Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[NH2:27][OH:28]>C(O)C>[OH:28][N:27]=[CH:1][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: NO
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(4-formyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step B) (0.8 g, 2.07 mmol) in ethyl alcohol (15 mL) was added hydroxylamine (50% aqueous solution, 0.136 g, 4.1 mmol), and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give a yellow oil, which was purified by flash column chromatography on silica gel using 50% ethyl acetate in hexanes as eluant to give 0.7 g of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([N+:29]([O-:31])=[O:30])[CH:22]=2)[CH:16]=1.O>O1CCCC1>[CH3:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:28]=[CH:27][C:24]([CH:25]=[CH:5][C:3]#[N:4])=[C:23]([N+:29]([O-:31])=[O:30])[CH:22]=2)[CH:16]=1
Reactant: Cc1ccnc(-c2ccc(C=O)c([N+](=O)[O-])c2)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(-c2ccc(C=CC#N)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 240 mg) in tetrahydrofuran (10 ml) was added a solution of diethyl cyanomethylphosphonate (0.971 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 30 minutes. Then to the resultant mixture was added a solution of 4-(4-methylpyridin-2-yl)-2-nitrobenzaldehyde (1.21 g) in tetrahydrofuran (15 ml) dropwise at 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, filtered and dried to give 4-(4-methylpyridin-2-yl)-2-nitrocinnamonitrile (1.22 g) as a mixture of regioisomers.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][S:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:11])[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:21][C:22]1[N:23]=[C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([C:37]([F:40])([F:39])[F:38])=[O:36])=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C=O)C>[F:40][C:37]([F:38])([F:39])[S:35]([C:32]1[CH:33]=[CH:34][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][S:10]([CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[O:11])=[CH:18][CH:17]=3)[N:23]=2)=[CH:30][CH:31]=1)=[O:36]
Reactant: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(S(=O)C(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
14 mg (0.55 mmol) 95% sodium hydride were given to a solution of 126 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfinylmethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 6 ml water the resulting precipitate was collected and combined with additional material obtained by extraction of the aqueous phase at pH=3 with ethyl acetate, drying (sodium sulfate) and evaporation. Purification by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1) gave 130 mg (77%) powder.
Reaction SMILES: C([Mg]Br)C(C)C.[Mg].C(Br)C(C)C.[CH3:13][C:14]([OH:24])([CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:15][CH:16]=[CH2:17].[CH2:25]([CH2:32][NH:33][CH:34]([CH3:38])[C:35](=[O:37])[CH3:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>C(OCC)C.[Cl-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Ti+2]>[CH2:25]([CH2:32][NH:33][CH:34]([C:35]([CH3:36])([OH:37])[CH2:17][CH2:16][CH2:15][C:14]([CH3:13])([OH:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[CH3:38])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)C(C)NCCc1ccccc1
Reactant: C=CCC(C)(O)CCCC(C)C
Agent: [Ti+2]
Agent: CC(C)C[Mg]Br
Agent: [Cl-]
Solvent: CC(C)CBr
Solvent: CCOCC
Product: CC(C)CCCC(C)(O)CCCC(C)(O)C(C)NCCc1ccccc1
Reaction time: 18 h
Yield: 15.6 %

Procedure:
To a solution of isobutylmagnesium bromide prepared from 14.6 g of magnesium, 68.5 g of isobutyl bromide and 500 ml of diethyl ether was added a solution of 34 g of 4,8-dimethyl-1-nonen-4-ol in 100 ml of diethyl ether dropwise under ice-cooling. After completion of the addition, 2.5 g of titanocene dichloride was added to the above solution at room temperature and the mixture was stirred at that temperature for 18 hours. Then, 38.2 g of 3-(benzylmethylamino)-2-butanone was added dropwise under ice-cooling and the mixture was stirred at that temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. The ether was distilled off, and after addition of chloroform, the residue was washed with a saturated aqueous solution of sodium chloride and a small amount of aqueous sodium hydrogen carbonate. After drying over anhydrous sodium sulfate, the chloroform was distilled off and the residue was subjected to silica gel column chromatography (elution with 95% methylene chloride-5% triethylamine) to give 11.3 g of 2-(benzylmethylamino)-3,7,11-trimethyl-3,7-dodecanediol [Compound (71)]. Yield 17%.
Reaction SMILES: [CH3:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[C:4]([NH:8]C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.Br[C:26]1[C:27]([C:32]#[N:33])=[N:28][CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CO.ClCCl.O.CCCCCC>[CH3:1][C:2]1[C:3]2=[C:26]3[C:27](=[C:32]([NH2:33])[N:8]=[C:4]2[CH:5]=[CH:6][CH:7]=1)[N:28]=[CH:29][CH:30]=[CH:31]3
Reactant: N#Cc1ncccc1Br
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc2nc(N)c3ncccc3c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from step 2) (1.0 eq.) and 3-bromopicolino-nitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% ethyl acetate in toluene to give a semipure solid, which was then swirled in hot 10% ethyl acetate in hexane, filtered, and dried to give a pure solid. 1H NMR (acetone d-6): δ 9.22 (d, 1H), 8.90 (d, 1H), 7.82-7.85 (dd, 1H), 7.54 (d, 1H), 7.45 (t, 1H), 7.19 (d, 1H), 6.6 (br, 2H), 2.98 (s, 3H). LRMS [M+H]=210.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[S:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:12].C(O)C>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1ccc(C(=O)CBr)s1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Cn2cc(Cl)cnc2=O)s1

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 2-bromoacetyl-5-methylthiophene (1.30) g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 2 h. the mixture was concentrated to ca. 10 ml, diluted with ethyl acetate (100 ml), washed with water (×3) and brine, dried (MgSO4) and evaporated to a gum. The gum was triturated with diethyl ether and the resulting solid dissolved in ethanol and treated with charcoal. Evaporation of the solvent followed by recrystallisation of the residue twice from ethyl acetate gave the title pyrimidinone (205 mg) m.p. 199°-203° C., εmax (EtOH) 226.5 nm (ε8,570), 261.5 nm (ε9,280), 297 nm (ε11,630).
Reaction SMILES: [CH2:1]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:29](Br)[CH:30]=[CH2:31].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH2:31]([N:19]1[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:17]([CH:14]2[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:8]3[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:28][CH:27]=3)[CH2:12][CH2:13]2)[C:18]1=[O:26])[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: CCCCc1ccc(C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)n(C2CCN(C(=O)c3ccc(CCCC)cc3)CC2)c2ccccc21
Temperature: 120 °C
Reaction time: 72 h
Yield: 66.1 %

Procedure:
1-[1-(4-Butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (197.2 mg, 0.522 mmol), allyl bromide (260 μL, 3.0 mmol) and cesium carbonate (excess) were added to dimethyl formamide (3 mL) and the suspension was stirred at 120° C. in a sealed tube for 72 hours. The reaction was allowed to cool to room temperature and diluted with water (9 mL) then extracted with ethyl ether (2×10 mL). The combined organic phase was dried over sodium sulfate and purified by column chromatography on silica gel using ethyl ether as the eluent. The product fractions were combined and concentrated to give an oily residue. The residue was triturated with ethyl ether and the white crystals that formed were collected by filtration. Vacuum drying yielded 1-allyl-3-[1-(4-butyl-benzoyl)-piperidin-4-yl]-1,3-dihydro-benzoimidazol-2-one (144 mg, 66%) as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:15][C:14]([CH:23]=O)=[CH:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CO.[CH3:27][NH2:28].[BH4-].[Na+].[ClH:31].C(=O)([O-])O.[Na+]>CO>[ClH:31].[ClH:31].[F:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:15][C:14]([CH2:23][NH:28][CH3:27])=[CH:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN
Reactant: O=Cc1cc(-c2ccccn2)n(S(=O)(=O)c2ccc(F)c(F)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccn2)n(S(=O)(=O)c2ccc(F)c(F)c2)c1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
1-[(3,4-Difluorophenyl)sulfonyl]-5-(pyridin-2-yl)-1H-pyrrole-3-carbaldehyde (100 mg) was dissolved in methanol (20 mL), 40% methylamine methanol solution (112 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (33 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate), and dissolved in methanol (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from a mixed solvent (1:10) of methanol-tetrahydrofuran to give the title compound as colorless crystals (yield 89 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.CO>O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]2[NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:21][CH:22]=1
Reactant: O=Cc1ccc(OCCCCCl)cc1
Reactant: Nc1ccccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: ClCCCCOc1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 65.1 %

Procedure:
A mixture of copper (II) acetate monohydrate (7.76 g), 1,2-diaminobenzene (2.10 g), 4-(4-chlorobutoxy]benzaldehyde (Step A) (5.0 g) is slowly heated to reflux in water (10 mL) and methanol (100 mL) and stirred at reflux for 1 hour. The mixture is cooled and a brown precipitate filtered off. The precipitate is suspended in methanol (100 mL) and hydrogen sulfide bubbled through for 30 minutes followed by nitrogen. The mixture is heated to reflux, cooled and filtered. All the filtrates are combined and 0.880 ammonium hydroxide added until just basic. The filtrates are diluted with an equal volume of water and the resulting pale-grey precipitate collected. The precipitate is recrystallized from methanol/water to give 3.8 g of the title compound.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C(OCC)(=O)C>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]([O:20][C:3](=[O:4])[NH:2][CH3:1])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: CN=C=O
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOC(C)=O
Product: CNC(=O)OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 96.5 %

Procedure:
5.7 g (0.1 mol) of methyl isocyanate and a few drops of dibutyl-tin dilaurate were added, while stirring, to 25.8 g (0.1 mol) of 1-(2,4-dichlorophenyl)-1-hydroxy-2-(1,2,4-triazol-1-yl)-ethane in 250 ml of ethyl acetate. The mixture was stirred overnight at 60°-65° C. It was then allowed to cool and the crystalline precipitate was filtered off and washed with ether. 30.4 g (97% of theory) of 1-(2,4-dichlorophenyl)-1-methylcarbamoyloxy-2-(1,2,4-triazol-1-yl)-ethane of melting point 204° C. were obtained.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=S)[NH:19][CH2:20][Si](C)(C)C)=[CH:14][C:13]=1[Br:26])(=[O:9])[CH3:8].IC.[F:29][C:30]([F:48])([F:47])[C:31]1[CH:36]=[C:35]([C:37]([C:39]([F:42])([F:41])[F:40])=[CH2:38])[CH:34]=[C:33]([C:43]([F:46])([F:45])[F:44])[N:32]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OC)(C)(C)C>[C:7]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:38][C:37]([C:35]3[CH:36]=[C:31]([C:30]([F:29])([F:47])[F:48])[N:32]=[C:33]([C:43]([F:46])([F:44])[F:45])[CH:34]=3)([C:39]([F:42])([F:41])[F:40])[CH2:20][N:19]=2)=[CH:14][C:13]=1[Br:26])(=[O:9])[CH3:8]
Reactant: C=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)C(F)(F)F
Reactant: CC(=O)OCc1ccc(C(=S)NC[Si](C)(C)C)cc1Br
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CI
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(=O)OCc1ccc(C2=NCC(c3cc(C(F)(F)F)nc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
Under argon atmosphere, t-BuOK (0.36 g) was slowly added to 2-bromo-4-{[(trimethylsilyl)methyl]carbamothioyl}benzyl acetate (1.0 g) and iodomethane (0.45 g) in THF at −10° C., and the resultant mixture was stirred for 30 minutes at the same temperature. 2,6-bis(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (1.1 g) was added to the reaction mixture, and then n-Bu4NF in THF (0.25 ml, 1M solution) was slowly added to the mixture at −10° C. under argon atmosphere. After stirring the resultant blend for 30 minutes at the same temperature, the blend was allowed to slowly warm to room temperature. The blend was stirred at room temperature overnight. The blend was diluted with t-BuOMe, and washed with 1N HCl and brine. The organic layer was dried over MgSO4. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to get the targeted product (0.58 g).
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)C.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=2[O:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[OH-].[Li+].O>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([O:22][C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([OH:3])=[O:12])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
2-Chloro-nicotinic acid ethyl ester (10 g), benzo[1,3]dioxol-5-ol (sesamol, 8.2 g), and cesium carbonate (21 g) were mixed in anhydrous dioxane (40 mL) and the resulting slurry heated to reflux for 16 h. In a separate flask, lithium hydroxide (12.9 g) was dissolved in water (80 mL) with warming and then added to the refluxing mixture, which was heated for an additional 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo to remove the dioxane. Concentrated hydrochloric acid was added dropwise until the pH=3. The acidified solution was then extracted with ethyl acetate (7×100 mL) to yield crude product, which was recrystallized from ethyl acetate to yield the purified title compound (10.8 g).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[C@@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:54][CH:55]([CH2:68][C:69]1[CH:74]=[CH:73][C:72]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)=[CH:71][CH:70]=1)[C:56]([NH:58][CH:59]1[CH2:64][CH2:63][CH2:62][N:61]([CH2:65][CH2:66][CH3:67])[CH2:60]1)=[O:57]>CN(C=O)C.C(OCC)(=O)C>[CH2:76]([O:75][C:72]1[CH:73]=[CH:74][C:69]([CH2:68][CH:55]([NH:54][C:10](=[O:12])[CH:9]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:20])=[CH:19][CH:18]=2)[CH3:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[C:56](=[O:57])[NH:58][CH:59]2[CH2:64][CH2:63][CH2:62][N:61]([CH2:65][CH2:66][CH3:67])[CH2:60]2)=[CH:70][CH:71]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1
Reactant: CCCN1CCCC(NC(=O)C(N)Cc2ccc(OCc3ccccc3)cc2)C1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)Cc1ccc(N(C)C)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN1CCCC(NC(=O)C(Cc2ccc(OCc3ccccc3)cc2)NC(=O)C(CC(C)C)N(C)Cc2ccc(N(C)C)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
To a solution of (S)-2-[(4-dimethylamino-benzyl)-methyl-amino]-4-methyl-pentanoic acid (0.28 g, 1.01 mmol) in 15 mL of DMF was added HBTU (0.38 g, 1.01 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol). The mixture was stirred for 30 minutes at 0° C. A solution of 2-amino-3-(4-benzyloxyphenyl)-N-(1-propyl-piperidin-3-yl)propionamide (0.40 g, 1.01 mmol) in 15 mL of DMF was added to the reaction mixture. The reaction mixture was allowed to reach the room temperature and was stirred for another 30 minutes. The mixture was diluted with 40 mL of ethyl acetate, washed with 1N HCl (2×10 mL), saturated NaHCO3 (2×10 mL) and saturated solution of brine (2×10 mL). The organic layer was separated, dried with Na2SO4 and evaporated to dryness. The crude residue was purified by chromatography (silica gel, 6:4 hexane/ethyl acetate). The purified product was crystallized from methylene chloride and petroleum ether to give the title compound (0.34 g, 49%) as a white powder; mp 131-133° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].[OH2:23].[OH2:24].O.O.O.O.C(OO)(=O)C1C(=CC=CC=1)C(O)=O.O.O.O.O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2]>ClCCl.CO>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([F:10])[C:7]=1[S:8]([CH3:9])(=[O:24])=[O:23]
Reactant: CSc1c(F)cc(C2=C(c3ccccc3)C(=O)OC2)cc1F
Reactant: O
Agent: O=C(O)c1ccccc1C(=O)OO
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)c1c(F)cc(C2=C(c3ccccc3)C(=O)OC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
Unpurified 4-[3,5-difluoro-4-(methylthio)-phenyl]-3-phenylfuran-2(5H)-one (8.9 g, 27 mmol) and magnesum monoperoxyphthalate hexahydrate (17.2 g, 27 mmol) were combined in a mixture of dichloromethane (200 mL) and methanol (60 mL), and stirred overnight at room temperature. The slurry was poured into water, and extracted with dichloromethane (1×200 mL, 2×50 mL). The combined extracts were washed with water and dilute sodium bicarbonate, and the aqueous sodium bicarbonate wash extracted with dichloromethane (50 mL). The combined extracts were dried with magnesium sulfate, filtered and concentrated. The residue was treated again with magnesium monoperoxyphthalate hexahydrate (8.5 g., 25 mmol), in a mixture of dichloromethane (120 mL) and methanol (30 mL), stirring overnight at room temperature. The reaction mixture was poured into water, and extracted with dichloromethane (2×200 mL). The combined extracts were washed with dilute ammonium chloride (100 mL), and dilute sodium chloride (100 mL), dried with magnesium sulfate, and concentrated to give 6.7 g yellow solids. The crude product was dissolved in dichloromethane (20 mL), and crystallized by adding a mixture of 40% ethyl acetate/60% hexanes (15 mL). The product was filtered, and the filtrate purified by silica gel chromatography using 40% ethyl acetate/60% hexanes to give a total of 5.3 g yellow solids (56%). The 4-[3,5-difluoro-4-(methylsulfonyl)phenyl]-3-phenylfuran-2(5H)-one was recrystallized from ethyl acetate to give white solids. MP 203.5-203.8° C. 1H NMR (CDCl3/400 MHz) 7.35-7.44 (m, 5H), 6.97 (d, 2H, J=9.0), 5.11 (s, 2H), 3.29 (s, 3H). ESHRMS m/z 351.0536 (M+H+, Calcd 351.0502). Anal. Calcd for C17H12F2O4S: C, 58.28; H, 3.45. Found: C, 57.69; H, 3.72.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[S:14].[O-]CC.[Na+].[C:20]([CH2:22][C:23](OCC)=[O:24])#[N:21].S(=O)(=O)(O)O>C(O)C.O>[NH2:21][C:20]1[N:12]([CH2:11][CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:13](=[S:14])[NH:15][C:23](=[O:24])[CH:22]=1
Reactant: NC(=S)NCCc1nc2ccccc2[nH]1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(=O)[nH]c(=S)n1CCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a suspension of 1-[2-(1H-benzimidazol-2-yl)ethyl]thiourea (0.44 g, 2.0 mmol, obtained from Example 12(a)) in absolute ethanol (5 mL) at 80° C. were added, over 2 h, a solution of sodium ethoxide (21% w/v, 2.2 mL, 6.0 mmol) and a solution of ethyl cyanoacetate (0.64 mL, 6.0 mmol) in absolute ethanol (1.3 mL). The reaction was kept at 80° C. for an additional 3 h. After cooling to r.t., water (75 mL) was added and the pH adjusted to ˜7 using concentrated sulfuric acid. The solid that formed was collected by filtration, washed with water and dried in vacuo to give the title compound (0.55 g, 96% yield).