bottle was added concentrated HCl (1 mL) and Pearlman's catalyst (Pd(OH)2, 20% on carbon, 50 mg). The solution was shaken under 50 psi of hydrogen gas for 8 h. The catalysts was removed by filtration through Celite, and the filter cake was washed with ethanol (20 mL). The solvent was removed by rotary evaporation, and the residue was basified with saturated aqueous sodium bicarbonate to pH 8-9. Solid sodium chloride (2 g) was added, and the solution was extracted with chloroform (4×20 mL). The combined chloroform extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to afford 490 mg of the desired compound as a light brown viscous liquid (92.7%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:17]=[C:16]([Cl:18])[C:15]([NH2:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]>CC(O)=O>[C:1]([NH:19][C:15]1[C:16]([Cl:18])=[CH:17][C:9]([Cl:8])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: Nc1cc(C(=O)O)c(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C(=O)O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Acetic anhydride (27 mL) was added to 2,4-dichloro-5-aminobenzoic Acid 1-3 (8.0 g, 0.041 mol) in glacial AcOH (150 mL). The solution was stirred at room temperature for 30 min and concentrated to yield the desired acetamide 1-4 as a white solid (9.6 g, 96%). 1H NMR (400 MHz, CD3OD) δ2.19 (s, 3H), 7.62 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH3:18][S:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[NH2:24]>>[F:17][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])=[N:7][C:2]([NH:24][C:23]2[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:21]([CH2:20][S:19][CH3:18])[CH:22]=2)=[N:3][CH:4]=1
Reactant: CSCc1cc(N)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: COc1cc(F)ccc1-c1nc(Nc2cc(CSC)cc(C(F)(F)F)c2)ncc1F

Procedure:
Intermediate 40.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-[(methylsulfanyl)methyl]-5-(trifluoromethyl)aniline. The residue was purified by chromatography (hexane to hexane/ethyl acetate 15%) to give the desired product.
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].[Br:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:15]=1[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([O:11][CH2:16][C:15]1[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:14]=1[Br:13])=[O:10]
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Reactant: Clc1cccc(Br)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1c(Cl)cccc1Br
Yield: 98 %

Procedure:
1 cis/trans 2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropane carboxylic acid (2.3 g), 2-bromo-6-chlorobenzylbromide (2.85 g) and potassium carbonate (1.6 g) were stirred together in acetone (30 ml) under reflux for 6 hours. The reaction mixture was cooled, diluted with water, and extracted three times with 50 ml portions of diethyl ether. The combined ether extracts were washed with water and with aqueous sodium bicarbonate solution (three times), dried over magnesium sulphate and evaporated to give the orange title product (4. g, 98%) m.p. 61°-67° C.
Reaction SMILES: [CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1.O>[CH:1]1([O:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccccn1
Reactant: O=C(O)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccn1)C(OC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A solution of rac-cyclopentyloxy-(3,4-dichloro-phenyl)-acetic acid (from Example 1, 50 mg, 0.17 mmol) and triethylamine (0.07 mL, 0.52 mmol) in toluene (5 mL), previously cooled to 0° C. was treated with 2,4,6-trichlorobenzoyl chloride (0.03 mL, 0.19 mmol) and the mixture was stirred at 0° C. After 1 h, 2-aminopyridine (20 mg, 0.21 mmol) and 4-dimethylaminopyridine (5 mg, 0.035 mmol) were added and the stirring was continued for 1 h at 0° C. The reaction was checked for completion, then it was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The product was purified by chromatography (Biotage Flash 12M column, 80/20 hexanes/ethyl acetate) to give rac-2-cyclopentyloxy-2-(3,4-dichloro-phenyl)-N-pyridin-2-yl-acetamide (48 mg, 76% yield) as a white foam: EI-HRMS m/e calculated for C18H18N2O2Cl2 (M+) 364.0745, found 364.0746.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]=1[OH:22])([CH3:11])([CH3:10])[CH3:9].O.[ClH:24]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:24][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([C:16]1[CH:17]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:13]([OH:22])=[C:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=1)=[O:5]
Reactant: CC(C)=CC(=O)Cl
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(Cl)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
In a 12 L round bottom flask, equipped with internal thermometer, mechanical stirrer, addition funnel and septum inlet, is placed a solution of 3,3-dimethylacryloylchloride (146 g, 1.23 mol) in CH2Cl2 (1000 mL). The stirred solution is cooled in a CH2Cl2 -dry ice bath to -10° C., and then TiCl4 (1M in CH2Cl2, 1476 mL, 1.47 mol, 1.2 eq) is added via canula at a rate such that the reaction mixture does not warm above -5° C. The solution is stirred for 10 min after addition is complete, and then a solution of 2,6-di-tert-butylphenol (253.4 g, 1.23 mol, 1.0 eq) in CH2Cl2 (500 mL) is added dropwise via addition funnel. The rate of addition is adjusted to maintain the reaction temperature below 0° C. After addition is complete, the cold bath is removed, and the mixture is allowed to stir at ambient temperature for 4 h. TLC analysis (EtOAc:hexane, 1:9) indicates the reaction to be complete. H2O (2 L) is added carefully, and the mixture is transferred to a 6 L extraction funnel. The organic phase is separated, washed with additional H2O (2×1000 mL), dried over Na2SO4, filtered, and returned to the 12 L reaction vessel. Ethereal HCl (1M, Aldrich, 2000 mL) is added. After stirring 2 h, the solution is transferred to the 6 L separatory funnel, and washed with H2O (3×1 L). The organic phase is dried over Na2SO4, filtered into a 10-L round bottom flask, and rotary evaported. The residue is taken up in 1 L pentane, and kept at -4° C. overnight. The resulting crystalline solid is filtered off and dried to give 3-chloro-1-(3, 5-di-tert-butyl-4-hydroxyphenyl )-3-methylbutan-1-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2C)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:21][O:22]C1C(N)=CC=CC=1>>[CH3:21][O:22][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: COc1ccccc1N
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 59 %

Procedure:
(RK1-1-27C) I This compound was prepared according to the procedure described for compound 11a except using o-anisidine. Recrystallization from DCM/Hexanes obtained the required product as white crystals, (164 mg, 59%). Mp=141-143° C.; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=8.8 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H), 7.56 (dd, J=8.0, 1.6 Hz, 1H), 7.11 (td, J=7.9, 1.5 Hz, 1H), 7.02 (br s, 1H), 6.94 (td, J=7.6, 1.2 Hz, 1H), 6.74 (dd, J=8.0, 1.2 Hz, 1H), 3.62 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[O:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(O)c1ccc(C(=O)[O-])cc1
Reactant: Oc1ccc(F)cc1F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.9 %

Procedure:
To the solution of 4-(1-hydroxyethyl)benzoate (300 mg. 1.67 mmol) in tetrahydrofuran (80 mL) was added triphenylphosphine (570 mg, 2.2 mmol) and 2,4-difluorophenol (159 mg, 1.67 mmol), the mixture was stirred for 30 minutes at room temperature, then diisopropylazodicarboxylate (568.3 mg, 2.2 mmol) was added dropwise to the solution at 0° C. The mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and the residue was purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl 4-(1-(2,4-difluorophenoxy)ethyl)benzoate (151 mg, 33%) as oil. 1H-NMR (300 MHz, CD3OD) δ 8.03 (d, J=8.1 Hz, 2H), 7.460 (d, J=8.1 Hz, 2H), 6.86-6.72 (m, 3H), 5.29 (q, 1H), 3.91 (s, 3H), 1.67 (d, J=6.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])=[O:20])=[CH:15][CH:14]=1)[C:6]([CH3:22])=[C:5]2[CH2:23][C:24]([OH:26])=[O:25].ClC1C=CC=C(C(OO)=[O:35])C=1>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:21])(=[O:35])=[O:20])=[CH:15][CH:14]=1)[C:6]([CH3:22])=[C:5]2[CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=C(CC(=O)O)c2cc(F)c(F)cc2C1=Cc1ccc(S(C)=O)cc1
Solvent: CC(C)=O
Product: CC1=C(CC(=O)O)c2cc(F)c(F)cc2C1=Cc1ccc(S(C)(=O)=O)cc1

Procedure:
To 5,6-difluoro-2-methyl-1-(ρ-methylsulfinylbenzylidene)-indene-3-aceticacid (0.005 mole) in acetone (15 ml.) is added, slowly with stirring, m-chloroperbenzoic acid (0.005 mole). The mixture is heated and evaporated to near dryness at 40°. The solid is washed with boiling water (4×50 ml.) and dried yielding 5,6-difluoro-2-methyl-1-(ρ-methylsulfonylbenzylidene)-indene-3-acetic acid, M.P. 228-230°. (R1 =hydrogen; R2 =CH3 ; R3 =5-fluoro; R4 =6-fluoro; R5 =CH3 --SO2 --).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[CH:4][C:3]=1[F:22].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[O:11][C:6]3[C:5]([F:21])=[CH:4][C:3]([F:22])=[C:2]([NH2:1])[C:7]=3[C:8](=[O:20])[CH:9]=2)=[CH:13][C:14]=1[F:19])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 2.2 h
Yield: 96 %

Procedure:
1.66 g of Compound 26 was dissolved in 20 ml of pyridine, the solution was cooled on ice, 0.46 ml of acetic anhydride was added and the mixture was stirred at room temperature for 2.2 hours. Then, the reaction solution was added to 100 ml of ice water and the precipitated crystals were collected by filtration to give 1.82 g (96%) of Compound 27.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:9][N:10]([CH2:21][CH:22](OC)OC)S(C1C=CC(C)=CC=1)(=O)=O>ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]2[C:27]([CH:22]=[CH:21][N:10]=[CH:9]2)=[CH:28][C:29]=1[F:30]
Reactant: COC(CN(Cc1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc(C)cc1)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Fc1cc2ccncc2cc1Cl
Reaction time: 0.5 h

Procedure:
343.6 (2.54 mol) of AlCl3 were suspended in 1.1 l of dichloromethane and were stirred for 30 min with a mechanical stirrer. To this suspension, a solution of 204 g (0.51 mol) (N-(3-chloro-4-fluoro-benzyl)-N-(2,2-dimethoxy-ethyl)-4-methyl-benzene-sulfonamide (55) was added and the mixture was stirred at room temperature for 5 h. After standing overnight, the reaction suspension was poured on ice, the organic layer was separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed twice with 1 N NaOH and saturated NaHCO3-solution, dried with MgSO4 and evaporated. The obtained crude product was purified by silicagel chromatography (heptane/ethyl acetate 1:1), which gave 61.3 g of the title compound. Rt=0.73 min (Method B). Detected mass: 182.1 (M+H+).
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=S.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([NH2:38])=[CH:33][CH:32]=[CH:31]2.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[OH:46].C(Cl)CCl>C(Cl)Cl.CC#N>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([NH:38][C:1]1[O:46][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[N:39]=1)=[CH:33][CH:32]=[CH:31]2
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1ccccc1O
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Solvent: ClCCCl
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4c(Nc5nc6ccccc6o5)cccc4c3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Thiocarbonyl diimidazole (113 mg, 0.65 mmol) was added to a mixture of 6-(6,7-dimethoxyquinolin-4-yloxy)naphthalene-1-amine (150 mg, 0.43 mmol), in CH2Cl2 (5 mL) at ambient temperature. After stirring for 3 h, the mixture was concentrated and the derived isothiocyanate was dissolved in MeCN (2 mL). A solution of 2-aminophenol (50 mg, 0.45 mmol) in MeCN (2 mL) was added and the mixture was stirred for 48 h at which point EDC (125 mg, 0.65 mmol) was introduced. The reaction was heated at 80° C. for 2 h. After cooling to ambient temperature, the suspension was filtered and the resulting solid was washed well with MeOH to furnish the title as a tan solid. MS (ESI, pos. ion) m/z: 464.1 (M+1). Mass Calc'd for C28H21N3O4: 463.48.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][Cl:32]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:21])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:29][CH2:30][CH2:31][Cl:32])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH2:6][CH2:7]1
Reactant: ClCCCBr
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCl

Procedure:
Using 5 g of of N-(trans-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 131), 120 ml of methylisobutylketone, 3.5 g of potassium carbonate, and 2.4 ml of 1-bromo-3-chloropropane, a reaction similar to that conducted in Example 106 was carried out. As a result, 5.63 g of N-(trans-4-methylcyclohexyl)-4-(3-chloropropoxy)-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[OH-].[K+].O>C(O)C>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)N1CCN(Cc2ccc(Oc3ccccc3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(Oc2ccc(CN3CCNCC3)cc2)cc1
Yield: 97.7 %

Procedure:
1-acetyl-4-((4-phenoxyphenyl)methyl)piperazine (316 mg) was dissolved in ethanol (20 ml), and aqueous potassium hydroxide solution (3 ml, potassium hydroxide 1 g) was added, followed by heating the mixture to reflux for 4 hours. Water was added to the reaction mixture and the mixture was extracted 3 times with chloroform. Organic layers were combined and dried over anhydrous sodium sulfate, followed by removal of chloroform to obtain 267 mg of 1-((4-phenoxyphenyl)methyl)piperazine. Yield: 98%.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6](C(Cl)=O)=[CH:5][CH:4]=1)[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([NH2:24])[C:22]([CH3:26])([CH3:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.[C:27]([O-:30])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]([NH:24][C:27](=[O:30])[C:5]3[CH:6]=[CH:10][CH:11]=[C:3]([CH2:1][CH3:2])[CH:4]=3)[C:22]([CH3:26])([CH3:25])[O:21][N:20]=2)=[CH:17][CH:18]=1
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: CC1(C)ON=C(c2ccc(Cl)cc2)N1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCc1cccc(C(=O)NN2C(c3ccc(Cl)cc3)=NOC2(C)C)c1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
4-Ethylbenzoyl chloride (78.4 mg, 0.466 mmol) and 3-(4-chloro-phenyl)-5,5-dimethyl-[1, 2,4]oxadiazol-4-ylamine (100 mg, 0.444 mmol) were dissolved in 4 mL of ethyl acetate in a 20 mL vial. With magnetic stirring, an aqueous solution of K2CO3 (2 mL, 0.166 g/mL) was added, and the mixture was stirred at room temperature for 18-64 hours. The reaction mixture was transferred to a separatory funnel. The organic phase was removed and evaporated to dryness under vacuum at room temperature and then at 50° C. for 30 minutes. The residue was triturated with a solution of 10% ether in hexane (7 mL) for 3-8 hours with magnetic stirring, and the resultant flocculent precipitate was removed and triturated again with 5% ether in hexane. Vacuum oven drying at 50° C. for 30 minutes yielded N-[3-(4-chloro-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-3-ethyl-benzamide in 90% purity. 1H-NMR (300 MHz, CDCl3) δ (ppm): 7.72 (d, 2H), 7.6 (d, 2H), 7.35 (d, 2H), 7.25 (d, 2H), 2.7 (q, 2H), 1.63 (s, 6H), 1.22 (t, 3H). Some analogs were purified by trituration with pentane, hexane, or heptane, or alternatively, by column chromatography using an ethyl acetate/hexane gradient.