Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])[CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][O:9][C:5]1[CH:4]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:8]=[CH:7][N:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A mixture of 4-(chloromethyl)-2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]pyridine (0.472 g), methyl 2-(3-hydroxyphenyl)acetate (0.249 g), anhydrous potassium carbonate (0.415 g) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-4-pyridylmethoxy]phenyl]acetate as a colorless oil (0.597 g, 90%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[CH2:39]Cl)[CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:39][C:38]2[CH:41]=[CH:42][CH:43]=[C:36]([C:28]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:26]([O:25][CH3:24])[CH:27]=3)[CH:37]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: CCOc1ccc(N(Cc2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:31])[C@@:7]12[O:30][CH2:29][O:28][C@@H:8]1[CH2:9][C@@H:10]1[C@:24]2([CH3:25])[CH2:23][C@H:22]([OH:26])[C@H:21]2[C@H:11]1[CH2:12][CH2:13][C:14]1[C@:19]2([CH3:20])[CH:18]=[CH:17][C:16](=[O:27])[CH:15]=1)(=O)C.O.C(=O)([O-])[O-].[Ca+2]>CO>[OH:26][C@H:22]1[CH2:23][C@@:24]2([CH3:25])[C@@H:10]([CH2:9][C@H:8]3[O:28][CH2:29][O:30][C@:7]32[C:6](=[O:31])[CH2:5][OH:4])[C@H:11]2[C@H:21]1[C@:19]1([CH3:20])[C:14]([CH2:13][CH2:12]2)=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]1
Reactant: CC(=O)OCC(=O)[C@@]12OCO[C@@H]1C[C@H]1[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]12C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: O
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@H]1OCO[C@]12C(=O)CO
Yield: 56 %

Procedure:
1.5 g of 21-acetoxy-11β-hydroxy-16α,17α-methylenedioxy-1,4-pregnadiene-3,20-dione is dissolved in 510 ml of methanol and 111 ml of water and refluxed under agitation with 1.5 g of calcium carbonate for 24 hours. The calcium carbonate is removed by vacuum-filtering; the filtrate is concentrated to turbidity and poured on water. After the usual working-up process, the crude product is purified on 115 g of silica gel with a methylene chloride-acetone gradient (0-20% acetone), thus isolating 758 mg of 11β,21-dihydroxy-16α,17α-methylenedioxy-1,4-pregnadiene-3,20-dione, mp 220°-223° C. (decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:29]([CH3:30])=[CH:28][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:25]([O-])=O)=[C:18]([N:20]([CH3:24])[C:21](=[O:23])[O-:22])[CH:19]=2)=[CH:11][C:10]=1[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:25][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:28]=[C:29]([CH3:30])[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([CH3:31])[CH:11]=2)=[CH:19][C:18]=1[N:20]([CH3:24])[C:21](=[O:23])[O:22][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)[O-])c2)cc(C)c1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: Cc1cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 11 h
Yield: 171.6 %

Procedure:
A mixture of 1.71 g of N-[5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)-2-nitrophenyl]-N-methylcarbamate, 0.2 g of 10% palladium on carbon and 100 ml of methanol was stirred vigorously at room temperature for 11 hours under a hydrogen atmosphere. The catalyst was filtered off from the reaction mixture and the filtrate was concentrated by evaporation, whereby 1.56 g of the title compound were obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=CC=1)#N.[C:18]([OH:21])(=[O:20])[CH3:19].Cl>>[C:18]([C:19]1[CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=[CH:3][CH:1]=1)([OH:21])=[O:20]
Reactant: CC(=O)O
Reactant: N#Cc1cccc(-c2ccnc3ccnn23)c1
Agent: Cl
Product: O=C(O)c1cccc(-c2ccnc3ccnn23)c1

Procedure:
A sample of 7-(m-cyanophenyl)pyrazolo[1,5-a]pyrimidine is heated with acetic acid-hydrochloric acid to give 7-(m-carboxyphenyl)pyrazolo[1,5-a]pyrimidine. The preceding compound is heated with sulfur tetrafluoride for 20 hours at 150° C. to give the product of the example, m.p. 104°-106° C.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]([F:39])([F:38])[C:10]1[CH:11]=[C:12]([C@H:20]([O:22][C@@H:23]2[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]([C:35]([OH:37])=[O:36])[CH2:26][CH2:25][O:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>CO.C1(C)C=CC=CC=1>[F:39][C:9]([F:38])([F:8])[C:10]1[CH:11]=[C:12]([C@H:20]([O:22][C@@H:23]2[C@@H:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:27]([C:35]([O:37][CH3:1])=[O:36])[CH2:26][CH2:25][O:24]2)[CH3:21])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C[C@@H](O[C@H]1OCC[C@@H](C(=O)O)[C@@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Yield: 73 %

Procedure:
Trimethylsilyldiazomethane (2.0M in hexanes, 3.5 mL, 7 mmol) was added in portions over 1 hour to a solution of (2R,3R,4R)-2-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}tetrahydro-3-phenyl-2H-pyran-4-carboxylic acid (WO 00/56727A1; 3.2 g, 6.9 mmol) in a mixture of methanol (10 mL) and toluene (7 mL). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane (80:20), to give the title compound as a colorless solid (2.4 g, 73%).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[N:17]=[C:18]([CH3:22])[O:19][C:20](=[O:21])[C:15]=3[C:14]3[CH:13]=[C:12]([F:23])[CH:11]=[CH:10][C:9]=3[N:8]=2)=[CH:3][CH:2]=1.[OH2:30].[OH-].[Na+].Cl>O1CCCC1>[C:18]([NH:17][C:16]1[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:2][CH:3]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:20]([OH:30])=[O:21])=[CH:13][C:12]([F:23])=[CH:11][CH:10]=2)(=[O:19])[CH3:22]
Reactant: Cc1nc2c(-c3ccc(-c4ccccc4)cc3)nc3ccc(F)cc3c2c(=O)o1
Reactant: O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Reaction time: 4 h

Procedure:
A 1.8 g portion of 5-[1,1'-biphenyl]-4-yl-9-fluoro-3-methyl-1H-[1,3]oxazino[4,5-c]quinolin-1-one was dissolved in 50 ml of tetrahydrofuran. To this was added 10 ml of water containing 0.94 ml of 1N sodium hydroxide. This mixture was stirred for 4 hours, then poured into 500 ml of water and acidified to pH 4 with 3% aqueous hydrochloric acid. The resulting solid was collected, washed with water and dried at 110° C. in vacuo, giving 1.6 g of the desired product as a white solid mp 256°-259° C.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)=[O:6].[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:23]1([C:29]2[N:33]=[C:32]([N:34]3[CH2:39][CH2:38][N:37]([C:5]([NH:7][CH:8]4[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:9]4)=[O:6])[CH2:36][CH2:35]3)[S:31][N:30]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)OCC(Cl)(Cl)Cl)C1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)C1
Yield: 13 %

Procedure:
A mixed solution of tert-butyl 3-{[(2,2,2-trichloroethoxy)carbonyl]amino}piperidine-1-carboxylate (555 mg, 1.48 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (400 mg, 1.62 mmol) and diisopropylethylamine (0.257 ml, 1.48 mmol) in dimethyl sulfoxide (4.9 ml) was stirred at 70° C. for 4 days. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 90.9 mg (13.0%) of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[CH2:9][NH:8][CH2:7][CH2:6]2.I[CH2:17][CH2:18][F:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:19][CH2:18][CH2:17][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1
Reactant: FCCI
Reactant: COc1cc2c(cc1[N+](=O)[O-])CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CN(CCF)CC2
Temperature: 65 °C

Procedure:
6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline (222 mg, 1.07 mmol) was taken in acetonitrile (5 mL), treated with 1-iodo-2-fluoroethane (0.40 g, 2.3 mmol) and potassium carbonate (500 mg, 3.62 mmol, Aldrich). The mixture was heated at 65° C. for 16 h, cooled, and partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to provide 2-(2-fluoroethyl)-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroisoquinoline which was taken directly to the next step without determination of yield. 1H NMR (400 MHz, CDCl3) δ ppm 2.89-3.04 (m, 6 H), 3.77 (s, 2 H), 3.94 (s, 3 H), 4.62-4.80 (dt, JHF=47.6, J=4.6 Hz, 2 H), 6.82 (s, 1 H), 7.63 (s, 1 H); ESIMS (M+H)+=255.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:25](Cl)(=[O:27])[CH3:26]>C(=S)=S>[C:25]([C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH2:7]2)=[CH:12][CH:11]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CC(C)CC1Cc2ccccc2CN1C(=O)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C(CC(C)C)C2
Temperature: 45 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixed liquid of 193 mg of 3-isobutyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline, 533 mg of aluminum chloride, and 5 mL of carbon disulfide was added 157 mg of acetyl chloride at 44° C., followed by stirring at 45° C. for 1 hour. The reaction liquid was concentrated under reduced pressure, and 2N hydrochloric acid and ice were added thereto, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and then with brine, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation to obtain 202 mg (yield 91%) of a title compound as a yellow oily substance.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[C:13]2[S:12][CH2:11][C@H:10]([NH:14]C(=O)OC(C)(C)C)[C:9](=[O:22])[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[NH2:14][C@@H:10]1[C:9](=[O:22])[NH:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([Br:2])[C:13]=2[S:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CSc2c(Br)cccc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CSc2c(Br)cccc2NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 mL of a solution of hydrogen chloride in dioxane (4 M) are added to a 25 mL round-bottomed flask containing 500 mg of 20 (1.34 mmol). The mixture is stirred for 4 hours at room temperature under argon. A white precipitate forms, which is filtered off by suction and washed with 3 mL of dioxane and then 5 mL of isopropyl ether. 386 mg of amine 21 (beige-coloured solid) are thus obtained in the form of hydrochloride.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[C:13]([S:18][CH3:19])[NH:12]4)[CH2:5][C@H:4]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:3]1.[Br:28]Br>C(Cl)Cl>[Br:28][C:9]1[CH:10]=[C:11]2[C:17]3[C:14]([CH2:15][C@@H:16]4[C@@H:6]([C:7]=3[CH:8]=1)[CH2:5][C@H:4]([NH:20][C:21](=[O:27])[N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[CH2:3][N:2]4[CH3:1])=[C:13]([S:18][CH3:19])[NH:12]2
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(SC)c(c34)C[C@H]2N(C)C1
Reactant: BrBr
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4[nH]c(SC)c(c34)C[C@H]2N(C)C1
Reaction time: 0.33 h

Procedure:
A solution is prepared from 11.2 g of 3-(6-methyl-2-methylthio-8α-ergolinyl)-1,1-diethylurea (29 mmol) in 400 ml of methylene chloride p.a. and, at room temperature, 1.45 ml of bromine (26 mmol) dissolved in 100 ml of methylene chloride p.a. is added dropwise thereto within 20 minutes. After 15 minutes of agitation, the solvent is distilled off under vacuum, the residue is taken up in methylene chloride and methanol, and crystallized by adding ethyl acetate with a small amount of diisopropyl ether and by removing the readily volatile solvents by distillation.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)[CH:7]=1)=[O:4].Br[CH2:29][C:30]#[N:31].CCN(C(C)C)C(C)C>C(#N)C>[C:30]([CH2:29][NH:1][C@@H:2]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)[CH:7]=1)=[O:4])#[N:31]
Reactant: N#CCBr
Reactant: CNc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccc(F)cc3)n(C)n2)ccn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(F)cc3)NCC#N)n(C)n2)ccn1
Temperature: 60 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a rt solution of 23.D (750 mg, 2036 μmol) and bromoacetonitrile (244 mg, 2036 μmol) in acetonitrile was added n,n-diisopropylethylamine (426 μl, 2443 μmol). After stirring at 60° C. for 2 hr, organic solvents were removed under reduced pressure. Purification of the residue by flash chromatography on silica gel using 0-12% MeOH/CH2Cl2 for elution gave the title product 23.E as yellow syrup (706 mg, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:25])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([NH2:24])=[O:23])[CH:15]=1.S(OC)(O[CH3:30])(=O)=O>>[CH3:30][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:25])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([NH2:24])=[O:23])[CH:15]=1
Reactant: Cc1cc(O)c(C(=O)C=Cc2cccc(OCC(N)=O)c2)c(=O)n1C
Reactant: COS(=O)(=O)OC
Product: COc1cc(C)n(C)c(=O)c1C(=O)C=Cc1cccc(OCC(N)=O)c1

Procedure:
According to the same manner as that of Example a-25 except that 0.78 g of 4-hydroxy-3-[3-[3-(aminocarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone was used in place of 4-hydroxy-3-[3-[3-(2-hydroxyethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone, and 0.5 ml of dimethyl sulfate was used in place of iodomethane, 0.18 g of 4-methoxy-3-[3-[3-(aminocarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (68a)] was obtained as a yellow crystal.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH2:19]([C:23]1[C:35]([NH2:36])=[C:34]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:26]2[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:25]=2[CH:24]=1)[CH:20]([CH3:22])[CH3:21]>C1(C)C=CC=C(C)C=1>[CH2:19]([C:23]1[C:35]([N:36]2[CH2:2][CH2:3][N:4]=[C:5]2[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:34]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:26]2[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:25]=2[CH:24]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)Cc1cc2c(oc3ccccc32)c(CC(C)C)c1N
Reactant: O=C(NCCCl)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1cccc(C)c1
Product: CC(C)Cc1cc2c(oc3ccccc32)c(CC(C)C)c1N1CCN=C1c1ccccc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
N-(2-chloroethyl)benzamide (3.1 g, 16.88 mmol) was dissolved in 40 mL anhydrous m-xylene under nitrogen. Phosphorus pentachloride (5.27 g, 25.3 mmol) was then carefully added and the mixture heated to reflux under nitrogen for 2 h. The solution was allowed to cooled to room temperature and 2,4-diisobutyldibenzo[b,d]furan-3-amine (5.49 g, 18.57 mmol) was added. The reaction mixture was heated to reflux for 20 h. After cooling, the precipitate was filtered and the solid imidazoline product was collected and washed with toluene followed by hexanes. The resultant crude product was dissolved in methylene chloride and washed twice with 50% NaOH. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford title product (5.5 g, 77%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Br:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([S:19](Cl)(=[O:21])=[O:20])=[C:14]([F:23])[CH:13]=1>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:19]([C:15]2[CH:16]=[C:17]([F:18])[C:12]([Br:11])=[CH:13][C:14]=2[F:23])(=[O:21])=[O:20])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: CC(=O)c1sc(N)nc1C
Product: CC(=O)c1sc(NS(=O)(=O)c2cc(F)c(Br)cc2F)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and 4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in the synthetic METHOD B to give a white solid (21.0 mg) with purty >90%: MS (pos) m/z 411.2, 413.2.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2c(C(=O)O)sc(N3CCOCC3)c2C#N)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 84.3 %

Procedure:
To a suspension of ethyl 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.077 g, 0.21 mmol) in THF/MeOH/water (1:1:1) (6 mL) was added sodium hydroxide (0.2 g, 5 mmol). The reaction mixture was allowed to stir at 50° C. for 6 h and was concentrated. The residue was acidified to pH 1-2 with 1N HCl and was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (77) (0.061 g, 86%). LCMS: (FA) ES+ 345. 1H NMR (400 MHz, d6-DMSO) δ: 7.27-7.31 (m, 2H), 6.95-6.99 (m, 2H), 3.80 (s, 3H), 3.76-3.78 (m, 4H) and 3.56-3.58 (m, 4H).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:24]=[O:25].O>O1CCCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][C:9]1[C:10]([F:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:24]=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl-(2,4-difluoro-phenoxy)-dimethyl-silane (36, 5.90 g, 24.1 mmol) in tetrahydrofuran (100 mL), under an atmosphere of nitrogen, cooled in a −78° C. acetone/dry ice bath, was added n-butyllithium (2.50 M in hexane, 10.6 mL, 26.5 mmol) slowly. The reaction was allowed to stir for 1 hour, then N,N-dimethylformamide (2.24 mL, 29.0 mmol) was added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated The compound was isolated by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give a colorless oil (37, 5.0 g, 76.0%). MS(ESI) [M+H+]+=272.2.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([OH:34])=O)(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:39][CH2:40][CH:41]=[CH2:42]>>[CH2:40]([NH:39][C:32](=[O:34])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:29])=[O:28])[CH:41]=[CH2:42]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: C=CCN
Product: C=CCNC(=O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 66.7 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 38 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 570 [M+H]+.