Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:30]([F:33])([F:32])[F:31])[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[C:20]([N+:27]([O-])=O)[CH:19]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>O.C(OCC)(=O)C>[NH2:27][C:20]1[CH:19]=[C:18]([C:15]2[CH2:14][C:13]([C:8]3[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([Cl:5])[CH:7]=3)([C:30]([F:33])([F:32])[F:31])[O:17][N:16]=2)[CH:26]=[CH:25][C:21]=1[C:22]([NH2:24])=[O:23]
Reactant: NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Yield: 102.1 %

Procedure:
In a mixture of 10 mL of water, 2 mL of acetic acid and 0.52 g of reduced iron, a solution of 0.84 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-nitro benzoic acid amide in 10 mL of ethyl acetate was added dropwise at 75° C. with stirring. After the completion of the addition dropwise, it was stirred at the same temperature further for 2.5 hours. After the completion of the reaction, insoluble material was removed by hot filtration, 20 ml of water was added in the filtrate, and the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (10 ml×2). The combined organic phases were washed with 10 ml of saturated sodium hydrogen carbonate aqueous solution, and then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.80 g of the crude aimed product as yellow crystal. The resulting product was used as such without purification for the next step.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.[C:30]([C@:32]([CH3:40])([CH2:36][CH2:37][CH2:38][CH3:39])[C:33](O)=[O:34])#[N:31]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:30]([C:32]([CH3:40])([CH2:36][CH2:37][CH2:38][CH3:39])[C:33]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:21][CH:22]=1)=[O:34])#[N:31]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCC[C@@](C)(C#N)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCC(C)(C#N)C(=O)Oc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
a solution of 22.7 g of DCCI in 20 ml of CH2Cl2 is added at 0° to a mixture of 18.6 g of 4,4'-dihydroxy-1,1'-biphenyl, 15.5 g of (S)-2-cyano-2-methylhexanoic acid, 1.2 g of 4-dimethylaminopyridine and 100 ml of CH2Cl2, and the mixture is stirred at room temperature for 2 hours. The precipitate is filtered off with suction, the filtrate is concentrated and chromatography over silica gel gives 4'-(2-cyano-2-methylhexanoyloxy)-4-hydroxy-1,1'-biphenyl (optically active).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N+:23]([O-:39])=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)cc[n+]1[O-]

Procedure:
To a solution of 370 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)acetamide obtained in stage b) of Example 7 in 20 mL of dichloromethane are added, under argon, and with stirring, 704 mg of 3-chloroperbenzoic acid. After stirring for 1 hour 30 minutes at a temperature in the region of 20° C., 156 mg of 3-chloroperbenzoic acid are added. The solution is stirred overnight and then diluted with dichloromethane and washed three times with saturated aqueous sodium hydrogen carbonate solution. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. After chromatography on a column of silica, eluting with a dichloromethane/methanol/28% aqueous ammonia mixture (gradient from 100/0 to 90/9/1 by volume), 280 mg of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}-1-oxidopyridin-2-yl)acetamide are obtained in the form of a yellow wax, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][I:2].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[S:14])[NH:5]1>CC(C)=O>[IH:2].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([S:14][CH3:1])[NH:5]1
Reactant: CI
Reactant: CC1NC(=S)Nc2ccccc21
Solvent: CC(C)=O
Product: CSC1=Nc2ccccc2C(C)N1
Product: I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
Methyl iodide (0.43 ml, 6.94 mmol) was added to a solution of 4-methyl-3,4-dihydro-1H-quinazoline-2-thione (410 mg, 2.30 mmol) in acetone (5 ml). The mixture was stirred for 15 min (r.t.), and the title compound (500 mg, 67%) was isolated from the reaction mixture by filtration.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH:8]1[CH:11]([CH2:12][O:13][Si](C(C)(C)C)(C)C)[CH2:10][CH:9]1[OH:21])(C)C.Cl[Si](C)(C)C>CO>[OH:6][CH2:7][CH:8]1[CH:11]([CH2:12][OH:13])[CH2:10][CH:9]1[OH:21]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)C1CO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: OCC1CC(O)C1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,3-Bis(((1,1-dimethylethyl)dimethylsilyl)oxymethyl)cyclobutanol (6.3 g, 17.5 mmol) from Step C was combined with 5.3 mL (43 mmol) of chlorotrimethyl-silane in 103 mL of methanol. The reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 0.5 h then concentrated under reduced pressure to an oil. Residual chlorotrimethylsilane was removed by coevaporation with methanol (3×30 mL) to give title compound in quantitative yield and this crude product was carried on to the next step without purification; 1H NMR (CD3OD) δ 1.94-2.14 (m, 2H), 2.17-2.37 (m, 2H), 3.53 (d, 2H), 3.68 (dd, 1H), 3.85 (dd, 1H), 4.39 (m, 1H); MS DCI-NH3M/Z: 133 (M+H)+, 150 (M+NH4)+.
Reaction SMILES: C(S[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=1[O:26][CH3:27])[C:14](=[O:28])[CH:13]=[CH:12]2)C1C=CC=CC=1.ClN1C(C)(C)C(=O)N(Cl)C1=O.[S:40](Cl)(Cl)(=[O:42])=[O:41].[F:45][C:46]1[C:51]([F:52])=[C:50]([F:53])[C:49]([F:54])=[C:48]([F:55])[C:47]=1[OH:56]>CC#N.CC(O)=O.O>[Br:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[C:19]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([S:40]([O:56][C:47]4[C:46]([F:45])=[C:51]([F:52])[C:50]([F:53])=[C:49]([F:54])[C:48]=4[F:55])(=[O:42])=[O:41])=[CH:18][CH:17]=3)[CH:12]=[CH:13][C:14]2=[O:28])[CH:24]=1
Reactant: COc1ccc(Br)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 0 °C
Yield: 85 %

Procedure:
6-(Benzylthio)-1-(5-bromo-2-methoxyphenyl)quinolin-2(1H)-one (5.48 g, 12.11 mmol) was diluted with MeCN (38.0 ml), AcOH (1.444 ml) and water (0.950 ml), and the mixture was cooled to 0° C. 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (3.58 g, 18.17 mmol) was added in portions and the reaction was stirred in the ice bath for 5 minutes until complete conversion to the sulfonyl chloride (reaction went from heterogeneous yellow mixture to yellow solution upon addition). With the solution at 0° C., 2,3,4,5,6-pentafluorophenol (2.68 g, 14.54 mmol) was added, followed by TEA (6.75 ml, 48.5 mmol), and the reaction was allowed to warm to RT for 20 min. Water was added and the organics were extracted with DCM (×3), followed by drying via phase separator. The organics were then concentrated in vacuo and purified via MPLC eluting with 0-100% ethyl acetate in heptanes (with 10% DCM additive) to yield perfluorophenyl 1-(5-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (5.92 g, 10.27 mmol, 85% yield) as a white solid. MS (ESI, pos. ion) m/z: [M+1] 576.0
Reaction SMILES: Cl.Cl.N[C@H:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[N:13][CH:12]=[CH:11]2)=[O:6].C=O.[CH3:26]C(O)=O.[BH3-][C:31]#[N:32].[Na+]>CO>[CH3:26][N:32]([CH3:31])[C@H:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[N:13][CH:12]=[CH:11]2)=[O:6]
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Reactant: N[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccccc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To (R)-2-amino-N-(isoquinolin-6-yl)-2-phenylacetamide dihydrochloride (E2) in MeOH was added CH2O (37%), AcOH and NaCNBH3. After stirring for 1.5 hours the solution was poured into NaHCO3(sat) and extracted with EtOAc, dried (Na2SO4), filtered and concentrated. Column chromatography Hexanes/EtOAc gave pure (R)-2-(dimethylamino)-N-(isoquinolin-6-yl)-2-phenylacetamide. To (R)-2-(dimethylamino)-N-(isoquinolin-6-yl)-2-phenylacetamide was added CH2Cl2 and HCl (4N in dioxane) and the solvents were evaporated to give pure (R)-2-(dimethylamino)-N-(isoquinolin-6-yl)-2-phenylacetamide dihydrochloride (E3).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:6]=2)[O:1][CH2:2][CH2:3]1
Reactant: O=C1CCOc2ccccc21
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=C1CCOc2ccc(S(=O)(=O)Cl)cc21
Temperature: 40 °C

Procedure:
To a solution of 4-chromanone (0.59 g, 4.0 mmol) in CHCl3 (10 mL) was added chlorosulfonic acid (1.0 mL, 15 mmol) and heated to 40° C. for 1 h. After cooling to rt, the solution was poured onto ice and extracted with CH2Cl2 (10 mL). The organic layer was washed with 1 M HCl (3×10 mL) and the combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to afford 4-oxochroman-6-sulfonyl chloride as a grey solid in quantitative yield. 1H NMR (CD3OD) δ 8.41 (s, 1H), 8.05 (d, 1H), 7.13 (d, 1H), 4.7 (t, 2H), 3.0 (t, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[H-].[Na+].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][S:2][C:3]1[C:4]2[N:11]([CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[CH3:1][S:2][C:3]1[C:4]2[C:5](=[CH:9][N:10]([CH2:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)[N:11]=2)[N:6]=[CH:7][N:8]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CSc1ncnc2cn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2cc3ncnc(SC)c3n2)cc1
Product: COC(=O)c1ccc(Cn2ncc3ncnc(SC)c32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (400 mg) in N,N-dimethylformamide (8 mL) was added 60% sodium hydride (98 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Then, methyl 4-(bromomethyl)benzoate (606 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) to give methyl 4-{[7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidin-1-yl]methyl}benzoate (251 mg) and methyl 4-{[7-(methylthio)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate (450 mg) both as pale-yellow solids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:18][CH:19]([CH3:21])[CH3:20])[CH:16]=3)[CH2:11][C:10](=[O:24])[N:9]2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([OH:35])[CH2:34][NH:33][CH2:32]3)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:46]([O:48][CH3:49])=[O:47]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:49][O:48][C:46]([N:33]1[CH2:34][C:31]([C:28]2[CH:29]=[CH:30][C:25]([N:9]3[C:10](=[O:24])[CH2:11][C:12]4[C:17](=[CH:16][C:15]([O:18][CH:19]([CH3:20])[CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=4)[C@@H:8]3[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:26][CH:27]=2)([OH:35])[CH2:32]1)=[O:47]
Reactant: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CNC3)cc1)C(=O)C2
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC(O)(c2ccc(N3C(=O)Cc4cc(OC)c(OC(C)C)cc4[C@@H]3c3ccc(Cl)cc3)cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of (S)-1-(4-chloro-phenyl)-2-[4-(3-hydroxy-azetidin-3-yl)-phenyl]-7-isopropoxy-6-methoxy-1,4-dihydro-2H-isoquinolin-3-one (example 56) (40 mg, 0.081 mmol) in DCM (2 ml) was immersed in an ice-bath. DIPEA (Fluka) (0.043 ml, 0.243 mmol) was added, followed by methyl chloroformate (Fluka) (8.17 μl, 0.105 mmol). Afterwards the reaction was stirred in an ice-bath for 30 min. The reaction mixture was taken up in aqueous NaHCO3 solution. The organic phase was extracted two times with DCM. The organic layers were pooled, dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by preparative. TLC (DCM/MeOH 9:1; Rf range from 0.31 to 0.46 was scratched from the plate). The silicagel was taken up in 20 ml DCM/MeOH 1:1. The silicagel was filtered off. The filtrate was evaporated in vacuo to obtain the title compound as white solid.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[O:4]1[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3]1
Reactant: O=C1CCCCC1
Reactant: OCCNCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: OCCN1CCOC12CCCCC2
Temperature: 80 °C
Reaction time: 12 h
Yield: 45.3 %

Procedure:
To a 50 mL flask containing diethanolamine (9,7 mL, 100 mmol) was added cyclohexanone (10,4 mL, 100 mmol, 1 eq.) and potassium carbonate (pulverized and dried at 160° C., 13,8 g, 100 mmol, 1 eq.). The reaction was stirred at 80° C. for 12 h. The reaction was cooled to room temperature and diluted with dichloromethane before filtering off potassium carbonate. The crude mixture diluted in cyclohexane was washed with water at 0° C. Drying with sodium sulfate and evaporation afforded the title product (8,4 g, 45% yield). 1H NMR (CDCl3, 400 MHz) d?(ppm): 3,91 (t, J=6,7 Hz, 2H); 3,60 (m, 2H); 3,00 (t, J=6,7 Hz, 2H); 2,70 (t, J=5,3 Hz, 2H); 1,72-1,50 (m, 7H); 1,43-1,30 (m, 2H); 1,21-1,04 (m, 1H). 13C NMR (CDCl3, 129,9 MHz) d?(ppm): 94,9; 63,2; 59,2; 50,3; 49,0; 32,6 (2C); 25,6; 23,3 (2C).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][C:8]([NH:10][C:11]1[S:12][C:13]2[C:14](=[C:16]([CH3:28])[C:17]3[N:18]=[C:19]([NH:23][C:24](=[O:27])[CH2:25]Cl)[S:20][C:21]=3[CH:22]=2)[N:15]=1)=[O:9]>O1CCOCC1>[CH2:1]([N:3]([N:23]([C:24](=[O:27])[CH3:25])[C:19]1[S:20][C:21]2[C:17](=[C:16]([CH3:28])[C:14]3[N:15]=[C:11]([N:10]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:8](=[O:9])[CH3:7])[S:12][C:13]=3[CH:22]=2)[N:18]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCNCC
Reactant: Cc1c2nc(NC(=O)CCl)sc2cc2sc(NC(=O)CCl)nc12
Solvent: C1COCCO1
Product: CCN(CC)N(C(C)=O)c1nc2c(C)c3nc(N(C(C)=O)N(CC)CC)sc3cc2s1
Reaction time: 3 h

Procedure:
20 gm of diethylamine were added to 11.5 gm of 2,6-bis-(chloroacetyl-amino)-4-methyl-benzo[1,2-d:5,4-d']bisthiazole in 80 ml of dioxane and the mixture was boiled for 3 hours. Then it was evaporated to dryness in vacuo, and the residue (12 gm) was chromatographed on a dry 300 gm-silicagel column with benzene/chloroform (1:1) as the mobile phase. The title compound was obtained first; 9.0 gm (66% of theory), melting point 191°-192° C., were obtained after recrystallization from alcohol.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25](O)[CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH3:35])[CH2:29][CH2:28]1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25]=[CH:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH3:35])[CH2:29][CH2:28]1
Reactant: CCCC1CCC(CC(O)c2c(C)cc(OCC)c(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(C=Cc2c(C)cc(OCC)c(F)c2F)CC1

Procedure:
0.55 g of p-toluenesulfonic acid monohydrate was added to the compound (6) having been dissolved in 120 mL of toluene, and the mixture was heated under stirring by using a Dean-Stork trap until completion of azeotrope of water. After terminating the reaction by adding water, the aqueous layer was extracted with toluene, washed with a saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography and then subjected to recrystallization to obtain 2.01 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-propylcyclohexyl)ethene (Compound 1-1-3-17) as colorless crystals.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH2:9]([O:16][CH2:17][CH:18]=[CH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[CH2:9]([O:16][CH2:17][CH:18]1[CH2:19][CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=CCOCc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1CC1COCc1ccccc1
Reaction time: 16 h

Procedure:
31.2 g of ethyl diazoacetate are added to a solution of 0.3 mol of allyl benzyl ether in 150 ml of ether with the aid of a push-syringe. After stirring for 16 hours, 31.2 g of ethyl diazoacetate are added again. After 24 hours the mixture is filtered. The organic phase is washed with saturated NaHCO3 solution and then treated in customary manner. Chromatography over silica gel (dichloromethane) allows the expected product to be obtained.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH2:16][OH:17])[CH:12]=[CH:13][CH:14]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(N(CC)CC)C>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:17][CH2:16][C@@H:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[O:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@H](OC1CCCCO1)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](O[C@H]2CCCCO2)c2cccc(Cl)c2)cc1

Procedure:
Into toluene (20 ml) were added (R)-2-(3-chlorophenyl)-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)ethanol obtained in 3) above (6.0 g) and triethylamine (4.7 g) and further, under ice-cooling and dropwise, p-toluenesulfonyl chloride (4.9 g), and the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with water and the organic layer was further washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off to obtain a colorless oily compound mentioned above (9.1 g, 94.8%).
Reaction SMILES: CN(C)C=O.[CH3:6][N:7]([CH2:14][CH2:15][OH:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>O>[CH3:6][N:7]([CH2:14][CH2:15][O:16][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: CN(CCO)c1ccccn1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(C=O)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
In a 2l three necked, round bottom flask, 500 ml dimethylformamide is added, followed by addition of 100 g of 2-(N-methyl-N-(2-pyridyl)amino)ethanol (II) and 100 g of 4-fluorobenzaldehyde (III) was added to the reaction mixture and it was stirred for 10 minutes at room temperature and 80 g of potassium tertiary butoxide was added to the reaction mixture. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 5-10° C. and under the cold conditions, 1.5 l of water was added and stirred for 15 min. The mixture was extracted with 4×500 ml of ethyl acetate. The combined organic layer was washed with 3×1 l water. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to give 148 g (88%) of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy)benzaldehyde (IV).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38])=[CH:23][CH:22]=3)=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:44].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][S:32]([CH2:33][CH2:34][CH2:35][C:36]([F:41])([F:42])[C:37]([F:40])([F:39])[F:38])=[O:44])=[CH:23][CH:22]=3)=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
Dissolve 6-(4-methoxy-phenyl)-5-{4-[4-(4,4,5,5,5-pentafluoro-pentylsulfanyl)-butoxy]-phenoxy}-naphthalen-2-ol (0.313 g, 0.516 mmol) in MeOH (15 mL). Add sodium periodate (0.122 g, 0.570 mmol) in H2O (2 mL). Stir overnight at room temperature. Extract with EtOAc (30 mL). Wash with H2O (15 mL), NaHCO3 (saturated solution, 15 mL), brine (20 mL). Dry the organics (Na2SO4), filter and concentrate in vacuo. Purify by radial chromatography (eluting with 50% EtOAc, 48% Hexanes, 2% MeOH) to afford 0.185 mg (58%) of the desired 6-(4-Methoxy-phenyl)-5-{4-[4-(4,4,5,5,5-pentafluoro-pentane-sulfinyl)-butoxy]-phenoxy}-naphthalen-2-ol as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.79 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.47 (m, 3H), 7.19 (m, 1H), 7.02 (m, 1H), 6.82 (d, J=8:8 Hz, 2H), 6.57 (s, 4H), 3.76 (m, 5H), 2.65-2.84 (m, 4H), 2.10-2.25 (m, 4H), 1.79-1.93 (m, 4H). MS (ion spray): ES+: 623 (M+1); ES−: 621 (M−1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:16][N:14]([CH3:15])[CH:13]=[C:2]([CH3:3])[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)c1ccccc1
Product: CC(=CN(C)C)C(=O)c1ccccc1

Procedure:
A mixture of 57.0 g of propiophenone in 150 ml of N,N-dimethylformamide dimethyl acetal was stirred and heated at reflux for 24 hours. Then the solvent was removed in vacuo to give a yellow oil. The oil was subjected to Kugelrohr distillation to give 69.8 g of 3-dimethylamino-2-methylacrylophenone as a yellow oil, B.P. 100° C. (0.050 mm Hg).