Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:11]([O-])([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)NCCC2

Procedure:
To a solution of 1,2,3,4-tetrahydoquinoline (6.5 g, 0.049 mol) in conc. Sulfuric acid (118 mL) at 0° C. was added a solution of con. nitric acid (4.9 mL) in conc. Sulfuric acid (12 mL) drop-wise over 3 hours so as to maintain the temperatute <5° C. The reaction mixture was then poured onto crushed ice and neutralized with solid potassium carbonate. The mixture was extracted with EtOAc (2×500 mL), the combined organic extracts were washed with water, dried and concentrated to give the crude product which was purified by column chromatography on silica-gel using EtOAc/hexane as eluent to obtain the title compound as an orange solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][C:30]1[CH:31]=[C:32]([CH:61]=[CH:62][C:63]=1[F:64])[C:33]([NH:35][NH:36][C:37](=[O:60])[C@H:38]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]#[N:57])=[C:52](Cl)[C:51]=1C)[C@@H:39]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH3:40])=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].[CH2:65]([Cl:67])Cl>>[Si:42]([O:41][C@H:39]([CH3:40])[C@@H:38]([NH:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]#[N:57])=[C:65]([Cl:67])[C:55]=1[CH3:54])[C:37]1[O:60][C:33]([C:32]2[CH:61]=[CH:62][C:63]([F:64])=[C:30]([O:29][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[CH:31]=2)=[N:35][N:36]=1)([C:45]([CH3:48])([CH3:46])[CH3:47])([CH3:44])[CH3:43]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)c(O[Si](C)(C)C(C)(C)C)c2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: ClCCl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O[Si](C)(C)C(C)(C)C)c3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl

Procedure:
Triphenylphosphine (1.0 g, 3.85 mmol) was dissolved in 25 mL of DCM followed by addition of I2 (977 mg, 3.85 mmol) and TEA (779 mg, 7.70 mmol) at 0° C. 3-(tert-butyldimethylsilyloxy)-N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-fluorobenzohydrazide (1.25 g, 1.93 mmol) in 35 mL DOA was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stir. The temperature was allowed to rise to room temperature and stirred for additional 10 min. The reaction was quenched with 100 mL saturated sodium thiosulfate and extracted with EtOAc. The crude mixture was chromatographed to give the product (1.10 g). 1H NMR (400 MHz, DMSO-d6, δ in ppm): 7.71 (m, 1H), 7.70 (d, J=9 Hz, 1H), 7.65 (m, 1H), 7.03 (d, J=9 Hz, 1H), 6.53 (d, J=9 Hz, 1H), 5.15 (d, J=9 Hz, 1H), 4.80 (m, 1H), 2.44 (s, 3H), 1.51 (d, J=6 Hz, 3H), 1.13 (s, 9H), 0.83 (s, 9H), 0.36 (s, 6H), 0.19 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([NH:10]C(OC(C)(C)C)=O)=[CH:8][CH:7]=[N:6][CH:5]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[N:6][CH:5]=1
Reactant: COC(=O)c1cnccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cnccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Formula 505 where R1, R3 and R4 are H; W, Y and Z are —C═; and X is —N═: 4-tert-Butoxycarbonylamino-nicotinic acid methyl ester (9.08 g, 36.0 mmol) was dissolved in 50/50 TFA/DCM (100 mL) solution and stirred for 2 hours at room temperature. Concentration of the mixture under reduced pressure was followed by re-dissolution in DCM (100 mL), washing with saturated sodium bicarbonate, drying over sodium sulfate, and concentration under reduced pressure. The corresponding de-protected product of Formula 505, 4-amino-nicotinic acid methyl ester (5.43 g, 99.1%) was obtained was obtained in sufficient purity to be carried forward for use in the next step. MS (Cl) M/E: 153.1.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14](OC)=[O:15])[N+:10]([O-:18])=[C:9]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1>C(Cl)Cl.[OH-].[Na+]>[N:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][CH3:23])=[O:21])[N:10]3[O:18][C:14](=[O:15])[N:13]=[C:11]3[N:12]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)Nc1cc(N2CC=CCC2)nc2nc(=O)on12

Procedure:
32.3 G. of dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide are stirred at room temperature for 3 hours in a mixture of methylene chloride and 3% sodium hydroxide. The two phases are separated and the aqueous phase is made acid, there being obtained methyl 5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-pyrimidine-7-carbamate, having a melting point of 210°-212° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8](=[O:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(OCC)(=O)C>P([O-])([O-])([O-])=O>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)C[C@H](O)COC(=O)c1ccccc1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C[C@H](O)C[C@H](O)COC(=O)c1ccccc1
Temperature: 27 °C
Reaction time: 60 h

Procedure:
A large test tube was charged with 5 ml of Medium A described hereinbefore and, after sterilization, inoculated with one of the microorganisms indicated in Table 1 and Table 2. Aerobic shake culture was carried out at 27° C. for 2 to 3 days. From a 1.5 ml portion of the resulting culture, the cells were harvested by centrifugation and suspended in 0.5 ml of 100 mM phosphate buffer (pH 6.5) containing 0.05% of (5S)-6-benzoyloxy-5-hydroxy-3-oxohexanoic tert-butyl ester and 8% of glucose. The suspension was put in a test tube equipped with a threaded stopper and the reaction was carried out under shaking at 27° C. for 20 hours. After the reaction, 4 volumes of ethyl acetate were added to the reaction mixture and after thorough mixing, the cells were centrifugally removed. The supernatant was analyzed by high-performance liquid chromatography for the amount of (3R,5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced per ml of the reaction mixture and the diastereomer ratio (=(3R,5S)/(3S,5S) ratio). The results are shown in Table 1 and Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:26]#[N:27])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=2)[S:12][C:13]=1[C:14]1[NH:18][N:17]=[N:16][CH:15]=1.COC1C=C(OC)C=CC=1C[NH2:33].CCN(C(C)C)C(C)C.C(O)CCC.C(Cl)Cl.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>CO.O>[NH2:33][C:21]1[CH:20]=[C:19]([C:11]2[S:12][C:13]([C:14]3[NH:18][N:17]=[N:16][CH:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]=2[C:26]#[N:27])[CH:24]=[CH:23][N:22]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(-c2cnn[nH]2)c1-c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCCCO
Solvent: O
Product: N#Cc1c(-c2ccnc(N)c2)sc(-c2cnn[nH]2)c1-c1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A solution of 4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)-5-(1H-1,2,3-triazol-5-yl)thiophene-3-carbonitrile (0.103 g, 0.247 mmol), 2,4-dimethoxybenzylamine (0.247 g, 1.48 mmol) and DIPEA (0.0959 g, 0.742 mmol) in 1-Butanol (15 g, 2.0E2 mmol) was irradiated in microwave at 170° C. for 2 hrs. The mixture was concerntrated and the residue was purified by column chromatography to afford desired intermediate. LC/MS (FA) ES+ 563, 565. To the intermediate in DCM (5.9 mL, 93 mmol) was added TFA (2 mL, 20 mmol) and the mixture was stirred for 10 min. The reaction mixture was concerntrated and the residue in MeOH was treated with sodium bicarbonate and water. The mixture was concentrated and the mixture was purified by column chromatography to afford the title compound (48 mg, 47.0%). LC/MS (FA) ES+ 413, 415. 1H NMR (400 MHz, d4-methanol) δ: 8.03 (1H, d, J=6.26 Hz), 7.74 (1H, d, J=1.93 Hz), 7.54 (1H, dd, J=8.27, 1.97 Hz), 7.46 (1H, d, J=8.26 Hz), 7.05 (1H, s), 7.01 (2H, m)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][C:7](=[O:9])[CH3:8])[CH3:2].CN1C=CN=C1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CCCC)CCCC)CCC>[Ti](Cl)(Cl)(Cl)Cl.O.ClC1C=CC=CC=1>[C:7]([NH:6][CH:5]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:9])[CH3:8]
Reactant: CCOC(=O)CNC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: Clc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: -10 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A chlorobenzene solution (45.0 ml) of N-acetylglycine ethyl ester (1.50 g, 10.33 mmol) and N-methylimidazole (1.02 g, 12.40 mmol) was cooled to −10° C., and palmitoyl chloride (2.84 g, 10.33 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 45 minutes at the same temperature, titanium tetrachloride (6.86 mg, 36.16 mmol) and tributylamine (7.66 g, 41.32 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −10° C. Water (20 mL) was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. It was confirmed by comparative analysis with sample product using HPLC that the organic layer contained 3.33 g of the title compound (yield: 84%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][C:7](=[O:9])[CH3:8])[CH3:2].CN1C=CN=C1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.ClCCl>[C:7]([NH:6][CH:5]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:9])[CH3:8]
Reactant: CCOC(=O)CNC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: -45 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A dichloromethane solution (45.0 ml) of N-acetylglycine ethyl ester (1.50 g, 10.33 mmol) and N-methylimidazole (1.02 mg, 12.40 mmol) was cooled to −45° C., and palmitoyl chloride (2.84 g, 10.33 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 20 minutes at the same temperature, titanium tetrachloride (6.86 mg, 36.16 mmol) and triethylamine (4.18 g, 41.31 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −45° C. Water (20 mL) was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. It was confirmed by comparative analysis with sample product using HPLC that the organic layer contained 2.81 g of the title compound (yield: 71%).
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([C:21]([O:25][N:26]1N=NC2C=CC=C[C:27]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.CNOC.C([O-])(O)=O.[Na+]>CN(C=O)C.CCN(CC)CC>[CH3:21][O:25][N:26]([CH3:27])[C:9](=[O:10])[CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
To a solution of 3,3-diphenylpropionic acid (CAS RN: [606-83-7], 1.5 g) in DMF (17 mL) was added TBTU (2.98 g) and Et3N (2.1 mL) at 0° C. The reaction mixture was stirred at rt for 10 min and again cooled down to 0° C. N,O-dimethylhydroxylamine hydrochloride (0.78 g) was added and the mixture was stirred at rt for 1 hour. A saturated aqueous solution of NaHCO3 was added, the phases were separated and the inorganic one was extracted with TBME (2×). The combined organic layers were washed with 1N aqueous KHSO4 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:1) to yield the title compound (1.52 g, 85%) as a colorless oil, MS (ESI+): m/z=270.2 ([M+H]+).
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[C:9]1([N:8]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: O=C1C=CC(=O)N1c1ccccc1
Temperature: 10 °C

Procedure:
N-phenylmaleimide was synthesized in accordance with a method described in "Organic Synthesis", Vol.41, page 93. That is, 196 parts of maleic anhydride and 2,000 parts of benzene were charged into a four-necked flask. 186 parts of aniline dissolved in 200 parts of benzene were added dropwise to the resulting solution at 25° C. over one hour. The resulting product was cooled to 10° C. and crystals thus formed were filtered off and dried in vacuo to give 370 parts of a pale yellow solid substance. 316 parts of the produced pale yellow substance, 65 parts of anhydrous sodium acetate and 670 parts of acetic anhydride were charged into a flask fitted with a stirrer and a reflux cooler and heated gradually over an hour. Stirring was continued for one hour while the temperature was maintained at 100° C. The resulting product was poured into ice water to precipitate crystals. The crystals were filtered, washed with petroleum ether and dried to give 220 parts of yellow crystals. The melting point and the purity by liquid chromatography of the produced crystals were measured and found to be 88° C. and 97.5%, respectively. The produced maleimide compounds are shown in Table 1-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>CO>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCCNCC1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CO
Product: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
Combine 1-ethoxycarbonyl[1,4]diazepane (36.6 g, 212 mmol) and 2-chlorobenzimidazole (18.0 g, 106 mmol). Heat to 130° C. After 4 hours, cool to ambient temperature and add hot methanol to dissolve the reaction mixture. Partition the methanol solution between dichloromethane (700 mL) and a solution of sodium hydroxide (20 g) in water (500 mL). Separate the layers and extract the aqueous layer three times with dichloromethane. Combine the organic layers, extract with brine, dry over Na2SO4, filter, and evaporate in vacuo to give a solid. Triturate the solid with ethyl acetate (100 mL) and cool to 0° C. Collect solid by filtration and dry in vacuo to give 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.C(=O)(OCC)OCC.Br.[CH3:21][CH:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][CH2:31][CH:32]([CH2:34][CH2:35][CH2:36][C:37]([OH:41])([CH:39]=[CH2:40])[CH3:38])[CH3:33])[CH3:28])[CH3:23]>[Br-].[Zn+2].[Br-]>[CH3:9][C:8]1[C:2]([CH3:1])=[C:3]2[C:5]([CH2:40][CH2:39][C:37]([CH2:36][CH2:35][CH2:34][CH:32]([CH2:31][CH2:30][CH2:29][CH:27]([CH2:26][CH2:25][CH2:24][CH:22]([CH3:21])[CH3:23])[CH3:28])[CH3:33])([CH3:38])[O:41]2)=[C:6]([CH3:11])[C:7]=1[OH:10]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: Br
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(=O)OCC
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a mixture consisting of 23.3 g (0.153 mol) of 2,3,5-trimethylhydroquinone, 23.2 g (0.153 mol) of zinc bromide, 52.9 ml of diethyl carbonate and 4.3 g of 47% hydrobromic acid, was added dropwise, under stirring at 50±5° C. over one hour, 46.2 g (0.153 ml) of isophytol (purity: 98.1%). Further, the resulting mixture was stirred for one hour at the same temperature. The reaction liquid was washed several times with 50 ml of water, followed by concentrating under a reduced pressure, whereby 66.7 g of the title compound was obtained as a brown oil (yield: 99.1 %, GLC purity: 98.0%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:21]=[O:22])C>CCOCC>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:21]=[O:22])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a 150 ml flask was added 1,4-dibromonaphthalene (2.0 g, 7.0 mmol) and anhydrous ether (50 ml). After cooling to 0° C. n-BuLi (3.1 ml of 2.5 M in hexanes, 7.7 mmol) was added dropwise and stirred for 20 minutes after which anhydrous DMF (1.62 ml, 21 mmol) was added. The reaction was then warmed to ambient temperature and after 1 h the reaction was quenched with water (10 ml), stirred for 10 minutes, and extracted with ether (3×). The ether layer was dried over anhydrous Na2SO4, passed through a silica plug, and concentrated to afford 1.02 g (62%) of product as a pure off-white solid: 1H NMR (300 MHz, DMSO-d6): δ 7.80–7.85 (2H, m), 8.10 (1H, d, J=7.7 Hz), 8.20 (1H, d, J=7.7 Hz), 8.32 (1H, m). 9.24 (1H, m), 10.42 (1H, s).
Reaction SMILES: COC1C=CC(CO)=CC=1OCC1C=CC(C(F)(F)F)=CC=1.C[O:24][C:25](=[O:59])[CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[C:41]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=3)[CH:40]=2)=[C:33]2[C:29]=1[CH2:30][CH2:31][CH2:32]2>>[CH3:46][O:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][S:37][C:34]2[CH:35]=[CH:36][C:28]([O:27][CH2:26][C:25]([OH:59])=[O:24])=[C:29]3[C:33]=2[CH2:32][CH2:31][CH2:30]3)=[CH:40][C:41]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:51][CH:50]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OC)c(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCC2
Agent: COc1ccc(CO)cc1OCc1ccc(C(F)(F)F)cc1
Product: COc1ccc(CSc2ccc(OCC(=O)O)c3c2CCC3)cc1OCc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 78A. MS m/z 295 (M-Cl). Step 3. Preparation of {7-[4-Methoxy-3-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (Compound 78C)
Reaction SMILES: [I-:1].[CH2:2]([P+:6]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:8][OH:9])[CH2:3][CH2:4][CH3:5].COC1C=CC(O)=CC=1.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29].II>C(#N)C>[I-:1].[CH2:10]([P+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:8][O:9][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH2:11][CH2:12][CH3:13]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCC[P+](CCO)(CCCC)CCCC
Agent: COc1ccc(O)cc1
Agent: II
Agent: [I-]
Solvent: CC#N
Product: C=C(C)C(=O)OCC[P+](CCCC)(CCCC)CCCC
Reaction time: 2 h

Procedure:
Into a 1 L-four-necked flask equipped with a stirrer, a thermometer and a distillation line, was added the obtained tri-n-butyl(2-hydroxyethyl)phosphonium iodide dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure with stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 76.4 g (0.731 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature. Upon dropping, yellow coloration that was believed to have been caused by isolation of iodine occurred.
Reaction SMILES: [Br-:1].[CH2:2]([P+:6]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:8][OH:9])[CH2:3][CH2:4][CH3:5].COC1C=CC(O)=CC=1.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(#N)C>[Br-:1].[CH2:10]([P+:6]([CH2:2][CH2:3][CH2:4][CH3:5])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:7][CH2:8][O:9][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH2:11][CH2:12][CH3:13]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCC[P+](CCO)(CCCC)CCCC
Agent: COc1ccc(O)cc1
Agent: [Br-]
Solvent: CC#N
Product: C=C(C)C(=O)OCC[P+](CCCC)(CCCC)CCCC
Reaction time: 2 h

Procedure:
Into a 1 L-four-necked flask equipped with a stirrer, a thermometer and a distillation line, was added the obtained tri-n-butyl(2-hydroxyethyl)phosphonium bromide dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure with stirring and about 200 ml of acetonitrile was distilled out. A condenser having a calcium chloride tube was installed and 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 75.8 g (0.725 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:18]1[CH2:19][CH2:20][N:15]([C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCOCC2)CC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl-4-oxo-1-piperidine carboxylate (8.0 g, 40 mmol) and morpholine (3.6 g, 42 mmol) in benzene (16 mL) was added p-toluenesulfonic acid (40 mg) and the resulting solution was refluxed using a Dean-Stark trap for 24 h. After cooling to rt, the solution was concentrated under vacuum to afford the title compound a as a thick reddish-orange oil which was used without any further purification (11.1 g, ˜quant). 1H NMR (400 MHz, CDCl3): δ 7.36 (s, 1H), 3.94 (br s, 2H), 3.74 (m, 4H), 3.54 (m, 2H), 2.80 (m, 4H), 2.16 (br s, 2H), 1.47 (s, 9H).