Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([CH3:24])([CH3:23])[CH2:10]1.[CH3:25][N:26]1[C:31](C)([CH3:32])[CH2:30]C(O)[CH2:28][C:27]1([CH3:36])[CH3:35].[NH2-].[Li+]>C1(C)C(C)=CC=CC=1>[O:1]=[C:2]1[CH2:8][CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:17][C:18]([O:20][CH:21]2[CH2:28][C:27]([CH3:36])([CH3:35])[N:26]([CH3:25])[C:31]([CH3:32])([CH3:30])[CH2:22]2)=[O:19])[C:11]([CH3:23])([CH3:24])[CH2:10]1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: CCOC(=O)CN1C(C)(C)CC(N2C=CC=CCC2=O)CC1(C)C
Agent: [Li+]
Agent: [NH2-]
Solvent: Cc1ccccc1C
Product: CN1C(C)(C)CC(OC(=O)CN2C(C)(C)CC(N3C=CC=CCC3=O)CC2(C)C)CC1(C)C
Reaction time: 5 h

Procedure:
A solution of 7.5 g (0.022 mole) of ethyl 4-(2-oxo-1-azepinyl)-2,2,6,6-tetramethylpiperidin-1-ylacetate and 4.2 g (0.024 mole) of 1,2,2,6,6-pentamethylpiperidin-4-ol in 50 ml of xylene is heated for one hour at 120° C. in the presence of 0.1 g of lithium amide esterification catalyst. The xylene-ethanol azeotropic mixture is slowly distilled off using an oil bath held at 150° C. to heat the reaction vessel. After five hours, four drops of acetic acid is added to the reaction mixture and the xylene solvent is removed by distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C:9]1=[O:26].[ClH:27].C(OCC)C>C(OCC)(=O)C>[ClH:27].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[C:9]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(c3ccccc3F)C2=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C1N(c2ccccc2F)CCN1C1CCNCC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 52 %

Procedure:
tert-Butyl 4-(3-(2-fluorophenyl)-2-oxoimidazolidin-1-yl)piperidine-1-carboxylate (235 mg, 0.647 mmol) was dissolved in ethyl acetate (3.0 mL). 2N Hydrogen chloride in diethyl ether (5.0 mL, 10.00 mmol) was added to the mixture. Reaction stirred at room temperature for 22 hours. Solids were filtered off, washed with diethyl ether and then dried in vacuo. Title compound was obtained as white solid in 52% yield. MS (M+H)+=264.1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=[O:3])[CH3:2].I([O-])(=O)(=O)=[O:21].[Na+]>C(OCC)(=O)C.O.[Ru](=O)(=O)(=O)=O>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:11](=[O:21])[CH2:12]1)(=[O:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)OCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Ru](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCCC1CCN(C(=O)OC(C)(C)C)C(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Step B (0.275 g, 1.01 mmol) was dissolved in ethyl acetate (5 mL). A solution of sodium periodate in water (0.5 g in 5 mL) and ruthenium tetroxide (13 mg, 0.10 mmol) was added, and the heterogeneous reaction stirred vigorously overnight at room temperature. An additional portion of sodium periodate in water was added (0.5 g in 5 mL) and the reaction stirred overnight. The reaction was quenched with 10% sodium thiosulfate, and filtered through celite. The phases were separated, and the organic phase dried over magnesium sulfate. Filtration and evaporation gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[C:13]1([CH2:19][CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][NH:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)c(CNCCc2ccccc2)c1
Temperature: 0 °C
Yield: 82 %

Procedure:
2-Chloro-5-nitro-benzaldehyde (5 g, 27 mmol) and 2-phenylethylamine (4.1 g, 33.75 mmol) were dissolved in methanol, cooled to 0° C., and sodium cyanoborohydride (2.1 g, 33.75 mmol) was added. The reaction was adjusted to pH 6 with acetic acid and warmed to room temperature for 6 h. The reaction mixture was quenched with ice and diluted with water. The pH was adjusted to 11 with sodium hydroxide and the mixture was extracted with methylene chloride. The organic extracts were washed with water and brine and dried briefly over sodium sulfate. Filtration of the mixture and concentration of the filtrate in vacuo yielded the title compound (82%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)=[O:16].[CH:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])[CH3:25]>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:30]2[CH2:31][CH2:32][N:27]([CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: O=C(NCCCCCCCCCCCCO)c1ccc(Cl)nc1
Reactant: CC(C)N1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To 2.78 g of N-(12-hydroxydodecyl)-6-chloropyridine-3-carboxamide was added 4.15 g of 1-isopropylpiperazine and the mixture was stirred at 160° C. for 30 minutes. The reaction solution was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate and distilled off under reduced pressure. The residue was chromatographed over a silica gel column to afford 2.2 g of the title compound as a crystal.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:4]=2[CH:3]=1.[Cu][C:18]#[N:19].O.[OH-].[Na+]>CN(C)C=O>[C:18]([C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:4]=2[CH:3]=1)#[N:19]
Reactant: CC(C)NC1=NS(=O)(=O)c2sc(Br)cc2N1
Reactant: N#C[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC1=NS(=O)(=O)c2sc(C#N)cc2N1
Temperature: 150 °C
Yield: 2 %

Procedure:
To a solution of 6-bromo-3-isopropylamino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (243 mg, 0.75 mmol) in dry N,N-dimethylformamide (2 ml) was added copper(I) cyanide (135 mg, 1.5 mmol) and the mixture was heated at 150° C. for 2 h under nitrogen. The dark mixture was allowed to cool to room temperature and water was added. The suspension was made basic by the addition of 1 N sodium hydroxide, filtered and the filtrate was acidified by the addition of 4 M hydrochloric acid. The resulting precipitate was purified by preparative hplc on a Source RPC 15 column using acetonitrile/water (20:80) with 0.1% TFA as eluent to afford 4 mg (2%) of the pure title compound; LC-MS: m/e 271 ((M+1)+).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])=[O:9].[Br:18]N1C(=O)CCC1=O.ClCCl>FC(F)(F)C(O)=O>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([Br:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1sc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sulfuric acid (98% strength; 12 mL) was added to a solution of 3-nitrothiophene-2-carboxylic acid methyl ester (Barker et al., Synth. Commun. 1995, 25, 3729; 20.8 g) in trifluoroacetic acid (60 mL). At 0° C., N-bromosuccinimide (21.9 g) was added in portions over a period of 45 minutes. After a further 30 minutes, the mixture was warmed to room temperature and poured into ice-water. The organic phase obtained by extraction with dichloromethane was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The product with the molecular weight of 266.07 (C6H4BrNO4S) was obtained in this way; MS (ESI): 266 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[C:20]=2[CH:19]=[CH:18]1.C(=O)([O-])O.[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:17]1[C:25]2[C:20](=[C:21]([C:2]3[N:3]=[C:4]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: c1cc(-c2nc(N3CCOCC3)c3sccc3n2)c2cc[nH]c2c1
Yield: 25.3 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno-[3.2-d]pyrimidine 4 (120 mg), 4-indole-boronic acid (110 mg), sodium hydrogen carbonate (120 mg) and PdCl2(PPh3)2 (30 mg) in DME (3 ml) and water (1 ml) were heated in a microwave for 90 min at 130° C. Dichloromethane/water extraction and purification on silica gave 199 (40 mg). NMR: (400 MHz, CDCl3): 3.95 (4H, t, J=4.5), 4.13 (4H, t, J=4.5), 7.30-7.38 (2H, m), 7.52 (1H, d, J=8.1), 7.55-7.59 (2H, m), 7.75 (1H, d, J=5.5), 8.22 (1H, d, J=7.4), 8.30 (1H, br) MS: (ESI+): MH+ 337
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=1)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].C([NH+](CC)CC)C>CN1CCCC1=O.O>[O:17]=[C:10]([NH:9][C:6]1[CH:5]=[N:4][C:3]([C:1]2[NH:20][N:19]=[N:18][N:2]=2)=[CH:8][N:7]=1)[CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCC(=O)Nc1cnc(C#N)cn1
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CCC(=O)Nc1cnc(-c2nnn[nH]2)cn1
Yield: 43 %

Procedure:
A mixture of methyl 4-[(5-cyanopyrazin-2-yl)amino]-4-oxo-butanoate A4 (0.168 g, 0.7173 mmol), sodium azide (0.141 g, 0.076 mL, 2.15 mmol) and triethylammonium chloride (0.156 g, 0.146 mL, 1.11 mmol) was stirred 4 h at 150° C. in 1-methyl-2-pyrrolidinone (10 mL). The mixture was cooled down and diluted with water. After acidification with aqueous hydrochloric acid (1N), the filtrate was extracted twice with ethyl acetate. The combined organic phases were combinated, dried over sodium sulfate and concentrated. The residue was suspended in ethyl acetate and filtered to methyl 4-oxo-4-[[5-(1H-tetrazol-5-yl)pyrazin-2-yl]amino]butanoate A36 (0.085 g, 43% yield). M.p.: 270-274° C. LC-MS (Method F): RT 0.49, 278 (M+H+)
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[CH2:1]([NH:7][C:28]([C:17]1[N:18]([CH3:27])[C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:16]=1)=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: Cn1c(C(=O)O)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Product: CCCCCCNC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)n1C

Procedure:
Using essentially the same procedure as Example 20, Step B, but using hexylamine (0.020 mL, 0.12 mmol), 4,5-di-(4-chlorophenyl)-1-methylimidazole-2-carboxylic acid (20 mg, 0.060 mmol) from Example 20, Step A was converted to the title compound. HPLC/MS: 430 (M+1), 432 (M+3); Rt=4.91 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:3]=1.C([O-])=O.[NH4+].O>C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1C=Cc1ccccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Oc1ccc(Cl)cc1CCc1ccccn1
Temperature: 60 °C
Yield: 90.7 %

Procedure:
To a solution of 24.0 g (74.57 mmol) 4-chloro-2-[2-(pyridin-2-yl)vinyl]-phenol in 400 ml ethanol is added 1.0 g palladium on charcoal 10% followed by 23.5 g (373 mmol) ammonium formate. The reaction mixture is then heated in an oil bath at 60° C. for 6 hours under a nitrogen atmosphere. The reaction mixture is filtered through celite, and the filtrate evaporated in vacuo to leave a colorless solid. Distilled water is added to the residue, which is extracted with 500 ml and then 300 ml DCM. The organic extracts were dried using MgSO4 and concentrated in vacuo to give the title compound as a colourless solid (15.81 g, 91%), m.p. 135-137° C. δH (250 MHz, CDCl3) 8.52-8.49 (dd, J=5.8,1.7 Hz, 1H), 7.65 (dt, J=7.8,1.7 Hz, 1H), 7.26-7.17 (m, 2H) 7.11 (d, J=2.6 Hz, 1H), 7.04 (dd, J=8.6, 2.6 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 3.31-3.26 (m, 2H), 3.10-3.05 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:40])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:32]2[N:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][N:33]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:38]([C:35]1[CH:36]=[N:37][C:32]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:40])=[O:5])[S:12][CH:13]=2)=[N:33][CH:34]=1)[CH3:39]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(N3CCOCC3)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(N3CCOCC3)cc2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.4 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)(4-morpholin-4-ylbenzyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (200 mg) synthesized in Example 408-1 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (at this time point, the object product had been extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=20:1) to give the title compound (111 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])(=O)=O.[CH2:15]([O:17][CH2:18][CH2:19][NH2:20])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][NH:20][CH2:19][CH2:18][O:17][CH2:15][CH3:16]
Reactant: CCOCCN
Reactant: CS(=O)(=O)OCCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCCNCCc1ccccc1Br

Procedure:
3.5 g of 2-(2-bromophenyl)ethyl methanesulfonate, 5.59 g of 2-ethoxyethanamine, 8.67 g of potassium carbonate and 70 cm3 of tetrahydrofuran are stirred under the reflux of the solvent under an inert atmosphere for 48 h. The heating is stopped, then the reaction mixture is filtered. The insoluble material is washed twice with ethyl acetate. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). The product obtained is purified by flash chromatography over silica (column: 330 g; particle size: 20-40 μm, spherical; eluent: 100% ethyl acetate to 90% ethyl acetate/10% methanol gradient). After concentrating the fractions under reduced pressure, 2.45 g of 2-(2-bromophenyl)-N-(2-ethoxyethyl)ethanamine are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)(=[O:19])=[O:18]
Reactant: CN1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
1-Methylpiperidin-4-ol (4 g, 34.7 mmol) was dissolved in CH2Cl2 (70 ml) at 0° C. followed by the addition of Et3N (10 ml, 69.4 mmol, 2 eq.) and methanesulfonyl chloride (2.7 ml, 34.7 mmol, 1 eq.). The mixture was stirred at RT for 3 h and quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the crude product (6.7 g).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([NH2:11])[CH:10]=1)[CH3:2].C(N(CC)CC)C.[C:20](Cl)([CH3:22])=[O:21]>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([NH:11][C:20](=[O:21])[CH3:22])[CH:10]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOCc1ccc(C)c(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1ccc(C)c(NC(C)=O)c1

Procedure:
N-(5-ethoxymethyl-2-methyl-phenyl)-acetamide VII-e was prepared as described for intermediate II-i using 5-ethoxymethyl-2-methyl-phenylamine I-e (5 g, 30.26 mmol), dry triethylamine (12.23 mL), DCM (60 mL) and AcCl (4.32 mL) to give the desired intermediate VII-e as a white solid (5.39 g, 86%). 1H NMR (300 MHz, CDCl3) δ 7.69 (s, 1H), 7.15 (d, J=7.7 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.46 (s, 2H), 3.53 (q, J=7.0 Hz, 2H), 2.23 (s, 3H), 2.18 (s, 3H), 1.23 (t, J=7.0 Hz, 3H).
Reaction SMILES: B(F)(F)F.CCOCC.C(C1OC1)Cl.[CH:15]([NH:18][C:19](=O)[C:20]([C:22]1[S:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:21])([CH3:17])[CH3:16]>CCOCC>[CH:15]([NH:18][CH2:19][CH:20]([C:22]1[S:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[OH:21])([CH3:17])[CH3:16]
Reactant: COc1ccc(C(=O)C(=O)NC(C)C)s1
Agent: FB(F)F
Solvent: ClCC1CO1
Solvent: CCOCC
Product: COc1ccc(C(O)CNC(C)C)s1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
To freshly distilled boron trifluoride etherate (61.0 mmoles) dissolved in 30 ml anhydrous ether, distilled epichlorohydrin (4.19 g, 46.0 mmoles) is added at such a rate to cause the solution to reflux. After addition, the solution is heated at reflux for 1.5 hr with vigorous stirring. The reaction mixture is cooled and most of the ether is removed with a pipette and the solid residue is dried with a stream of dry nitrogen. Anhydrous methylene chloride (50 ml) and the N-isopropyl-5-methoxy-2-thiopheneglyoxylamide (8.0 g, 39.0 mmole), described above, is added and the solution is stirred at room temperature for 56 hr. The methylene chloride is evaporated and replaced with 50 ml anhydrous methanol. The solution is cooled to 0° C. and sodium borohydride (4.0 g) is added portionwise over a period of 4 hr. The mixture is brought to room temperature, stirred for 24 hr then quenched with ice-water. The aqueous solution is extracted several times with ether. The combined ether extract are washed with water and brine, dried (MgSO4) and concentrated. The product is purified by chromatography on silica gel (400 g, chloroformmethanol, 8:2). Evaporation of the eluate and recrystallization of the residue from hexane gives the title compound; mp 81° C, γmaxCHCl3 3300, 3100, 1650, 1505, 1220 cm-1.
Reaction SMILES: [OH:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]=2)[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[C:41](=O)(O)[O-].[Na+].CI>CN(C=O)C>[CH3:41][O:15][C:14](=[O:16])[C:13]1[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:19]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:40][CH:39]=2)[CH:12]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(O)cc2)cc(C(=O)O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(O)cc2)cc(C(=O)OC)c1
Yield: 96.7 %

Procedure:
A mixture of 0.30 g (0.54 mmol) of 3-[3-(4-hydroxyphenoxy) propoxy]-5-(octadecyloxy)benzoic acid, 0.14 g (1.62 mmol) of sodium bicarbonate and 0.67 ml (10.8 mmol) of methyl iodide in 5 ml of DMF was stirred and heated at 40° for 48 hours. The solvent was removed at reduced pressure, the residue was extracted with ethyl acetate and the extract was washed with water. The dried extract was concentrated to a solid which was triturated with hexane and filtered to give 0.298 g (97% yield, mp 88°-90°) of 3-[3-(4-hydroxyphenoxy)propoxy]-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH2:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][C:26](=[O:28])[OH:27])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:50]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[C@H:51]([C:62]([O:64]N1C(=O)CCC1=O)=O)[CH2:52][C:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[NH:55][CH:54]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[NH:50]([C:72]([O:74][C:75]([CH3:76])([CH3:77])[CH3:78])=[O:73])[C@@H:51]([C:62]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH2:42])=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][C:26](=[O:27])[OH:28])=[O:22])[CH2:17][CH2:18][S:19][CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:64])[CH2:52][C:53]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[NH:55][CH:54]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Yield: 61.1 %

Procedure:
In the same manner as in (1) of Example 1, 10.45 g (0.015 mole) of Boc-Trp-Met-Asp-Phe-NH2 [cf. (1) of Example 3] was condensed with 9.00 g (0.022 mole) of Boc-Trp-OSu. The resulting reaction liquid was concentrated, and a precipitate was formed by adding 1N citric acid and washed with water. Recrystallization thereof from methanol-water gave 8.09 g of Boc-D-Trp-Trp-Met-Asp-Phe-NH2 ; yield 61.1%, m.p. 225°-227° C.