Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][CH2:7][CH2:8][CH2:9]C.[CH3:11][CH2:12][O:13][CH2:14][CH3:15]>>[CH2:6]([C:11]1[CH:15]=[CH:14][O:13][CH:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCOCC
Reactant: CCCCC
Agent: [Li]C(C)(C)C
Product: CCCCc1ccoc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
The iodo-product obtained from Step B above (2.2 g, 8.8 mmol) was dissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 M solution of t-butyllithium in pentane (10.4 mL, 17.7 mmol) was added dropwise. After 20 min, cooling bath was removed. Reaction was continued for 2.5 hr and quenched with H2O (20 mL). The aqueous mixture was stirred overnight and separated. The aqueous layer was extracted with ether (30 mL). The combined organic layers were washed with brine, dried by Na2SO4, and filtered through a Celite pad. Removal of solvent gave 1.10 g (100%) of 3-butylfuran as a reddish-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C@H:21](CS([O-])(=O)=O)[CH2:22][CH3:23].S(=O)(=O)(O)O>CN(C=O)C.O>[CH3:20][C@@H:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)[CH2:22][CH3:23]
Reactant: COC(=O)COc1ccc(O)cc1
Reactant: CC[C@H](C)CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](C)Oc1ccc(OCC(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl 4-hydroxyphenoxyacetate (25.50 g, 140.0 mmol) and potassium carbonate (18.67 g, 135.0 mmol) in 70 ml of DMF is heated to 75°, with stirring, for 40 min. The above methanesulfonate (10.66 g, 70.0 mmol) in 5 ml of DMF is added slowly over 5 min. The reaction mixture is allowed to stand at 60° overnight. To the cooled reaction mixture is added ice water, followed by cold sulfuric acid to bring it to pH 4-5. Additional water is added and the mixture is extracted with ether (3X). The combined ether extracts are washed with 1% sulfuric acid/1% potassium dihydrophosphate, with 1% potassium dihydrophosphate (2X), then hexane is added and the organic layer is washed with 10% sodium hydroxide (5X), with water and with brine; dried; filtered and the filtrate evaporated to give methyl (R)-(-)-4-(1-methylpropoxy)phenoxyacetate, [α]D20 -20.67.
Reaction SMILES: [Na].[CH2:2]([C:9]1[N:13]([CH3:14])[N:12]=[N:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:20][N:21]=O)CC(C)C.CCOCC>C(O)C.O>[OH:20][N:21]=[C:2]([C:9]1[N:13]([CH3:14])[N:12]=[N:11][N:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)CCON=O
Reactant: Cn1nnnc1Cc1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: Cn1nnnc1C(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.2 %

Procedure:
To a suspension of sodium hydroxyde (115 mg, 2.9 mmol) in 1.5 mL ethanol was added 500 mg of 5-benzyl-1-methyl-1H-tetrazole (2.9 mmol). The mixture was stirred 15 min at room temperature. A solution of isoamylnitrite (353 mg, 3 mmol) in 1 mL ethanol was then added dropwise and the mixture was stirred at room temperature for 16 h. Ether and water were then added and the layers were separated. The aqueous phase was washed with ether and then acidified with HCl 0.1M. The resulting neutral solution was extracted 3 times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated to afford 272 mg of the title compound (Z:E mixture) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH:22][C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])=[O:15])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN(C)CCN
Product: CCN(CC)C(=O)c1ccc(NCCN(C)C)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 14 h
Yield: 89.9 %

Procedure:
Following general procedure 2B, N,N-diethyl-4-fluoro-3-nitrobenzamide (0.534 g, 2.22 mmol) and N1,N1-dimethyl-1,2-ethanediamine (0.22 mL, 2.02 mmol) were stirred at 85° C. for 14 h. The crude product was purified through dissolution in 1 N HCl and extraction with Et2O (2×15 mL). The aqueous phase was adjusted to pH 11 with 5 N NaOH and then extracted with CH2Cl2 (4×15 mL). The combined CH2Cl2 phases were dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound (0.560 g, 82%) as an orange oil. 1H-NMR (CD3OD): δ 8.22 (d, J=2.8 Hz, 1H), 7.56 (dd, J=8.4 Hz, J=2.8 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 3.53–3.40 (overlapping t, J=6.4 Hz, and br s, 6H), 2.67 (t, J=6.4 Hz, 2H), 2.33 (s, 6H), 1.22 (t, J=7.6 Hz, 6H). MS (ESI) (M+H)+=309
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[H][H].Br[CH:12]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14]>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:1][CH:2]=1
Reactant: [H][H]
Reactant: Cc1ccc(O)cc1
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Cl)cc1Oc1ccc(C)cc1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a 0° C. suspension of KH (530 mg, 1.0 eq) in DMF (10 mL) was quickly added p-cresol (500 mg, 4.63 mmol), and the reaction mixture was stirred at room temperature. After stirring 10 minutes hydrogen evolution had subsided, and 50 mg of 18-crown-6 was added followed by the product of Step A (1.22 g, 1.0 eq). The reaction mixture was stirred 2.5 hours and was then concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (140×30 mm) eluted with 5% ethyl acetate/hexane to yield 0.744 g (55%) of the title compound.
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(Cl)CC/C=C\CCCCCCCC.[C:29]([O-:32])(=[O:31])[CH3:30].[K+].C(O)(=O)C>>[C:29]([O:32][CH2:1][CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:31])[CH3:30]
Reactant: CCCCCCCC/C=C/CCCCl
Reactant: CC(=O)[O-]
Agent: CCCCCCCC/C=C\CCCCl
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCCCCCC=CCCCOC(C)=O
Reaction time: 10 h

Procedure:
495 g (2.2 moles) of the mixture of trans-4-tridecenyl chloride and cis-4-tridecenyl chloride synthesized in Example 1, 432 g (4.4 moles) of potassium acetate, and 264 g (4.4 moles) of acetic acid were mixed under an atmosphere of nitrogen (N2) and stirred at 180°-185° C. for 10 hours. Thereafter, this mixture was washed with 600 g of purified water and then with 600 g of a 5% aqueous solution of sodium bicarbonate. The resulting organic layer was purified by distillation. Thus, there was obtained 548 g (2.2 mole) of 4-tridecenyl acetate having a trans to cis ratio of 78:22 and a purity of 98%. This product is a sex pheromone component of the tomato pinworm (Keiferia lycopersicella) known as an insect pest of tomato fields principally in the United States of America.
Reaction SMILES: C[O-].[Na+].[C:4]([OH:8])(=[O:7])[CH2:5][SH:6].Cl[CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CO>[C:4]([OH:8])(=[O:7])[CH2:5][S:6][CH2:10][C:11]#[C:12][CH2:13][C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)CS
Reactant: CCCCCCC#CCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCC#CCC#CCSCC(=O)O
Reaction time: 0.5 h

Procedure:
3.85 ml of a 30% solution of sodium methoxide in methanol were added dropwise to a solution of 742 μl of thioglycolic acid in 8 ml of methanol, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then a solution of 2 g of 1-chloro-2,5-dodecadiyne in 20 ml of methanol was added under an inert atmosphere. The mixture was maintained under stirring for 15 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The oily residue obtained crystallized at cold temperature. 3-Thia-5,8-pentadecadiynoic acid was recrystallized from diisopropyl ether.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:22][C:23]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CCO)CC1
Reaction time: 1 h
Yield: 65 %

Procedure:
50 g of 4-piperdine ethanol and 49.2 g of sodium hydrogencarbonate were dissolved in 480 ml of water, in which 55.2 ml of benzyloxycarbonyl chloride was gradually dropped under ice-cooling conditions, followed by agitation for 1 hour as it is. The reaction solution was extracted with chloroform and dried with anhydrous magnesium sulfate. The sulfate was filtered off and the solvent was distilled off, after which the resultant residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:hexane=30:70) to obtain 66.0 g of the captioned compound (yield:65%).
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].[OH-].[Na+]>CO>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O
Yield: 92.5 %

Procedure:
A solution of methyl 8-methylsulfonyl-12-acetoxyheptadecanoate (29.4 g., 0.07 mole) and 20% aqueous sodium hydroxide (70 ml.) in methanol (70 ml.) is stirred at room temperature for 17 hours. The resulting solution is evaporated in vacuo at ~100° C. to an oily residue which is dissolved in water. The aqueous solution is extracted with ether and the organic extract discarfed. Then, the aqueous phase is acidified to Congo Red with 6N hydrochloric acid and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo at ~100° C. providing crude title compound as a viscous oil (23.6 g., 93%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[N:33]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)Cl>[CH:11]([C:4]1[S:3][C:2]2[NH:1][C:15](=[O:17])[N:41]([CH2:40][CH2:39][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:7](=[O:9])[C:6]=2[CH:5]=1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(C(C)C)sc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cc2c(=O)n(CCN3CCOCC3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution (15 mL) of methyl 2-amino-5-isopropylthiophene-3-carboxylate (1.0 g) in methylene chloride were added triphosgene (1.8 g) and triethylamine (3.0 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-morpholin-4-ylethanamine (2.3 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (15 mL), sodium methoxide (1.0 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.29 g, 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:16][N:17]1[C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]([CH3:25])=[N:18]1>O1CCCC1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:22]([C:21]2[N:17]([CH3:16])[N:18]=[C:19]([CH3:25])[CH:20]=2)=[O:23])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(O)c2)n(C)n1
Yield: 89.6 %

Procedure:
In the same manner as in Reference Example 11 and using 3-aminophenol (2.11 g, 19.3 mmol), triethylamine (2.81 mL, 20.3 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (3.07 g, 19.4 mmol) and tetrahydrofuran (30 mL) as starting materials, the title compound (4.00 g, 90%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]3)[CH2:9][N:8]([C:22](=[O:30])[NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:22]([NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)=[O:30])[C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Reaction time: 1 h
Yield: 99.4 %

Procedure:
The t-butyl 5-bromo-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (54.2 mg, 0.105 mmol) obtained in Example 1 was dissolved in methylene chloride (0.5 mL). Thereafter, trifluoroacetic acid (0.5 mL) was added to the above obtained solution at room temperature, and the obtained mixture was then stirred for 1 hour. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and a solid was then collected by filtration, followed by drying, to obtain the captioned compound (43.2 mg, 100%) in the form of a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:11][C:10]([CH2:12][CH3:13])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:12]([C:10]1[S:11][C:4]2=[N:3][C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)=[CH:7][C:6](=[O:8])[N:5]2[N:9]=1)[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nn2c(=O)cc(Cl)nc2s1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nn2c(=O)cc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2s1
Temperature: 150 °C

Procedure:
To a solution of 7-chloro-2-ethyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (2.0 g, 9.27 mmol, 1.0 equiv) in 50 mL of anhydrous acetonitrile in a microwave vial is added tert-butyl 1-piperazinecarboxylate (2.073 g, 11.13 mmol, 1.2 equiv) followed by N,N-diisopropylethylamine (4.86 mL, 27.8 mmol, 3.0 equiv). The mixture is heated in a microwave reactor for 25 min at 150° C. Upon completion, the mixture is concentrated in vacuo to give crude tert-butyl 4-(2-ethyl-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate as a yellow oil. This material is advanced directly to the next step.
Reaction SMILES: [CH3:1][C:2]1[N+:10]([O-:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH2:27]([N:29](CC)[CH2:30][CH3:31])[CH3:28].N1CCCC1>ClCCl>[N:29]1([C:4]([C:3]2[C:2]([CH3:1])=[N+:10]([O-:11])[CH:9]=[CH:8][CH:7]=2)=[O:6])[CH2:30][CH2:31][CH2:28][CH2:27]1
Reactant: Cc1c(C(=O)O)ccc[n+]1[O-]
Reactant: CCN(CC)CC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: C1CCNC1
Product: Cc1c(C(=O)N2CCCC2)ccc[n+]1[O-]
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a suspension of 2-methylnicotinic acid-1-oxide (0.701 g) and N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1.243 g) in dichloromethane (30 ml) was added dropwise a solution of triethylamine (0.570 g) in dichloromethane (5 ml) and followed a solution of pyrrolidine (0.407 g) in dichloromethane (5 ml) under stirring at cooling in an ice-bath. After completion of the addition, the mixture was allowed to stand to room temperature overnight. The reaction mixture was washed with water and dried over sodium sulfate. Removal of the solvent gave a crude product. The crude product was purified by column chromatography on silica gel with a mixture of chloroform and methanol (50:1) as an elunet to give 3-(1-pyrrolidinylcarbonyl)-2-methylpyridine-1-oxide (0.530 g).
Reaction SMILES: CC([N:5]([C@H:9]([CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18]Br)=[CH:13][CH:12]=1)[C:6](=[O:8])[O-:7])(C)C.[NH2:33][C:34]1[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[O:31]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:32])[N:22]1[CH2:21][C@@H:9]([NH:5][C:6](=[O:8])[O:7][C:11]([CH3:16])([CH3:12])[CH3:10])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:33]=[C:34]3[C:39]([CH:40]([OH:42])[CH3:41])=[CH:38][CH:37]=[CH:36][N:35]3[CH:18]=2)=[CH:15][CH:16]=1
Reactant: CC(O)c1cccnc1N
Reactant: CC(C)(C)N(C(=O)[O-])[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CN4C(=O)c5ccccc5C4=O)NC(=O)OC(C)(C)C)cc3)nc12
Yield: 174.7 %

Procedure:
A mixture of 1,1-dimethylethyl{(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (1.90 g, 3.79 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.523 g, 3.79 mmol), and solid sodium bicarbonate (0.398 g, 4.72 mmol) in isopropanol (24 mL) was refluxed for 3.0 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried (Na2SO4), and concentrated to give the title compound (1.79 g, 87%) as a light pink solid.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:15]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:15]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: Clc1ccc(C(Cl)Cn2ccnc2)c(Cl)c1
Reactant: COC(=O)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
415 mg of methyl 4-mercaptobenzoate were dissolved in 3 ml of dry dimethylformamide, and 108 mg of a 55% w/w suspension of sodium hydride in mineral oil were then added to the resulting solution, whilst ice-cooling, after which the mixture was stirred at room temperature for 30 minutes. 567 mg of a solution of 1-[2-chloro-2-(2,4-dichlorophenyl)ethyl]imidazole dissolved in 3 ml of dry dimethylformamide were then added to the resulting solution, and the mixture was heated at 60° to 70° C. for 7 hours. At the end of this time, the resulting mixture was treated and purified similarly to the procedure described in Example 1, to give 317 mg of the title compound as colorless crystals, melting at 121°-124° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][S:24][C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:44](O)([CH3:47])([CH3:46])[CH3:45].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:44]([O:21][C:20](=[O:22])[C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:17])[CH2:23][S:24][C:25]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)O
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
2(R)-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionic acid is reacted with t-butyl alcohol and dicyclohexyl carbodiimide (DCC) in 4-(dimethylamino) pyridine (DMAP) and tetrahydrofuran (THF) at room temperature to form 2(R)-(9H-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionic acid tert-butyl ester.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.S(Cl)([Cl:18])=O.N1C=CC=CC=1.CCOCC>O1CCCC1>[Cl:18][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCl)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 98.8 %

Procedure:
A mixture of methyl 4-hydroxymethyl-2-nitrobenzoate (1.49 g), thionyl chloride (1.08 g), dry pyridine (0.1 g), dry ether (70 ml) and dry tetrahydrofuran (20 ml) was stirred overnight. The reaction mixture was washed in turn with 1N hydrochloric acid and sat. sodium bicarbonate solution, dried over magnesium sulfate and evaporated to give methyl 4-chloromethyl-2-nitrobenzoate (1.60 g).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](C(O)=O)=[CH:3][CH:2]=1.[N-:16]=[C:17]=[O:18].[CH2:19]([CH:21]([NH:24][OH:25])[CH2:22][CH3:23])[CH3:20]>>[OH:25][N:24]([CH:21]([CH2:22][CH3:23])[CH2:19][CH3:20])[C:17]([NH:16][C:4]1[CH:3]=[CH:2][C:1]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:18]
Reactant: CCC(CC)NO
Reactant: [N-]=C=O
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Product: CCC(CC)N(O)C(=O)Nc1ccc(-c2ccccc2)cc1

Procedure:
Using the general method of Compound 76, 4-biphenylcarboxylic acid (1.3 g, 6.5 mmole) was converted to the isocyanate then reacted with N-(1-ethylpropyl)hydroxylamine (1.0 g, 10 mmole) to provide 0.54 g of the desired product as a white crystalline solid, m.p. 183°-184° C. Analysis: Calculated for C18H22N2O2 : %C, 72.46; %H, 7.43; %N, 9.39; Found: %C, 72.38; %H, 7.15; %N, 9.26.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][Br:18])=[CH:13][CH:12]=1.[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[Br-:18].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([P+:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cn1c(-c2ccc(CBr)cc2)nc2ccccc21
Solvent: Cc1ccccc1C
Product: Cc1ccc(-c2nc3ccccc3n2C)cc1[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
A stirred solution of 90.4 g (0.3 mole) of 1-methyl-2-(4-bromomethylphenyl)benzimidazole and 78.7 g (0.3 mole) of triphenylphosphine in xylene is heated at reflux for 19 hours. Compound B is then isolated by filtration, washed with additional portions of xylene, and dried.