Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[N:11][C:12](=O)[NH:13][N:14]=2)[CH:4]=1.C(Cl)(Cl)[Cl:19].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:19][C:12]1[N:13]=[N:14][C:9]([C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[CH:7][CH:6]=2)=[CH:10][N:11]=1
Reactant: ClC(Cl)Cl
Reactant: O=c1ncc(-c2cccc(C(F)(F)F)c2)n[nH]1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(-c2cnc(Cl)nn2)c1

Procedure:
A 37.2 g. portion of 6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazin-3(2H)-one in 250 ml. of chloroform is refluxed overnight and then cooled. A 250 ml. portion of phosphorus oxychloride and 1.7 g. of N,N-dimethylformamide are added and the mixture is refluxed for 4.5 hours and then concentrated to a brown oil. This oil is dissolved in methylene chloride and poured into ice-water. The mixture is filtered through silica gel giving crystals which are recrystallized from hexane, giving 3-chloro-6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine as reddish plates.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:13](=O)[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH2:18][C:19]([CH3:21])=[CH2:20].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>ClCCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:7][C:8]1[C:9]([CH2:18][C:19]([CH3:21])=[CH2:20])=[C:10]([OH:17])[C:11]([CH3:16])=[C:12]([CH3:15])[C:13]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: C=C(C)CC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: C=C(C)Cc1c(C)c(Nc2ccccc2)c(C)c(C)c1O
Temperature: 90 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
Titanium tetrachloride (2.58 ml, 23.4 mmol) was added dropwise to a solution of pyridine (7.60 ml, 93.6 mmol) in 1,2-dichloroethane (40 ml) and, after completion of the addition, the reaction mixture was heated under reflux for 30 minutes in an argon atmosphere. After cooling of the reaction mixture, a solution of 3,5,6-trimethyl-2-(2-methyl-2-propenyl)-1,4-benzoquinone (2.40 g, 11.7 mmol) and aniline (3.35 ml, 35.1 mmol) in 1,2-dichloroethane (5 ml) was added thereto and the mixture was stirred at 90° C. for 2 hours in an argon atmosphere. The reaction mixture was cooled and filtered through Cerite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 98:2). The resulting compound was dissolved in tetrahydrofuran (10 ml) and to the solution was added a solution of sodium hydrosulfite (12 g, 69 mmol) in water (30 ml). The mixture was stirred at room temperature for 30 minutes. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The extract was combined with the organic phase and the mixture was washed with water and dried and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate, 95:5) to obtain the desired compound as oil (1.41 g ield: 42.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10]([N:17]=[CH:18][N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[N:24]1([CH:30]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38]CN)=[CH:34][CH:33]=2)[CH3:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C.C(O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][CH2:38][C:35]4[CH:34]=[CH:33][C:32]([CH:30]([N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)[CH3:31])=[CH:37][CH:36]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CC(c1ccc(CCN)cc1)N1CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(c1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)N1CCCCC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 62.8 %

Procedure:
A mixture of methyl 5-(4-chlorophenyl)-3-(dimethylaminomethyleneamino)thiophene-2-carboxylate (0.2 g), 2-[4-(1-piperidin-1-ylethyl)phenyl]ethanamine dihydrochloride (0.19 g), N,N-diisopropylethylamine (0.20 g) and ethanol (4 ml) were stirred at 70° C. for 3 hr. The reaction mixture was allowed to cool, ethyl acetate was added, and the precipitate was collected by filtration to give the title compound (186 mg) as a colorless powder.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].ClC1C2C(=CC=CC=2)C(CNC(O)C(C)CO)=C2C=1C=CC=C2.[Cl:29][C:30]1[C:43]2[C:34](=[C:35]([CH:48]=O)[C:36]3[C:41]([C:42]=2[O:44][CH2:45][CH2:46][OH:47])=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1.[NH2:50][C:51]([CH3:56])([CH2:54][OH:55])[CH2:52]O>>[CH3:1][S:2]([O:5][CH2:56][C:51]([NH:50][CH2:48][C:35]1[C:36]2[C:41]([C:42]([O:44][CH2:45][CH2:46][OH:47])=[C:43]3[C:34]=1[CH:33]=[CH:32][CH:31]=[C:30]3[Cl:29])=[CH:40][CH:39]=[CH:38][CH:37]=2)([CH3:52])[CH2:54][OH:55])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)O
Reactant: CC(N)(CO)CO
Reactant: O=Cc1c2ccccc2c(OCCO)c2c(Cl)cccc12
Agent: CC(CO)C(O)NCc1c2ccccc2c(Cl)c2ccccc12
Product: CC(CO)(COS(C)(=O)=O)NCc1c2ccccc2c(OCCO)c2c(Cl)cccc12

Procedure:
Using the reductive amination procedure outlined in 2B, 4-chloro-10-(2-hydroxyethoxy)-9-anthracenecarbaldehyde (38A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((4-chloro-10-(2-hydroxyethoxy)-9-anthracenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate. 3/10H2O.1/10i-PrOH mp 156°-158° (dec), (i-PrOH/Et2O), (C, H, Cl, N, S)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][C:24]([Cl:28])=[CH:23][CH:22]=4)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Sn](CCCC)(CCCC)CCCC.C(OCC)(=O)C.N>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:28][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19]([S:16]([N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:4]=[CH:3][C:2]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)=[CH:7][N:6]=3)=[O:9])[CH2:11][CH2:12]1)(=[O:18])=[O:17])=[CH:27]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C(c1ncc(Br)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ncc(-c2ccccn2)cn1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 100 °C
Reaction time: 9 h
Yield: 51 %

Procedure:
At room temperature, 1-[(5-bromopyrimidin-2-yl)carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (500 mg) and (pyridin-2-yl)tributyltin (418 mg) were dissolved in N,N-dimethylformamide (10 ml). To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (69 mg), followed by stirring at 100° C. for 9 hours. After cooling to room temperature, ethyl acetate and ammonia solution were added. The resulting mixture was separated by ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate. The filtrate was concentrated and the residue was purified by chromatography on a silica gel column (4% methanol—methylene chloride). The resulting fraction was added with ethanol, followed by concentration. Diethyl ether was then added to the concentrate. Colorless powder thus precipitated was collected by filtration and dried, whereby the free form (254 mg) of the title compound was obtained. The resulting free form was dissolved in methylene chloride, followed by the addition of 1N hydrochloric acid (in ethanol) to make the solution acidic. After concentration, ethyl acetate and diethyl ether were added, followed by concentration. Colorless powder thus precipitated was collected by filtration and dried, whereby the title compound was obtained.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:29]2([CH3:30])[CH:9]([CH:10]=[CH:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][C@@H:7]([O:32][C:33](=[O:35])[CH3:34])[CH2:6]1)(=[O:3])[CH3:2].C([O-])(=[O:38])C.[Na+]>C(O)(C)(C)C>[C:1]([O:4][C@@H:5]1[C@@:29]2([CH3:30])[C:9](=[CH:10][C:11](=[O:38])[C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:8][C@@H:7]([O:32][C:33](=[O:35])[CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=O)O[C@@H]1CC2C=C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(=O)O[C@@H]1CC2=CC(=O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 114.7 %

Procedure:
A solution of 0.3 g of 1α,3β-diacetoxycholest-6-ene in 30 ml tert-butanol was treated with 0.3 g mercuric bromide and 0.03 g sodium acetate. The stirred mixture was irradiated with light of 254 nm wavelength at room temperature during 5 hours. After filtration and extraction with 300 ml hexane, there was obtained a quantity of 0.21 g of 1α,3β-diacetoxycholest-5-en-7-one. M.P. = 121°-122°C.
Reaction SMILES: C(OC1C=C(OCC2C=CC=CC=2)C(Cl)=CC=1C1C(C2C=CC(CN)=CC=2)=CN(COCC[Si](C)(C)C)N=1)C1C=CC=CC=1.C(N(CC)CC)C.O=C1CCC(=O)N1[O:59][C:60](=[O:86])[C:61]1[CH:69]=[CH:68][C:67]([C:70]2[C:71]3[C:76]([O:77][C:78]4[C:83]=2[CH:82]=[CH:81][C:80](=[O:84])[CH:79]=4)=[CH:75][C:74]([OH:85])=[CH:73][CH:72]=3)=[C:63]([C:64]([OH:66])=[O:65])[CH:62]=1>C(Cl)Cl>[OH:85][C:74]1[CH:75]=[C:76]2[C:71](=[CH:72][CH:73]=1)[C:70]([C:67]1[C:63]([C:64]([OH:66])=[O:65])=[CH:62][C:61]([C:60]([OH:86])=[O:59])=[CH:69][CH:68]=1)=[C:83]1[C:78](=[CH:79][C:80](=[O:84])[CH:81]=[CH:82]1)[O:77]2
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1
Agent: C[Si](C)(C)CCOCn1cc(-c2ccc(CN)cc2)c(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.6 %

Procedure:
To a mixture of 4-[3-(2,4-bis-benzyloxy-5-chloro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-benzylamine (0.02 g, 0.03 mmol) and triethylamine (0.02 ml, 0.15 mmol) in DCM (1 ml) was added 4-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalic acid 2,5-dioxo-pyrrolidin-1-yl ester (0.016 g, 0.03 mmol). The mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The mixture was purified by column chromatography using ethyl acetate and hexanes as eluent to give N-4-[3-(2,4-bis-benzyloxy-5-chloro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-benzyl)-6-(6-hydroxy-3-oxo-3H-xanthen-9-yl)-isophthalic acid as a yellow solid (0.0126 g, 40%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([OH:49])([CH3:48])[CH3:47])[CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>O>[CH2:13]([C:15]1[N:16]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([OH:49])([CH3:47])[CH3:48])[CH:41]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2cccc(C(C)(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(CC)n(-c2cccc(C(C)(C)O)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({2-ethyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.54 g) was added, and the mixture was stirred at 90° C. for 24 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.39 g, 65%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.Cl.[C:24](Cl)(=[O:40])[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][CH2:38][CH3:39]>O.ClCCl>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:5]([NH:6][C:24](=[O:40])[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][CH2:38][CH3:39])[C:4]([O:3][CH3:2])=[O:15])=[CH:13][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Yield: 90.9 %

Procedure:
300 ml of dichloro methane (DCM) was added to (L)-tyrosine methyl ester HCl salt (23.16 g, 0.1 mol), and 28 ml of triethyl amine (TEA, 0.2 mol) was added thereto, thereby dissolving HCl salt. The reactor was temperature-lowered to 0° C. by using an ice bath, and 27.49 g of palmitoyl chloride (0.1 mol) was slowly added, following by stirring for 3˜4 hours. 200 ml of water was added to the reacted material, followed by extraction with 500 ml of ethyl acetate. Drying over sodium sulfate followed by filtering was carried out. The solvent was removed from the filtrate by rotary evaporation, followed by solidification with hexane and ethyl acetate, thereby obtaining a white solid (39.4 g, 90.8% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.C([Li])CCC.[C:26](=[O:28])=[O:27].Cl>C(OCC)C.C(OCC)(=O)C.O>[CH3:9][S:8][C:6]1[CH:5]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:26]([OH:28])=[O:27])[CH:7]=1
Reactant: CSc1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CSc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
2-bromo-4-methylmercapto-6-[3-(trifluoromethyl)phenoxy] pyridine (5.00 g, 0.0137 mol) was dissolved in about 200 ml of diethyl ether. While cooling in a dry ice-acetone bath in an argon atmosphere, the obtained solution was mixed with n-butyl lithium [9.3 ml (ca. 1.63 M in hexane solution), 0.0137×1.1 mol] and then stirred for about 10 minutes. After the interior of the reactor was replaced with a carbon dioxide gas, the solution was removed from the bath and stirred at room temperature for about one hour. The obtained reaction solution was mixed with about 15 ml of a 4 N aqueous hydrochloric acid solution. The obtained solution was distributed in ethyl acetate-water and then washed with saturated brine. The organic phase separated from the solution was dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@@H:8]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:9][N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:6])[CH3:3].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:55]1([CH2:61][CH2:62][CH2:63][CH2:64][NH2:65])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[C:55]1([CH2:61][CH2:62][CH2:63][CH2:64][NH:65][C:12](=[O:14])[C@@H:11]2[CH2:15][CH2:16][CH2:17][N:10]2[CH2:9][C@@H:8]([NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:3])[CH3:22])=[O:6])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: NCCCCc1ccccc1
Reactant: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)O)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 82 %

Procedure:
Using the procedure described in ample 1e, a solution of 1-[2-(S)-[[(1,1-dimethylethoxy)carbonyl]amino]-4-methylpentyl]-L-proline (200 mg), DCC (197 mg, 0.955 mmol), DMAP (102 mg, 0.83 mmol), HOBT (155 mg, 1.012 mmol), triethylamine (177 uL, 1.27 mmol) in DMF (1.0 mL) and CH2Cl2 (2 mL) was treated with 4-phenylbutylamine (150 uL) to provide 233 mg (82%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([CH:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)O)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].N1C=CC=CC=1.[F:40][C:41]([F:52])([F:51])[C:42]([O:44]C(=O)C(F)(F)F)=[O:43].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:33])[C:5]([CH2:17][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:6]([O:44][C:42](=[O:43])[C:41]([F:52])([F:51])[F:40])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCCC(Oc1ccccc1)(C(=O)OCC)C(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(OC(=O)C(F)(F)F)C(Cc1ccc(OCc2ccccc2)cc1)(Oc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-[(4-Benzyloxyphenyl)-hydroxymethyl]-2-phenoxy-hexanoic acid ethyl ester (13.4 mmol) in anhydrous CH2Cl2 (100 mL) and pyridine (134 mmol) was cooled to 0° C. and treated with trifluoroacetic anhydride (26.9 mmol). The mixture was stirred for 2 h and gradually warmed to ambient temperature. An aqueous solution of 1N HCl (150 mL) was added and the mixture was stirred vigorously. The solution was partitioned and the organic layer was washed twice with water and brine, dried over Na2SO4, and concentrated in vacuo to produce 2-(4-benzyloxybenzyl)-2-phenoxy-3-(2,2,2-trifluoroacetoxy)hexanoic acid ethyl ester as an oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[N:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C=O)C>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([O:14][N:13]=[C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: ON=C1CCCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(ON=C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
Following method A, potassium t-butoxide (37 g, 320 mmol) was added in portions to a cooled (2° C.) solution of cyclohexanone oxime (35 g, 300 mmol) in DMF (350 mL). The cooled reaction mixture was stirred for 20 minutes and then 1-chloro-4-nitrobenzene (50 g, 320 mmol) was added in portions. The reaction mixture was stirred at ˜10° C. for 30 minutes and then allowed to warm to room temperature and stirred for an additional 4 hours. The reaction mixture was concentrated under reduced pressure to remove the DMF and then treated with water (300 mL). The precipitate was collected by filtration and washed with water. Recrystallization of the crude material from isopropanol and column chromatography provided cyclohexanone O-(4-nitro-phenyl)-oxime (48 g). Cyclohexanone O-(4-nitro-phenyl)-oxime (48 g, 205 mmol) was dissolved in warm isopropanol (350 mL) and 12 N hydrochloric acid (94 mL) was added. The reaction mixture was heated to reflux for 3.5 hours and then cooled in an ice bath. The solid was collected by filtration, washed with water and cold isopropanol, and dried in an oven to give 8-nitro-1,2,3,4-tetrahydro-dibenzofuran (33 g, 150 mmol). A mixture of 8-nitro-1,2,3,4-tetrahydro-dibenzofuran (11 g, 50 mmol) and Raney nickel (˜11 g wet weight) in ethanol (200 mL) was hydrogenated at 50 PSI on a Parr shaker overnight. The mixture was filtered through Celite® and the filtrate was concentrated. The crude solid was recrystallized from hexane to give 6,7,8,9-tetrahydro-dibenzofuran-2-YLAMINE (7.6 g). Mp 71-72° C.
Reaction SMILES: [C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].[OH-].[Na+]>CO.O>[C:1]1([N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OCc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2B (3.637 g, 13.3 mmol) in methanol was added dropwise at 0° C. a solution of NaBH4 added to 3.9 g NaOH dissolved in 7.8 mL H2O. The solution was allowed to stir at room temperature overnight. Water was added and the product was extracted with ether (2×) and washed with brine (2×). The combined ether extracts were dried over MgSO4. The solvent was removed and the product was purified using flash chromatography with a hexanes and then ethyl acetate. The ethyl acetate fraction was collected and the solvent removed to reveal 2.667 g (74%) of a honey yellow crystal solid. 1H NMR (CDCl3): δ4.63 (d, 2H), δ6.97–7.06 (m, 6H), δ7.09 (m, 2H), δ7.20–7.28 (m, 6H); m/z 298.1 (M++Na), 276.1 (M++H), 258.1 (M+−H2O).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][S:2]([CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)=[O:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)CCc1ccc2c(c1)OCO2

Procedure:
3 g of 5-{2-(methylthio)ethyl}-1,3-benzodioxole was dissolved in 100 ml of chloroform. An equimolar amount of m-chloroperbenzoic acid was added to the solution under stirring under reflux with dry ice/alcohol to conduct the reaction for 1 h. 300 ml of chloroform and 300 ml of water were added thereto and then sodium carbonate was added to the mixture until the aqueous layer became alkaline. After separation of the layers, the chloroform layer was washed with water twice and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The oily product was purified according to silica gel column chromatography (chloroform:methanol=20:1) to obtain 1.6 g of the intended compound in the form of a colorless oil.