Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.[C:19](C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.CI>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[CH3:19][O:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Reactant: COC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CI
Solvent: ClCCl
Product: COC[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (2.57 g, 9.9 mmol) in CH2Cl2 (50 mL) was added AgOTf (4.07 g, 15.8 mmol) and 2,6-di-tert-butylpyridine (4.4 mL, 19.8 mmol). The reaction mixture was cooled to 0° C. (external temperature, ice bath) and MeI (0.98 mL, 15.8 mmol) was slowly added. The resulting slurry was stirred at 0° C. for 1.5 h and at room temperature for 1.5 h. The slurry was diluted with CH2Cl2 and filtered through celite. The filtrate was concentrated to dryness, dissolved in Et2O, and washed with HCl (1N) and brine. The aqueous layers were backextracted with Et2O and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (10% to 75% to 100% EtOAc/Hexanes) to provide (2S,4S)-1-tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.11 g, 78%). 1H-NMR: 400 MHz, (CDCl3) δ: (mixture of rotamers, major reported) 4.20 (t, 1H), 3.71 (s, 3H), 3.67 (m, 1H), 3.34 (m, 2H), 3.30 (s, 3H), 3.16 (t, 1H), 2.43 (m, 2H), 1.74 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[NH:13][C:14](=[O:23])[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22].[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[K+].[Cl-].[NH4+]>CN(C)C=O>[Cl:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:15]=1[C:14]([NH:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][C:3]([CH2:2][O:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:12]2)=[O:23]
Reactant: Oc1ccccc1
Reactant: O=C(Nc1cccc2cc(CBr)cnc12)c1c(Cl)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2cc(COc3ccccc3)cnc12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 3-bromomethyl-8-(2,6-dichlorobenzoylamino)quinoline (120 mg) and phenol (30.3 mg) in dimethylformamide was added potassium tert-butoxide (72.2 mg), and the mixture was stirred for 1 hour at ambient temperature. The mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 8-(2,6-dichlorobenzoylamino)-3-phenoxymethylquinoline (87.1 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[O:3]1.[CH3:17][C:18]1[O:19][C:20]([C:26]([F:29])([F:28])[F:27])=[C:21]([C:23](O)=[O:24])[N:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[Cl-].[Na+].O.O>[CH3:17][C:18]1[O:19][C:20]([C:26]([F:29])([F:27])[F:28])=[C:21]([C:23]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)=[CH:10][CH:11]=2)=[O:24])[N:22]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
To a stirred solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (420 mg, 1.917 mmol) in anhydrous DMF (9.6 mL) was added 2-methyl-5-(trifluoromethyl)oxazole-4-carboxylic acid (449 mg, 2.300 mmol) followed by DIPEA (1.0 mL, 5.75 mmol) and the mixture was stirred at room temperature for 10 minutes. HATU (875 mg, 2.300 mmol) was added and the mixture stirred at room temperature for 16 hours. The mixture was taken up in 1:1 mixture of brine and water and extracted with EtOAc. The organic portion was dried over sodium sulfate, filtered and concentrated to afford a brown oil, which was purified by flash column chromatography to afford the title compound as pale yellow solid after drying (360 mg, 47% yield). LC/MS, ESI-MS(+): 397.1, RT: 1.49 (Condition E).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:19]([N:22]=[C:23]=[O:24])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:23](=[O:24])[NH:22][CH2:19][CH2:20][CH3:21])=[CH:9][CH:8]=2)=[CH:17][CH:18]=1
Reactant: CCCN=C=O
Reactant: CCC(O)(c1ccc(O)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CCCNC(=O)Oc1ccc(C(O)(CC)c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
12.3 g. of 4-fluoro-4'-hydroxy-α-ethyl-benzhydrol, 4.68 g. of n-propyl-isocyanate and 0.7 g. of anhydrous, powdered potassium carbonate in 61 ml. of acetonitrile containing 15 μlit. of a 50% aqueous ethanol solution are refluxed under stirring. When the reaction is complete, the reaction mixture is cooled to room temperature, potassium carbonate is filtered off and acetonitrile is distilled off under reduced pressure. The residue is dissolved in benzene, the benzene solution is shaken with a 5% aqueous sodium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered, and benzene is distilled off under reduced pressure. Crystallization of the residue from a mixture of ethyl acetate and n-hexane yields 13.6 g. of the desired compound, melting at 107° to 108° C.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:24]2[N:25]=[CH:26][CH:27]=[CH:28][C:23]2=[N:22][N:21]=1.C([O-])(O)=O.[Na+].P([O-])([O-])([O-])=O.Cl>>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[N:24]4[N:25]=[CH:26][CH:27]=[CH:28][C:23]4=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: Sc1nnc2cccnn12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc4cccnn34)CS[C@H]12

Procedure:
7-ACA (1.36 g., 5 mmole) was added portionwise to a solution of 0.68 g. (4.5 mmole) of 3-mercapto-s-triazolo[4,3-b]pyridazine and 0.84 g. (10 mmole) of NaHCO3 in 20 ml. of 0.1 M pH 7.4 phosphate buffer at 40°-50° . The mixture was heated at 80°-85° for 40 min., treated with a small amount of active carbon and acidified with dil. HCl to pH 4 to precipitate 7-amino-3-(s-triazolo[4,3-b]pyridazin-3-ylthiomethyl)-3-cephem-4-carboxylic acid which was collected, washed with 20 ml. of water and dried in vacuo on P2O5 to yield 0.81 g. (49%), M.p. > 300°.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[O:21][C:22]([C:29]([F:32])([F:31])[F:30])=[CH:23][C:24]=1[S:25](Cl)(=[O:27])=[O:26]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:24]2[CH:23]=[C:22]([C:29]([F:32])([F:30])[F:31])[O:21][C:20]=2[CH3:19])(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Cc1oc(C(F)(F)F)cc1S(=O)(=O)Cl
Product: Cc1oc(C(F)(F)F)cc1S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine (0.182 mmol) was reacted with 2-methyl-5-(trifluoromethyl)furan-3-sulfonyl chloride (0.5 mmol) to form N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-methyl-5-(trifluoromethyl)furan-3-sulfonamide. 1H NMR (CDCl3) δ 2.2 (s, 3H), 5.3 (s, 1H), 6.0 (dt, 1H), 6.8 (s, 1H), 6.95 (s, 1H), 7.0-7.3 (m, 3H), 7.4 (dd, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:1][N:2]1[C@@H:6]2[CH2:7][CH:8]([O:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH2:9][C@H:3]1[CH2:4][CH2:5]2
Reactant: CS(=O)(=O)Cl
Reactant: CN1C2CCC1CC(O)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1[C@@H]2CC[C@H]1CC(OS(C)(=O)=O)C2
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Tropine (14.2 g, 100 mmol) was dissolved in CH2Cl2 (210 ml) and triethylamine (23 ml, 160 mmol) was added. Methanesulfonyl chloride (9.3 ml, 120 mmol) was added rapidly dropwise which caused the methylene chloride solution to reflux gently. The mixture was stirred one hour further; then extracted with cold 0.5 molar sodium hydroxide, water, and brine, dried by filtration through phase separating paper and concentrated to yield 13.8 g (65%) of title product as a yellow solid; NMR 4.88 (t, J=5Hz, 1H), 3.10-3.05 (m, 2H), 2.94 (s, 3H), 2.22 (s, 3H), 2.20-2.10 (m, 2H), 2.02-1.88 (m, 6H).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[N:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[OH:3][CH2:4][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[N:18][C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1
Reactant: CCOC(=O)CCCOc1cnc2c(n1)CCCC2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCCOc1cnc2c(n1)CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
1.84 g (7.0 mmol) of 2-(3-ethoxycarbonylpropoxy)-5,6,7,8-tetrahydroquinoxaline was dissolved in 10 ml of tetrahydrofuran (THF), and the solution was ice-cooled. The resultant solution was dropwise added to a suspension of 319 mg (8.4 mmol) of lithium aluminum hydride in 15 ml of THF under ice cooling, followed by stirring for 2 hours at the same temperature as used in the ice cooling above, to thereby effect a reaction. To the resultant reaction mixture was added 2N HCl to thereby acidify the mixture and form a precipitate. The resultant mixture was subjected to filtration to filter off the precipitate, which was then washed with water. The filtrate was extracted with chloroform twice to obtain an extract. The extract was dried over mirabilite, and the solvent was distilled off in vacuo. The resultant residue was purified by silica gel column chromatography. That is, the residue was charged in a column of 50 g of silica gel (C-200, manufactured and sold by Wako Pure Chemical Industries, Ltd.) and eluted with chloroform-methanol (200:1), to thereby obtain 1.55 g of 2-(4-hydroxybutoxy)-5,6,7,8-tetrahydroquinoxaline (yield: 100%).
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:17])=[O:5])C.[O-:18][C:19]#[N:20].[K+].C(O)(=O)C>O>[C:11]1([C:10]2[C:6]3[C:4](=[O:5])[NH:20][C:19](=[O:18])[NH:17][C:7]=3[S:8][CH:9]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=O)c2c(-c3ccccc3)csc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Amino-4-phenyl-thiophene-3-carboxylic acid ethyl ester (2.0 g, 8.1 mmol), and Potassium Cyanate (Aldrich, 2.0 g, 24.3 mmol) were added to glacial acetic acid (VWR, 20 ml) and stirred at ambient temperature for 18 h. The reaction was diluted with water (50 ml) and the resultant precipitate filtered, washed with water and dried to a damp cake. The solid was suspended in water (100 ml) and made alkaline to pH 12-14 by the addition of concentrated sodium hydroxide. The resultant suspension was heated at 100° C. for 2 h with stirring, then cooled to ambient temperature and acidified by the addition of glacial acetic acid. The resulting solid was collected by filtration, washed with water and dried in vacuo at 40° C. to give 5-Phenyl-1H-thieno[2,3-d]pyrimidine-2,4-dione as a white solid. Yield=(1.1 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=2)[N:7]=1.C(N(C(C)C)[CH:17]([CH3:19])[CH3:18])C.C(I)(C)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([O:13][CH:17]([CH3:19])[CH3:18])=[O:12])[N:10]=2)[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1nc2ccc(Cl)nn2n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: CC(C)OC(=O)c1nc2ccc(Cl)nn2n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
2.14 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine-2-carboxylic acid and 5.57 ml of N-ethyldiisopropylamine were dissolved in 30 ml of N,N-dimethylformamide; 3.23 ml of isopropyl iodide was added, followed by stirring at room temperature for 10 hours and at 50° C. for 3 hours. After cooling, water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate. The desired fraction was collected and concentrated under reduced pressure to yield 2.21 g of the title compound.
Reaction SMILES: [CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[O:20][C:19]=2[CH3:29])[O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[O:20][C:19]=2[CH3:29])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:14])=[CH:16][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccccn2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccn2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A solution of 4-{cyclohexyl[2-methyl-5-(pyridin-2-yl)furan-3-yl]methoxy}benzoic acid (86 mg), ethyl 3-(methylamino)propanoate (34 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (50 mg), hydroxybenzotriazole monohydrate (40 mg) and triethylamine (36 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and 1N hydrochloric acid, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.4 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (85 mg, 81%).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]3)[O:3]1.[CH:21](I)([CH3:23])[CH3:22]>>[CH:21]([N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([B:4]3[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)[C:15]1=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)I
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Product: CC(C)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 9, Step 1 starting from 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one and isopropyl iodide. LCMS (M+H)+=316.1.
Reaction SMILES: C([O:9][C:10](=[O:36])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([S:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:16][CH2:17][S:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C1C=CC=CC=1>O1CCOCC1.O>[C:28]([S:27][CH:15]([CH2:16][CH2:17][S:18][C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:14][CH2:13][CH2:12][CH2:11][C:10]([OH:36])=[O:9])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(CCCCC(CCSC(=O)c1ccccc1)SC(=O)c1ccccc1)OC(=O)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCC(CCSC(=O)c1ccccc1)SC(=O)c1ccccc1

Procedure:
In overview, 6,8-Bisbenzoylmercaptooctanoic acid was prepared by a three step procedure from commercially available a-lipoic acid. The lipoic acid was first reduced to 6,8-bismercaptooctanoic acid with sodium borohydride in water under slightly alkaline conditions. The product was benzoylated with three equivalents of benzoyl chloride in the presence of triethylamine to scavenge the HCl byproduct to produce 6,8-bisbenzoylmercaptooctanoic benzoic anhydride. The anhydride was selectively hydrolyzed with dioxane/water to produce 6,8-bisbenzoylmercaptooctanoic acid without any undesired hydrolysis of the benzoylthio ester groups. The product was purified by column chromatography on Silica Gel. The purified acid was dissolved in methanol and converted to the sodium salt by the slow addition of an aqueous solution containing one mole equivalent of sodium bicarbonate.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].FC(C(O)=O)(F)F.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[C:38]1([NH:44][C:45]([NH:1][C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])[CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H](N)CC(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCNC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)Nc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of Leu-DTrp-βAla-OEt.TFA (40.6 mg) obtained in Example 51-(1) in chloroform (2 ml) were added TEA (20 μl) and phenyl isocyanate (15 μl) at room temperature under nitrogen. The reaction mixture was stirred for 1 h, and concentrated under reduced pressure. The residue was purified by dry column flash chromatography (Merck, Kieselgel 60) with chloroform/methanol=10/1 for elution to give the product (39.6 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=2)[OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:26]=[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41](O)=[O:42])[C:28](=[O:34])[C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:32][C:29]([CH3:33])([CH2:30][CH3:31])[C:28](=[O:34])[C:27]([N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@H:36]1[C:41]([O:10][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]=1)[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:42])=[O:26]
Reactant: CC(C)(C)OC(=O)COc1cccc([C@H](O)CCc2ccccc2)c1
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(C)(C)C(=O)C(=O)N1CCCC[C@H]1C(=O)O[C@H](CCc1ccccc1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A solution of alcohol 3 (342 mg, 1.0 mmol) in CH2Cl2 (3 mL) was treated with (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic acid (23, 255 mg, 1.0 mmol, prepared from L-pipecolic acid in 4 steps following literature procedures by Holt et al. J. Amer. Chem. Soc., 1993, 115, 9925-9938), followed by 1,3-dicyclohexylcarbodiimide (DCC, 247 mg, 1.2 mmol), and 4-(dimethylamino)-pyridine (DMAP, 85 mg, 0.70 mmol) under a nitrogen atmosphere. The resulting bright yellow suspension was allowed to stir overnight. The mixture was then filtered through glass wool and chromatographed (silica gel, 20% EtOAc/hexanes) to give (1R)-3-Phenyl-1-(3-(tert-butoxycarbonylmethoxy)phenyl]-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarboxylate (470 mg, 82%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) (single diastereomer, mixture of rotamers) 7.50-6.90 (m, 9 H), 5.93 (t, J=6.0 Hz, 1 H), 5.46 (d, J=3.4 Hz, 0.83 H, pipercolate α-H of rotamer A), 4.67 (s, 2 H), 3.50 (d, J=12.9 Hz, 1 H), 3.32 (td, J=12.5, 3.0 Hz, 1 H), 2.75 (m, 2 H), 2.53 (d, J=13.6 Hz, 1 H), 2.41 (m, 1 H), 2.22 (m, 1 H), 2.97-2.71 (m, 6 H), 1.62 (s, 9 H), 1.38 (s, 3 H), 1.35 (s, 3 H), 1.03 (t, J=7.4 Hz); 13C NMR (CDCl3, 75 MHz) (single diastereomer, mixture of rotamers) 208.3, 175.0, 170.0, 168.0, 167.5, 158.5, 141.7, 141.2, 130.2, 128.9, 128.7, 126.5, 120.2, 114.7, 113.6, 82.8, 66.1, 51.6, 47.1, 44.5, 38.2, 32.9, 32.0, 28.4, 26.8, 25.3, 24.0, 23.4, 21.6, 9.2. HRMS(FAB): (M+Na)+ calcd: 602.3094, found: 602.3090.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH:10]=[CH:9][C:8]=1[CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1.[C:29](=[O:31])=[O:30].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH2:21][C:8]1[CH:9]=[CH:10][C:11]([CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:12][C:7]=1[C:29]([OH:31])=[O:30]
Reactant: O=C=O
Reactant: Brc1cc(COC2CCCCO2)ccc1COC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1cc(COC2CCCCO2)ccc1COC1CCCCO1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
n-Butyllithium (1.57 M hexane solution; 8.33 ml, 13.1 mmol) was added dropwise to a solution of 2-bromo-1,4-bis[(tetrahydropyran-2-yl)oxymethyl]benzene (3.55 g, 9.22 mmol) obtained from Example 1-(2) in tetrahydrofuran (30 ml) with stirring at −78° C. After the mixture was stirred at the same temperature for 20 minutes, carbon dioxide gas was introduced thereto for 40 minutes. The resulting mixture was stirred at the same temperature for 1 hour, and then the reaction was stopped by addition of a saturated aqueous solution of ammonium chloride. The mixture was warmed to 0° C., and then the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure to afford the residue. The residue was subjected to chromatography on a silica gel (100 g) column (eluent; ethyl acetate:hexane=1:3) to give the title compound (1.63 g, 50% yield) as a colorless oil.