Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][O:17][CH:18]1[CH2:21][N:20]([CH2:22][CH2:23][NH:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N:30]=2)[CH2:19]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH3:16][O:17][CH:18]1[CH2:21][N:20]([CH2:22][CH2:23][NH:24][C:25]2[N:26]=[N+:27]([O-:38])[C:28]3[CH:37]=[C:36]4[C:32]([CH2:33][CH2:34][CH2:35]4)=[CH:31][C:29]=3[N+:30]=2[O-:4])[CH2:19]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: COC1CN(CCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1CN(CCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
H2O2 (70%, 1.4 mL, ca. 28 mmol) was added dropwise to a stirred solution of TFAA (4.0 mL, 28 mmol) in DCM (30 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 34 (890 mg, 2.8 mmol) and TFA (1.1 mL, 14 mmol) in DCM (35 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 35 (390 mg, 42%) as a red solid: mp 152° C. (dec.); 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.30 (br s, 1H, NH), 4.04 (p, J=5.8 Hz, 1H, CHO), 3.67-3.72 (m, 2H, CH2N), 3.54 (dt, J=5.9, 5.5 Hz, 2H, CH2N), 3.25 (s, 3H, OCH3), 3.11 (dt, J=7.4, 0.9 Hz, 2H, H-6), 3.06 (dt, J=7.4, 1.1 Hz, 2H, H-8), 2.95-2.99 (m, 2H, CH2N), 2.78 (t, J=5.9 Hz, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7); 13C NMR δ 155.6, 149.4, 145.8, 138.0, 129.8, 115.8, 111.6, 69.9, 61.5 (2), 58.0, 56.0, 39.5, 33.4, 32.4, 25.6; MS (APCI) m/z 332 (MH+, 100%). Anal. calcd for C16H21N5O3.0.15CH2Cl2: C, 56.4; H, 6.2; N, 20.4. Found: C, 56.2; H, 6.1; N, 20.4%.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][C:16]1[C:21](Cl)=[N:20][C:19]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][O:29][CH3:30])=[CH:18][N:17]=1)[CH2:9][C@@H:10]([OH:14])[CH2:11][O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:1]([N:8]1[CH2:15][C:16]2[N:17]=[CH:18][C:19]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH2:28][O:29][CH3:30])=[N:20][C:21]=2[O:14][C@@H:10]([CH2:11][O:12][CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC1CCCN1c1cnc(CN(Cc2ccccc2)C[C@@H](O)COC)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC1CCCN1c1cnc2c(n1)O[C@@H](COC)CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of (2R)-1-[benzyl({3-chloro-5-[2-(methoxymethyl)pyrrolidin-1-yl]pyrazin-2-yl}methyl)amino]-3-methoxypropan-2-ol (578 mg) in DMF (10 mL) was added potassium tert-butoxide (179 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 10→50% ethyl acetate/hexane) to give the title compound (467 mg, 88%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)#[N:2].C([O-])([O-])=O.[K+].[K+].[CH2:45]([N:47]([CH2:51][CH3:52])[C:48](Cl)=[O:49])[CH3:46]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][CH:38]=1)[CH2:6][N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH2:10][CH2:9]1)[C:29]1[CH:34]=[CH:33][C:32]([O:35][C:48](=[O:49])[N:47]([CH2:51][CH3:52])[CH2:45][CH3:46])=[CH:31][CH:30]=1)#[N:2]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(O)cc2)CC1
Reactant: CCN(CC)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Oc1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)cccc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of COMPOUND 117 (42 mg, 0.082 mmol) in DMF (1 mL) were added K2CO3 (40 mg, 0.29 mmol) followed by diethylcarbamoyl chloride (20 μL, 0.16 mmol) and the mixture was stirred at room temperature overnight to afford COMPOUND 141 as a white solid (35 mg, 67%) following work-up and purification. 1H NMR (CDCl3) δ 0.93-1.01 (m, 1H), 1.00 (d, 3H, J=5.7 Hz), 1.10-1.18 (m, 7H), 1.50-1.58 (m, 1H), 1.70-1.73 (m, 3H), 2.14 (t, 1H, J=10.8 Hz), 2.31 (s, 6H), 2.54 (t, 1H, J=11.4 Hz), 2.73-2.88 (m, 3H), 3.15-3.36 (m, 5H), 3.50-3.56 (m, 1H), 3.74 (s, 2H), 3.87-3.93 (m, 1H), 6.51 (d, 2H, J=7.2 Hz), 6.87 (d, 2H, J=7.8 Hz), 6.95-6.99 (m, 3H), 7.41-7.50 (m, 4H), 8.44 (br s, 1H). 13C NMR (CDCl3) δ 13.80, 14.59, 19.53, 29.33, 30.74, 31.32, 36.87, 40.26, 42.17, 42.56, 43.96, 48.78, 52.59, 57.57, 60.99, 112.84, 114.95, 119.36, 122.75, 127.68, 128.77, 129.55, 130.48, 130.83, 131.43, 134.47, 139.03, 142.64, 143.52, 146.07, 155.18, 170.24. ES-MS m/z 610 (M+H). Anal. Calcd. for C37H47N5O3.0.8H2O: C, 71.19; H, 7.85; N, 11.22. Found. C, 71.09; H, 7.68; N, 11.16.
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5].C[O-].[Na+].[NH3:14]>C(O)CCC>[NH:5]=[C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[NH:14])[NH:10]1
Reactant: N#Cc1ccccc1C#N
Reactant: N
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCO
Product: N=C1NC(=N)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To 180 mi of n-butanol were fed 21 g (0.06325 mole) of a phthalonitrile represented by the formula (XXI) and 8.54 g (0.1581 mole) of sodium methoxide. The mixture was stirred at room temperature for 1 hour while blowing NH3 gas thereinto and, then, stirred with heating at 70°-80° C. for 3 hours (while blowing NH3 gas). After being cooled to room temperature, n-BuOH was removed by distillation. The concentrate was dissolved in 800 ml of chloroform and was washed well with water and with hot water. Water in the organic layer was removed with magnesium sulfate and chloroform was removed by distillation. The residue was recrystallized from hexane to obtain 21 g (yield: 95.1%) of a compound having the following formula (XXII). The compound is in the form of light yellow crystals and shows no melting point and a decomposition point of 205° C. The IR spectrum of this compound is shown in FIG. 8. ##STR53##
Reaction SMILES: [NH2:1][C:2]1[NH:6][NH:5][C:4](=[O:7])[C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[CH3:19].O=[C:21]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH2:22][C:23](OCC)=[O:24].Cl.O1CCOCC1>C(O)C>[CH3:19][C:10]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][C:3]1[C:4]([OH:7])=[N:5][N:6]2[C:23]([OH:24])=[CH:22][C:21]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[N:1][C:2]=12
Reactant: Cc1c(Cc2c(N)[nH][nH]c2=O)cccc1C(F)(F)F
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1c(Cc2c(O)nn3c(O)cc(C4CCOCC4)nc23)cccc1C(F)(F)F

Procedure:
To a suspension of 5-amino-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1,2-dihydro-3H-pyrazol-3-one (136 mg, 0.5 mmol) in ethanol (1 mL) were added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (100 mg, 0.5 mmol) and 4 M HCl solution in dioxane (25 uL, 0.1 mmol). The reaction mixture was irradiated (microwave) at 110° C. for 30 minutes. Reaction was cooled down. The precipitate was collected by filtration. It was washed with acetic acid (1 mL), then methanol (1 mL) and dried. The titled compound was obtained. (52 mg, 25%); LC/MS: MS (ES+) m/e 408 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69 (dd, J=12.51, 4.17 Hz, 1H) 1.73-1.80 (m, 3H) 2.46 (s, 3H) 2.72 (s, 1H) 3.34-3.45 (m, 2H) 3.83 (s, 2H) 3.93 (br. s., 2H) 5.51 (s, 1H) 7.15 (d, J=7.58 Hz, 1H) 7.29 (t, J=7.71 Hz, 1H) 7.54 (d, J=8.34 Hz, 1H) 11.46 (s, 1H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[NH:9]1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([C:21]#[N:22])[CH:10]([CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC2CCCC2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(c2ccc(Cl)cc2)C(CC2CCCC2)NC(C(=O)O)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 34b (0.4 g, 0.77 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-cyclopentylmethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.5 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1.Cl[CH2:19][C:20](=[O:22])[CH3:21].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:19][C:20](=[O:22])[CH3:21])[CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:4]=2[CH:3]=1
Reactant: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)CN1CCc2c(c(=O)oc3cc(C)c(C)cc23)C1
Yield: 63.4 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-8,9-dimethyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (30 g, 0.13 mole), 1-chloro-2-propanone (23.6 g, 0.25 moles), and triethylamine (27.3 g, 0.27 moles) in 550 ml of absolute ethanol is stirred at reflux for 21 hours. The reaction mixture is evaporated, and the residue is partitioned between dichloromethane (700 ml) and water (500 ml). The two-phase mixture is made basic with conc. ammonium hydroxide, the layers are separated, and the aqueous phase is extracted with fresh dichloromethane. The combined organic layers are backwashed with water, dried over sodium sulfate, and evaporated. Recrystallization of the residue from absolute ethanol yielded the product (23.5 g), mp 136°-138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.N[C:25](N)=[O:26]>>[O:26]=[C:25]1[N:12]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[NH:1]1
Reactant: NC(N)=O
Reactant: CCOC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2N)CC1
Product: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(C(F)(F)F)ccc32)CC1
Temperature: 100 °C

Procedure:
56.27 parts of ethyl 4-[2-amino-4-(trifluoromethyl)-phenylamino]-1-piperidinecarboxylate and 15.6 parts of urea are mixed thoroughly in a mortar. The mixture is stirred and heated on an oil-bath at 170°-180° C for 3 hours. The reaction mixture is cooled to 100° C and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding ethyl 4-[1,3-dihydro-2-oxo-5-(trifluoromethyl)-2H-benzimidazol-1-yl]-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[C:21]([F:24])([F:23])[F:22].[C:26]1(=[O:31])[CH2:30][CH2:29][CH:28]=[CH:27]1.[Li+].[OH-].O>O.C(COC)OC>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:28]2[CH2:29][CH2:30][C:26](=[O:31])[CH2:27]2)=[CH:8][C:7]=1[C:21]([F:22])([F:23])[F:24]
Reactant: COC(=O)CCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Reactant: O=C1C=CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)CCc1ccc(C2CCC(=O)C2)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-trifluoromethyl-phenyl]-propionic acid methyl ester (preparation 2) (4.6 mmol) and [(1,4-hydroquinone)-rhodium(COD)]BF4 (Son et al., J. Am. Chem. Soc. 2005, 127, 12238) (2 mol %) in water/dimethoxyethane (1:1, 20 mL, degassed) was added 2-cyclopenten-1-one (4.6 mmol) and LiOH (8 mol %). The mixture was warmed to 50° C. and stirred overnight. Additional water was added, and the mixture was extracted with dichloromethane. The organic phase was separated, dried and concentrated in vacuo to afford the title compound as a brown oil. 1H NMR (300 MHz, DMSO) δ 7.72-7.56 (m, 2H), 7.54-7.39 (m, 1H), 3.62 (s, 3H), 3.53-3.36 (m, 1H), 3.08-2.95 (m, 2H), 2.70-2.47 (m, 3H), 2.43-2.21 (m, 4H), 2.02-1.83 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.C([O:12][C:13](=[O:31])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1/[CH:23]=[C:24]1/[C:25](=[O:30])[NH:26][C:27](=[O:29])[S:28]/1)C>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([OH:31])=[O:12])=[C:17]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[N:26]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=3)[C:25]2=[O:30])[CH:18]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CCOC(=O)COc1ccc(Br)cc1/C=C1\SC(=O)NC1=O
Product: O=C(O)COc1ccc(Br)cc1CC1SC(=O)N(Cc2cccc(Cl)c2)C1=O

Procedure:
Prepared from 3-chlorobenzyl bromide and 4-bromo-2-[2,4-dioxothiazolidin-(5Z)-ylidenemethyl]phenoxyacetic acid ethyl ester according to GP13, GP14 and GP16: LC/MS (an10p8): Rt 2.6 min, m/z 484 [M+H]+. 1H NMR (DMSO-d6): δ 3.02-3.10 (m, 1H), 3.54-3.60 (m, 1H), 4.69 (s, 2H), 4.75 (s, 2H), 5.09-5.14 (m, 1H), 6.89-6.92 (m, 1H), 7.18 (m, 1H), 7.33-7.43 (m, 5H), 13.01 (br s, 1H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>>[CH3:19][N:20]([CH3:22])/[CH:21]=[C:9]1\[C:8](=[O:13])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10]\1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)/C=C1/CCCC(c2ccccc2)C1=O
Yield: 101.2 %

Procedure:
A mixture of 2-phenylcyclohexanone (871 mg, 5.0 mmol) and of tert.-butoxy-bis(dimethylamino)methane (90%, 1.5 mL, 7 mmol) was stirred at 110° C. for 75 min. The reaction was evaporated to dryness under reduced pressure to give the crude title compound (1.16 g, 100%) as a red oil which was used directly in the next step without further purification. MS ISP (m/e): 230.2 (100) [(M+H)+].
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[O:14][C@@H:11]([O:12][CH3:13])[C@@H:10]1[OH:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:36]([O:35][C@@H:10]1[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:15]([CH2:25][O:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:14][C@H:11]1[O:12][CH3:13])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
Methyl 3,4-di-O-benzyl-6-O-(4-chlorobenzyl)-β-D-glucopyranoside (0.233 g, 0.467 mmol) was dissolved in 5 mL CH2Cl2. Acetic anhydride (53 μL, 0.560 mmol) and DMAP (0.114 g, 0.934 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. The solution was filtered through silica, eluted with EtOAc and concentrated. Purification by flash column chromatography on silica gel (30% EtOAc/Hexanes) gave 224 mg (89%) of 20 as a colorless oil. [α]24D: −0.5° (c 0.79, CH2Cl2); IR (thin film). 2867, 1747, 1233, 1087, 1060 cm−1; 1H-NMR (CDCl3) δ 7.35–7.27 (m, 12H), 7.20–7.18 (m, 2H), 5.00 (dd, J=7.9, 8.8 Hz, 1H), 4.81 (d, J=10.7 Hz, 1H), 4.80 (d, J=11.6 Hz, 1H), 4.68 (d, J=11.3 Hz, 1H), 4.59 (d, J=12.5 Hz, 1H), 4.56 (d, J=10.7 Hz, 1H), 4.52 (d, J=12.2 Hz, 1H), 4.30 (d, J=7.9 Hz, 1H), 3.74–3.67 (m, 4H), 3.51–3.37 (m, 4H), 1.99 (s, 3H); C-NMR (CDCl3) δ 169.8, 138.2, 138.0, 136.8, 129.2, 128.7, 128.6, 128.2, 128.1, 128.0, 102.0, 83.2, 78.1, 75.3, 75.2, 73.2, 72.9, 68.9, 56.9, 21.2; FAB MS m/z (M+Na)+: calcd 563.1813, obsd 563.1817.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH:16]([NH2:18])[CH3:17])[CH2:10][CH2:9][CH:8]([S:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>ClCCl>[Cl:19][C:20]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:21]=1[C:22]([NH:18][CH:16]([C:5]1([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:6][CH2:7][CH:8]([S:11][CH2:12][CH:13]2[CH2:14][CH2:15]2)[CH2:9][CH2:10]1)[CH3:17])=[O:23]
Reactant: CC(N)C1(CC2CC2)CCC(SCC2CC2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)c1ccc(Cl)cc1Cl)C1(CC2CC2)CCC(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1-{1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexyl}ethyl)amine (0.1 g; 0.3745 mmol), 2,4-dichlorobenzoyl chloride (0.1174 g; 0.56175 mmol) and triethylamine (0.0567 g; 0.56175 mmol) were dissolved in dichloromethane and stirred for one hour at room temperature. The reaction was evaporated and partitioned between ethyl acetate and saturated bicarbonate solution. The organic layer was dried and evaporated and the residue was purified by silica chromatography using ethyl acetate hexanes to yield 2,4-dichloro-N-(1-{1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexyl}ethyl) benzamide. (130 mg, 79%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH:16]2[O:28][C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(Oc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(i), by alkylating tert-butyl (3RS,4RS)-4-(4-benzyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-benzyloxy-phenyl)-3-(naphthalen-2-yloxy)-piperidine-1-carboxylate as a colourless, amorphous solid; MS: 523 (M)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[I:13][C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([OH:24])=[CH:16][CH:15]=1>>[I:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)c1cc(I)ccc1O
Product: COC(=O)c1cc(I)ccc1OCc1ccc2ccccc2c1
Yield: 68 %

Procedure:
Using the procedure described in Example 5, 2-bromomethylnaphthalene was reacted with methyl 5-iodosalicylate to give methyl 5-iodo-2-(naphth-2-ylmethoxy)benzoate (68%). Using conventional procedures the ester was hydrolysed with base to give the corresponding acid; the acid chloride was prepared by reaction with oxalyl chloride; and the acid chloride was reacted with ethanolic ammonia to give 5-iodo-2-(naphth-2-ylmethoxy)benzamide (84% from the ester), m.p. 163° C. The benzamide so obtained was reacted with trifluoroacetic anhydride in the presence of pyridine and dimethoxyethane as reaction solvent. There was thus obtained 3-cyano-4-(naphth-2-ylmethoxy)phenyl iodide (72%), m.p. 108°-110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:40]=[CH:39][C:29]([CH2:30][N:31]2[C:35](=[O:36])[CH:34]([CH3:37])[NH:33][C:32]2=[O:38])=[CH:28][CH:27]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:33]4[CH:34]([CH3:37])[C:35](=[O:36])[N:31]([CH2:30][C:29]5[CH:39]=[CH:40][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:32]4=[O:38])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Product: COc1ccc(CN2C(=O)C(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Yield: 86.5 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (141 mg) described in Preparation Example 51 and by the reaction and treatment in the same manner as in Example 1, the title compound (183 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:17]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:17][C:6]=1[CH3:7]
Reactant: Cc1cccnc1C(=O)c1cc(C)c(C)o1
Reactant: N
Solvent: CO
Product: Cc1cc(O)c(-c2ncccc2C)nc1C
Temperature: 160 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(3-methylpyridin-2-yl)-methanone (930 mg), methanol (7.5 ml), and a 28% aqueous ammonia solution (9 ml) were placed in a sealed tube and was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6,3′-trimethyl-[2,2′]bipyridin-3-ol (109 mg, yield 86%).