Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:18]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:19]([C:25](O)=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:53]>ClCCl>[C:1]([N:18]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[C@H:19]([C:25]([F:53])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: NCCCC[C@@H](C(=O)O)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: NCCCC[C@@H](C(=O)F)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Bis-FMOC-L-Lysine (5 g, 8.46 mmol) (Bachem) was dissolved in dichloromethane (50 mL). Pyridine (0.69 mL, 8.46 mmol) (Aldrich) and cyanuric fluoride (1.14 g, 8.46 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford bis-FMOC-L-lysyl fluoride as a white powder. (Yield 1.14 g, 23%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].C(S[CH:10]([C:36]1[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:37]=1)[C:11]1[CH2:16][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13][CH:12]=1)(=O)C>CS(C)=O.C(OCC)(=O)C>[C:1]([S:3][CH:12]1[CH2:13][CH2:14][N:15]([C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][C:11]1=[CH:10][C:36]1[CH:40]=[CH:39][N:38]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:37]=1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOC(=O)CCn1ccc(C(SC(C)=O)C2=CCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCn1ccc(C=C2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
Potassium thioacetate (5.91 g) was added to a solution of 5-((acetylsulfanyl){1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methyl)-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (3.00 g), in dimethyl sulfoxide (30 ml). The mixture was stirred at 80° C. for 4 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, and washed successively with water and a saturated aqueous sodium chloride solution. After the extract was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using ethyl acetate and hexane (1:9 to 2:3) as eluents to afford a crude product of 4-(acetylsulfanyl)-3-({1-[2-(ethoxycarbonyl)ethyl]-1H-pyrazol-3-yl}methylidene)-1-(triphenylmethyl)piperidine (2.93 g) as a mixture of geometric isomers.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:9]1[CH:11]([CH2:12][C:13]([NH2:15])=[O:14])[CH2:10]1>CO.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[NH:8][N:7]=[CH:6][CH:5]=1.[CH2:10]1[CH:11]([CH2:12][C:13]([NH2:15])=[O:14])[CH2:9]1
Reactant: O=[N+]([O-])c1ccn[nH]1
Agent: [Pd]
Agent: NC(=O)CC1CC1
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccn[nH]1

Procedure:
1 g of 5-nitro-1H-pyrazole-3-cyclopropylmethylcarboxamide is dissolved in 30 ml of methanol and 2 ml of acetic acid. This mixture is hydrogenated in the presence of 110 mg of Pd/C under 5 bar until reaction is complete. The mixture is filtered through celite, evaporated to dryness and purified by column chromatography (silica gel, methanol:DCM=1:30).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1([CH3:29])[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:8][CH:9]=2)[O:4]1.[H][H]>C(O)C.[Pd]>[ClH:1].[CH3:2][C:3]1([CH3:29])[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:23][CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])=[CH:8][CH:9]=2)[O:4]1
Reactant: CN(C)CCOc1ccc2c(c1)OC(C)(C)C=C2c1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1cccc(C(F)(F)F)c1
Yield: 74.2 %

Procedure:
To a solution of 2,2-dimethyl-7-dimethylaminoethyloxy-4-(3-trifluoromethylphenyl)-2H-chromene hydrochloride (4.96 g) in ethanol (75 ml) was added 10% palladium on charcoal. The mixture was hydrogenated under hydrogen (1 atmosphere pressure) at ambient temperature (about 18° C.) until no further hydrogen was taken up. The mixture was filtered and the solvent removed from the resulting filtrate under reduced pressure to yield the title compound (3.7 g), m.p,. 188°-190° C.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:3]1.O[C@@H:21]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1>>[F:19][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:18])([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:8]([O:10][C@@H:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C(O)[C@](O)(c1ccc(F)cc1)[C@@H]1CCC(F)(F)C1
Product: O=C(O[C@@H]1CCNC1)[C@](O)(c1ccc(F)cc1)[C@@H]1CCC(F)(F)C1

Procedure:
Using (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-fluorophenyl)acetic acid and t-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate, the title compound was prepared by a method similar to Steps 2 and 3 of Referential Example 12.
Reaction SMILES: C[O-].[Na+].[CH2:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C([O:15][CH2:16][CH:17]1[O:19][CH2:18]1)CCC.ClCl>CO.CCOCC>[CH2:4]([O:10][CH2:18][CH:17]([CH2:16][OH:15])[OH:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCO
Reactant: CCCCOCC1CO1
Agent: C[O-]
Agent: ClCl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCCOCC(O)CO
Temperature: 155 °C

Procedure:
4.7g of a solution containing 22.7% sodium methylate in methanol is added to 61.2g of dehydrated n-hexanol. The methanol is eliminated by heating the mixture to 155°C. After cooling the mixture to 130°C, 39g of tertio-butyl-glycidyl-ether is introduced gradually over a two hour and 50 minute period. This ether has a boiling point of 87°-88°C under 88 mm of mercury and a purity of 95% as determined by measurement of the epoxide function. The secondary products which it contains are chlorinate derivatives having a chlorine content of 0.58%. The reaction is completed by heating the mixture at reflux for one hour.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([C:27]([F:30])([F:29])[F:28])([C:23]([F:26])([F:25])[F:24])[OH:22])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:31][S:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([S:32][CH3:31])[CH:38]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:21]([C:27]([F:29])([F:30])[F:28])([C:23]([F:25])([F:26])[F:24])[OH:22])=[N:11]1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CSc1cccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)c1
Temperature: 88 °C
Reaction time: 2 h
Yield: 11.2 %

Procedure:
5-(4-Bromo-phenyl)-1-(2,4-difluoro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (50.0 mg, 0.10 mmol) prepared in Step 2 of Preparation 22, 3-(methylthio)-phenylboronic acid (25.0 mg, 0.15 mmol), Pd(PPh3)4 (11.5 mg, cat.), ethanol 0.5 mL and a 2N sodium carbonate solution (0.5 mL) were added to 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 6.1 mg of the titled compound as a yellow liquid.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[N:11]=[C:12]([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:22])[CH2:16]2)[S:13][CH:14]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:8][C:14]1[S:13][C:12]([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:22])[CH2:16]2)=[N:11][C:10]=1[Cl:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CN(c2nc(Cl)cs2)CCCN1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1CN(c2nc(Cl)c(Br)s2)CCCN1
Temperature: 23 °C
Reaction time: 0.13 h
Yield: 55.8 %

Procedure:
n-bromosuccinimide (80 mg, 0.449 mmol) was combined with a solution of 4-(4-chloro-1,3-thiazol-2-yl)-1,4-diazepan-2-one (100 mg, 0.432 mmol) in CHCl3 (6 ml) and stirred at 23° C. for 8 minutes. The solution became dark was immediately diluted with ethyl acetate, and washed successively with aq. sodium thiosulfate (sat.), aq. NaHCO3 (sat.) and brine. The organic fraction was dried (Na2SO4), filtered and concentrated to afford 4-(5-bromo-4-chloro-1,3-thiazol-2-yl)-1,4-diazepan-2-one (75 mg, 0.241 mmol, 55.9% yield) as a yellow oil of sufficient purity for subsequent transformations.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1>CC#N>[Br:32][C:18]1[CH:17]=[C:16]([CH2:15][N:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:24])[CH3:23])[CH2:14][CH2:13]2)[CH:21]=[CH:20][C:19]=1[NH2:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(Cc2ccc(N)c(Br)c2)CC1
Temperature: 0 °C
Yield: 32 %

Procedure:
A solution of 4-{4-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperazin-1-ylmethyl}-phenylamine (as prepared in the previous step, 204 mg, 0.582 mmol) in CH3CN (6 mL) was cooled to 0° C. and treated dropwise with NBS as a solution in CH3CN (6 mL). The solvents were evaporated in vacuo. The residue was taken up in EtOAc and washed with satd aq NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification of the residue on a 20-g Isolute SPE column on a FlashMaster system with 25-50% EtOAc-hexane afforded the title compound (80.9 mg, 32%) as an off-white solid. Mass spectrum (ESI, m/z): Calcd. for C19H34N3OSiBr, 428.2/430.2 (M+H). found 428.1/430.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:39])[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([CH:26]([CH3:28])[CH3:27])=[CH:14][C:10]=1[C:11]([N:36]1[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][N:30]([CH3:39])[CH3:29])[CH2:34][CH2:35]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN(C)CCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)N2CCN(CCN(C)C)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
2,4-Bis-benzyloxy-5-isopropyl-benzoyl chloride (200 mg, 0.5 mmol) was dissolved in DCM (5 ml), treated with 1-(2-dimethylaminoethyl)piperazine (83.6 mg, 0.53 mmol) and triethylamine (0.2 ml, then stirred for 1 hour at room temperature. The reaction mixture was diluted with DCM, washed with water and, dried (MgSO4) and evaporated to give 0.25 g of the title compound. MS: [M+H]+ 516.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:25])[CH3:24].O>CN(C)C=O>[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:14]1[CH2:15][CH2:16][N:11]([C:7]2[C:4]3[CH:5]=[CH:6][S:2][C:3]=3[CH:10]=[CH:9][CH:8]=2)[CH2:12][CH2:13]1)(=[O:25])[CH3:24]
Reactant: c1cc(N2CCNCC2)c2ccsc2c1
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 55.5 %

Procedure:
1.0 g (3.9 mmol) of 1-Benzo[b]thiophen-4-yl-piperazine hydrochloride was suspended in 20 ml of dimethylformamide (DMF), and potassium carbonate (1.3 g, 9.4 mmol) and 4-bromobutyl acetate (0.7 ml, 4.8 mmol) were added thereto followed by stirring at 80° C. for 6 hours. The reaction mixture was cooled to room temperature, then water was added thereto and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1), then concentrated under reduced pressure to obtain 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate (0.72 g) as light yellow oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.FC1C=CC([CH:18]=[O:19])=C(C)C=1>Cl>[F:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][C:11]=1[CH:18]=[O:19]
Reactant: Cc1cccc(F)c1
Reactant: Cc1cc(F)ccc1C=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C=O)c(F)c1
Temperature: 60 °C
Yield: 76.2 %

Procedure:
100.89 g of aluminum chloride (mol. Wt. 133.34; 756.6 mmol) and about 503.54 g of 3-fluorotoluene (mol. Wt. 110.13; 4,572 mmol) were charged to a 2 liter Parry -brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 60° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 200 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 17 hours (the reaction temperature was maintained at 60° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 3-fluorotoluene, and left about 79.65 g of a benzaldehyde mixture consisting of 4-fluoro-2-methylbenzaldehyde (88.4%) and 2-fluoro-4-methylbenzaldehyde (11.6%) (mol. Wt. 138.14; 576.6 mmol; yield of approximately 76.2%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[S:3][C:4]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(S)cc1
Reactant: COC(=O)CCc1sc(Cl)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1sc(Sc2ccc(O)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
A mixture of methyl 3-(2-chloro-4-phenyl-5-thiazolyl)propionate (380 mg), 4-hydroxythiophenol (341 mg), potassium carbonate (373 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and-concentrated to give methyl 3-[2-(4-hydroxyphenylthio)-4-phenyl-5-thiazolyl]propionate (464 mg, yield 93%) as colorless crystals. The crystals were recrystallized from toluene-hexane. melting point: 153–155° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9]2=[O:16]>OS(O)(=O)=O.O=S(=O)=O>[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:1]([O-:4])=[O:2])[C:11](=[O:15])[NH:10][C:9]2=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C1NC(=O)c2cc(F)ccc21
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C1NC(=O)c2cc([N+](=O)[O-])c(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To 753 mmol fuming nitric acid at 0° C. was added dropwise 150 ml 20% oleum. 150.6 mmol 5-fluoro-isoindole-1,3-dione was then added portionwise and the resulting suspension was allowed to warm to room temperature over 4 hours and then stirred for a further 16 h at room temperature and finally was heated at 50° C. for 3 h. The reaction mixture was poured onto ice and the resulting mixture was filtered and the filter cake dried in vacuo to afford the title compound as a yellow solid (68% yield). MS (m/e): 209.1 ([M−H]−, 100%).
Reaction SMILES: ClCCCC([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=O.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>>[CH3:18][C:19]1[N:23]2[CH2:9][CH2:8][CH:7]=[C:12]([C:11]3[CH:12]=[CH:7][C:8]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:10]=3)[C:22]2=[CH:21][N:20]=1
Reactant: Cc1ncc[nH]1
Reactant: CS(=O)(=O)Nc1ccccc1C(=O)CCCCl
Product: Cc1ncc2n1CCC=C2c1ccc(NS(C)(=O)=O)cc1

Procedure:
Combine 100 g (0.36 mol) of N-[(4-chloro-1-oxobutyl)phenyl]methanesulfonamide with 400 g (4.88 mol) of 2-methylimidazole and heat to 175° C. for 22 hr under argon. Crystallization from methylene chloride provides the title compound.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1.O.C(O)C.C([O-])(=O)C.[Na+]>C(O)C.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH:18][C:1]2[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH:2]=2)=[CH:13][CH:12]=1
Reactant: O=C1CCCC(=O)C1
Reactant: NNc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1C=C(NNc2ccc(F)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
The title compound was prepared by a modification of a published procedure (Brueckner R. et al., European Patent EP 1 424 337 A1 (2004)). To a stirred solution of cyclohexane-1,3-dione (10 g, 0.089 mol) in ethanol (50 mL) and water (150 mL) was added portionwise under nitrogen over 15 minutes 4-fluorophenyl hydrazine hydrochloride (14.5 g, 0.089 mol). After 10 minutes 120 mL of 3:1 (v/v) water/ethanol was added in three portions. Solid sodium acetate (7.2 g) was then added portionwise over 45 minutes. The mixture was stirred for another 30 minutes at room temperature. The brown solid was collected, washed with 2×30 mL of 3:1 (v/v) water/ethanol and water, and dried in vacuo overnight to provide the title compound (16.48 g). MS (ES): [M+H]+ @m/z 221.1.
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)=[O:2].[H-].[Na+].I[CH2:14][CH3:15].CO>CN(C)C=O>[CH2:14]([N:7]1[CH:8]=[C:3]([CH:1]=[O:2])[C:4](=[O:10])[NH:5][C:6]1=[O:9])[CH3:15]
Reactant: CCI
Reactant: O=Cc1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCn1cc(C=O)c(=O)[nH]c1=O
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
A suspension of 5-formyluracil (0.84 g, 6.0 mmol) in anhydrous dimethylformamide (12 mL) under a nitrogen atmosphere was cooled to −40° C. The reaction mixture was treated with sodium hydride (60% mineral oil dispersion, 0.26 g, 6.6 mmol), stirred 30 min., then treated with iodoethane (0.53 mL, 6.6 mmol). The mixture warmed to 20° C. over 3 h., then was brought to 40° C. for 48 h. At this time the reaction mixture was cooled to room temperature, treated with methanol (5 mL) and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel eluted with a gradient of ethyl acetate in hexanes (1:3 to 1:2 to 1:1) to leave the product (0.25 g) as a white powder. MS (ESI-POS): [M+H]+=169.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([S:8][C@@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1.[H-].[Na+].I[CH3:30].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([S:8][C@@H:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][N:11]([CH3:30])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC[C@@H](Sc1cc(Cl)ccc1C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C[C@@H](Sc1cc(Cl)ccc1C#N)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the product from Example 4 step (a) (92 mg) in THF (5 ml) was added sodium hydride (60% in oil; 10 mg) followed by iodomethane (60 μl). The mixture was stirred at room temperature for 2 days then poured into water and extracted with diethyl ether (three times). The combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated off to give the sub-title compound (100 mg) as an oil.
Reaction SMILES: [Na+].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([O-:15])=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:14][C:13](=[O:15])[CH:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:11][CH:10]=1)[CH3:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2ccccc2)cc1
Temperature: 90 °C
Yield: 86.8 %

Procedure:
To a mixture of 2.28 g of 2-(p-isobutylphenyl)propionic acid sodium salt in 20 ml of dimethylformamide was added 2.52 g of benzyl chloride and the whole was heated at 90° C. for 3 hours. After the reaction was complete, the solvent was removed by distillation under reduced pressure to leave a residue, to which was added water. The resulting mixture was extracted with ether and the extract was dehydrated. The ether was removed by distillation to give an oily product. Distillation of this product under reduced pressure yielded 2.57 g of 2-(p-isobutylphenyl)propionic acid benzyl ester as a colorless oil, boiling at 108°-110° C./0.1 mmHg. Analysis-Calculated for C20H24O2 : C, 81.04; H, 8.16. Found: C, 80.92; H, 8.02.