Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12]Cl)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26][NH2:27].C(N(CC)CC)C.O>CS(C)=O>[O:1]1[C:5]2[C:6]([O:10][CH2:11][CH2:12][NH:27][CH2:26][CH2:25][CH2:24][C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=4)[NH:20][CH:19]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: ClCCOc1cccc2c1OCC2
Reactant: NCCCc1c[nH]c2ccc(F)cc12
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4c3OCC4)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 77.2 %

Procedure:
A solution of 2-(2,3-dihydrobenzofuran-7-yloxy)ethylchloride (0.38 g, 1.9 mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (0.93 g, 4.8 mmol), triethylamine (0.48 g, 4.8 mmol) in anhydrous DMSO (20 ml) was allowed to stir at 90° C. for 12 hours. The mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.52 g (77%) of product as a yellow oil.
Reaction SMILES: C(O)CCC.[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>CC(O)CC>[CH:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCO
Solvent: CCCCO
Solvent: CCC(C)O
Product: CCCCCCCC=O

Procedure:
Simple aliphatic alcohols such as 1-butanol and 2-butanol underwent little or no oxidation, even when heated at 100° C. (Entries 18 and 19). This observed selectivity for activated alcohols was confirmed by oxidation of a mixture of 4-methoxybenzylic alcohol (5 mmol) and 1-octanol (5 mmol), which resulted in complete oxidation of the benzylic alcohol with no formation of 1-octanal.
Reaction SMILES: C(O[C:4]([S-])=[S:5])C.[K+].[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[NH2:18])[C:14]([CH3:20])([CH3:19])[C:13](=[O:21])[C:12]2([CH3:23])[CH3:22].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>O>[SH:5][C:4]1[NH:18][C:17]2[CH:16]=[C:15]3[C:11](=[CH:10][C:9]=2[N:8]=1)[C:12]([CH3:23])([CH3:22])[C:13](=[O:21])[C:14]3([CH3:19])[CH3:20]
Reactant: CCOC(=S)[S-]
Reactant: CC1(C)C(=O)C(C)(C)c2cc(N)c(N)cc21
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [K+]
Solvent: O
Product: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
20 ml of water and 17.0 g of purified potassium ethylxanthate were added to 20.0 g of 5,6-diamino-1,1,3,3-tetramethyl-2-indanone, dissolved in 200 ml of alcohol, in a 750 ml sulfonation flask equipped with stirrer, thermometer, reflux condenser. The mixture was left to boil at reflux overnight, then diluted with 200 ml of water, neutralized with 20 ml of glacial acetic and stirred at 60°-70° C. for an additional 1 hour. After cooling to 20° C., the crystals were removed by filtration under suction. There were obtained 18.8 g (78.9% of theory) of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno(5,6-d)-imidazol-6(1H)-one with a melting point above 300° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[CH3:26][O:27][CH2:28]Cl>O.O1CCCC1>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:26][O:27][CH3:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: COCCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)COC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a mixture of diisopropylamine (9.4 mL, 67 mmol) and tetrahydrofuran (150 mL) was added dropwise n-butyl lithium (2.4 M n-hexane solution, 25 mL, 61 mmol) at −78° C., which was stirred for 30 minutes at the same temperature. Tributyltin hydride (16 mL, 61 mmol) was added dropwise to the reaction mixture at the same temperature, and stirred for 30 minutes at 0° C. The reaction mixture was cooled to −78° C., and chloromethyl methyl ether (4.6 mL, 61 mmol) was added dropwise thereto. The reaction mixture was gradually warmed to room temperature. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:30) to obtain the title compound (18 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5](=[CH2:9])[C:6]([O-])=[O:7].CN(C)CCCN=C=NCC.[CH2:22]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:23]=[CH2:24]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([C:6](=[O:7])[N:25]([CH2:22][CH:23]=[CH2:24])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH2:9]
Reactant: C=C(CC(=O)OC)C(=O)[O-]
Reactant: C=CCNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCN(Cc1ccccc1)C(=O)C(=C)CC(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 48.8 %

Procedure:
587 mg of 2-methylene-succinate 4-methyl ester (4.07 mmol), 781 mg of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (4.07 mmol) and 75 mg of 4-(dimethylamino)pyridine (0.61 mmol) were added to the reaction solution containing 300 mg of allylbenzylamine (2.04 mmol) dissolved in methylene chloride solution (0.5 M) with stirring for 10 hrs at room temperature. After the resulting mixture was washed with 5% HCl solution (10 ml), the mixture was diluted with ethyl acetate, washed with 10 ml of solution mixture mixed with saturated NaHCO3 solution and saturated NaCl solution to separate into an organic layer and water layer. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resultant was purified by Silica gel column chromatography with a solvent mixture mixed with EtOAc and hexanes (1:1) as an eluant to give 272 mg of 3-(allyl-benzyl-carbamoyl)-but-3-enoic acid methyl ester (o) (yield: 49%).
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][C:7](C)(C)C)=[O:5].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[NH2:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C[C@H](N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@H](N)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of tert-butyl (3S)-3-amino-3-phenylpropanoate (5.04 g, 22.9 mmol) in 2.25 M methanolic hydrogen chloride (100 ml) was heated under reflux for 2½ hours. The mixture was cooled to room temperature, basified with saturated aqueous sodium carbonate solution to pH 8 and the phases separated. The aqueous layer was extracted with dichloromethane (4×). The combined organic solutions were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound, 3.97 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a suspension of 4-bromophenylacetic acid (2.15 g) and potassium carbonate (2.76 g) in N,N-dimethylformamide (15 mL) was added methyl iodide (0.94 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1-5/1) to give methyl 4-bromophenylacetate (2.09 g). This material was dissolved in tetra hydrofuran (50 mL). To the solution was added methylmagnesium bromide (3.0 mol/L diethyl ether solution, 7.0 mL) under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added 1 mol/L hydrochloric acid (30 mL), and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-2/1) to give 1-bromo-4-[2-hydroxy-2-(methyl)propyl]benzene (1.58 g) This material was dissolved in N,N-dimethylformamide (20 mL) To the solution was added 55% sodium hydride (0.32 g) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To this mixture were added benzyl bromide (0.98 mL) and tetra(n-butyl)ammonium iodide (0.51 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=99/1-95/5) to give 4-[2-benzyloxy-2-(methyl)propyl]-1-bromobenzene (1.2 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 46 using this material instead of 1-bromo-2-fluoro-4-methoxy-benzene.
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:9]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC1CCNCC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1

Procedure:
The mixture of 42.0 g of diphenylmethanol, 25.25 g of 4-hydroxypiperidine and 49.4 g of p-toluenesulfonic acid monohydrate is placed in a flask fitted with a thermometer and an air condensor. The reaction vessel is connected to a vacuum pump and heated to 155°-160° until the evolution of water ceases. Upon cooling, the glassy residue is partitioned between 500 ml of diethyl ether and 200 ml of 2 N aqueous sodium hydroxide, the ethereal solution is separated and washed with water and saturated aqueous sodium chloride, dried and evaporated, to yield the 4-diphenylmethoxy-piperidine melting at 56°; (its hydrochloride, prepared in isopropanol-diethyl ether, melts at 175°-177°).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].OS(O)(=O)=O>S([O-])([O-])(=O)=O.[Ag+2].O>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[Br:1])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1
Reactant: BrBr
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Reaction time: 3 h

Procedure:
Bromine (17.4 ml) was added dropwise over 40 min to a stirred mixture of 4-tert-butylnitrobenzene (59.5 g, 332 mmol), silver(II) sulfate (56.5 g, 181 mmol), H2SO4 (300 ml), and H2O (33 ml) at RT. The mixture was stirred for a further 3 h and then poured into 0.1 M Na2S2O5/H2O (1 L)
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.BrC1C=CC(C(Cl)=O)=CC=1.Br[C:35]1[CH:65]=[CH:64][C:38]([C:39]([N:41]([CH2:62][CH3:63])[C:42]2[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=2[CH:50]2[CH2:59][CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[C:55]([O:60][CH3:61])[CH:56]=3)[CH2:51]2)=[O:40])=[CH:37][CH:36]=1.[NH2:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]1.CC(C)([O-])C.[Na+]>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.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:62]([N:41]([C:42]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[CH:44][C:43]=1[CH:50]1[CH2:59][CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[C:55]([O:60][CH3:61])[CH:56]=2)[CH2:51]1)[C:39](=[O:40])[C:38]1[CH:64]=[CH:65][C:35]([NH:66][CH2:67][CH2:68][N:69]2[CH2:74][CH2:73][CH2:72][CH2:71][CH2:70]2)=[CH:36][CH:37]=1)[CH3:63]
Reactant: CCN(C(=O)c1ccc(Br)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: NCCN1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCN(C(=O)c1ccc(NCCN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 4-bromobenzoyl chloride according to an analogous synthetic method to Preparation Example 86, to a suspension of the resulting 4-bromo-N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (299 mg) in 1,4-dioxane (10 ml) were sequentially added 1-(2-aminoethyl)piperidine (0.13 ml), sodium tert-butoxide (88 mg), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (23 mg) and tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (13 mg), and the solution was stirred overnight at 100° C. The solution was let to cool, then the insoluble material was filtered through celite pad, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate-tetrahydrofuran system) to provide the title compound (253 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.C(N(CC)CC)C.Br[CH:19]([C:25](OCC)=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[N:9]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25](=[O:26])[NH:10]2
Reactant: COc1ccc(N)c(N)c1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(OC)cc2[nH]c1=O

Procedure:
A solution of 4-methoxy-o-phenylenediamine (9.5 g) and triethylamine (7 g) in ethanol (100 ml) was cooled to 0°-5° and stirred in an atmosphere of nitrogen. Diethyl bromomalonate (23.7 g) in ethaol (50 ml) was added during 30 minutes. The temperature of the mixture was maintained at 0°-5° for a further 6 hours and then allowed to rise to 20° and stirred at this temperature for 16 hours. The solid was filtered off, stirred with dilute hydrochloric acid (400 ml., 0.2N), filtered off, washed with water, dried and crystallised from a mixture of ethyl acetate and methanol, m.p. 229°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:24]([F:25])([F:26])[O:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCNCC1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a cold (0 C) solution of 4-(4-trifluoromethoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.15 g, 2.8 mmol) in DCM (3 ml) was added TFA (2 ml). The resulting solution was stirred for 1 hr. Solvent was then removed under reduced pressure. The crude solid was taken-up in AcOEt (15 ml) and washed with NaHCO3 sat (2×5 ml), water (5 ml) and finally with brine (5 ml). The organic layer was dried over MgSO4 and the solvent was removed under vacuo to yield the desired 1-(4-trifluoromethoxy-benzenesulfonyl)-piperazine as a white solid (753 mg, 87% yield).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1.S(Cl)(Cl)=O.C(Cl)Cl>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[CH2:16][C:17](=[O:19])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH2:1][C:8]=2[CH:13]=1
Reactant: COc1ccc(CC(=O)O)c(Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(c1)Cc1ccccc1C(=O)C2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-benzyl-4-methoxyphenylacetic acid (14.2 g, 0.055 m) in benzene (120 mL) and thionyl chloride (28 mL) was refluxed for 1 hour and concentrated. The acid chloride was dissolved in dry methylene chloride (40 mL), and the solution was added dropwise under argon to a solution of AlCl3 (14.7 g, 0.11 mol) in methylene chloride (600 mL). The reaction was stirred under an argon atmosphere for 2.5 hours at room temperature, then was quenched with ice-water (200 mL). The layers were separated, and the organic phase was washed sequentially with 10% NaOH solution, water, and dil. HCl. The resulting solution was diluted with ether (200 mL), dried over MgSO4, and concentrated. The solid residue was triturated with ether/hexane (1:1) and 9.35 g of the title compound was collected by filtration: Mp 105-106° C.; 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 4.1 (s, 2H), 4.2 (s, 2H), 6.7 (d, 1H), 6.82 (s, 1H), 7.30 (m, 4H), 8.1 (d, 1H).
Reaction SMILES: [Br-].O=[C:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[N+]1CCCC1.[NH2:26][C:27]1[CH:35]=[C:31]([C:32]([OH:34])=[O:33])[C:30]([OH:36])=[CH:29][CH:28]=1>C(O)(=O)C>[C:32]([C:31]1[CH:35]=[C:27]([N:26]2[C:6]3[CH2:7][CH2:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[C:5]=3[CH:4]=[C:3]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:28]=[CH:29][C:30]=1[OH:36])([OH:34])=[O:33]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1C(=[N+]2CCCC2)CCc2ccccc21)c1ccccc1
Agent: [Br-]
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
A well stirred mixture of 3.98 g of tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide (Example 1a), 1.53 g of 5-aminosalicylic acid and 10 ml of acetic acid is heated at reflux for 15 minutes. The reaction mixture is allowed to stand at ambient temperature and then diluted with 10 ml of acetic acid. The resulting solid is collected by suction filtration, washed with 50 ml of petroleum ether and then dried under high vacuum for 72 hours to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6](Br)[CH:7]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:18][N:19]([CH3:21])[CH3:20].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[CH3:20][N:19]([CH2:18][C:14]1[N:13]([C:6]2[CH:7]=[C:2]([CH:3]=[C:4]([C:9]([F:10])([F:12])[F:11])[CH:5]=2)[NH2:1])[CH:17]=[CH:16][N:15]=1)[CH3:21]
Reactant: CN(C)Cc1ncc[nH]1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: CN(C)Cc1nccn1-c1cc(N)cc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 49.2 %

Procedure:
3-Amino-5-bromobenzotrifluoride (6 g, 25 mmol) and 1-(1H-imidazol-2-yl)-N,N-dimethylmethanamine (3.7 g, 29.6 mmol) were dissolved in anhydrous DMSO (25 mL). To this was added CuI (0.95 g, 7.5 mmol), 8-hydroxy quinoline (0.72 g, 7.5 mmol) and K2CO3 (6.9 g, 50 mmol). The mixture was stirred vigorously and degassed with N2 for 15 minutes. The flask was then equipped with a condenser and heated at 120° C. for 18 h. The resultant heterogeneous mixture was cooled to rt, poured into 14% aq. NH4OH (100 mL) and extracted with EtOAc (3×300 ml). The combined extracts were dried over NaSO4 and concentrated in vacuo. The residue was chromatographed over silica gel eluting with MeOH/DCM (5:95) to furnish 3.5 g of the desired product as a tan colored material: 285 m/z (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:4]=1[CH:5]=[O:6].[C:12]([O:16]C)(=[O:15])[CH:13]=[CH2:14]>>[CH:5]([C:4]1[CH:7]=[C:8]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH:14]=[CH:13][C:12]([OH:16])=[O:15])=[O:6]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(I)cc1C=O
Product: COc1ccc(C=CC(=O)O)cc1C=O

Procedure:
In order to implement this procedure, 2-methoxy-5-iodobenzaldehyde (V) was used as starting material, which, through a Heck-type reaction with methyl acrylate followed by in situ hydrolysis of the ester gave 3-formyl-4-methoxycinnamic acid (VI). Alternatively, the coupling reaction may be carried out with acrylic acid, therefore avoiding the hydrolysis step. The 3-formyl-4-methoxycinnamic acid (VI) was reacted with 3 equivalents of Deoxo-Fluor® solution in toluene or tetrahydrofuran, preferably Deoxo-Fluor® 50% in toluene. Dichloromethane the is the preferred reaction solvent between 0° and a reflux temperature, preferably 250. Upon completion of the reaction (determined by thin-layer chromatography) the mixture is diluted with dichloromethane and percolated through a silica gel bed under an inert atmosphere to remove the by-products from the fluorination reaction, giving a solution of 3-difluoromethyl-4-methoxy cinnamyl fluoride (VII).