Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].S([O:20][CH2:21][C:22]1([CH:28]=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(C)(=O)=O.CCOCC(OCC)COCC.Cl>COCCOCCOC>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[S:1][CH2:28][C:22]1([CH:21]=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)OCC1(C=O)CCCCC1
Reactant: O=C(c1ccccc1)c1ccccc1S
Agent: CCOCC(COCC)OCC
Agent: Cl
Solvent: COCCOCCOC
Product: O=CC1(CSc2ccccc2C(=O)c2ccccc2)CCCCC1
Reaction time: 24 h
Yield: 18.1 %

Procedure:
A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethyline, and 150 ml of diglyme was stirred and held at relux for 24 h. The mixture was cooled, poured into dil. HCl and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column (5% EtOAc-Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[O:2].C(Cl)(=O)C([Cl:15])=O>O1CCCC1.CN(C)C=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:15])=[O:8])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Commercially available 4-formylbenzoic acid (5.0 g, 33.3 mmol) was dissolved in a mixture of anhydrous tetrahydrofuran (100 ml) and anhydrous N,N-dimethylformamide (1 ml) and the mixture was cooled with stirring to 0° C. To the resulting mixture was added dropwise oxalyl chloride (3.8 ml, 43.3 mmol). The mixture was stirred at room temperature for 30 minutes and then at 40° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure and then in vacuo to afford 4-formylbenzoyl chloride. 4-(2,2,3,3-Tetrafluoropropoxy)aniline (646 mg, 2.9 mmol), described in Chem. Pharm. Bull., 44 (2), 314 (1996), and N,N-diisopropylethylamine (1.21 ml, 7.0 mmol) were dissolved in anhydrous tetrahydrofuran (8 ml) and the mixture was cooled to 0° C. with stirring. To the resulting mixture was added dropwise a solution of 4-formylbenzoyl chloride (561 mg, 3.33 mmol) obtained above in anhydrous tetrahydrofuran (2 ml). This mixture was stirred at room temperature for 17 hours and then at 40° C. for 20 minutes. At the end of this time, saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture in an ice bath and the mixture was partitioned between ethyl acetate and water. The organic layer was washed sequentially with 0.5N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution, water, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to give 4-formyl-4′-(2,2,3,3-tetrafluoropropoxy)benzanilide (634 mg, yield 62%) as pale yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:19])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH:17]=[O:18])([CH3:16])[CH2:8][CH2:7]2)([O-:3])=[O:2].CC(=CC)C.Cl([O-])=[O:26].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.O>[N+:1]([C:4]1[C:5]([CH3:19])=[C:6]2[C:11](=[C:12]([CH3:15])[C:13]=1[CH3:14])[O:10][C:9]([CH3:16])([C:17]([OH:26])=[O:18])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C=O)CC2
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
2.3 g of 6-nitro-2-formyl-2,5,7,8-tetramethylchroman was dissolved in 150 ml of t-butanol and 23 g of 2-methyl-2-butene was added at room temperature. An aqueous solution prepared by dissolving 5.8 g of sodium chlorite and 7.6 g of sodium dihydrogen phosphate dehydrate in 60 ml of water was added dropwise at room temperature, followed by stirring at room temperature for 2 hours. After the completion of the reaction, the reaction solution was poured into water and then extracted with ether. The organic layer was partitioned with an aqueous 5% sodium hydrogen carbonate solution and the ether layer was discarded. The pH of the aqueous layer was adjusted to 4 with 10% hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the resulting crystal was washed with hexane to obtain 1.6 g of the objective product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[CH2:13][O:12][C:11]1=[O:14]
Reactant: ClCCCCCBr
Reactant: O=C1NC(c2ccc(F)c(F)c2)CO1
Product: O=C1OCC(c2ccc(F)c(F)c2)N1CCCCCCl

Procedure:
Prepared by Procedure G and Scheme C1 using 4-(3,4-difluorophenyl)-1,3-oxazolidin-2-one and 1-bromo-5-chloropentane.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([O:20][C:21]([NH:23][C@@H:24]([CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:25]([OH:28])[CH2:26]O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>O1CCCC1>[CH2:13]([O:20][C:21]([NH:23][C@@H:24]([CH2:29][S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:25]([O:28][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:26][O:9][CH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@@H](CSc1ccccc1)[C@@H](O)CO)OCc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H](COCc1ccc([N+](=O)[O-])cc1)[C@H](CSc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 61.5 %

Procedure:
p-Nitrobenzoyl chloride (20.8 g, 0.112 mol) was added at 3–10° C. to a 0° C. to 5° C. solution of (2R, 3R)-3-benzyloxycarbonylamino-4-phenylthio-1,2-butanediol 14 (39.0 g) and triethylamine (39.1 ml, 0.280 mol) in tetrahydrofuran (300 ml). The resulting mixture was stirred for one hour with ice-cooling. Methanesulfonyl chloride (10.4 ml, 0.135 mol) was added dropwise at 2–12° C. and the mixture was stirred with ice-cooling for one hour. Any insoluble matter was filtered off and washed with ethyl acetate. The filtrate and the washing were combined and concentrated under vacuum. The resulting residue was dissolved in ethyl acetate (300 ml) and washed successively with water (50 ml), a 0.5 M aqueous citric acid solution (50 ml), a saturated aqueous solution of sodium hydrogencarbonate (50 ml) and saturated brine (50 ml), dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene (400 ml)/diisopropyl ether (300 ml) to give (2R, 3R)-3-benzyloxycarbonylamino-4-phenylthio-2-methanesulfonyloxy-1-(4-nitrobenzyloxy)butane (38.6 g, 51% yield from (2R, 3R)-3-benzyloxycarbonylamino-4-phenylthio-1,2-butanediol 14) as colorless crystals. 1H NMR (CDCl3, 300 MHz) δ 8.5–8.0 (m, 4H), 7.5–7.2 (m, 10H), 5.44 (ddd, J=6.9, 5.1, 2.3 Hz, 1H), 5.11 (s, 2H), 5.09 (brd d, 1H), 4.57 (dd, J=12.0, 6.9 Hz, 1H), 4.50 (dd, J=12.0, 5.1 Hz, 1H), 4.21 (m, 1H), 3.25 (dd, J=14.0, 6.2 Hz, 1H), 3.05 (s, 3H), 3.05 (dd, J=14.0, 8.2 Hz, 1H) IR (KBr): 3347, 1725, 1699, 1531, 1514, 1349, 1283, 1172, 1109, 1028, 925 cm−1, [α]D25: −14.0° (cl.01,CHCl3); Elemental Analysis (C26H26N2O9S2): Calculated: C, 54.35; H, 4.56; N, 4.88; Found: C, 54.49; H, 4.19; N, 4.75.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11](=[O:14])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15](O)[CH2:16][CH2:17][OH:18].C(OCC)(OCC)OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.O>[C:1]([O:9][CH2:10][C:11]1([CH2:12][OH:13])[O:18][CH2:17][CH2:16][CH2:15][O:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CO)COC(=O)c1ccccc1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCC1(CO)OCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of the mixture (0.5 g) containing 3-hydroxy-2-oxopropyl benzoate, 1,3-propanediol (0.932 ml, 12.9 mmol), triethyl orthoformate (0.428 ml, 2.58 mmol), and p-toluenesulfonic acid monohydrate (44.5 mg, 0.234 mmol) was stirred at room temperature for 4 days. Another mixture consisting of the mixture (4 g) containing 3-hydroxy-2-oxopropyl benzoate, 1,3-propanediol (7.46 ml, 103 mmol), triethyl orthoformate (3.42 ml, 20.6 mmol), and p-toluenesulfonic acid monohydrate (356 mg, 1.87 mmol) was stirred at 40° C. overnight. Two reaction mixtures were combined, water and ethyl acetate were added, and the organic layer was taken out. The organic layer was dried over magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was dissolved in n-heptane/ethyl acetate (2/1) and toluene and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=3/2) to obtain the title compound (4.2 g).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9](O)=[O:10]>>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[F:15])[C:9]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:10]
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccc(F)c(Cl)c1
Yield: 89 %

Procedure:
Using cyclopropylamine and 3-chloro-4-fluorobenzoic acid in the general procedure for coupling of amines to carboxylic acids, the title compound was obtained (89% yield) as a white solid. 1H NMR (DMSO-d6,400 MHz): δ=8.56 (d, J=3.5 Hz, 1 H), 8.03 (dd, J=7.3, 2.3 Hz, 1 H), 7.85 (ddd, J=8.6, 4.8, 2.3 Hz, 1 H), 7.52 (t, J=9.0 Hz, 1 H), 2.83 (tq, J=7.4, 3.9 Hz, 1 H), 0.66-0.75 (m, 2 H), 0.53-0.61 ppm (m, 2 H). ESI-MS: m/z 214.0 (M+H)1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([Cl:19])[CH:13]=1.[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][Br:20])=[C:14]([Cl:19])[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C=Cc2ccc(C)c(Cl)c2)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C=Cc2ccc(CBr)c(Cl)c2)c(Cl)c1

Procedure:
4-(2-Chloro-4-methoxystyryl)-2-chlorobenzyl bromide was prepared from 27.8 g. of 2,3'-dichloro-4-methoxy-4'-methylstilbene, 17.8 g. of N-bromosuccinimide and 0.5 g. of benzoyl peroxide in carbon tetrachloride according to the procedure of Example 10(b); yield 23.0 g., m.p. 106°-108° C.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:19]CC1.[OH2:23].CC(C)=O.C(#N)C>>[C:1]1([CH:7]([OH:19])[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[OH:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Solvent: CC(C)=O
Solvent: CC#N
Product: OC(c1ccccc1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
Catalytic dihydroxylation reaction of trans-stilbene by using LDH-osmate of the formula IIa LDH-osmate of the formula IIa (0.02 Eq. Wt.), N-methylmorpholine-N-oxide (1.5 Eq. Wt.) and trans-stilbene (1.0 Eq. Wt) in the mixed solvent of water/acetone/acetonitrile (in the volume ratio of 1:1:1) were stirred at room temperature for 6 hours. After the reaction LDH-osmate catalyst was filtered off and washed with methanol. The combined filtrates were concentrated under reduced pressure. The pure product, 1,2-diphenyl-1,2-ethandiol was obtained by removing the solvent at reduced pressure followed by column chromatography. (yield 93%). The experimental results in the Examples 9 to 24 were tabulated in Table 1&2.
Reaction SMILES: CCCC[OH:5].CCCC[OH:10].CCCC[OH:15].CCCC[OH:20].[Ti:21].[Cl-].[Zr+4:23].[Cl-].[Cl-].[Cl-].N>C(O)C>[OH-:5].[Ti+4:21].[OH-:10].[OH-:15].[OH-:20].[OH-:5].[Zr+4:23].[OH-:5].[OH-:5].[OH-:5]
Reactant: [Ti]
Reactant: CCCCO
Agent: [Zr+4]
Agent: N
Agent: [Cl-]
Solvent: CCO
Product: [OH-]
Product: [Ti+4]

Procedure:
An equimolar quantity of titanium n-butoxide [Ti(OC4H9)4 ] and zirconium chloride (ZnCl4) is dissolved respectively in an appropriate amount of anhydrous ethyl alcohol. After two ethyl alcohol solutions are mixed, the mixture is added dropwise to an excess of aqueous ammonia solution to obtain a white co-precipitate of titanium hydroxide with zirconium hydroxide. The co-precipitate is collected by filtration and then washed with de-ionized water until the solution is free of chloride ion. After being dried at 100° C. the co-precipitate is calcined in air at 500° C. for 2 hours to obtain the support of this example. 3.4 ml of 1.0M nickel nitrate solution is mixed well with the above support, the mixture is then dried at 90° C. whereby a supported catalyst which contains as 2wt% of nickel is obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>CN(C=O)C.O>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cccc(Cn2nnc3ccccc32)c1
Reaction time: 0.42 h

Procedure:
To a solution of benzotriazole (3 g) in DMF (38 mL) at r.t. was added a solution of 10N NaOH (2.75 mL). After stirring for 25 min., 3-trifluoromethylbenzyl bromide (4.39 mL) was added. The mixture was further stirred for 30 min., diluted with H2O, and extracted with EtOAc. The EtOAc extract was washed brine (2×), water, brine, dried (MgSO4) and concentrated. The residue was stirred in diethyl ether/hexane to afford 3.96 g of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[CH:12]=[CH2:13].CCCCCC.CCOCC>C1COCC1.C(Br)C=C.[Zn]>[C:1]1([CH2:7][CH2:8][CH:9]([OH:10])[CH2:13][CH:12]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCBr
Reactant: O=CCCc1ccccc1
Agent: [Zn]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a mixture of 3-phenylpropionaldehyde (1.06 mL, 8 mmol, 1 eq) and activated zinc (628 mg, 9.6 mmol, 1.2 eq) in THF (3.2 mL) at 0° C. was added one drop of allyl bromide. After the reaction was initiated, the remaining allyl bromide (total 0.831 mL, 9.6 mmol, 1.2 eq) was added slowly. The contents were stirred overnight at room temperature. After 20 hours the reaction was quenched with saturated aq. NH4Cl solution (15 mL), extracted with ether (3×20 mL) and the combined organic phases washed with brine (15 mL). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give crude 1-phenyl-hex-5-en-3-ol as a yellow oil. Column chromatography (hexane:ether, 85:15, 80:20, 75:25) gave a colourless oil, (966 mg, 69% yield). 1H NMR (400 MHz, CDCl3) δ 1.80-1.85 (m, 3H, CCH2CH2, +COH), 2.19-2.26 (m, 1H, CHOHCH2CH), 2.33-2.39 (m, 1H, CHOHCH2CH) 2.69-2.76 (m, 1H, PhCH2CH2), 2.82-2.89 (m, 1H, PhCH2CH2), 3.69-3.74 (m, 1H, CHOH), 5.16-5.19 (s, 1H, CHCH2 (cisH)), 5.19-5.20 (d, 1H, CHCH2 (trans H)), 7.21-7.26 (m, 3H, PhCH2), 7.30-7.34 (m, 2H, PhCH2); 13C NMR (100 MHz, CDCl3) δ 32.0 (PhCH2CH2), 38.4 (CH2CH2CH), 42.0 (CHOHCH2CH), 69.9 (CHOH), 118.1 (CHCH2), 125.7 (Ph), 128.4 (Ph), 128.5 (Ph), 134.6 (CHCH2), 142.0 (Ph); IR (v, cm−1) 3385 (OH), 3027 (Ar), 2932 (CH2), 1641 (CH═CH2), 1496 (Ph), 916 (CH═CH2); MS (GCT, CI+) m/z 194.2 [M+NH4]+ HRMS required for C12H20NO: 194.1545, found 194.1543.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOc3ncccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53(c)] with 2-chloro-pyrimidine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[2-(pyrimidin-2-yloxy)-ethoxy]-phenyl]-piperidine-1-carboxylate as a colourless solid; MS: 556 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:13]([CH3:14])=[C:12]([C:15]3[N:19]([C:20]4[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=4)[N:18]=[CH:17][CH:16]=3)[C:11](=[O:28])[N:10]([CH3:29])[C:9]2=[O:30])[CH:5]=[CH:6][CH:7]=1.[C:31](OCC)(=O)[CH3:32]>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C[CH2-].C[CH2-].[Zn+2]>[CH3:29][N:10]1[C:11](=[O:28])[C:12]([C:15]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[N:18]=[CH:17][CH:16]=2)=[C:13]([CH3:14])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH2:31][CH3:32])[CH:3]=2)[C:9]1=[O:30]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(Br)c1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [CH2-]C
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCc1cccc(-n2c(C)c(-c3ccnn3-c3ccc(C#N)cc3)c(=O)n(C)c2=O)c1
Temperature: 60 °C

Procedure:
To a solution of 4-[5-[1-(3-bromophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 34) (15.5 mg) and bis(tri-t-butylphosphine)palladium (1.0 mg) in tetrahydrofuran (1.0 ml) was added zinc diethyl (1.0 M normal hexane solution, 0.06 ml) and the resulting mixture was stirred at 60° C. for thirty minutes. To the reaction mixture was added ethyl acetate (30 ml) and the mixture was washed with water (10 ml) and saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography to afford 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-ethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (3.6 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[N:16]1([CH2:23][CH2:24][O:25][C:26]2[CH:45]=[CH:44][C:29]([O:30][C:31]3[C:40]4[C:35](=[CH:36][C:37]([O:41][CH3:42])=[CH:38][CH:39]=4)[CH:34]=[CH:33][C:32]=3O)=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.C(Cl)Cl>[Cl-].[Na+].O>[N:16]1([CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([O:30][C:31]3[C:40]4[C:35](=[CH:36][C:37]([O:41][CH3:42])=[CH:38][CH:39]=4)[CH:34]=[CH:33][C:32]=3[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:44][CH:45]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(O)ccc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Add trifluoromethanesulfonic anhydride (7 mL, 42 mmol) into a solution of 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-ol (15 g, 37 mmol), triethylamine (20 mL) and methylene chloride (500 mL) at −50° C. Warm the reaction mixture to room temperature and stir for 1 hour at that temperature. Cool the reaction mixture to −78° C. and add brine (20 ml). Warm the reaction to room temperature. Separate layer and wash the organic layer with saturated sodium bicarbonate solution (100 mL) and brine. Dry the organic layer with magnesium sulfate, filter and evaporate solvent under reduced pressure. Chromatograph the residue on a silica gel column eluting the material with a step gradient of methanol/dichloromethane (0 to 10%) to get 20 g (99%) of trifluoro-methanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-phenoxy]-6-methoxy-naphthalen-2-yl ester.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]4[C:27]3=[O:36])[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: Cc1cccc(-c2ncc[nH]2)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nccn2CCCCCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(6-Methyl-2-pyridyl)imidazole (2.16 g) and sodium t-butoxide (1.57 g) in 50 mL dry DMF was added N-(6-bromohexyl)phthalimide (4.72 g). The resulting solution was stirred at room temperature for 3 h and then at 60° C. for 3.5 h. The solution was poured into H2O (80 mL) and then extracted three times with EtOAc (3×100 mL). The combined EtOAc extract was dried with anhydrous Na2SO4, and then evaporated to dryness. The product was purified by a silica gel column using EtOAc as the eluent. Yield: about 4.2 g.