Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH:20]([OH:22])[CH2:19][CH:18]1[CH2:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](Cl)(C1C=CC=CC=1)([C:35]1[CH:42]=[CH:41][C:38]([O:39][CH3:40])=[CH:37][CH:36]=1)[C:27]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[CH:29][CH:28]=1>N1C=CC=CC=1.CN(C1C=CC=CN=1)C>[CH2:1]([O:8][C:9](=[O:25])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH:20]([OH:22])[CH2:19][CH:18]1[CH:23]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:24][CH:26]([C:27]1[CH:34]=[CH:33][C:30]([O:31][CH3:32])=[CH:29][CH:28]=1)[C:35]1[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[CH:41][CH:42]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(NCCCCCCN1CC(O)CC1CO)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2CCCCCCNC(=O)OCc2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 436.1 %

Procedure:
Compound 29 (6 g, 17 mmol) was co-evaporated with anhydrous pyridine three times and then dissolved in pyridine (60 mL). To this solution dimethylamino pyridine (0.207 g, 1.7 mmol) and DMT-Cl (6 g, 17.9 mmol, 1.05 equiv.) were added at room temperature. The reaction mixture was stirred at room temperature for 16 h. The excess DMT-Cl was quenched by the addition of methanol (25 mL). The solution was dried under reduced pressure. To the residue was suspended in ethyl acetate (300 mL) and washed with saturated bicarbonate solution, brine and water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. 24.2 g of the crude product was obtained after removal of the solvent. Upon purification over silica gel using 2% MeOH/DCM compound 30 (8.7 g, 79%) was obtained as white foamy solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)O.[C:9]([NH2:12])(=[O:11])[CH3:10]>O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.P.[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W].[W]>[C:9]([NH:12][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)(=[O:11])[CH3:10]
Reactant: CC(N)=O
Reactant: Oc1ccc(O)cc1
Agent: [W]
Agent: P
Solvent: O
Product: CC(=O)Nc1ccc(O)cc1
Reaction time: 1.5 h

Procedure:
An intimate mixture of hydroquinone (5.5 g), acetamide (3.5 g) and phosphotungstic acid (0.3 g) was placed in a well stoppered stainless steel tube from which air has been displaced with nitrogen. The tube was kept in a temperature controlled oven at 280°-300° C. for 1.5 hrs. The tube was then removed from the oven, cooled, opened, contents extracted with ethyl acetate, crystallized and products analyzed by gas chromatography. Pure standard substances were used for calibration. The products were also analyzed and identified by GC-mass spectroscopy techniques. The conversion of hydroquinone was 95% by wt. and selectivity to N-acetyl para aminophenol was 86%. Pure N-acetyl para aminophenol could be isolated from the products by column chromatography using alumina.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([OH:26])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>[OH-].[Na+]>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([OH:26])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(O)n(Cc3cccc(C(=O)OC)c3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1nc(N)c2nc(O)n(Cc3cccc(C(=O)O)c3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
2-Butoxy-8-hydroxy-9-(3-methoxycarbonylbenzyl)adenine (0.10 g, 0.27 mmol) obtained by Example 1 was added to 5% sodium hydroxide solution (10 ml) and the solution was stirred at room temperature for 2 hours. After the reaction mixture was neutralized with concentrated hydrochloric acid, the resulting solid was filtered and washed with methanol to give the captioned compound (0.06 g, 0.17 mmol, yield: 61%) as a white solid.
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3][N:2]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C[OH:18].[OH-].[Na+].OO>C1COCC1.CCOCC.O>[OH:18][CH:7]1[CH2:6][CH2:5][CH:4]2[CH:9]([CH2:1][N:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC2CC=CCC2C1
Reactant: CO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CCC(O)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of tert-butyl 3a,4,7,7a-tetrahydro-1H-isoindole-2(3H)-carboxylate (48.18 g, 215.8 mmol) in THF (500 mL) was added a solution of BH3-DMS in THF (2 M in THF, 130 mL, 260.0 mmol) dropwise at 0° C. The reaction mixture was warmed slowly to rt and stirred overnight, then cooled down to 0° C. again. Methanol (120 mL) was added dropwise to the above mixture, and followed by a mixture of NaOH aqueous solution (3 M, 75 mL, 225 mmol) and H2O2 (30% in water, 75 mL). The resulting mixture was stirred at 60° C. for 1.5 h, then cooled down to rt, and diluted with Et2O (500 mL) and water (450 mL), then extracted with EtOAc (450 mL×3). The combined organic phases were washed with brine (500 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as orange oil (49.04 g, 94.2%), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH2:38])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[C:20]([O:35][CH3:36])[CH:19]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:40](=O)[CH2:41][CH2:42][CH3:43].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:39])[CH2:7][CH:8]([NH:38][CH2:40][CH2:41][CH2:42][CH3:43])[C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[C:20]([O:35][CH3:36])[CH:19]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC=O
Reactant: COc1cc(CC(=O)Nc2ccc(C(N)CC(=O)OC(C)(C)C)cc2)ccc1NC(=O)Nc1ccccc1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: CCCCNC(CC(=O)OC(C)(C)C)c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A mixture of 3-amino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}phenyl)-propanoic acid tert-butyl ester [53 mg, Reference Example 7(b)], butyraldehyde (14 mg), sodium acetate (16 mg) and 4 Å molecular sieves (0.2 g) in methanol (5 ml) was stirred at ambient temperature under an atmosphere of nitrogen and then treated with sodium cyanoborohydride (13 mg). After stirring for 1 hour the reaction mixture was treated dropwise with hydrochloric acid (0.5 ml, 1M) then poured into 10% aqueous potassium carbonate solution (10 ml). The mixture was extracted with ethyl acetate (30 ml). The organic phase was dried over magnesium sulphate and then evaporated. The residue was subjected to flash chromatography on silica gel eluting with ethyl acetate to give the title compound (44 mg) as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1>CN(C)C=O.C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 88 %

Procedure:
6,7-Dimethoxy-4-(4-nitrophenoxy)quinoline (1.00 g) was dissolved in N,N-dimethylformamide/ethyl acetate (30 ml/15 ml), 10% palladium hydroxide-carbon (69 mg) was added, and the admixture was stirred at room temperature under hydrogen for 17 hours. The reaction mixture was filtered using Celite. The filtrate was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation to obtain 799 mg of the title compound (yield: 88%).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC[O-].[Na+].Cl.[CH2:21]([C:25]1[NH:26][CH:27]=[C:28]([CH2:30]Cl)[N:29]=1)[CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:21]([C:25]1[NH:26][CH:27]=[C:28]([CH2:30][C:5]([NH:4][C:1](=[O:3])[CH3:2])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:29]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCc1nc(CCl)c[nH]1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(CC(NC(C)=O)(C(=O)OCC)C(=O)OCC)c[nH]1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-n-Butyl-4-hydroxymethylimidazole (33.3 g) is dissolved in methanol (50 ml), and thereto is added 18% hydrogen chloride-methanol solution (160 ml), and the mixture is evaporated under reduced pressure to remove the solvent. To the resulting residue is added toluene (150 ml), and thereto is added dropwise thionyl chloride (52 ml) under ice-cooling. The mixture is stirred at 50° C. for two hours, and concentrated to dryness under reduced pressure to give 2-n-butyl-4-chloromethylimidazole hydrochloride (58.3 g) as oil. Separately, diethyl N-acetylaminomalonate (140.8 g) is added to a solution of sodium ethylate (44 g) in ethanol (500 ml) with ice-cooling under argon atmosphere, and the mixture is stirred at 0° C. for 15 minutes. To the mixture is added dropwise a solution of 2-n-butyl-4-chloromethylimidazole hydrochloride obtained above in ethanol (250 ml), and the mixture is stirred at room temperature overnight. The mixture is evaporated under reduced pressure to remove the solvent, and to the resulting residue are added ethyl acetate (1 liter) and saturated aqueous ammonium chloride solution (500 ml). The aqueous layer is extracted with ethyl acetate, and the extract is combined with the organic layer, and evaporated. To the resulting residue is added 10% hydrochloric acid, and the mixture is neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate to give 2 n butyl-4-{2-acetylamino-2,2-bis(ethoxycarbonyl)ethyl}imidazole (56.8 g) as powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20]/[C:21](=[N:28]\[S@@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH3:35][C:36](=[CH2:40])[CH2:37][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][CH2:20][C@@:21]([NH:28][S@@:29]([C:31]([CH3:33])([CH3:32])[CH3:34])=[O:30])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:37][C:36]([CH3:40])=[CH2:35])[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=C(C)C[Mg]Cl
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCC/C(=N\[S@](=O)C(C)(C)C)c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=C(C)C[C@](CCCN(C(=O)OC(C)(C)C)[C@@H](C)c1ccc(Br)cc1)(N[S@](=O)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (S)-1-(4-bromophenyl)ethyl((E)-4-((R)-tert-butylsulfinylimino)-4-phenylbutyl)carbamate (1.97 g, 3.59 mmol) in dry THF (60 mL) was cooled to −78° C. A solution of 2-methylallylmagnesium chloride (0.5M in THF, 14.4 mL, 2 equiv) was added slowly. After 2 h, the mixture was warmed to rt and stirred for 1 h. LC-MS found reaction completed. The mixture was quenched with satd aq NH4Cl (10 mL), diluted with ether (100 mL), washed with water (30 mL), brine (25 mL), dried over Na2SO4. Filtration and concentration gave crude tert-butyl (S)-1-(4-bromophenyl)ethyl((S)-4-((R)-1,1-dimethylethylsulfinamido)-6-methyl-4-phenylhept-6-enyl)carbamate (2.30 g) which was used for next steps without further purifications. LC-MS Method 1 tR=2.53 min, m/z 605, 607(M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:31]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:35][CH2:34][CH2:33][CH2:32]1>CS(C)=O.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:39][CH2:38][CH2:37][CH2:36][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCCN1CCCC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NCCCN4CCCC4)c3)C(C)(C)C2=O)cc1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 15.1 %

Procedure:
To a solution of 100 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) below in 2 mL of dimethyl sulphoxide are added 120 mg of 3-pyrrolidin-1-ylpropan-1-amine. The solution is stirred at a temperature of 100° C. for 1 hour 40 minutes. After cooling to a temperature in the region of 20° C., the reaction medium is diluted with water, the suspension is filtered and the precipitate is purified by chromatography on a column of silica, eluting with a dichloromethane/methanol/28% aqueous ammonia mixture (gradient from 100/0 to 75/20/5 by volume). 18.5 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-(3-pyrrolidin-1-ylpropyl)urea are obtained in the form of a pale yellow powder, the characteristics of which are as follows:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([SiH2][O:24][C:25](C1C=CC=CC=1)(C1C=CC=CC=1)[CH:26]1[CH2:30][N:29]([CH:31]2[CH2:38][CH2:37][CH2:36][CH:35]([OH:39])[CH2:34][CH2:33][CH2:32]2)[C:28](=[O:40])[C:27]1([CH3:42])[CH3:41])(C)(C)C>O1CCCC1>[OH:39][CH:35]1[CH2:34][CH2:33][CH2:32][CH:31]([N:29]2[CH2:30][CH:26]([CH2:25][OH:24])[C:27]([CH3:41])([CH3:42])[C:28]2=[O:40])[CH2:38][CH2:37][CH2:36]1
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1CN(C2CCCC(O)CCC2)C(=O)C1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(C2CCCC(O)CCC2)CC1CO
Reaction time: 2 h

Procedure:
Tetrabutyl ammonium fluoride (0.76 mL, 1 M in tetrahydrofuran, 0.76 mmol) was added to a stirred solution of the product of Example 5J (0.30 g, 0.60 mmol) in tetrahydrofuran (5 mL) at room temperature. The resulting solution was stirred for two hours and then partitioned with ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 20-100% ethyl acetate in hexanes to give the titled product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].I[CH2:25][CH3:26].O>CN(C)C=O.C(O)C>[CH2:25]([O:15][C:8]([C:6]1[CH:5]=[CH:4][C:3]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:2]([F:1])[CH:7]=1)([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:26]
Reactant: CCOC(=O)C(C)(O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(OCC)c1ccc(-c2ccccc2)c(F)c1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, ethyl 2-(2-fluoro-biphenyl-4-yl)-2-hydroxy-propionate (Japanese Patent Unexamined Publication No. 52-105,144) (15.0 g) was dissolved in N,N-dimethylformamide (300 ml) and then sodium hydride (4.16 g, 60% oily) was added under ice-cooling, after which the resulting mixture was stirred for one hour. Subsequently, iodoethane (10.4 ml) was added and the resulting mixture was stirred for 12 hours. To the reaction mixture were added a small amount of water and ethanol, and thereafter, the solvent was removed by azeotropic distillation using toluene. To the residue was added ethyl acetate and the resulting mixture was neutralized with a saturated aqueous sodium bicarbonate solution and then subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain ethyl 2-ethoxy2-(2-fluoro-biphenyl-4-yl)-propionate.
Reaction SMILES: [C:1](Cl)(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH:27][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C(N(CC)CC)C.CCCCCC.C(OCC)C.C(O)(=O)C>ClCCl.CCCCCC>[C:1]([O:27][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34])(=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCCC/C=C\CCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 1 h

Procedure:
A solution of nervonoyl chloride (26 mmol, 10.0 g) in dichloromethane (50 mL) was added drop-wise to a cooled solution (0° C.) of N-hydroxysuccinimide (26 mmol, 3.0 g) and triethylamine (52 mmol, 5.2 g) in dicholoromethane (200 mL). The reaction was stirred for one hour after the addition was complete. TLC analysis (80:18:2 hexane-diethyl ether-acetic acid) indicated complete reaction. The reaction mixture was poured into hexane, filtered and concentrated to dryness. Recrystallisation from ethanol yielded succinimidyl nervonate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[S:38](Cl)(=[O:40])=[O:39]>C1COCC1>[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=[CH:30][C:29]=1[S:38]([NH:20][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:6]([Cl:19])[CH:5]=1)(=[O:40])=[O:39]
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Yield: 51.8 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge, 144 mg, 0.52 mmol) in THF. 137 mg (52%) of 97 was obtained as a pale yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[C:12]3[CH:13]=[CH:14][C:15]4[C:19](=[O:20])[O:18][CH2:17][C:16]=4[C:11]=3[CH2:10][CH2:9]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[CH:32]1[CH2:34][O:33]1>CCO>[OH:33][CH:32]([C:23]1[CH:24]=[CH:25][C:26]2[C:27](=[O:31])[O:28][CH2:29][C:30]=2[C:22]=1[CH3:21])[CH2:34][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH:8]2[C:12]3[CH:13]=[CH:14][C:15]4[C:19](=[O:20])[O:18][CH2:17][C:16]=4[C:11]=3[CH2:10][CH2:9]2)[CH2:2][CH2:3]1
Reactant: O=C1OCc2c1ccc1c2CCC1CN1CCNCC1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(CC3CCc4c3ccc3c4COC3=O)CC2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
6-(Piperazin-1-ylmethyl)-1,6,7,8-tetrahydro-3H-indeno[4,5-c]furan-3-one (40 mg, 0.15 mmol) and 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (55 mg, 0.29 mmol), were added to a 5 mL microwave tube containing a stir bar; to the mixture was added EtOH (2.5 mL). The tube was capped, degassed and purged with N2. It was then placed in a microwave reactor and heated at 150° C. for 30 min; LC indicated formation of the desired product. The solution was concentrated to dryness, dissolved in MeOH (3.5 mL), filtered and was then subjected to purification by mass-directed HPLC to give 6-({4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}methyl)-1,6,7,8-tetrahydro-3H-indeno[4,5-c]furan-3-one. LC-MS (IE, m/z): 463 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[C:40]([O:43][CH:44](Br)[CH3:45])(=[O:42])[CH3:41]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([N:13]1[C@H:18]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:17](=[O:23])[NH:16][C@H:15]([CH:24]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25]2)[C:14]1=[O:33])[C:10]([O:12][CH2:45][CH2:44][O:43][C:40](=[O:42])[CH3:41])=[O:11]
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)O)c1ccc(F)cc1F
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOC(=O)[C@@H](c1ccc(F)cc1F)N1C(=O)[C@@H](C2Cc3ccccc3C2)NC(=O)[C@H]1CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoic acid (example 22) (0.130 g) was stirred in anhydrous DMF (1 mL) and anhydrous potassium carbonate (0.020 g, 0.5 eq.) was added. The mixture was stirred at room temperature for 1 hour then cooled to −10° C. (ice-salt bath). The heterogeneous mixture was treated with 1-bromoethyl acetate (0.120 mL, excess) and stirred for 3.5 hours keeping the bath temperature between −10 and −5° C. It was then partitioned between DCM and 1M HCl aq. (20 mL each). The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure to give a purple gum; this was purified by SPE cartridge (5 g, silica eluted with (i) cyclohexane x2, (ii) DCM x2, (iii) diethl ether x2, (iv) ethyl acetate x2, (v) methanol x2 to give I -(acetyloxy)ethyl (2R)-(2,4-difluorophenyl)[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]ethanoate (0.081 g) as a yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:29][C:28]1[CH:30]=[CH:31][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 11 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (5.48 g) and 4-isopropylaniline (3.90 mL) as starting materials, 5-benzyloxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (5.94 g) was obtained. melting point: 170.4° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]2[C:12](=[O:15])[NH:13][N:14]=[C:4]2[C:3]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([N:13]1[C:12](=[O:15])[N:5]2[C:6]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[N:2]([CH3:1])[C:3](=[O:16])[C:4]2=[N:14]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)c2n[nH]c(=O)n2c2cccnc21
Solvent: CC(=O)O
Product: CC(=O)n1nc2c(=O)n(C)c3ncccc3n2c1=O

Procedure:
A mixture of 1.8 g. of 5-methyl-pyrido(2,3-e)(1,2,4)-triazolo(4,3-a)pyrazine-1,4-(2H,5H)dione in 25 ml. of acetic anhydride and 50 ml. of acetic acid was stirred and refluxed for 5 hours.