Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH:2]([C:4]1[CH:5]=[CH:6][C:7](C)=[C:8](S(O)(=O)=O)[CH:9]=1)=[O:3].CC1C=CC([CH:20]=[O:21])=CC=1.OS(O)(=O)=O.O=S(=O)=O>>[CH3:20][O:21][C:7]1[CH:6]=[CH:5][C:4]([CH:2]=[O:3])=[CH:9][CH:8]=1
Reactant: Cc1ccc(C=O)cc1S(=O)(=O)O
Reactant: Cc1ccc(C=O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Agent: [Na]
Product: COc1ccc(C=O)cc1

Procedure:
The sodium salt of 5-formyl-2-methylbenzenesulphonic acid used as starting material for the bis-stilbene compound of the formula (88) is obtained by sulphonating 4-methylbenzaldehyde with oleum containing 66% of SO3 and purification via the barium salt. In a similar manner the sodium salt of 5-formyl-2methoxybenzenesulphonic acid, used as starting material for the bis-stilbene compound of the formula (89), is obtained from 4-methoxybenzaldehyde. ##SPC61##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][C:4]=1[C:14](=[O:16])[CH3:15].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH:21]=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:15][C:14]([C:4]2[CH:5]=[CH:6][C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[CH:8][C:3]=2[O:2][CH3:1])=[O:16])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COc1cc(-c2cccs2)ccc1C(C)=O
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccs2)ccc1C(=O)C=Cc1ccc(F)c(F)c1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
The 2′-methoxy-4′-(thien-2-yl)acetophenone (0.30 g, 1.3 mmol) from Ex-57A and 3,4-difluorobenzaldehyde 0.19 g, 1.3 mmol) were mixed in tetrahydrofuran (THF, 10 mL). Cesium carbonate (1.2 g, 3.9 mmol) was added, and the mixture was stirred at reflux overnight. Upon cooling to room temperature, the mixture was filtered, the filtrate was treated with 0.5 M HCl, and extracted with dichloromethane. The organic phase was dried and evaporated. Silica gel chromatography gave 0.32 g (69%) of the desired 3-(3,4-difluorophenyl)-1-[2-methoxy-4-(thien-2-yl)phenyl]-2-propen-1-one product, m.p. 73-79° C. 1H-NMR (300 MHz, CDCl3): 7.70 (d, 1H), 7.25-7.40 (m, 2H), 6.98-7.15 (m, 7H), 6.49 (d, 1H), 3.89 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:44]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[CH2:21][CH2:22][Br:44])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCBr)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In methylene chloride (70 ml) were dissolved 1,4-bis(tert-butoxycarbonyl)-2-(2-hydroxyethyl)piperazine (2.01 g) and triphenylphosphine (1.98 g). Under ice cooling, carbon tetrabromide (3.07 g) was added to the resulting solution, followed by stirring at room temperature for 2.5 hours. The reaction mixture was extracted with a 10% aqueous solution of sodium thiosulfate. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate an distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (hexane:ethyl acetate=4:1) using as a carrier silica gel, whereby the title compound (2.20 g) was obtained as colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][O:6][CH2:7][CH2:8][OH:9].N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24]
Reactant: OCCOCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOCc1cccc(Br)c1

Procedure:
A solution of 2-(3-bromobenzyloxy)ethanol [Aromatic Intermediate 25, step a] (3 g), imidazole (2.2 g) and tert-butyldimethylchlorosilane (2.2 g) in DCM (50 mL) was stirred at RT for 17 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (×2). The combined organic phases were dried and evaporated in vacuo. The crude product was purified by silica gel chromatography, gradient elution 10 to 40% ethyl acetate in isohexane. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a colourless oil. Yield 3.8 g.
Reaction SMILES: [CH3:1][C:2]([CH3:27])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17][C:18]([NH:20][C:21]([CH2:23][Cl:24])=[O:22])=[O:19])[C@H:10]1[O:25][CH3:26])[CH3:8].[ClH:28]>CO>[Cl:24][CH2:23][C:21]([NH:20][C:18]([O:17][CH:11]1[CH2:12][CH2:13][C:14]([CH2:15][Cl:28])([OH:16])[CH:9]([C:6]2([CH3:8])[O:7][CH:5]2[CH2:4][CH:3]=[C:2]([CH3:1])[CH3:27])[CH:10]1[O:25][CH3:26])=[O:19])=[O:22]
Reactant: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: Cl
Solvent: CO
Product: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CCl)C1C1(C)OC1CC=C(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of O-(chloroacetylcarbamoyl)fumagillol (100 mg) in methanol (2 ml) was added 0.4N hydrochloric acid (1 ml), which was stirred for one hour at room temperatures. Resulting precipitates were collected by filtration and recrystallized from methanol-water to afford 4-O-(chloroacetylcarbamoyl)-2(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (96 mg, yield 90%) colorless crystals.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([NH:53][CH:54]([CH3:56])[CH3:55])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:53]([CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)[CH:54]([CH3:56])[CH3:55])=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)NC1CCCCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C(C)C)C2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with N-cyclohexyl-N-isopropylamine (Fluka) to give the title compound. HR-MS (ES, m/z) calculated for C45H60Cl2N5O3 [(M+H)+] 788.4068, observed 788.4062.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:14](#[N:17])[CH:15]=[CH2:16]>C(O)(C)(C)C>[C:1]([CH:5]1[CH2:6][C:7]([CH2:16][CH2:15][C:14]#[N:17])([CH2:16][CH2:15][C:14]#[N:17])[C:8](=[O:11])[C:9]([CH2:16][CH2:15][C:14]#[N:17])([CH2:16][CH2:15][C:14]#[N:17])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC#N
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(C)(C)C1CC(CCC#N)(CCC#N)C(=O)C(CCC#N)(CCC#N)C1
Yield: 75.2 %

Procedure:
A solution of 4-t-butylcyclohexanone (15.4g) and crushed KOH (0.5g) in tert.butanol (62.4g) was stirred and kept at or below 30° C. while acrylonitrile (21.2g) was added dropwise. During the addition a solid began to precipitate. When addition was complete the thick slurry was stirred for a further hour before the solid was collected by filtration. The solid was washed with water, then crystallised from 2-ethoxyethanol to yield 27.5g of 4-t-butyl-2,2,6,6-tetra(β-cyanoethyl)cyclohexanone, m.p. 175°-178° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2[OH:24])=[CH:4][CH:3]=1.[CH2:27](Cl)Cl.C(O)(C(F)(F)F)=O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:22][CH3:23])[C:9]=3[CH:8]2[O:24][CH3:27])=[CH:25][CH:26]=1
Reactant: ClCCl
Reactant: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2OC

Procedure:
A solution of 21 (6.7 mg, 0.019 mmol) in a 1:1 solution of CH2Cl2:MeOH was stirred with TFA (3 μL, 0.038 mmol) at room temperature for 2 hours when complete conversion was observed by LCMS. The solution was dried in vacuo and the residue was washed with hexanes to yield 7 mg of the product 22. EI MS (m/z) 355.4 [MH+].
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:23]2[C:24]([CH3:40])=[C:25]([NH:29]C(=O)OCC4C=CC=CC=4)[CH:26]=[CH:27][CH:28]=2)=[CH:6][N:5]=1)=[CH:15][CH:14]=[C:13]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH:12]=3)(=[O:3])[NH2:2]>C1COCC1.CO.[Pd]>[NH2:29][C:25]1[C:24]([CH3:40])=[C:23]([C:7]2[C:8]3[C:16]4[C:11](=[CH:12][C:13]([N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:4]([C:1]([NH2:2])=[O:3])=[N:5][CH:6]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCOCC4)ccc3c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(N4CCOCC4)ccc3c12
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
A solution of benzyl 3-(1-carbamoyl-7-morpholino-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.2735 g, 0.511 mmol) and 10% Pd/C (0.109 g, 0.102 mmol) in THF (12.8 mL) and MeOH (19.2 mL) was hydrogenated. After 1.5 hr, the reaction was flushed with nitrogen and filtered through a wad of CELITE®. The filtrate was concentrated in vacuo, dissolved in CH2Cl2, dried over MgSO4, and concentrated in vacuo to give the desired product (0.196 g, 0.450 mmol, 88% yield) as a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][NH:6][CH:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.[CH3:26][O:27][C:28]1[C:29](=O)[C:30](=[O:34])[C:31]=1[O:32]C>>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][NH:6][CH:7]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[C:10]([NH:14][C:29]2[C:30](=[O:34])[C:31](=[O:32])[C:28]=2[O:27][CH3:26])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NCc2cccc(F)c2)c2cccc(N)c2)cc1
Product: COc1ccc(C(NCc2cccc(F)c2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1
Yield: 90.3 %

Procedure:
In a similar manner to that described in Example (1c), 3-[(3-fluorobenzyl amino)-(4-methoxyphenyl)methyl]phenylamine (409 mg) [prepared as described in step (b) above] and 3,4-dimethoxy-3-cyclobutene-1,2-dione (173 mg) were reacted, to afford the title compound (490 mg) as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[C:17]1([S:14]([N:9]2[C:10]3[C:6](=[C:5]([O:4][CH2:3][CH2:2][N:23]=[N+:24]=[N-:25])[CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(OCCCl)cccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCOc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A suspension of 4-(2-chloroethoxy)-1-(phenylsulfonyl)-1H-indole (3.35 g, 10 mmol) and sodium azide (1.95 g, 30 mmol) in anhydrous dimethylformamide is stirred under nitrogen for 20 hr at 60° C., poured into water and extracted with diethyl ether. The extracts are combined, washed sequentially with 1N HCl, H2O and saturated NaCl, dried over MgSO4 and concentrated in vacuo to afford the title product as an off-white solid, 3.3 g (96%), identified by NMR and mass spectral analyses.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14].B(Br)(Br)Br.C([O-])(O)=O.[Na+].C(OCC)C>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16]
Reactant: COc1ccc(NC(=O)C(F)(F)F)c(OC)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Nc1ccc(O)cc1O)C(F)(F)F
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of N-(2,4-dimethoxy phenyl)-2,2,2-trifluoro-acetamide (2.50 g; 10 mmol) in CH2Cl2 (20 mL) cooled to −10° C. was added 1 M BBr3 (CH2Cl2; 24 mL; 24 mmol) under N2 atmosphere. The mixture was allowed to warm to room temperature over 2 hours and poured onto H2O (150 mL). Saturated aqueous NaHCO3 (100 mL) and diethylether (100 mL) was added to dissolve any precipitated material. The organic layer was Isolated, washed with H2O (50 mL), dried (MgSO4), filtered and the eluate evaporated to dryness to yield 1.85 g (83%) of the desired compound as a greyish solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: COC(=O)C1CCNCC1
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(C(=O)c2ccc3cc(OC(C)=O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 129.7 %

Procedure:
A mixture of 6-acetoxy-2-naphthoic acid (1 g, 4.34 mmol, 1.0 eq), methyl piperidine-4-carboxylate (684 mg, 4.78 mmol, 1.1 eq), HBTU (2.47 g, 6.51 mmol, 1.5 eq) and TEA (658 mg, 6.51 mmol, 1.5 eq) in DCM (20 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (200 mL). The combined organic layers were washed with water (100 mL*2) and brine (100 mL), dried over Na2SO4 and concentrated to give methyl 1-(6-acetoxy-2-naphthoyl)piperidine-4-carboxylate as a yellow oil (2 g, yield: 100%). ESI-MS: 356.0 (M+H)+. 1HNMR (400 MHz, DMSO-d6) δ: 8.05 (d, 1H), 8.01-7.96 (m, 2H), 7.73 (s, 1H), 7.53-7.51 (m, 1H), 7.40-7.37 (m, 1H), 3.63 (s, 3H), 3.18-2.95 (m, 2H), 2.71-2.65 (m, 3H), 2.34 (s, 3H), 1.97-1.76 (m, 2H), 1.61-1.50 (m, 2H).
Reaction SMILES: [NH:1]1[C:57](=[O:58])[C@H:48]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[CH:52][CH:51]=2)[NH:47][C:45](=[O:46])[C@H:43]([CH3:44])[N:42]([CH3:59])[C:40](=[O:41])[C@H:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:31][C:29](=[O:30])[C@H:25]([CH:26]([CH3:28])[CH3:27])[NH:24][C:22](=[O:23])[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[N:15](C(OCC2C=CC=CC=2)=O)[C:13](=[O:14])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(O)=O>[Pd].CO>[NH:1]1[C:57](=[O:58])[C@H:48]([CH2:49][C:50]2[CH:51]=[CH:52][C:53]([OH:56])=[CH:54][CH:55]=2)[NH:47][C:45](=[O:46])[C@H:43]([CH3:44])[N:42]([CH3:59])[C:40](=[O:41])[C@H:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:31][C:29](=[O:30])[C@H:25]([CH:26]([CH3:28])[CH3:27])[NH:24][C:22](=[O:23])[C@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[NH:15][C:13](=[O:14])[C@H:2]1[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)[C@@H]1NC(=O)[C@H](CCCCN)N(C(=O)OCc2ccccc2)C(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](C)N(C)C(=O)[C@H](Cc2ccccc2)NC1=O
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CC(C)[C@@H]1NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](C)N(C)C(=O)[C@H](Cc2ccccc2)NC1=O
Reaction time: 2 h

Procedure:
A dry mixture of 20.3 mg of the product of Example 12 or 13 and 4.4 mg of 10% palladium on carbon are combined with 1.5 ml of a 5:95 mixture on a volume basis of 88% formic acid and methanol. The mixture is stirred for 2 hours and filtered through Celite which had been prewashed with 5% formic acid and methanol followed by washing with two 1 ml portions of methanol. The filtrate is freeze-dried affording a residue of 17 mg of "Cyclo(D-Trp-Lys-Val-Phe-N-Me-Ala-Tyr)."
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:17][C:18](=[O:30])[CH2:19][CH2:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([OH:28])=[C:23]([F:29])[CH:22]=1)C>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:24]3[C:23]([F:29])=[CH:22][C:21]([CH2:20][CH2:19][C:18]([OH:30])=[O:17])=[CH:26][C:25]=3[F:27])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: O=C(O)CCc1cc(F)c(OCc2cccnc2SC2CCCC2)c(F)c1
Yield: 79.4 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.037 g, 0.16 mmol) obtained in Step C of Preparation Example 8 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.037 g, 0.16 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.050 g, 79%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:14]([OH:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[OH:16].CN(C=O)C.I[CH2:23][CH2:24][CH3:25]>O>[Br:3][C:4]1[C:5]([O:16][CH2:23][CH2:24][CH3:25])=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][C:14]=1[OH:15]
Reactant: CCOC(=O)c1cc(O)c(Br)c(O)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cc(C(=O)OCC)cc(O)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% oil, 10.1 g) was added to a mixture of ethyl 4-bromo-3,5-dihydroxybenzoate (30.0 g) and DMF (200 mL), and the resultant mixture was stirred at 0° C. for 30 minutes in a nitrogen atmosphere. 1-Iodopropane (11.2 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (14.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]([O:8][CH:9]([C:11](OCC)=[O:12])[CH3:10])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])([N+:16]([O-:18])=[O:17])[CH:5]=[CH:4][C:3]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:46]([O-:48])=[O:47])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:45])([F:44])[F:43])[CH:32]([O:49][CH:50]([C:52](OCC)=[O:53])[CH3:51])[C:31]=1[Cl:57].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2]1[CH:7]([O:8][CH:9]([CH2:11][OH:12])[CH3:10])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:26])([F:28])[F:27])([N+:16]([O-:18])=[O:17])[CH:5]=[CH:4][C:3]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:46]([O-:48])=[O:47])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]([F:44])([F:43])[F:45])[CH:32]([O:49][CH:50]([CH2:52][OH:53])[CH3:51])[C:31]=1[Cl:57]
Reactant: CCOC(=O)C(C)OC1C(Cl)=C(OC2=C(Cl)C(OC(C)C(=O)OCC)C(c3ccccc3C(F)(F)F)([N+](=O)[O-])C=C2)C=CC1(c1ccccc1C(F)(F)F)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(CO)OC1C(Cl)=C(OC2=C(Cl)C(OC(C)CO)C(c3ccccc3C(F)(F)F)([N+](=O)[O-])C=C2)C=CC1(c1ccccc1C(F)(F)F)[N+](=O)[O-]

Procedure:
A solution of 2-chloro-α,α,α-trifluoro-p-tolyl-3-(1-carbethoxyethoxy)-4-nitrophenyl ether (17.32 g, 0.04 mole in dry ether (500 ml) is treated at -10° C. with a suspension of lithium aluminum hydride (1.9 g) in ether (approximately 100 ml) added with stirring over ten seconds. The termperature increases to about 0° to 10° C. and after a total of 45 seconds, the reaction mixture is quenched by pouring, with stirring, onto ice/dilute sulfuric acid. The ether phase is washed with water, dried, filtered through activated silica gel, and the solvent removed to give 2-chloro-α,α,α-trifluoro-p-tolyl-3-(1-hydroxymethylethoxy)-4-nitrophenyl ether as a dark oil, yield 14 g.
Reaction SMILES: [H-].[Na+].CS([O:7][CH2:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[C@H:18]2[C@H:22]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@H:21]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@@H:20]([CH2:39][O:40][CH3:41])[O:19]2)=[C:11]([NH:42][CH2:43][CH:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:10]=1)(=O)=O.[CH3:57][N:58]1[CH2:63][CH2:62][CH:61](O)[CH2:60][CH2:59]1>O1CCCC1>[Si:24]([O:23][C@@H:22]1[C@H:21]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])[C@@H:20]([CH2:39][O:40][CH3:41])[O:19][C@H:18]1[N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:9]([CH2:8][O:7][CH:61]1[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]1)=[N:10][C:11]=2[NH:42][CH2:43][CH:44]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COC4CCN(C)CC4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 11.9 %

Procedure:
Sodium hydride (42 mg of an 80% dispersion in mineral oil, 1.4 mmol) was added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (preparation 16) (540 mg, 0.7 mmol) and 1-methyl-4-piperidinol (160 mg, 1.4 mmol) in tetrahydrofuran (10 ml). The reaction mixture was heated at reflux for 24 hr and then the solvent removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with dichloromethane:methanol (95:5) to give the title compound (68 mg). MS: 818 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[Na+].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)#[N:16].O>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
A solution of N-(4-pyridyl)piperazine (0.33 g) in dry dimethylformamide (15 ml) was treated with sodium hydride (0.14 g) (45-55% dispersion in oil). The reaction mixture was then stirred for 30 minutes at ambient temperature under argon. 4-Cyanobenzyl bromide (0.41 g) was added and the mixture heated slowly to 80° C. and then maintained at this temperature for 2 hours. The resulting mixture was then poured into water, basified with aq.NaHCO3 solution and then extracted with diethyl ether. The organic extracts were then washed with aq.NaHCO3, water. brine, dried (MgSO4) and evaporated. The residue was recrystallised from toluene/hexane to give 1-(4-pyridyl)-4-(4-cyanobenzyl)piperazine (0.08 g) as a solid. m.p. 137-138° C.; microanalysis, found: C, 73.3; H, 6.5; N, 19.8%; C17H18N4 requires: C, 73.4; H, 6.5; N, 20.1%; NMR: (CDCl3) 2.56(t,4H); 3.35(t,4H); 3.61(s,2H); 6.67(dd,2H); 7.49(d,2H); 7.63(d,2H); 8.28(dd,2H); MS: m/z 279(MH)+.