Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:9])([O:6][CH2:7][CH3:8])[O:2][CH:3](Cl)[CH3:4].[C:10]([NH:13][C:14]1[C:15]([I:29])=[C:16]([C:26]([O-:28])=[O:27])[C:17]([I:25])=[C:18]([NH:21][C:22](=[O:24])[CH3:23])[C:19]=1[I:20])(=[O:12])[CH3:11].[K+].[I-].[Na+]>CN(C=O)C>[C:22]([NH:21][C:18]1[C:17]([I:25])=[C:16]([C:26]([O:28][CH:3]([O:2][C:1]([O:6][CH2:7][CH3:8])=[O:9])[CH3:4])=[O:27])[C:15]([I:29])=[C:14]([NH:13][C:10](=[O:12])[CH3:11])[C:19]=1[I:20])(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Reactant: CCOC(=O)OC(C)Cl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 40 °C
Reaction time: 65 h

Procedure:
1-Chloroethyl ethyl carbonate (1.68 g, 11.0 mmol) was added at room temperature to a solution of potassium 3,5-di(acetylamino)-2,4,6-triiodobenzenecarboxylate (6.52 g, 10.0 mmol) and sodium iodide (0.30 g, 2.0 mmol) in dry DMF (100 ml). After stirring at 60° C. for 2 hours and at 40° C. for 65 hours the solvent was removed at reduced pressure. The residue was suspended in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 2.45 g Purity by HPLC: 98.5% 1H-NMR(DMSO-d6): delta=1.24(CH2CH3); 1.63(CHCH3); 2.02(COCH3); 4.20(CH2CH3); 6.93(CHCH3); 10.03 ppm (NH). FAB/MS: 731 (M+H+)
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)[C@H:3]([C:5](OCC)=[O:6])[CH3:4].CN(C1C=CC(C(O)(C(F)(F)F)C(F)(F)F)=CC=1)CC(OCC)=O>>[CH3:1][N:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:17]([F:20])([F:18])[F:19])[C:21]([F:23])([F:24])[F:22])=[CH:12][CH:11]=1)[CH:3]([CH3:4])[CH2:5][OH:6]
Reactant: CCOC(=O)[C@H](C)N(C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCOC(=O)CN(C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Product: CC(CO)N(C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 84 %

Procedure:
Prepared in the manner of Example 23 except ethyl N-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}alaninate was substituted for ethyl N-methyl-N-{4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-glycinate. Purification by flash chromatography (4:1 hexanes/EtOAc) afforded the title compound as a pink oil (84%). 1H NMR (CDCl3) δ 7.48 (d, 2H), 6.86 (br d, 2H), 4.04 (m, 1H), 3.56 (m, 2H), 2.72 (s, 3H), 1.03 (d, 3H). Anal. Calc. C13H15NO2F6: C, 47.14; H, 4.56; N, 4.23. Found: C, 46.89; H, 4.61; N, 3.93. HRMS (MH+) Calc.: 332.1085. Found: 332.1073.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].I[C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:31]2[CH:40]=[CH:39][C:34]3[O:35][C:36]([CH3:38])=[CH:37][C:33]=3[CH:32]=2)=[CH:15]/[CH2:16][O:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:20]([CH3:30])[CH:19]=2)=[CH:10][CH:9]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[CH3:30][C:20]1[CH:19]=[C:18]([O:17][CH2:16]/[CH:15]=[C:14](/[C:31]2[CH:40]=[CH:39][C:34]3[O:35][C:36]([CH3:38])=[CH:37][C:33]=3[CH:32]=2)\[C:11]2[CH:12]=[CH:13][C:8]([C:6]#[C:5][CH2:4][N:2]([CH3:3])[CH3:1])=[CH:9][CH:10]=2)[CH:29]=[CH:28][C:21]=1[O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Under nitrogen atmosphere, 3-(N,N-dimethylamino)propyne (250 mg, 3.00 mmol) was added to a degassed solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]-furan-5-yl)allyloxy]-2-methylphenoxy]acetate (370 mg, 0.63 mmol; prepared as described in example 25) in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL) The solution was cooled to 0° C., tetrakis(triphenylphosphine)palladium (71 mg, 0.06 mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[2-methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-[3-(dimethylamino)-propynyl]phenyl]-allyloxy]phenoxy]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].CC1C2C=C3[C:33]4([C:41]5[C:36](=CC=[CH:39][CH:40]=5)[NH:35][C:34]4=O)COC3=CC=2ON=1.Br.BrCC1C=NC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:33][C:41]1[CH:36]=[N:35][CH:34]=[CH:39][CH:40]=1)[C:10]3=[O:18]
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: Br
Agent: BrCc1cccnc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc2c(c1)OCC21C(=O)N(Cc2cccnc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 3-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6-methoxy-1′-(pyridin-3-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (63%) as a colorless solid: mp 164-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.56 (s, 1H), 8.55 (d, J=3.9 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.33-7.13 (m, 3H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 6.61-6.51 (m, 2H), 6.37 (dd, J=8.4, 2.1 Hz, 1H), 5.08 (d, J=15.6 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.86 (d, J=15.6 Hz, 1H), 4.72 (d, J=9.0 Hz, 1H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.7, 162.1, 161.6, 149.3, 148.8, 141.5, 135.2, 132.4, 131.5, 128.8, 124.0, 123.8, 123.7, 123.4, 120.5, 108.8, 107.5, 96.6, 80.4, 57.5, 55.5, 41.6; MS (ES+) m/z 359.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14])=O.S(Cl)([Cl:24])=O>>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([Cl:21])[C:3]=1[C:4]([Cl:24])=[N:6][C:7]1[C:12]([F:13])=[CH:11][N:10]=[CH:9][C:8]=1[F:14]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(Cl)c(C(=O)Nc2c(F)cncc2F)c(Cl)c1
Product: N#Cc1cc(Cl)c(C(Cl)=Nc2c(F)cncc2F)c(Cl)c1
Temperature: 85 °C
Reaction time: 56 h

Procedure:
A stirred suspension of 2,6-dichloro-4-cyano-N-(3,5-difluoropyridin-4-yl)-benzamide (1.35 g, 4.12 mmol) in thionyl chloride (14 mL) was heated at 85° C. for 5 hours and then at 80° C. for 56 hours under a nitrogen atmosphere. After cooling to room temperature, the volatiles were removed under reduced pressure to afford the title compound as an orange solid (1.5 g, quantitative). LCMS (Method D): RT=4.01 min, m/z: 346 [M+H+].
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:10]([NH:12][C@@H:13]([CH2:24][CH2:25][CH2:26][CH3:27])[C:14](=[O:23])[CH2:15][S:16][CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)=[O:11])=O)(C)(C)C.[ClH:32].CCCCCC>C(OCC)(=O)C>[ClH:32].[NH2:8][C@@H:9]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:10]([NH:12][C@@H:13]([CH2:24][CH2:25][CH2:26][CH3:27])[C:14](=[O:23])[CH2:15][S:16][CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)=[O:11]
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)CSCc1ccco1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCC[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)CSCc1ccco1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 59 %

Procedure:
(s)-3-((s)-2-tert-Butoxycarbonylamino-4-methylvalerylamino)-1-furfurylthio-2-heptanone (8.47 g) obtained in Example 1 was dissolved in ethyl acetate (25 ml), and 4N hydrogen chloride-containing ethyl acetate solution (25 ml) was added to the solution. After the mixture was stirred at room temperature for 50 minutes, hexane (50 ml) was added to the mixture. Then, the resultant crystals were filtered, and washed with hexane to give the titled product (4.31 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]>>[N:1]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CCCCCCCl
Reactant: C1COCCN1
Product: N#CCCCCCN1CCOCC1

Procedure:
Using morpholine and 6-chloro-hexanenitrile as substrates. MS (ion spray) m/z 183.
Reaction SMILES: C(N1CCN(CCC[O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][N:23](C4CCC5N(C(C(F)(F)F)=NN=5)N=4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)CC1)(=O)C>[Pd].CO>[NH:23]1[CH2:24][CH2:25][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1
Reactant: CC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc(C2CCNCC2)cc1
Yield: 94.3 %

Procedure:
Benzyl 4-(4-hydroxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (obtained as described in Example 4.1, preparation of starting materials) (37.7 g, 121.86 mmol) and 5% palladium on carbon (7.6 g, 3.57 mmol) in methanol (380 mL) were stirred under an atmosphere of hydrogen at 5 bar and 25° C. for 2 hours. The catalyst was removed by filtration, washed with MeOH and the solvents evaporated. The crude material was triturated with diethyl ether, then the desired product collected by filtration and dried under vacuum to afford 4-(piperidin-4-yl)phenol (20.36 g, 94%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][C:8]2=[N+:9]([O-:12])[O:10][N:11]=[C:7]2[CH:6]=1.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[N+:23]([C:6]1[C:7]2[C:8](=[N+:9]([O-:12])[O:10][N:11]=2)[CH:13]=[CH:14][C:5]=1[O:4][C:3]1[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:2]=1[Cl:1])([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1onc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc21
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Oc2ccc(C(F)(F)F)cc2Cl)ccc2c1no[n+]2[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)benzo-2,1,3-oxadiazole N-oxide (1.5 g, 4.5 mmol) is dissolved in 25 ml of ice-cold conc. sulfuric acid. To this is added dropwise 0.32 g (5.0 mmol) of nitric acid dissolved in 5 ml of conc. sulfuric acid. The mixture is allowed to stand for 30 minutes at 0°, and is then poured onto 100 g of ice. The solid is collected to give 4-nitro-5-(2-chloro-4-trifluoromethylphenoxy)benzo-2,1,3-oxadiazole N-oxide.
Reaction SMILES: [CH3:1][N:2]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[NH2:3].N1C=CC=CC=1.C(#N)C.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([NH:3][N:2]([CH3:1])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)N(C)N)cc1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N(C)NC(=O)c2c(F)cccc2Cl)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
Into a 100 mL three necked round bottom flask equipped with a magnetic stirrer, thermometer, and condenser, under an atmosphere of nitrogen, was added 2-methyl-2-[(4-methylphenyl)sulfonyl] hydrazine (9.5 g, 47.4 mmol), pyridine (3.75 g, 3.83 mL, 47.4 mmol), 4-dimethylaminopyridine (0.30 g, 2.4 mmol) and acetonitrile (50 mL). The resulting mixture was cooled to 10° C. and 2-fluoro-6-chlorobenzoyl chloride (8.99 g, 45.2 mmol) dropwise at a rate such that the temperature did not rise above 10° C. The cooling bath was removed and the mixture was allowed to stir at RT overnight. The solvent was removed from the reaction mixture in vacuo to give an off white solid and the solid was diluted with methylene chloride and extracted with 1N HCl (20 mL), saturated sodium chloride solution (20 mL), dried (Na2SO4), and the solvent removed in vacuo to give an off-white solid. This material was recrystallized from ethyl acetate to give 5.6 g (34.7% yield) of 1-(2-fluoro-6-chlorobenzoyl)-2-methyl-2-[(4-methylphenyl)sulfonyl] hydrazine as a crystalline solid: mp 135-136° C.; 1H NMR (CDCl3) δ 7.6-7.8 (m, 3H), 7.0-7.4 (m, 5H), 3.4 and 3.0 (singlets combined for 3H), 2.4 and 2.45 (singlets combined for 3H); 13C (CDCl3) 160.2, 144.7, 133.6, 132.7, 132.6, 132.1, 131.9, 130.2, 129.6, 129.0, 128.7, 125.7, 114.6, 114.3, 37.7, 21.7. Anal. Calcd. For C15H14ClFN2O3S: C, 50.49; H, 3.95; N, 7.85. Found: C, 50.55; H, 3.89: N. 7.81.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:13][C:12]([C:14]#[C:15][C@H:16]([N:18]([OH:22])[C:19]([NH2:21])=[O:20])[CH3:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>CC(C)=O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[S:13][C:12](/[CH:14]=[CH:15]\[C@H:16]([N:18]([OH:22])[C:19]([NH2:21])=[O:20])[CH3:17])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](C#Cc1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CC(C)=O
Product: C[C@H](/C=C\c1ccc(Cc2ccc(F)cc2)s1)N(O)C(N)=O
Reaction time: 24 h
Yield: 28.8 %

Procedure:
A solution of (R)-N-{3-[5-(4-fluorophenylmethyl)thien-2-yl]-1-methyl-2-propynyl}-N-hydroxyurea (0.50 g, 1.57 mmol), prepared as in step 4, quinoline (0.25 mL, 2.11 mmol), and 5% palladium on calcium chloride poisoned with lead (0.025 g) in acetone (15 mL) was allowed to stir under hydrogen (atmospheric pressure) for 24 hours. The solution was filtered through celite and solvents removed in vacuo. The resulting oil was taken up in ethyl acetate (50mL) and washed with aqueous 1M H3PO4 (3×25 mL) and aqueous NaHCO3 (3×25 mL). The solution was dried (MgSO4) after which the solvent was evaporated to yield a yellow oil. The residue was purified by chromatography on silica gel (50% ethyl acetate/hexane/1% acetic acid). The resulting solid was crystallized from hot ethyl acetate/hexane to yield 0.145g (29%) of Z-N-[3-(5-(4-Fluorophenylmethyl)-thien-2-yl)-1-[R]-methyl-2-propenyl]-N-hydroxyurea. m.p. 123°-4° C., MS. (DCI/NH3) m/e 321 (M+H)+, 338 (M+NH4)+. 1H NMR (DMSO-d6, 300 MHz) δ1.16 (d,J=6.3 Hz, 3H), 4.1 (s, 2H), 5.25 (m, 1H), 5.67 (rid, J=9.0, 11.7 Hz, 1H), 6.35 (s, 2H), 6.43 (d, J=11.7 Hz, 1H), 6.83 (d, J=3.6 Hz, 1H), 6.94 (d, J=3.6 Hz, 1H), 7.13 (m, 2H), 7.32 (m, 2H), 9.18 (s, 1H). Anal calcd for C17H17FN2O2S: C, 59.98; H, 5.35; N, 8.74. Found C, 59.79; H, 5.25; N, 8.71.
Reaction SMILES: Cl[S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3].[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[Cl:24]>>[Cl:24][C:19]1[C:20]([CH3:23])=[N:21][O:22][C:18]=1[NH:17][S:2]([C:5]1[S:6][C:7]([C:10]2[S:11][C:12]([CH2:15][CH3:16])=[CH:13][CH:14]=2)=[CH:8][CH:9]=1)(=[O:4])=[O:3]
Reactant: CCc1ccc(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: Cc1noc(N)c1Cl
Product: CCc1ccc(-c2ccc(S(=O)(=O)Nc3onc(C)c3Cl)s2)s1
Yield: 71.1 %

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamide was prepared in the same manner as in Example 2. Reaction of 2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene (Example 141C, 200 mg, 0.68 mmol) with 5-amino-4-chloro-3-methylisoxazole (91 mg, 0.68 mmol) yielded 188 mg of the final product (71% yield). A small portion of the product was further purified by preparative HPLC to give the pure sulfonamide as a tan colored solid.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].C[Si](C)(C)[NH:15][Si](C)(C)C.CO.O>CN(C=O)C>[I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([NH:15][C:8](=[O:7])[C:3]=12)=[O:6]
Reactant: O=C1OC(=O)c2c(I)cccc21
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=C1NC(=O)c2c(I)cccc21
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 67.7 %

Procedure:
3-Iodophthalic anhydride (598 mg, 2.18 mmol) was dissolved in DMF (14 mL), and the solution was added with an aqueous solution (10 mL) of hexamethyldisilazane (HMDS) (4.6 mL, 22 mmol) and methanol (0.44 mL, 11 mmol), followed by stirring at room temperature for 18.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure a and the residue was purified by slurry using chloroform to obtain 3-iodophtalimide (403 mg, yield 68%).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1C=C(O)CC(c2cc(Cl)cc(Cl)c2)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 5.1 g of 3,5-dichlorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 135°-137° C.). 1H NMR (CDCl3) δ2.78 (dd, 1H), 2.97 (dd, 1H), 3.63 (dd, 2H), 5.64 (dd, 1H), 7.31-7.40 (m, 3H).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]([OH:8])=[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[CH:2]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>O1CCCC1>[CH2:27]=[CH:26][C:25]([O:8][C:4]1[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])=[O:28]
Reactant: C=CC(=O)Cl
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Irgasan® DP300 5-chloro-2-(2,4-dichlorophenol) (triclosan), 23.5 g (0.081 mol) was dissolved in 300 ml of dry tetrahydrofuran in a 1-I jacketed kettle with agitator, addition funnel and reflux condenser. Then 10.6 ml of triethylamine was added to the solution with agitation. To the resulting solution was added dropwise 6.68 (0.0738 mol) g of acryloyl chloride. The reaction temperature was maintained at 20° C. with a circulating cooling bath. After the addition of acryloyl chloride was completed, the agitation and temperature conditions were maintained for 5 hours. Then the reaction product was kept overnight at room temperature, filtered to remove solid triethylamine hydrochloride and the filtrate rotovapped at room temperature under 100-110 mm Hg to concentrate the product. The remaining solution was dissolved in 100 ml heptane and washed with 5% Na2CO3 solution in DI water until basic; then with DI water until neutral. The heptane solution of the product was dried with MgSO4 in a refrigerator overnight, and filtered. The filtrate contained 25.3% triclosan acrylate as determined by bromination. FTIR spectrum confirmed the presence of the unsaturated ester of a phenol (1753 cm−1).
Reaction SMILES: [OH-].[K+].[CH2:3]([S:10][CH2:11][CH2:12][CH:13]([N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:14]([O:16]C)=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1.O>[CH2:3]([S:10][CH2:11][CH2:12][CH:13]([N:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[C:14]([OH:16])=[O:15])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(CCSCc1ccccc1)N(CC(C)C)S(=O)(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N(CC(C)C)C(CCSCc2ccccc2)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1.77 mmol of potassium hydroxide are added to 0.95 mmol of the compound obtained in Step C in a 3/1 mixture of dioxane/water. After stirring for 3 hours at 50° C., the dioxane is evaporated off, the residual aqueous phase is diluted with water, acidified to pH 2 by the addition of a 5% hydrochloric acid solution, and then extracted with ethyl acetate. The combined organic phases are washed, dried and filtered and then evaporated under reduced pressure. Chromatography on silica gel (dichloromethane/methanol: 93/7) allows the expected product to be isolated in the form of syrup.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.C(OP([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(OCC)=O)C.[H-].[Na+].O>C1COCC1.C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](/[CH:11]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:2]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cnc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44 %

Procedure:
3-Quinolinecarbaldehyde (5.03 g) was added to a mixture of ethyl diethylphosphonoacetate (9.31 g) and NaH (60% oil dispersion,0.791 g) in THF under ice cooling. The mixture was stirred at room temperature for 14 hours. To the mixture were added water and ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The residue was chromatographed on silica gel (hexane-ethyl acetate=10:1) followed by crystallization from CH2Cl2-cyclohexane to give the titled compound (3.20 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18]CC)=[O:17])[C:6]2=[O:21].C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.Cl>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(O)C>[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:14][CH2:15]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6]3=[O:21])=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1c(-c2ccc(CN)cc2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
350 mg of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was dissolved in 3.5 ml of toluene. 1.8 ml of ethanol, 1.8 ml of 2 M aqueous sodium carbonate solution, 235 mg of 4-aminomethylphenylboronic acid hydrochloride and 40 mg of bis(triphenylphosphine)palladium (II) chloride were added to the obtained solution, and they were heated under reflux in argon atmosphere for 6 hours. The reaction mixture was acidified with 1 N hydrochloric acid. After washing the aqueous layer with ethyl acetate, it was taken and then concentrated under reduced pressure. 2 ml of methanol and 1 ml of 1 N sodium hydroxide were added to the obtained residue, and they were stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 10 ml of water and then neutralized with 1 N hydrochloric acid. The crystals thus formed were taken by the filtration to obtain 241 mg of 8-(4-aminomethylphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid.