Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:8]2=[O:31])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:44]([NH:46][NH2:47])=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:16][C:17]1[O:18][CH:44]=[N:46][N:47]=1)[C:8]2=[O:31])([CH3:3])([CH3:2])[CH3:4]
Reactant: NNC=O
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)ccc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc(C(Cc2nnco2)N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)ccc1OC

Procedure:
5-(t-Butyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindoline-1,3-dione was prepared as described for Example 8 from 3-[5-(tert-butyl)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.7 mmol), carbonyldiimidazole (0.81 g, 5.0 mmol), formic hydrazide (0.35 g, 5.8 mmol), and phosphorus oxychloride (1.0 mL, 10.7 mmol) in acetonitrile (20 mL). The product was isolated as a white solid (800 mg, 38% yield): mp, 136.0-138.5° C.; 1H NMR (CDCl3) δ 1.35 (s, 9H, CH3), 1.44 (t, J=6.9 Hz, 3H, CH3), 3.79 (dd, J=5.9, 16.1 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.11 (q, J=7.1 Hz, 2H, CH2), 4.38 (dd, J=10.3, 15.8 Hz, 1H, CHH), 5.80 (dd, J=5.9, 10.4 Hz, 1H, NCH), 6.82 (d, J=8.2 Hz, 1H, Ar), 7.11-7.17(m, 2H, Ar), 7.70 (br s, 2H, Ar), 7.82 (br s, 1H, Ar), 8.29 (s, 1H, Ar); 13C NMR (CDC3) δ 14.71, 27.73, 31.08, 35.72, 51.78, 55.92, 64.44, 111.36, 112.58, 120.31, 120.63, 123.26, 128.94, 130.33, 131.14, 131.84, 148.41, 149.42, 153.02, 158.82, 164.07, 168.25, 168.39; Anal Calcd for C25H27N3O5+0.11 H2O: C, 66.51; H, 6.08; N, 9.31; H2O, 0.43. Found: C, 66.42; H, 5.83; N, 9,18; H2O, 0.43.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16](C1C=CC(OC)=C2C=1C=CN2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:34])[CH:15]=[C:16]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]
Reactant: Brc1ccc2cn[nH]c2c1
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2cn[nH]c2c1

Procedure:
3-(1H-Indazol-6-yl)-3-phenyl-acrylic acid ethyl ester CCXXVII was prepared from 6-bromo-1H-indazole using the procedure described for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [OH:1]O.Cl.[S:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:11]=2)[CH2:6][CH2:5]1.[OH-].[Na+]>S(=O)(=O)(O)O>[O:1]=[S:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[C:14](=[C:15]([CH3:20])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:11]=2)[CH2:6][CH2:5]1
Reactant: Cc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Reactant: OO
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cccc2c(N3CCS(=O)CC3)nc(N3CCNCC3)cc12
Reaction time: 2 h

Procedure:
8.4 gm (0.086 mol) of 34.8% hydrogen peroxide were added dropwise to a suspension of 28.5 gm (0.078 mol) of 1-thiomorpholino-3-piperazino-5-methyl-isoquinoline hydrochloride in 160 ml of 2 N sulfuric acid at 0°C, and the mixture was stirred for 2 hours at 15°-20°C. The mixture was then made alkaline with concentrated sodium hydroxide and exhaustively extracted with a mixture of chloroform and ethanol (3:1). The organic phase was isolated, washed with water and sodium chloride solution, dried and evaporated, and the residue was recrystallized from 150 ml of isopropanol. Yield: 11.6 gm (43% of theory); m.p. 201°-203°C.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1
Reactant: COC=Cc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCc1cccc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 65 %

Procedure:
A stirred solution of (methoxymethyl)triphenylphosphonium chloride (2.79 g, 8.13 mmol) in THF (50 mL) at 0° C. was treated dropwise with n-BuLi (1.6-M in hexanes, 5.08 mL, 8.13 mmol), stirred for 1 h, treated with a solution of 6-(triphenylmethoxy)methylpyridine-2-carboxaldehyde (1.54 g, 4.06 mmol) in THF (15 mL) and allowed to warm to room temperature overnight. The reaction was treated with saturated NH4Cl solution (5 mL), diluted with water (50 mL), extracted with EtOAc (2×50 mL) and the combined organic phase diluted with iso-hexane (50 mL), dried (MgSO4), filtered through silica and concentrated in vacuo to give 2-(2-methoxyethenyl)-6-(triphenylmethoxy)methylpyridine (1.58 g) as a yellow oil. A solution of this crude alkene and 10% Pd/C (216 mg, 0.203 mmol) in EtOAc (50 mL) was stirred under a hydrogen atmosphere for 16 h, filtered through Celite and concentrated in vacuo to give the title compound (1.08 g, 65%) as a yellow oil; NMR δH (400 MHz, CDCl3) 7.67–7.64 (1H, m), 7.52–7.49 (6H, m), 7.32–7.21 (10H, m), 7.09–7.07 (1H, m), 4.34 (2H, s), 3.69 (2H, t, J 6.5 Hz), 3.32 (3H, s) and 2.98 (2H, t, J 6.5 Hz); M/Z 410 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]1[C:16]([Cl:21])=[CH:17][C:18]([Cl:20])=[CH:19][N:10]1[C:9]2=[O:22])[CH3:5].S(=O)(=O)(O)O.[OH-].[Na+]>O>[Cl:21][C:16]1[C:11]2=[N:12][C:13]3[C:8]([C:9](=[O:22])[N:10]2[CH:19]=[C:18]([Cl:20])[CH:17]=1)=[CH:7][C:6]([CH:4]([CH3:5])[C:3]([OH:23])=[O:2])=[CH:15][CH:14]=3
Reactant: COC(=O)C(C)c1ccc2nc3c(Cl)cc(Cl)cn3c(=O)c2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc2nc3c(Cl)cc(Cl)cn3c(=O)c2c1
Temperature: 0 °C

Procedure:
A mixture of 1.4 g. of 2-(6,8-dichloro-11-oxo-11H-pyrido[2,1-b]quinazolin-2-yl)propionic acid methyl ester, 10 ml. of water, and 10 ml. of concentrated sulfuric acid is stirred for 4 hours at 120° (bath temperature). After cooling, the mixture is diluted with 10 ml. of ice water and adjusted with sodium hydroxide solution to a pH of 4-5. After extraction with ethyl acetate, drying, and concentration of the organic phase, 1.1 g. of 2-(6,8-dichloro-11-oxo-11H-pyrido[2,1-b]quinazolin-2-yl)propionic acid is obtained, m.p. 241° (dimethylformamide-water).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[CH:24][CH:23]=1.Cl>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:24][CH:23]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1ccc(Cl)cc1
Yield: 51 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 4-chloro-phenylhydrazine×HCl according to the method described for Example 1 in 51% yield.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][N:10]([CH3:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:12])=[O:8])([O:3]C)=O.C(OCC)C.[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][N:10]([CH3:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:12])=[O:8])=[O:3]
Reactant: COC(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1ccccc1
Reactant: CNC
Solvent: CCOCC
Product: CN(C)C(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1ccccc1

Procedure:
1-(2-Carbomethoxybenzoyl)-2-methyl-4-phenyl-3-thiosemicarbazide (5 g, 0.148 mole) was suspended in aqueous dimethylamine. The pH of the suspension was adjusted to about 3. A tacky precipitate was formed which became solid after addition of diethyl ether. This solid--title product--had a melting point of 140°-143°, yield 3.7 g.
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]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:28]=[N:29][CH:30]=1>>[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]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:24][C:25]2[CH:26]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:28]=[N:29][CH:30]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(F)c2)CC1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cncc(CN(c3ccc(F)c(F)c3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(3,4-difluorophenyl)amino]piperidine (625 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH:8](NCCNCCCC1C=CC=C(NCC2CC2)N=1)[C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.O1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(CC(=O)OC(C)(C)C)NCCNCCCc2cccc(NCC3CC3)n2)cn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Yield: 147 %

Procedure:
To a solution of diamine 2-7 (12.5 g, 25.8 mmol) and DIPEA (13.5 mL, 77.5 mmol) in CH2Cl2 (750 mL) at 0° C. was added p-NO2PhOCOCl (5.47 g, 27.1 mmol) in 4 portions. The resulting mixture was warmed to room temperature and 1,4-dioxane (750 mL) was added and refluxed for 6 h. After cooling, the solution was washed with 10% K2CO3 (3×400 mL) then brine. The organic layer was dried (Na2SO4), filtered, concentrated in vacuo, and purified by flash chromatography (silica, 50% EtOAc/hexanes) affording 9.0 g of cyclic urea 2-8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[CH2:10][C:11]1[N:12]=[C:13]([NH:16][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)[S:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[S:14][CH:15]=2)[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 90 °C
Yield: 79.4 %

Procedure:
A stirred suspension of 5-chloropyrimidin-2-one (688 mg), 4-chloromethyl-2-triphenylmethylaminothiazole (3.000 g), anhydrous sodium carbonate (1.086 g) and benzyltrimethylammonium chloride (20 mg) in dry N,N-dimethylformamide (25 ml) was heated at 90° C. After 1.5 h the reaction mixture was evaporated to dryness. The residue was suspended in ethyl acetate (250 ml) and washed with water (2×60 ml) and brine (60 ml), then dried and evaporated to a dark brown foam. The foam was subjected to column chromatography on silica developing and eluting with chloroform-ethanol, 24:1. This gave a brown foam which was triturated with diethyl ether to give a brown solid (2.03 g). A portion of the solid (360 mg) was recrystallised from ethyl acetate to give buff crystals of the title pyrimidinone (129 mg), m.p. 215°-216° C., λmax (EtOH) 268 nm (ε 8,630), 335 nm (ε 3,440).
Reaction SMILES: C([S:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10](=[N:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])[CH3:11])[CH2:6]1)(=O)C.C[O-].[Na+].Cl>CO>[SH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10](=[N:12][C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[O:14])[CH3:11])[CH2:6]1
Reactant: CC(=O)SC1CCN(C(C)=NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCC(S)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.3 %

Procedure:
A solution of 30 g of 3-acetylthio-1-(N-p-nitrobenzyloxycarbonylacetimidoyl)pyrrolidine in 1000 ml of methanol was cooled to -10° C. A solution of sodium methoxide in methanol (prepared from 1.8 g of sodium) was then added dropwise to the cooled solution, after which the mixture was stirred for 30 minutes, whilst gradually raising the temperature to 0° C. At the end of this time, 65.2 ml of 10% w/v hydrochloric acid were added to the reaction mixture, which was then concentrated to half of its original volume by evaporation in vacuo. A saturated aqueous solution of sodium chloride was added to the concentrate and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried, after which the solvent was distilled off under reduced pressure. The residue was purified by chromatography through a column of silica gel, eluted with a 2:1 by volume mixture of benzene and ethyl acetate, to give 20 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH+:8]([O-])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C[Si]([C:21]#[N:22])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:21]([C:6]1[N:1]=[C:2]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=[CH:4][CH:5]=1)#[N:22]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)[NH+]([O-])Cc1ccccn1
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
tert-Butyl 2-pyridylmethylcarbamate N-oxide (3.0 g, 13.3 mmol) was dissolved in nitroethane (50 ml), and trimethylsilyl cyanide (2.8 g, 28.6 mmol) and N,N-dimethylcarbamoyl chloride (1.7 g, 16.2 mmol) were added thereto. The mixture was stirred at room temperature for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (2:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (1.8 g, 58%) as white crystals.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9](=[O:24])/[CH:10]=[CH:11]/[C:12]2[S:22][C:21]3[N:23]4[C:14](=[CH:15][N:16]=[C:17]4[CH:18]=[CH:19][CH:20]=3)[CH:13]=2)[CH2:5][CH2:4]1.Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:29]1([CH2:28][CH2:27][CH2:26][N:3]2[CH2:8][CH2:7][CH:6]([C:9](=[O:24])/[CH:10]=[CH:11]/[C:12]3[S:22][C:21]4[N:23]5[C:14](=[CH:15][N:16]=[C:17]5[CH:18]=[CH:19][CH:20]=4)[CH:13]=3)[CH2:5][CH2:4]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)C1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of 0.675 g (1.756 mM) of (E)-1-(piperidin-4-yl)-3-(5-thia-1,8b-diazaacenaphthylen-4-yl)propen-1-one dihydrochloride, 0.52 g (2.63 mM) of 1-bromo-3-phenylpropane, and 0.86 ml (6.15 mM) of triethylamine in 30 ml of acetonitrile, and the mixture was refluxed for 1 day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate˜ethyl acetate/methanol: 4/1) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][Si:37]([CH3:44])([CH3:43])[CH2:38][CH2:39][O:40][CH2:41]Cl>>[Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[N:29]([CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:44])([CH3:43])[CH3:36])[C:28](=[O:33])[CH2:27]4)=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: C[Si](C)(C)CCOCCl
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (592 mg, 1 mmol) was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (354 μL, 2 mmol) to give 5-{4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH2:11]O)([CH3:10])[C:6]1=[O:13])=[O:4].S(Cl)([Cl:24])=O.CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9][CH2:8][C:7]([CH2:11][Cl:24])([CH3:10])[C:6]1=[O:13])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CCl)C1=O
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To 8.79 g of Compound 2-1 obtained in Production Example 1, 3.04 ml of thionyl chloride and 0.15 ml of DMF were added. The resulting mixture was stirred in an oil bath of 90° C. for 2.5 hours. After the reaction, water was added to the reaction solution thus obtained, and extraction with toluene was carried out. The organic layer thus extracted was washed with a saturated aqueous solution of sodium carbonate and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled away, and the residue was then purified by silica gel column chromatography to obtain 6.57 g of Compound 3-1-3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1.Cl[CH2:19][CH:20]=O>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:16][CH:19]=[CH:20][N:15]=2)[CH2:10][CH2:9]1
Reactant: NC(=S)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: O=CCCl
Solvent: CCO
Product: Clc1cncc(Cl)c1N1CCC(c2nccs2)CC1
Yield: 161.1 %

Procedure:
To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbothioamide 24 (23 mg, 0.079 mmol) in ethanol (2 mL) was added chloroacetaldehyde (50% wt in H2O) (0.26 mL, 0.16 mmol) and the mixture was heated at reflux for 17 h. The mixture was concentrated and chloroform (10 mL) was added to the residue. The solution was washed with water (10 mL) and extracted with chloroform (10 mL). The combined organic extracts were washed with brine (10 mL), dried (MgSO4) and concentrated under reduced pressure to furnish a brown oil (40 mg). The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1, then hexane, EtOAc, 1:1) to furnish the title compound as a pale brown solid (5 mg, 20%), LC-MS (ESI) Rt 2.79 min, m/z 314 (100%, M+).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([NH2:15])[CH:6]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.[Cl-].[NH4+]>C1COCC1.O.C(OCC)(=O)C>[NH2:15][C:7]1[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1
Reactant: CCOC(=O)c1cc(N)cc(S(C)(=O)=O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(N)cc(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
3-Amino-5-(methylsulfonyl)-benzoic acid ethyl ester (100 mg; 0.4 mmol) was dissolved in THF (4 ml), treated with lithium aluminiumhydride (33 mg; 0.9 mmol) and stirred for 18 hours at room temperature. The reaction mixture was treated in sequence with ethyl acetate (4 ml), water (0.5 ml), hydrochloric acid (5% solution in water; 0.5 ml) and a saturated aqueous ammoniumchloride solution (1.5 ml). The aqueous phase was extracted with dichloromethane and the organic phase was filtrated on a silica pad then dried and concentrated. 55 mg (0.27 mmol; 68% yield) of an orange oil were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[N:32]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[C:31]([NH:33][C:34](=[O:38])[CH:35]([CH3:36])[CH3:37])[N:32]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)n1

Procedure:
Example 68 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, 1H, J=8.0 Hz), 7.79 (br s, 1H), 7.66 (t, 1H, J=8.0 Hz), 7.45–7.41 (m, 2H), 7.04–7.00 (m, 2H), 6.89 (d, 1H, J=7.6 Hz), 6.85 (br s, 1H), 3.30 (dd, 2H, J=6.0, 12.0 Hz), 2.97 (d, 2H, J=11.6 Hz), 2.57–2.50 (m, 2H), 2.37–2.32 (m, 4H), 2.01–1.77 (m, 8H), 1.65–1.60 (m, 8H), 1.27 (d, 6H, J=7.2 Hz); ESMS m/e: 509.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH:7]=[CH2:8])(=O)[CH:2]=[CH2:3].[CH2:10](O)CCC>>[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:10])(=[O:9])[CH:7]=[CH2:8]
Reactant: CCCCO
Reactant: C=CC(=O)OC(=O)C=C
Product: C=CC(=O)OCCCC
Reaction time: 3.5 h
Yield: 91.2 %

Procedure:
According to another embodiment of the invention, the olefin acid anhydrides are reacted with alcohols to give high yields of the acrylate esters at room temperature. In particular, acrylic anhydride has been reacted with a series of alcohols ranging from C-1 to C-18 to give high yields of the acrylate esters at room temperature. The synthesis of acrylate esters by the reaction of alcohols with acrylic anhydride were found to proceed essentially to completion at room temperature to yield only the desired acrylate esters. The following mechanism is proposed for this reaction: ##STR3## No significant competing reactions were observed, such as the Michael addition reactions that often accompany the production of acrylate esters under reflux conditions. The following are representative of this embodiment: (1) the reaction of n-butyl alcohol with acrylic anhydride was completed in 3.5 hours and yielded 91.2% of n-butyl acrylate; (2) the reaction of n-octyl alcohol with acrylic anhydride was completed in 4 hours to obtain an 81.3% yield of n-octyl acrylate; and (3) the reaction of cis-12,13-epoxy-cis-9-octadecenol with acrylic anhydride was completed in 55 hours to give an 88.4% yield of cis-12, 13-epoxy-cis-9-octadecenyl acrylate.