Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[F:12][C:13]([F:20])([S:16]([O-:19])(=[O:18])=[O:17])[CH2:14][OH:15].[C:21]1([S+:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:12][C:13]([F:20])([S:16]([O-:19])(=[O:18])=[O:17])[CH2:14][O:15][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1.[C:34]1([S+:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=S(=O)([O-])C(F)(F)CO
Reactant: C=Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc(C(=O)OCC(F)(F)S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Under ice cooling, 2.0 g (12 mmol) of the 4-vinylbenzoyl chloride in methylene chloride was added dropwise to a mixture of 4.2 g (10 mmol) of triphenylsulfonium 1,1-difluoro-2-hydroxyethanesulfonate in Synthesis Example 1-13, 1.21 g (12 mmol) of triethylamine, 0.24 g (2 mmol) of N,N-dimethylaminopyridine, and 20 g of methylene chloride. The resulting mixture was stirred for 2 hours at room temperature. Thereafter, 11 g of 5% dilute hydrochloric acid was added to the reaction mixture. The organic layer was taken out and washed with water, from which methylene chloride was distilled off in vacuum. 30 g of methyl isobutyl ketone was added to the residue, which was washed with dilute aqueous ammonia and then with water. Thereafter, methyl isobutyl ketone was distilled off in vacuum. Diisopropyl ether was added to the residue. By decantation, the target compound, triphenylsulfonium 1,1-difluoro-2-(4-vinyl-benzoyloxy)-ethane-1-sulfonate was obtained. Colorless oil, 5.1 g (yield 86%). The compound has the following structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].F[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]#[N:23])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:22]#[N:23])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)c(F)c1
Reactant: N#Cc1ccc(F)c2ccccc12
Product: N#Cc1ccc(Oc2ccc(C=O)cc2F)c2ccccc12

Procedure:
4-(2-Fluoro-4-formyl-phenoxy)-naphthalene-1-carbonitrile was prepared from 3-Fluoro-4-hydroxybenzaldehyde and 4-Fluoro-naphthalene-1-carbonitrile following General Procedure A. 1H NMR (400 MHz, CDCl3) δ 9.99 (d, J=1.95 Hz, 1H), 8.38 (d, J=8.6 Hz, 1H), 8.27 (d, J=8.6 Hz, 1H), 7.77-7.84 (3H), 7.69-7.74 (2H), 7.29 (d, J=7.43 Hz, 1H), 6.83 (d, J=7.83 Hz, 1H).
Reaction SMILES: C(OC(=O)[N:7]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH3:31])[CH2:24][CH2:23]1)[C:8]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][CH:15]=1)=[O:9])(C)(C)C.[H-].[Na+].IC>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][N:22]([NH:7][C:8]([C:10]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][CH:11]=2)=[O:9])[CH2:27][CH2:26]1
Reactant: COCCN1CCN(N(C(=O)OC(C)(C)C)C(=O)c2cnc(-c3ccccc3)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COCCN1CCN(NC(=O)c2cnc(-c3ccccc3)nc2)CC1
Yield: 44.6 %

Procedure:
A solution of [4-(2-methoxy-ethyl)-piperazin-1-yl]-(2-phenyl-pyrimidine-5-carbonyl)-carbamic acid tert-butyl ester (0.21 mmol), NaH (60%, 0.66 mmol) and iodomethane (0.63 mmol) in DMF (8 mL) is stirred under N2 at rt overnight. The reaction mixture is quenched with water, and extracted with EtOAc. The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-2% methanol in DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid [4-(2-methoxy-ethyl)-piperazin-1-yl]-amide (32 mg, 44%) as a solid. MS: 342 (M+H).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:13]([O:16][CH:17](O)[C:18](O)=O)(=[O:15])[CH3:14]>C(Cl)(Cl)Cl>[C:13]([O:16][CH2:17][C:18]1[N:4]2[CH:5]=[CH:6][C:7]3[C:12]([C:3]2=[N:1][N:2]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(O)C(=O)O
Reactant: NNc1nccc2ccccc12
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1nnc2c3ccccc3ccn12

Procedure:
1-Hydrazinoisoquinoline was heated with excess acetoxyglycolic acid. The residue was cooled, dissolved in chloroform and washed with sodium carbonate solution. The chloroform extracts were dried and concentrated invacuo to provide the crude product which was purified by recrystallization from benzene.
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][C:20]=3[CH3:21])[NH:17][CH:16]=[C:15]4[CH:22]=[O:23])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.CC(=CC)C.Cl([O-])=[O:30].[Na+].O.OP([O-])(O)=O.[Na+].[Cl-].[NH4+]>O1CCCC1.C(O)(C)(C)C.O>[OH:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][C:20]=3[CH3:21])[NH:17][CH:16]=[C:15]4[C:22]([OH:30])=[O:23])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cc2[nH]cc(C=O)c2cc1-c1ccc(C2(O)CCC2)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cc1cc2[nH]cc(C(=O)O)c2cc1-c1ccc(C2(O)CCC2)cc1
Temperature: 25 °C
Reaction time: 62 h

Procedure:
A partial suspension of 5-[4-(1-hydroxycyclobutyl)phenyl]-6-methyl-1H-indole-3-carbaldehyde (130 mg, 0.426 mmol) in tetrahydrofuran (3 mL) and tert-butanol (3 mL) was treated with 2-methyl-2-butene (2.27 mL, 21.4 mmol) followed by a solution of sodium chlorite (538 mg, 6.4 mmol) and sodium phosphate monobasic hydrate (904 mg, 6.5 mmol) in water (2 mL) via glass pipet at room temperature. The reaction mixture was stirred vigorously at room temperature for 62 hours, and was poured into half-diluted saturated aqueous ammonium chloride solution (50 mL). The product was extracted with ethyl acetate (3×60 mL), and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified using reverse-phase chromatography to give the title compound.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].C[C@@H]1O[C@@H]([O:19][CH2:20][C@H:21]2[O:26][C@@H:25]([O:27][C:28]3[C:37](=[O:38])[C:36]4[C:35]([OH:39])=[CH:34][C:33]([OH:40])=[CH:32][C:31]=4[O:30][C:29]=3[C:41]3[CH:42]=[CH:43][C:44]([OH:48])=[C:45]([OH:47])[CH:46]=3)[C@H:24]([OH:49])[C@@H:23]([OH:50])[C@@H:22]2[OH:51])[C@H](O)[C@H](O)[C@H]1O>>[CH:42]1[C:41]([C:29]2[O:30][C:31]3[C:36](=[C:35]([OH:39])[CH:34]=[C:33]([OH:40])[CH:32]=3)[C:37](=[O:38])[C:28]=2[O:27][C@@H:25]2[O:26][C@H:21]([CH2:20][OH:19])[C@@H:22]([OH:51])[C@H:23]([OH:50])[C@H:24]2[OH:49])=[CH:46][C:45]([OH:47])=[C:44]([OH:48])[CH:43]=1.[O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@@H]1O[C@@H](OC[C@H]2O[C@@H](Oc3c(-c4ccc(O)c(O)c4)oc4cc(O)cc(O)c4c3=O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Agent: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Product: O=c1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(-c2ccc(O)c(O)c2)oc2cc(O)cc(O)c12

Procedure:
In this manner, the rhamnose residue is cleaved from rutin, thereby yielding the desired isoquercitrin as well as rhamnose.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9].[OH-].[K+].[CH2:20](Br)[CH:21]=[CH2:22].O>CS(C)=O>[CH2:22]([NH:10][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[O:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([Cl:1])[CH:3]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: NC(=O)c1cccnc1Oc1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCNC(=O)c1cccnc1Oc1cccc(Cl)c1

Procedure:
To a stirred solution of 2(3-chloro-phenoxy)-nicotinamide (0.084 g, 0.34 mmole) in methylsulfoxide (2 ml) was added potassium hydroxide powder (0.074 grams, 1.32 mmole) followed by allyl bromide ((0.082 grams, 0.68 mmole). After 1 hour the mixture was poured into water and extracted with methylene chloride. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a clear film (0.011 g). 1H NMR (400 mhz, CD3OD) d 4.37 (q, J=7.26 Hz, 1H), 4.82 (d, J=5.60 Hz, 1H), 5.26 (d, J=10.58 Hz, 1H), 5.40 (d J=17.0 Hz, 1H), 6.05 (m, 1H), 7.03 (m, 1H), 7.13 (m, 1H), 7.21 (m, 2H), 7.38 (t J=8.1 Hz, 1H), 8.30 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[C:14]([F:24])[CH:13]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.O>[NH2:1][CH2:4][C:5]1[N:6]=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][C:21](=[O:23])[O:20][N:19]=2)=[C:14]([F:24])[CH:13]=1
Reactant: [N-]=[N+]=NCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: NCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(-c2noc(=O)[nH]2)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 4.9 %

Procedure:
To a mixture of 118 mg of 3-{4-[4-azidomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-1,2,4-oxadiazol-5-one in 0.25 mL of dimethylformamide and 0.022 mL of water was added 31 mg of triphenylphosphine. The resulting mixture was stirred for 20 h at room temperature and then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/methanol 10/water 1/acetic acid 1) followed by chromatography on a SCX Waters column with gradient CH2Cl2/MeOH 30/70 to 7N NH3 in MeOH to give 5.5 mg of 3-{4-[4-aminomethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-fluoro-phenyl}-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:15])[CH:3]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>O1CCOCC1.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:7]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH3:16])[N:18]=[CH:19]3)=[CH:6][C:5]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:15])[CH:3]=1
Reactant: COC(=O)CCc1cc(Br)c(N)cc1C
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(N)cc1C
Temperature: 25 °C
Yield: 73.2 %

Procedure:
A solution of Intermediate 9 (460 mg) in 1,4-dioxane (5 ml, KANTO) was added with 1-methyl-1H-indazol-5-ylboronic acid (rgt1, 350 mg), cesium carbonate (410 mg, KANTO), and PdCl2dppf.CH2Cl2 (115 mg, Ald), and stirred at 90° C. for 18 hours. The reaction mixture was cooled to room temperature, and then added with water (30 ml) and ethyl acetate (30 ml×2) to perform extraction. The reaction mixture was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1), and the solvent was evaporated under reduced pressure by using a rotary evaporator to obtain the title compound (400 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH:7]=1.ClC1CCC(C(OCC)=O)=C(C2C=CC=CC=2)C=1.C(O[K])(C)(C)C.Cl>C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CCOC(=O)C1CC=C(Cl)C=C1c1ccccc1
Agent: CC(C)(C)O[K]
Agent: CCOC(=O)C1=C(c2ccccc2)C=C(Cl)CC1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1ccc(Cl)cc1-c1ccccc1
Reaction time: 48 h

Procedure:
To a stirred solution of ethyl 4-chloro-2-phenylcyclohexa-2,4-dienecarboxylate and ethyl 4-chloro-2-phenylcyclohexa-1,3-dienecarboxylate(200 mg, 0.762 mmol) in tert-BuOH(3 ml), tert-BuOK(103 mg, 0.914 mmol) was added by portion on a water bath. After stirring for 2 days, water was added to the reaction mixture and it was acidified with dil. HCl aq., extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. Concentration of the organic layer afford a mixture(200 mg) of ethyl 4-chloro-2-phenylbenzoate and 4-chloro-2-phenylbenzoic acid. 1H-NMR(ppm, 300 MHz, CDCl3) δ ester 7.79(1H, d, J=8.0 Hz), 7.10-7.50(7H), 4.07(2H, d, J=6.9 Hz), 0.98(3H, t, J=6.9 Hz); acid 7.91(1H, d, J=8.7 Hz)
Reaction SMILES: [NH:1]1[C:42](=[O:43])[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])[NH:35][C:33](=[O:34])[C@@H:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:24][C:22](=[O:23])[C@H:17]([CH2:18][C:19](=[O:21])[OH:20])[NH:16][C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C([O-])(O)=[O:45].[Na+]>C1COCC1>[NH2:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@@H:25]([C:33]([NH:35][C@H:36]([C:42]([OH:45])=[O:43])[CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])[CH2:18][C:19](=[O:21])[OH:20])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: N=C(N)NCCC[C@@H]1NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CC(=O)O)NC(=O)CNC1=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N=C(N)NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](CCCCN)C(=O)O
Reaction time: 4 h

Procedure:
6 g of BOC-Aha-N-succinimidyl ester are added to a solution of 3.05 g of cyclo-(Arg-Gly-Asp-D-Phe-Lys)(SEQ ID NO: 176) in 40 ml of 5% aqueous NaHCO3 and 40 ml of THF. The mixture is stirred for 4 hours and worked-up in the customary manner, affording cyclo-(Arg-Gly-Asp-D-Phe-Lys (BOC-Aha))(SEQ ID NO: 13); RT [C] 27.7; FAB 817. After the BOC group has been eliminated in HCl/dioxane, cyclo-(Arg-Gly-Asp-D-Phe-Lys(Nε-Aha)(SEQ ID NO: 14)×2 TFA; RT [C] 14.76; FAB 717 is obtained after the customary working-up. Cyclo-(Arg-Gly-Asp-D-Phe-Lys(Nε-FCA-Aha))(SEQ ID NO: 15)×TFA; RT [B] 23.8; FAB 1075 is obtained, in analogy with Example 1, by subsequent reaction with FCA-N-succinimidyl ester.
Reaction SMILES: CN(C=O)C.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:18][CH2:17][CH2:16][CH2:15][CH2:14][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1
Reactant: Oc1ccccn1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ClCCCCOc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
To a DMF solution (110 ml) containing 2-pyridinol (10 g, 105 mmol) and 1-bromo-4-chlorobutane (36 ml, 315 mmol) was added potassium carbonate (16 g, 116 mmol), followed by stirring at room temperature for 8 hours. Water (300 ml) was added to the reaction solution, and extraction with ethyl acetate (300 ml) was then conducted. The organic layer was washed with water (300 ml) twice and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1). The purified product was concentrated under reduced pressure to thereby obtain 3.32 g of oily colorless 2-(4-chlorobutoxy)pyridine.
Reaction SMILES: C(N(CC)CC)C.Br[C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([Cl:17])=[CH:11][CH:10]=1.[CH2:18]([OH:21])[C:19]#[CH:20].O>[Cu](I)I.C(OCC)(=O)C>[Cl:17][C:12]1[CH:11]=[CH:10][C:9]([C:20]#[C:19][CH2:18][OH:21])=[N:14][C:13]=1[O:15][CH3:16]
Reactant: COc1nc(Br)ccc1Cl
Reactant: C#CCO
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nc(C#CCO)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Triethylamine (70 mL) and bistriphenylphosphinepalladium(II) dichloride (756 mg) were added to 6-bromo-3-chloro-2-methoxypyridine (12.1 g), 2-propyn-1-ol (4.0 g) and copper iodide (210 mg) in a nitrogen atmosphere, and the mixture was stirred at room temperature for four hours. Water and ethyl acetate were added to the reaction solution, followed by filtration. The aqueous layer was adjusted to pH 3 or less with 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→5:5) to give the title compound as a light brown powder (8.60 g, 80%).
Reaction SMILES: CSC.[S:4]1[C:8]([CH2:9][C:10]2[CH:11]=[C:12]([CH:22]3[C@@H:27]([O:28]CC4C=CC=CC=4)[C@@H:26]([O:36]CC4C=CC=CC=4)[C@@H:25]([O:44]CC4C=CC=CC=4)[C@@H:24]([CH2:52][O:53]CC4C=CC=CC=4)[O:23]3)[C:13]3[C:18]([C:19]=2[O:20][CH3:21])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:6]2[CH:61]=[CH:62][CH:63]=[CH:64][C:5]1=2.O>C(Cl)Cl>[S:4]1[C:8]([CH2:9][C:10]2[CH:11]=[C:12]([C@H:22]3[C@H:27]([OH:28])[C@@H:26]([OH:36])[C@H:25]([OH:44])[C@@H:24]([CH2:52][OH:53])[O:23]3)[C:13]3[C:18]([C:19]=2[O:20][CH3:21])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][C:6]2[CH:61]=[CH:62][CH:63]=[CH:64][C:5]1=2
Reactant: COc1c(Cc2cc3ccccc3s2)cc(C2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)c2ccccc12
Solvent: CSC
Solvent: ClCCl
Solvent: O
Product: COc1c(Cc2cc3ccccc3s2)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.3 %

Procedure:
Under a nitrogen atmosphere, dimethylsulfide (1.6 ml) and a boron trifluoride-diethyl ether complex (0.79 ml, 6.23 mmol) were added to a solution of (3R,4R,5S,6R)-2-[3-(benzo[b]thiophen-2-ylmethyl)-4-methoxynaphthalen-1-yl]-3,4,5-trisbenzyloxy-6-benzyloxymethyltetrahydropyran (515 mg, 0.62 mmol) in methylene chloride (10 ml) under cooling with ice. The reaction mixture was stirred at room temperature for three days, then water (10 ml) was added under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried with sodium sulfate, and thereafter the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=methylene chloride:methanol (20:1)] to obtain the title compound (82 mg, 28%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1O>>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=1[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1c(Cl)cccc1Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3c(Cl)cccc3Cl)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2,6-dichlorophenol: ESMS m/e: 543.0 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C)C=O.C(O)(C)C.CCOCC>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:15][CH:14]=[CH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CC(C)O
Product: C=CCOC1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
A solution of N-acetyl-4-hydroxypiperidine (100 g.) in dimethylformamide (250 ml.) was added dropwise to sodium hydride (38 g., 50% mineral oil dispersion) under an atmosphere of nitrogen. The mixture was stirred for 2 hours then allyl bromide (93 g.) was added slowly whilst maintaining the reaction temperature at 25° C. by external cooling. The mixture was then stirred at room temperature overnight, diluted with isopropanol (20 ml) and ether (500 ml.), filtered, and evaporated in vacuo. Distillation of the residue gave N-acetyl-4-allyloxypiperidine (108.8 g.), b.p. 128° C./2 mm., identified spectroscopically.
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1([CH2:15][OH:16])[CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1.[Cl-].[NH4+]>ClCCl>[Si:17]([O:16][CH2:15][C:11]1([CH2:10][CH2:9][OH:8])[CH2:12][CH2:13][CH2:14]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: OCC1(CCOCc2ccccc2)CCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1(CCO)CCC1
Reaction time: 16 h
Yield: 96.2 %

Procedure:
To a solution of 1.6 g (7.27 mmol) of {1-[2-(benzyloxy)ethyl]cyclobutyl}methanol in 16 mL of dichloromethane was added 1.20 g (7.99 mmol) of t-butyldimethylsilyl chloride and 0.98 g (14.54 mmol) of imidazole and the contents stirred for 16 h. Saturated ammonium chloride was added and the layers separated. The organic layer was dried with magnesium sulfate and concentrated under vacuum. To the crude silyl alcohol was added 20 mL of methanol and 0.24 g of 10 wt % palladium on carbon. The reaction was stirred under an atmosphere of hydrogen for 16 h. The contents were filtered and the filtrate was concentrated under vacuum to afford 1.71 g (97%) of 2-[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]ethanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 3.57 (s, 2H), 3.55 (t, J=6 Hz, 2H), 1.87-1.59 (m, 8H), 0.87 (2, 9H), 0.05 (s, 6H).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[C:14]([CH:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)#[N:15].S([O-])(O)(=O)=O.[Na+].C(OCC)C.Cl.[NH2:38][CH:39]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:40]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)=[O:41]>ClCCl.N1C=CC=CC=1>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([C:40](=[O:41])[CH:39]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)[NH:38][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([C:14]#[N:15])[CH3:25])=[CH:47][CH:46]=1
Reactant: CC(C#N)CCCCCC(=O)O
Reactant: NC(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C#N)CCCCCC(=O)NC(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
8.2 g of 7-cyanooctanoic acid dicyclohexylamine salt are added to a mixture of 26 cm3 of a molar solution of sodium hydrogen sulphate and 60 cm3 of diethyl ether. The mixture is stirred for 15 minutes at 20° C. and the organic phase is then separated. The latter is dried over magnesium sulphate and filtered and the solvent is evaporated off under reduced pressure. The residue is treated with 13.2 g of thionyl chloride and heated to 50° C. for 3 hours. The mixture is concentrated under reduced pressure. The residual oil is dissolved in 5 cm3 of dichloromethane, and the solution obtained is added to a suspension, stirred and cooled at 5° C. of 7 g of 2-amino-1,2-bis(4-chlorophenyl)ethanone hydrochloride in 25 cm3 of dichloromethane containing 4.4 g of pyridine. After treatment, the product obtained is chromatographed on a column 2.8 cm in diameter containing 140 g of silica gel (50 to 200μ). The column is eluted with 1 liter of diisopropyl ether and then with 2.5 liters of a diisopropyl ether/ethyl acetate (90:10 by volume) mixture, collecting 250 cm3 fractions. The fractions from the last eluent mixture are concentrated to dryness under reduced pressure (0.2 kPa). 7.6 g (80%) of (RS)-1,2-bis(4-chlorophenyl)-2-(7-cyanooctanamido)ethanone are obtained in the form of a yellowish oil, which is used directly in the subsequent reaction.