Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[I-].[Na+]>CN(C)C(=O)C.CCOC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Temperature: 80 °C

Procedure:
A mixture of 1-(2-bromo-ethyl)-4-nitro-benzene (0.740 g, 3.22 mmol), morpholine (0.840 mL, 9.65 mmol), and sodium iodide (0.480 g, 3.22 mmol) in N,N-dimethylacetamide (3 mL) was heated at 80° C. for 10 min. The mixture was diluted with 30 mL EtOAc and washed with H2O (2×30 mL) and brine (30 mL) and dried over Na2SO4 to give the title compound as a yellow oil of sufficient purity to use in the next step. Mass spectrum (ESI, m/z): Calcd. for C12H16N2O3, 237.1 (M+H). found 237.2.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C([O-])([O-])=O.[Na+].[Na+].[Br:10][CH2:11][CH2:12][C:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Br-:10].[CH3:1][N+:2]([CH3:3])=[C:14]1[C:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11][O:15]1
Reactant: CNC
Reactant: O=C(Cl)C(CCBr)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 12 h
Yield: 53 %

Procedure:
To a solution of dimethylamine (2M in THF, 50 mL) and saturated aqueous Na2CO3 (100 mL) was added dropwise a solution of compound (E) in toluene (100 mL), prepared as described above, at 0° C. The resulting mixture was allowed to stir for 12 hours. The mixture was extracted with toluene (1×30 mL) and chloroform (3×100 mL). The combined extracts were washed with water (1×30 mL), dried over K2CO3. After evaporation to dryness and crystallization with methyl isobutyl ketone, the desired product (F) dimethyl(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide was obtained in 53% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[N+:13]([O-:16])(O)=[O:14].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:17](=[O:19])[CH3:18])=[C:7]([N+:13]([O-:16])=[O:14])[CH:6]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])O
Product: COC(=O)Cc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Reaction time: 0.33 h

Procedure:
A solution of 4-amino-phenyl acetic acid methyl ester (3 g, 18.2 mmol) in acetic anhydride (16 mL) was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0° C. temperature and fuming nitric acid (2.3 mL) was added dropwise. The ice bath was removed and the reaction mixture was stirred for another 20 minutes before pouring it onto iced water. The resulting yellow precipitate was filtered, washed with water and dried in vacuo at 50° C. to give 3.7 g of the product. 1H NMR 500 MHz (DMSO) δ 2.05 (s, 3H), 3.63 (s, 3H), 3.81 (s, 2H), 7.54 (d, 1H), 7.58 (dd, 1H), 7.87 (d, 1H), 10.2 (s, 1H).
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[CH3:10][C:11]1[NH:12][C:13](=[O:17])[CH2:14][S:15][CH:16]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(#N)C>[CH3:10][C:11]1[NH:12][C:13](=[O:17])[CH2:14][S:15][C:16]=1[CH:21]1[CH:22]=[CH:23][N:18]([C:5]([O:4][CH2:3][C:2]([Cl:9])([Cl:8])[Cl:1])=[O:6])[CH:19]=[CH:20]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC1=CSCC(=O)N1
Reactant: c1ccncc1
Solvent: CC#N
Solvent: O
Product: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SCC(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
2,2,2-Trichloroethylchloroformate (64 ml) was added dropwise to a stirred suspension of 5-methyl-2H-1,4-thiazin-3(4H)-one (50 g) in a mixture of acetonitrile (500 ml)-pyridine (75 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour and then, poured into cold water (1.5 l) The resulting precipitates were collected by filtration, recrystallized from ethanol to give 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (120 g, yield 80.7%) as pale yellow prisms.
Reaction SMILES: [Cl:1]Cl.[CH3:3][C:4]([CH3:45])([CH3:44])[C:5](=[O:43])[CH:6]([N:20]1[CH:23](SC)[CH:22]([CH:26]([O:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH3:27])[C:21]1=[O:42])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8].[N+](C1C=CC(C([O-])=O)=CC=1)([O-])=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][CH:23]1[N:20]([CH:6]([C:5](=[O:43])[C:4]([CH3:45])([CH3:44])[CH3:3])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:21](=[O:42])[CH:22]1[CH:26]([O:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:30])[CH3:27]
Reactant: ClCl
Reactant: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Agent: O=C([O-])c1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(OC(=O)OCc1ccc([N+](=O)[O-])cc1)C1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)C(C)(C)C)C1Cl
Temperature: -60 °C
Reaction time: 2 h

Procedure:
660 μl of a solution of chlorine in carbon tetrachloride containing 850 mg in 10 ml are added at -60° C. to a solution of 244 mg (0.395 mmol) of p-nitrobenzyl 4,4-dimethyl-2-[4-methylthio-3-(1-(p-nitrobenzyloxycarbonyloxy)-ethyl)-2-oxoazetidinyl]-3-oxo-pentanoate-p-nitrobenzoate in 16 ml of methylene chloride. The weakly yellow solution is stirred at -60° C. during the course of 2 hours and the solvent is removed in vacuo, 236 mg of a colorless non-crystalline solid being obtained. IR spectrum in CH2Cl2 : 2930, 2850, 1795, 1765, 1725, 1620, 1530, 1355 cm-1.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[NH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[NH:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NN1CCOCC1
Solvent: ClCCl
Product: O=C(NN1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a solution of 4-nitrophenyl chloroformate (27.8 g, 0.14 mole) in CH2Cl2 (350 mL) at 0° C. was added a solution of 4-aminomorpholine (10.2 g, 0.1 mole) and triethylaminie (10.2 g, 0.1 mole) in CH2Cl2 (40 mL) via addition finnel over 1 h. A white ppt formed during the addition. After the addition was complete, the ice bath was removed and the reaction was stirred an additional 1 h. The solid was collected by filtration, re-suspended in Et2O and filtered to give the desired product as a white solid (15 g, 62% yield).
Reaction SMILES: [CH:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([OH:8])=O)=[CH2:2].[C:15]([C:22]1NC=CN=1)(C1NC=CN=1)=[O:16].C([CH:29](C([O-])=O)[C:30]([O-])=[O:31])C.C(C(C([O-])=O)C([O-])=O)C.[Mg+2].[Mg+2]>Cl>[CH:1]([C:3]1[C:4]([F:14])=[C:5]([C:6](=[O:8])[CH2:29][C:30]([O:16][CH2:15][CH3:22])=[O:31])[CH:9]=[C:10]([F:13])[C:11]=1[F:12])=[CH2:2]
Reactant: C=Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CCC(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Product: C=Cc1c(F)c(F)cc(C(=O)CC(=O)OCC)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To a cooled solution (0° to 5° C.) of 3-ethenyl-2,4,5-trifluorobenzoic acid (6.0 g, 0.03 mol) (100 mL) was added carbonyl diimidazole (4.9 g, 0.030 mol). The mixture was then stirred at room temperature for 1 hour, heated with magnesium bis-(ethyl malonate) (8.7 g, 0.03 mol) and refluxed for 3 hours. The reaction was allowed to cool, treated with 3N HCl (30 mL) and stirred for 1.5 hours at room temperature. The reaction was partitioned between ether and water. The organic layer was dried and concentrated to provide 7.65 g (93%) of the desired product. An analytical sample was obtained by preparative TLC (SiOz, 9:1 hexane/EtOAC) Analysis Calcd: C 57.36, H 4.17, F 20.94;
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1)=O>O1CCCC1>[CH3:2][O:3][CH:4]=[CH:30][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (6.366 g, 18.5 mmol) in dry tetrahydrofuran (50 ml) under argon atmosphere at −78° C. slowly (ca. for 5 minutes) a 2.46 N solution of potassium tert-butoxide in tetrahydrofuran (8.2 ml, 20.2 mmol) was added and the reaction mixture was stirred at this temperature for 1 hour. A solution of methyl 4-formylbenzoate (E8) (2.531 g, 15.4 mmol) in tetrahydrofuran (10 ml) was added to the reaction mixture and the resultant suspension was stirred at −78° C. for 30 minutes. The cooling bath was removed and the reaction was stirred for 30 minutes allowing to warm up to room temperature. The reaction mixture was partitioned between benzene (150 ml) and water (150 ml), and the organic layer was washed successively with water (150 ml), brine (50 ml), and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silicagel (100 g) with toluene-triethylamine (100:0.25) as eluent to give the title compound (2.696 g, 91%) as a mixture of E and Z isomers (ca. 95:5). (E)-(E9): 1H NMR (CDCl3, HMDSO) δ: 3.67 (3H, s); 3.86 (3H, s); 5.81 (1H, d, J=13.5 Hz); 7.14 (1H, d, J=13.5 Hz); 7.25 (2H, d, J=8.5 Hz); 7.89 (2H, d, J=8.5 Hz). A small additional singlet at 3.80 ppm and 2 doublets at 5.23 (d, J=7.6 Hz); 6.22 ppm (d, J=7.6 Hz) in the 1H NMR spectrum of E9 was attributed to minor amounts (ca. 5%) of (Z)-(E9) isomer present in the product.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH:5]([CH2:9][CH:10]=O)[CH2:4][CH:3]=1.[CH:12](=[O:15])[CH2:13][CH3:14]>C(NCCCC)CCC.C(O)(=O)CCCCC.C(O)(=O)C>[CH3:14][C:13](=[CH:10][CH2:9][CH:5]1[CH2:4][CH:3]=[C:2]([CH3:1])[C:6]1([CH3:7])[CH3:8])[CH:12]=[O:15]
Reactant: CCC=O
Reactant: CC1=CCC(CC=O)C1(C)C
Solvent: CC(=O)O
Solvent: CCCCCC(=O)O
Solvent: CCCCNCCCC
Product: CC(C=O)=CCC1CC=C(C)C1(C)C
Temperature: 100 °C
Yield: 93.9 %

Procedure:
A 500 mL four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel was charged with 171 g (0.98 mol) of campholenic aldehyde (purity: 88%), 5.8 g (0.045 mol) of dibutyl amine and 5.3 g (0.046 mol) of hexanoic acid, and the contents in the flask were stirred while heating at 100° C. Then, 91 g (1.6 mol) of propionaldehyde was gradually dropped into the flask for 6 h, and the resultant mixture was aged for 1 h and then cooled. Thereafter, 3.2 g (0.053 mol) of acetic acid was added to the mixture to remove amines therefrom, thereby separating the mixture into two layers. The thus separated organic layer was washed with water and further separated into two layers, thereby obtaining 280 g (0.92 mol) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-but-2-en-1-al (purity as measured by gas chromatography: 63.4%) (yield based on theoretical amount: 94%).
Reaction SMILES: C(#N)C1C=CC=CC=1.ON1C(=O)C2=CC=CC=C2C1=O.[C:21]([OH:30])(=O)[CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=O>C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C.C1CCCCC1>[C:21]1(=[O:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1.[CH:21]1([OH:30])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(O)CCCCC(=O)O
Agent: [Rh+3]
Agent: CC(=O)[O-]
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: N#Cc1ccccc1
Solvent: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1
Yield: 11 %
Yield: 0.9 %

Procedure:
To 10 ml of benzonitrile were added 10 mmol of cyclohexane, 1 mmol of N-hydroxyphthalimide, 0.01 mmol of rhodium acetate [Rh(OAc)2 ]2, and 0.1 mmol of acetylacetonatocobalt Co(AA)3 and the resultant mixture was stirred under an oxygen atmosphere at a temperature of 75° C. for 16 hours. The products in the reaction mixture were analyzed by gas chromatography, and, as a result, cyclohexane was converted into cyclohexanone (yield 11%), cyclohexanol (yield 0.9%) and adipic acid (trace amount) with a conversion of 16%.
Reaction SMILES: [SH2:1].Cl[CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8]>CO>[SH:1][CH2:3][CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8]
Reactant: S
Reactant: CO[Si](CCCCl)(OC)OC
Solvent: CO
Product: CO[Si](CCCS)(OC)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
267.6 g of a methanol solution of 22% sodium hydrogensulfide anhydride (1.05 mol) was put into an autoclave with an internal volume of 1 liter and the air was replaced by nitrogen. 0.3 mol of hydrogen sulfide was then blown in and the system was pressurized to 0.9 kgf/cm2 to oversaturate hydrogen sulfide. After heating the system up to 90° C., 198.7 g (1.0 mole) of 3-chloropropyltrimethoxy silane was dripped for 3 hours, and during the dripping, 0.1 mol of hydrogen sulfide was blown into the system so that the pressure in the system was kept at 3.5 kgf/cm2. After the dripping, the system was aged for 2 hour at 90° C., followed by cooling. By-product salts produced in the reaction were filtered away. The composition was analyzed by means of gas chromatography. 3-mercaptopropyltrimethoxy silane was obtained with a yield of 93.5%.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1.C(O[C:44](=[O:62])[CH:45]=[C:46]([NH:54][C:55]1[CH:60]=[CH:59][C:58]([Br:61])=[CH:57][CH:56]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=1)CCC>CCCCCC>[Br:61][C:58]1[CH:59]=[C:60]2[C:55](=[CH:56][CH:57]=1)[N:54]=[C:46]([C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=1)[CH:45]=[C:44]2[OH:62]
Reactant: CCCCOC(=O)C=C(Nc1ccc(Br)cc1)c1cccc(F)c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Oc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Temperature: 250 °C
Reaction time: 1 h

Procedure:
Dowtherm A (a eutectic mixture of 26.5% diphenyl and 73.5% diphenyl oxide) (1.2 L) was charged into a round-bottom flask equipped with a condenser, magnetic stirrer, thermocouple, heating mantle with a variable voltage controller, and a nitrogen inlet, and heated to 250° C. To this was cautiously added in small portions 48 g (0.11 moles) of 3-(4-bromophenylamino)-3-(3-fluorophenyl)-acrylic acid butyl ester. As portions were added gas was evolved and foaming occurred. Crystals of product began to form and adhere to the sides. After all the material had been added the heating of the reaction was continued for 1 hour. The mixture was then cooled to room temperature and hexane was added. A solid product was collected by vacuum filtration and washed with hexane. After drying in a vacuum oven, 35.7 g (90%) of product was recovered.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:15][OH:16].C([O-])(O)=O.[Na+]>CO>[OH:16][NH:15][C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1)=[NH:2]
Reactant: NO
Reactant: COC(=O)Cc1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(C(=N)NO)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
To a solution of methyl (4-cyanophenyl)acetate (4.00 g, 27.8 mmol) in MeOH (20 mL), hydroxylamine hydrochloride (3.17 g, 45.7 mmol) and NaHCO3 (3.84 g, 45.7 mmol) is added. The suspension is stirred at 60° C. for 18 h before it is filtered and the filtrate is concentrated. The residue is dissolved in DCM, washed with water followed by brine, dried over MgSO4, filtered, concentrated and dried to give methyl [4-(N-hydroxycarbamimidoyl)-phenyl]-acetate (3.67 g) as a colourless oil; LC-MS: tR=0.50 min, [M+1]+=209.05.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.C(N([CH2:15][CH3:16])CC)C.[C:17]([O:20][CH2:21][CH3:22])(=O)[CH3:18].O>C(OC(C)COC)(=O)C.CC(C)=O>[CH:16]1([CH2:18][CH2:17][O:20][CH:21]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=2)[CH3:22])[CH2:15][CH2:4][CH2:3][CH2:2][CH2:9]1.[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CCN(CC)CC
Agent: C=Cc1ccc(O)cc1
Solvent: COCC(C)OC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: C=Cc1ccc(OC(C)OCCC2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
In 320 g of propylene glycol monomethyl ether acetate (PGMEA) was dissolved by heating 70 g of p-hydroxystyrene (VP-8000, manufactured by Nippon Soda Co., Ltd.), and after dehydrating by vacuum distillation the solution was cooled to 20° C. To the solution were added 0.35 g of pyridinium-p-toluenesulfonate and 22.4 g of cyclohexane ethanol. Then, after slowly adding 17.5 g of tert-butyl vinyl ether to the solution, the reaction was carried out at 20° C. for 5 hours. To the reaction liquid were added 0.28 g of triethylamine and 320 ml of ethyl acetate and the mixture was washed three times with 150 ml of distilled water. The solvent was distilled off and the residue was concentrated. The oil obtained was dissolved in 100 ml of acetone and 2 liters of distilled water was slowly added to the solution. A powder deposited was collected by filtration and dried to obtained 54 g of the desired product.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.[N:15]([O-:17])=[O:16].[Na+].II.C(OCC)(=O)C>O>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)c2c1C=CCO2
Reactant: O=N[O-]
Agent: II
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Temperature: 40 °C
Yield: 70 %

Procedure:
Into a reactor, equipped with a mechanic stirrer and a reflux condenser, 8-fluoro-2H-chromene-5-carboxylic acid amide (120 g;0.609 moles), sodium nitrite (96.6 g; 1.4 moles), iodine (31.2 g; 0.123 moles) and ethyl acetate (720 ml) were charged at room temperature and under inert gas. The mixture was heated under stirring at 40° C., then Oxistrong 15® (173.4 g) was added in 4 hours. At the end of the addition the reaction mixture was kept under stirring for 1 hour, then cooled at 20° C. Water (480 ml) was added and the mixture was kept under stirring for 1 hour. After filtration and wash of the panel with isopropyl acetate pre-cooled at 0° C. (2×120 ml) and then with water (150 ml), the solid was dried in oven under vacuum at 50° C. overnight obtaining 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide (112.7 g; titre 91%; 70% yield).
Reaction SMILES: [N+]([C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1)([O-])=O.[ClH:12]>O>[Cl:12][C:4]1[NH:5][CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[N:8]=1
Reactant: Cl
Reactant: O=[N+]([O-])c1c[nH]c([N+](=O)[O-])n1
Solvent: O
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Temperature: 95 °C
Reaction time: 7 h
Yield: 77.1 %

Procedure:
5.0 g of 2,4-dinitroimidazole (purity 92.3%) was added to 30 mL of 35 mass % hydrochloric acid. The reaction liquid was warmed to 95° C. and the reaction was performed for 7 hours. After the reaction, 43 g of water was added and the resultant mixture was cooled to 0° C. for crystallization. The crystals were filtered and dried to obtain 3.31 g of 2-chloro-4-nitroimidazole (yield 77.1%). This was identified to be 2-chloro-4-nitroimidazole by
Reaction SMILES: [CH2:1]([O:3][C:4]([CH3:31])([CH3:30])[CH2:5][S:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][N+:9]=1[C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:20]=2[N:21]=1)[CH3:2].C(Cl)[Cl:33]>Cl>[Cl-:33].[CH2:1]([O:3][C:4]([CH3:30])([CH3:31])[CH2:5][S:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[CH:11]=[CH:10][N+:9]=1[C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:22][C:20]=2[N:21]=1)[CH3:2]
Reactant: ClCCl
Agent: CCOC(C)(C)CSCc1c(C)c(OC)cc[n+]1-c1nc2ccc(C(F)(F)F)cc2[nH]1
Agent: Cl
Product: [Cl-]

Procedure:
450 mg of intramolecularly deprotonized 2-[[(2-ethoxy-2-methylpropyl)thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium cation were dissolved in methylene chloride, whereupon 2 ml of 4.7N methanolic hydrochloric acid were added thereto, the solution was concentrated and the residue was crystallized from ether. The 2-[[(2-ethoxy-2-methylpropyl)thio]methyl]-4-methoxy-3-methyl-1-[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium chloride obtained exhibited a melting point of 119°-120°.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]([CH3:13])[C:9]([O:11]C)=[O:10].Cl.O.C(OCC)(=O)C>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH:8]([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Temperature: 0 °C
Yield: 51.5 %

Procedure:
0.365 g of methyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate (Compound 3-1 of the present invention) was dissolved in 4 ml of 1,4-dioxane, to this was added a mixed solution of 1 ml of conc. hydrochloric acid and 1 ml of water while stirring, then, the mixture was heated for 5 hours and 45 minutes while stirring under reflux condition. Thereafter, the solution was allowed to cool, and ice water was poured into the reaction solution, ethyl acetate and saturated saline were added to the solution which was separated subsequently, and aqueous sodium hydrogen carbonate was added to the organic layer before separation, aqueous hydrochloric acid was added to the aqueous layer to acidify it, then, ethyl acetate was added before separation, the organic layer was washed with saturated saline, and dried over magnesium sulfate, then, concentrated to obtain 0.183 g of 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][NH2:9].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=O)[CH2:18][C:19](OCC)=[O:20]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:19](=[O:20])[CH2:18][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])=[N:9]1
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: NNc1ccccc1F
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2F)=NN1c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Fluorophenyl hydrazine (1.26 g, 9.99 mmol) and ethyl 3-(2-fluorophenyl)-3-oxopropanoate (2.10 g, 9.99 mmol, 1 equiv) were combined in acetic acid (20 mL) and placed into an oil bath preheated at 120° C. for 3 hours. The mixture was cooled of ambient temperature and concentrated in vacuo. The residue was concentrated from toluene (3×50 mL), providing the titled compound.