Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=O)[CH2:3]1.CC([O-])=O.[Na+].BrBr.[NH2:17][C:18]([NH2:20])=[S:19]>CC(O)=O>[NH2:20][C:18]1[S:19][C:5]2[C:6](=[O:8])[CH2:7][CH:2]([CH3:1])[CH2:3][C:4]=2[N:17]=1
Reactant: CC1CC(=O)CC(=O)C1
Reactant: NC(N)=S
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1CC(=O)c2sc(N)nc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
5-Methyl-cyclohexane-1,3-dione (70.0 g, 0.555 mol) and NaOAc (68.3 g, 0.832 mol) are suspended in AcOH (700 mL) and Br2 (88.7 g, 0.555 mol) is added drop-wise while maintaining the reaction temperature between 15 and 20° C. After complete addition, the reaction is stirred at RT overnight. Thiourea (42.2 g, 0.555 mol) is added in portions and the reaction mixture is heated to 100° C. for 1 h. After cooling to RT, the AcOH is removed in vacuo. The resulting crude product is diluted with water (1 L), adjusted to pH=7 with NaHCO3 solution (3 M) and the resulting mixture is extracted with EtOAc (3×1 L). The organic phase is washed with brine and dried over anhydrous Na2SO4. The solvent is evaporated in vacuo and the residue is recrystallized from hexane to give 2-amino-5-methyl-5,6-dihydro-4H-benzothiazol-7-one (87.2 g, 86% yield).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].Cl.[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O.C(OCC)(=O)C>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([S:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]
Reactant: SCc1ccccc1
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)SCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 124.8 %

Procedure:
Z-Arg-OH.HCl (6 g, 8.7 mmoles) and benzyl mercaptan (4.2 ml, 17.4 mmoles) are dissolved in dimethylformamide (DMF) and cooled to 0° C. DCC (3.6 g, 8.7 mmoles), dissolved in DMF, is then added to the above reaction mixture, stirred at 0° C. for 30 minutes, then stirred overnight at room temperature. The precipitate formed is removed by filtration and the filtrate is concentrated under vacuum to yield an oil. This oily residue is dissolved in ethyl acetate and washed, successively, with 0.1 N HCl, 5% NaHCO3, and saturated aqueous NaCl. The organic layer is dried over anhydrous Na2SO4 and the solvent removed by evaporation. The crude product is purified by silica gel column, using a CHCl3 /methanol system, yielding 4.5 g of the product.
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33]>C1COCC1>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[CH2:25][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:13]
Reactant: O=C1CCCCN1C1CCCCC1
Reactant: Fc1cccc(Cl)c1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2c(F)cccc2Cl)CCCN1C1CCCCC1
Temperature: -78 °C
Yield: 59 %

Procedure:
Dissolve 1-cyclohexyl-piperidin-2-one (0.2 g, 1.10 mmol) in dry THF (11 mL) cool to −78° C. and add lithium bis(trimethylsilyl)amide (1.66 mL of 1.0 M solution in THF, 1.66 mmol). After 15 min add 1-bromomethyl-2-chloro-6-fluorobenzene (0.49 g, 2.21 mmol), and allow the mixture to warm to room temperature over 15 h. Wash the mixture with brine, dry the organic layer over sodium sulfate and evaporate. Purify the residue by chromatography on silica gel (eluting 0% to 100% ethyl acetate in hexane) to give the desired product (0.21 g, 59%). MS (ES+) m/z=324 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[S:17](Cl)Cl.C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:38])[CH2:31][NH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:28]>C(Cl)Cl>[CH2:36]([O:35][C:33]([N:32]([CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:38])[S:17][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)CNC(=O)OCC
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: ClSCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 11 g quantity (0.05 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate was dissolved in 70 ml of methylene chloride, 5.2 g (0.05 mole) of sulfur dichloride was added to the solution with cooling, and 5 g (0.05 mole) of triethylamine was further added dropwise to the solution at -10° to -5° C. The mixture was stirred at 0° C. for one hour and further at room temperature for 2 hours. After cooling to -10° to -5° C., 8.8 g (0.05 mole) of N-ethoxycarbonylglycine ethyl ester was added dropwise to the mixture, and 5 g (0.05 mole) of triethylamine was further added dropwise to the mixture. The resulting mixture was stirred at 0° C. for 2 hours and thereafter allowed to stand overnight at room temperature. With addition of 100 ml of methylene chloride, the reaction mixture was washed with 100 ml of water three times. The methylene chloride layer was dried and then concentrated in a vacuum to give an oily product, which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities. Yield: 18.2 g (84.7%).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH2:9]N.N([O-])=[O:17].[Na+].C(=O)([O-])O.[Na+]>O>[F:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:8]=1[CH2:9][OH:17]
Reactant: NCc1c(F)cccc1F
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: OCc1c(F)cccc1F
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
75 g of 10% aqueous sulfuric acid solution was charged, and 14.3 g of 2,6-difluorobenzylamine obtained in Example 1 was dropwise added thereto under cooling. Then, under cooling, a solution comprising 10.4 g of sodium nitrite and 20 g of water was dropwise added thereto over a period of 30 minutes at a reaction temperature of from 10 to 20° C. After the completion of the dropwise addition, stirring was carried out at the same temperature for 1 hour. After the completion of the reaction, neutralization in an aqueous sodium hydrogencarbonate solution was carried out, and extraction with methylene chloride was carried out. Methylene chloride was recovered, followed by distillation under reduced pressure to obtain 12.4 g of 2,6-difluorobenzyl alcohol (103° C./26 mmHg) (yield: 86.1%, purity: 88.1%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:24])=[C:13]([F:23])[CH:14]=2)[N:9]=1.[CH:25]1([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1.O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:21]([O:20][C:18]([C:17]1[C:8]([N:28]([CH:25]2[CH2:26][CH2:27]2)[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:23])=[C:12]([F:24])[CH:11]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)CCNC1CC1
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CCN(c1nc2cc(F)c(F)cc2cc1C(=O)OCC)C1CC1
Temperature: 20 °C
Reaction time: 15 h
Yield: 65.6 %

Procedure:
3 g of sodium carbonate are added to a solution of 3.48 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline, prepared as described in Application Example 1, and 3 g of N-cyclopropyl-N-(b-ethoxycarbonylethyl)amine in 10 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 15 hours at this temperature. The reaction mixture is then cooled to approximately 20° C. and 30 cm3 of water and 4.5 cm3 of acetic acid are thereafter added. After settling has taken place, the reaction mixture is separated and washed with twice 10 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 3.3 g of crude 3-ethoxycarbonyl-6,7-difluoro-2-[N-cyclopropyl-N-(b-ethoxycarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent step.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]([CH3:24])([CH3:23])[CH2:7]1)[CH2:2][CH2:3][CH3:4].Cl[P:26]1[O:31][CH2:30][C:29]2([CH2:36][O:35][P:34](Cl)[O:33][CH2:32]2)[CH2:28][O:27]1>>[CH3:22][CH:15]([O:14][N:9]1[C:8]([CH3:23])([CH3:24])[CH2:7][CH:6]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[P:26]2[O:31][CH2:30][C:29]3([CH2:36][O:35][P:34]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]4[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([O:14][CH:15]([CH3:22])[C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:8]([CH3:24])([CH3:23])[CH2:7]4)[O:33][CH2:32]3)[CH2:28][O:27]2)[CH2:11][C:10]1([CH3:13])[CH3:12])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCCNC1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1
Reactant: ClP1OCC2(CO1)COP(Cl)OC2
Product: CCCCN(C1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1)P1OCC2(CO1)COP(N(CCCC)C1CC(C)(C)N(OC(C)c3ccccc3)C(C)(C)C1)OC2

Procedure:
The title compound is prepared as a viscous syrup from 4-n-butylamino-1-alpha-methylbenzyloxy-2,2,6,6-tetramethylpiperidine (made in Example 13A) and 3,9-dichloro-2,4,8,10-tetraoxa-3, 9-diphosphaspiro[5.5]undecane according to the procedure of Example 14.
Reaction SMILES: C([O:4][C:5]1([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:10][CH2:9][N:8](C)[CH2:7][CH2:6]1)(=O)C.[Cl:21]C(OCC)=O>C1C=CC=CC=1>[ClH:21].[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([C:5]2([OH:4])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[O:20])=[CH:14][CH:15]=1
Reactant: CC(=O)OC1(C(=O)c2ccc(F)cc2)CCN(C)CC1
Reactant: CCOC(=O)Cl
Solvent: c1ccccc1
Product: Cl
Product: O=C(c1ccc(F)cc1)C1(O)CCNCC1

Procedure:
To 27.9 grams (0.1 mole) of 4-acetoxy-4-(p-fluorobenzoyl)-1-methylpiperidine in 200 ml. of benzene was added 27.1 (0.25 mole) of ethyl chloroformate. The mixture was refluxed for 48 hours. The mixture was extracted with H2O, the organic solution was dried (MgSO4) and filtered. The filtrate was concentrated. To the resulting oil was added 250 ml. of 6 Normal HCl and the mixture was refluxed for seventy-two hours. Most of the water was removed under reduced pressure. Ethanol was added and the solution cooled. The solid which precipitated was collected by filtration and recrystallized from ethanol giving eighteen grams of 4-(p-fluorobenzoyl)-4-hydroxypiperidine hydrochloride. Melting point 241°-243° C.
Reaction SMILES: [CH3:1][C:2]1[CH:46]=[CH:45][CH:44]=[CH:43][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:42])[CH:8]([NH:21][C:22](=[O:41])[C@@H:23]([S:31]CC1C=CC(OC)=CC=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])=[O:10].C1(OC)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:46]=[CH:45][CH:44]=[CH:43][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:42])[CH:8]([NH:21][C:22](=[O:41])[C@@H:23]([SH:31])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])=[O:10]
Reactant: COc1ccc(CS[C@@H](Cc2ccccc2)C(=O)NC(C(=O)NCCc2ccccc2C)C(=O)NCCc2ccccc2C)cc1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1CCNC(=O)C(NC(=O)[C@@H](S)Cc1ccccc1)C(=O)NCCc1ccccc1C
Reaction time: 3 h

Procedure:
Combine of N,N′-di-(2-methylphenethyl)-2-((S)-2-(p-methoxybenzylmercapto)-3-phenylpropionylamino)malonamide (0.175 g, 0.274 mmol), mercury (II) acetate (0.108 g, 0.34 mmol), and anisole (0.3 mL) in dichloromethane (10 mL). Cool in an ice bath and degas by repeatedly applying vacuum and filling the vessel with nitrogen. Add trifluoroacetic acid (4 mL). After 3 hours, purge with hydrogen sulfide (gas) for about 10 minutes. Filter and evaporate in vacuo to give a residue. Combine the residue with carbon tetrachloride and evaporate in vacuo to remove most of the trifluoroacetic acid. Chromatograph the residue on silica gel eluting with 1/2 ethyl acetate/hexane and then 1/1 ethyl acetate/hexane to give the title compound.
Reaction SMILES: CN(C)CCO.C([Li])CCC.[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Br)(Br)(Br)[Br:25]>CCCCCCC.O>[Br:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:19]=1
Reactant: BrC(Br)(Br)Br
Reactant: c1ccc(-c2ccccn2)cc1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCCC
Product: Brc1cccc(-c2ccccc2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To N,N-dimethylethanolamine (0.8 mL, 8.00 mmol) in heptane (10 mL) cooled externally to 0° C. was added dropwise a 2.5 M n-butyllithium solution (6.40 mL) and the reaction mixture stirred for 30 minutes. 2-Phenylpyridine (12) (412 mg, 2.66 mmol) in heptane (5 mL) was then added and the reaction mixture stirred for a further 1 hour. The reaction was then cooled and carbon tetrabromide (3.18 g, 9.60 mmol) was added whilst maintaining the temperature at −78° C. The reaction was kept at −78° C. for 1 hour and then allowed to warm to ambient temperature. Water was cautiously added and extracted with TBME (×2), dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was purified by column chromatography eluting with 5% EtOAc in heptane to give the title compound. Yield: 300 mg, 48%; LC-MS tr 1.63 min; HPLC Purity: 97%; MS (ES+) m/z 234, 236 (M+H)
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[CH2:13][CH:12]2[CH2:16][CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CC([O-])(C)C.[K+].C1COCC1.[N:28](OCCC(C)C)=[O:29].Cl>C1COCC1>[CH2:1]([CH:8]1[C:14](=[O:15])[C:13](=[N:28][OH:29])[CH:12]2[CH2:16][CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)CCON=O
Reactant: O=C1CC2CCC(C2)C1Cc1ccccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C(=NO)C2CCC(C2)C1Cc1ccccn1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of 2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane in THF was added 2.5 eq. of 1M t-BuOK/THF (Aldrich) and the resulting mixture was stirred for 30 minutes. Isoamyl nitrite (1.5 eq.) was then added dropwise and the reaction mixture was stirred overnight. To the reaction mixture was added 3N HCl and this mixture was extracted with ethyl acetate and the organic extracts washed with water, dried, and concentrated under reduced pressure. The residue was triturated with ether/hexanes, the solvents decanted and the residue dried under reduced pressure to afford 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octane as a tan liquid (41% yield). This procedure is further described in Y. Kim, Tetrahedron Lett., 30(21), 2833-2636 (1989).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].[CH:31]([C:34]1[CH:35]=[CH:36][C:37]([O:51][CH3:52])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([CH3:50])=[CH:47][CH2:48]O)=[CH:42][CH:41]=2)[CH:39]=1)([CH3:33])[CH3:32]>C1C=CC=CC=1.O.C(OCC)(=O)C>[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:48]/[CH:47]=[C:46](/[C:43]2[CH:42]=[CH:41][C:40]([C:38]3[CH:39]=[C:34]([CH:31]([CH3:32])[CH3:33])[CH:35]=[CH:36][C:37]=3[O:51][CH3:52])=[CH:45][CH:44]=2)\[CH3:50])=[CH:28][CH:29]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(C)=CCO)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(C)C)ccc3OC)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Azodicarboxylic dipiperidide (0.756 g, 3.0 mmol) was added at 0-5° C. to a stirred solution of tributylphosphine (0.74 ml, 0.61 g, 3.0 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.50 g, 2.10 mmol) and 3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-en-1-ol (0.593 g, 2.0 mmol) in dry benzene (15 ml), the mixture warmed to room temperature, and stirred for 4 h. The resulting mixture was diluted with water (100 ml) and ethyl acetate (50 ml), the aqueous layer collected and further extracted with ethyl acetate (50 ml). The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica (10% ethyl acetate in n-heptane eluent) to give (E)-(S)-ethyl 2-ethoxy-3-{4-[3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-propionate as a colourless oil; 0.67 g (65%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:29]([NH:31][C@H:32]([C:43]([O:45][CH3:46])=[O:44])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:30])[CH2:11][C:12]1[N:16]=[CH:15][N:14](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:13]=1)=[O:8]>CN(C=O)C.O.SC(O)C>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:29]([NH:31][C@H:32]([C:43]([O:45][CH3:46])=[O:44])[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1)=[O:30])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)NC(=O)[C@@H]1CCC(=O)N1
Agent: CC(O)S
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1CCC(=O)N1
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To the solution containing 15.84 g (25 mmoles) of Glp-His(DNP)-Trp-OMe protected tripeptide in 100 ml of DMF and 40 ml of water, 4 ml of mercaptoethanol are added, then the pH-value of the solution is adjusted to 8 by adding TEA. The solution is left to stand at room temperature for 30 minutes, then evaporated to dryness under reduced pressure. The oily residue is thoroughly triturated with ether, filtered and dried. The thus-obtained product is dissolved in a little volume of methanol and crystallized by adding ether. The crystals are filtered and dried to give 10.92 g (93.5% yield) of the aimed compound, m.p.: 228°-232° C.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH:11]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][N:12]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:3][CH2:2]1.[OH:28]OS([O-])=O.[K+].[OH2:34]>CCO>[CH:1]1([S:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH:11]2[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][N:12]2[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])(=[O:28])=[O:34])[CH2:2][CH2:3]1
Reactant: O=S([O-])OO
Reactant: O
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1ccccc1SC1CC1
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1ccccc1S(=O)(=O)C1CC1
Temperature: 25 °C

Procedure:
To 160D (3.3 g, 8.43 mmol) in EtOH (25 mL) at 0° C. was added a solution of Oxone (11.4 g, 18.6 mmol) in water (60 mL). The mixture was stirred at rt over night. The precipitate was filtered. The filtrate was neutralized with sat. NaHCO3 and EtOH was removed under reduced pressure. The residue was extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to give crude 160E with >90% purity. 1H NMR of the crude 160E indicated a mixture of cis and trans isomer in ca 1:1 ratio and complicated by the presence of rotomers. LC-MS 424 (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN([CH:10]=[O:11])C.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([F:23])[CH:15]=1)#[N:13].C(N(CC)CC)C>C(Cl)Cl.Cl.CO>[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:11][CH3:10])=[O:19])=[C:16]([F:23])[CH:15]=1)#[N:13]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 25 °C

Procedure:
Oxalyl chloride (9.0 mL, 106.6 mmol) and DMF (0.5 mL) were added into a suspension of 4-cyano-2-fluorobenzoic acid (ABCR, 16 g, 96.9 mmol) in anhydrous DCM (300 mL) The resulting mixture was stirred at RT, and then evaporated under reduced pressure. The residue was taken up with anhydrous THF (150 mL) and added dropwise into a solution of methanol (50 mL) and triethylamine (25.8 mL, 193.8 mmol) at 4° C. The reaction mixture was diluted with a 0.1N aqueous solution of HCl (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with a semi-saturated aqueous solution of NaHCO3 (200 mL) and water (200 mL), dried (MgSO4) and concentrated under vacuum to give the title compound as a pale yellow solid (17.8 g, quantitative). HPLC (Method A) Rt 2.81 min (Purity: 93.9%).
Reaction SMILES: [Br-:1].[NH:2]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][P+:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][N:4]=[N:3]1.O1CCC[CH2:31]1.[N+:35](=[CH2:37])=[N-:36]>CCOCC>[Br-:1].[CH3:31][N:5]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][P+:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:2][N:3]=[N:4]1.[Br-:1].[CH3:37][N:35]1[N:2]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][P+:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]=[N:36]1
Reactant: C=[N+]=[N-]
Reactant: C1CCOC1
Reactant: c1ccc([P+](CCCCc2nnn[nH]2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOCC
Product: Cn1nnc(CCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: Cn1nnnc1CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.08 h

Procedure:
To a solution of the 4-(tetrazol-5-yl)butyltriphenylphosphonium bromide prepared in Example I (4.65 g.; 10.0 m moles) in 50 ml. of dry tetrahydrofuran is added a solution of diazomethane in ether until the reaction solution remains yellow for 5 minutes. Concentration followed by chromatographic purification affords the desired 4-(1-N-methyltetrazol-5-yl)butyltriphenylphosphonium bromide and 4-(3-N-methyltetrazol-5-yl)butyltriphenylphosphonium bromide.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]3[CH2:17][NH:16][C:15](=[O:18])[CH2:14]3)=[CH:10][CH:11]=2)[N:6]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN1C(=O)N(C)CCC1>O1CCCC1>[CH2:28]([N:16]1[CH2:17][CH:13]([C:9]2[CH:8]=[C:7]3[C:12]([C:4]([CH3:3])=[CH:5][N:6]3[CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:10]=2)[CH2:14][C:15]1=[O:18])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cn(CCCc2ccccc2)c2cc(C3CNC(=O)C3)ccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: Cc1cn(CCCc2ccccc2)c2cc(C3CC(=O)N(Cc4ccccc4)C3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A solution of sodium hydride (0.013 g) in tetrahydrofuran at 0° C., under argon, was treated with a solution of 4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one (0.184 g, Example 20) and benzyl bromide (0.094 g) in dry tetrahydrofuran. The mixture was allowed to warm to room temperature then treated with N,N′-dimethylpropyleneurea (0.05 g). After stiffing at room temperature overnight the solution was partitioned between ethyl acetate (15 ml) and 1N hydrochloric acid (15 ml). The organic phase was dried over magnesium sulphate then evaporated. The residue was subjected to preparative layer chromatography on silica using a mixture of ethyl acetate and hexane (3:7, v/v) as eluent to yield the title compound (0.18 g) as an oil. [Elemental analysis:—C, 79.16; H,6.98; N, 6.14%. Calculated for C29H30N2O.H2O:—C,79.04; H,7.33; N,6.36%].