Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=3[F:19])[C:10]([C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[C:9]([CH2:26][O:27][CH2:28][CH2:29][N:30]3C(=O)C4=CC=CC=C4C3=O)[NH:8][C:7]=12)#[N:2].CO.O.NN.C(Cl)(Cl)[Cl:47]>>[ClH:47].[NH2:30][CH2:29][CH2:28][O:27][CH2:26][C:9]1[NH:8][C:7]2[N:6]([N:5]=[CH:4][C:3]=2[C:1]#[N:2])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[C:10]=1[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)OC(=O)C1=C(COCCN2C(=O)c3ccccc3C2=O)Nc2c(C#N)cnn2C1c1cccc(F)c1F
Reactant: ClC(Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)OC(=O)C1=C(COCCN)Nc2c(C#N)cnn2C1c1cccc(F)c1F
Product: Cl
Temperature: 50 °C

Procedure:
To a solution of 1.3 g of isopropyl 3-cyano-7-(2,3-difluorophenyl)-5-[2-(phthalimido)ethoxymethyl]-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate in a mixed solvent of 12 ml of methanol and 12 ml of chloroform is added 142 μl of hydrazine hydrate and the mixture is refluxed at 50° C. for 5 hours. After the solvent is distilled off, to the residue is added aqueous sodium hydrogencarbonate and then extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate and ethanolic hydrochloric acid is added to convert into hydrochloride. The obtained crystals are recrystallized from methanol to give 0.4 g of isopropyl 5-(2-aminoethoxymethyl)-3-cyano-7-(2,3-difluorophenyl)-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate hydrochloride 1/4 hydrate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>CC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Br)c(OC)c1
Yield: 98.2 %

Procedure:
A solution of methyl 4-bromo-3-hydroxybenzoate of Step A (27 mmol), potassium carbonate (33 mmol), and dimethyl sulfate (32 mmol) in acetone (40 mL) was stirred at reflux temperature under nitrogen atmosphere for three hours. The mixture was cooled and 5 mL of water was added. The acetone was evaporated and 30 mL of water was added. The product was extracted into dichloromethane. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound (6.5 g, 99%) as a hard, white crystalline solid.
Reaction SMILES: [CH2:1]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:21][O:20]2)=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][N:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36].C(N(CC)CC)C>C(O)(C)C>[CH2:1]([N:8]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]([OH:20])[CH2:21][N:23]([CH2:24][CH2:25][N:26]2[N:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH3:22])=[CH:17][CH:18]=1)[S:9]([CH3:12])(=[O:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNCCn1ncc2ccccc2c1=O
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1ccc(C2CO2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN(CCn1ncc2ccccc2c1=O)CC(O)c1ccc(N(Cc2ccccc2)S(C)(=O)=O)cc1

Procedure:
2-[4-(N-Benzylmethanesulphonamido)phenyl]oxirane (1.5 g), N-methyl-2-(phthalazin-1-on-2-yl)ethylamine (1.4 g) and triethylamine (1.4 g) in isopropanol (50 ml) were stirred at reflux temperature for 5 hours. The solvent was evaporated, the residue dissolved in methylene chloride and washed three times with sodium carbonate solution and three times with brine. The organic layer was dried and evaporated to give an oil which was purified by column chromatography on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methylene chloride containing methanol (0% up to 2%). Combination and evaporation of the appropriate fractions gave a foam which was chromatographed a second time on silica, "Kieselgel 60" (Merck, Trade Mark), eluting with methyl isobutyl ketone (MIBK) containing acetone (0% up to 20%). The appropriate fractions were combined and evaporated then re-evaporated from diethyl ether to give the title compound as a foam, yield 450 mg.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[C:3]1=[O:21].[NH2:22][C:23]([NH2:25])=[S:24]>CC(C)=O>[BrH:1].[NH2:25][C:23]1[S:24][CH:2]2[CH2:10][C:9]3[CH:8]=[CH:7][C:6]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)=[CH:5][C:4]=3[C:3]2([OH:21])[N:22]=1.[NH2:25][C:23]1[S:24][CH:2]2[CH2:10][C:9]3[CH:8]=[CH:7][C:6]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)=[CH:5][C:4]=3[C:3]2([OH:21])[N:22]=1
Reactant: O=C1c2cc(-c3ccc(C(F)(F)F)cc3)ccc2CC1Br
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: Br
Product: NC1=NC2(O)c3cc(-c4ccc(C(F)(F)F)cc4)ccc3CC2S1
Reaction time: 4 h

Procedure:
1.06 g of 2-bromo-6-(4-trifluoromethylphenyl)indan-1-one are dissolved with 266 mg of thiourea in 10 ml of dry acetone and stirred at ice-bath temperature for 4 h. The precipitate is filtered off with suction, washed with acetone and dried in vacuo. The hydrobromide of 2-amino-5-(4-trifluoromethylphenyl)-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol is obtained with a melting point of 228-230° C.
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.[N+:20]([C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26])([O-:22])=[O:21].C(N(CC)CC)C.CCCCCC>C(Cl)Cl>[N+:20]([C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[NH:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3]1)=[O:26])([O-:22])=[O:21]
Reactant: NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A portion (200 mg) of the compound obtained in Example 81 was suspended in methylene chloride (10 ml) and to the suspension were added 2-nitrobenzoyl chloride (0.18 ml) and triethylamine (0.11 ml) under cooling with ice. The mixture was stirred for 30 minutes at room temperature. n-Hexane was added to the reaction mixture, and the crystals were collected by filtration and washed with water and n-hexane successively to yield 260 mg (81%) of the titled compound as brown crystals.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[F:12].CN(C=O)C.CCN(CC)CC.[CH3:25][O:26][CH2:27][C:28]#[CH:29]>C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:29]#[C:28][CH2:27][O:26][CH3:25])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CCOC
Reactant: COC(=O)c1ccc(Br)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC#Cc1ccc(C(=O)OC)cc1F
Temperature: 60 °C
Reaction time: 1.17 h

Procedure:
To methyl 4-bromo-3-fluoro-benzoate (2.50 g, 10.7 mmol), copper (I) iodide (204 mg, 1.07 mmol) and Pd(PPh3)2Cl2 (753 mg, 1.07 mmol) in a flask under Argon was added DMF (degassed for 30 min) and reaction cooled to 0 C. Et3N (1.95 mL, 14.0 mmol) was added followed by 3-methoxyprop-1-yne (997 μL, 11.8 mmol) and the mixture was allowed to stir at 60° C. for 70 min. The mixture was cooled, diluted with ethyl acetate and filtered. The filtrate was washed sequentially with 1 M HCl, 10% NH4OH and brine solutions. The organic layer was separated, dried and purified with silica gel using ethyl acetate-hexanes to give methyl 3-fluoro-4-(3-methoxyprop-1-ynyl)benzoate. ESI-MS m/z calc. 222.2, found 223.2 (M+1)+; Retention time: 1.53 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.75 (ddd, J=11.2, 8.8, 1.5 Hz, 2H), 7.50 (dd, J=7.9, 7.0 Hz, 1H), 4.37 (s, 2H), 3.92 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)[N:3]=1.[F:15][C:16]([F:22])([F:21])[CH2:17][N:18]=[C:19]=[S:20]>C(#N)C>[F:15][C:16]([F:22])([F:21])[CH2:17][NH:18][C:19](=[S:20])[NH:1][C:2]1[CH:6]=[N:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1cnn(-c2cccc(CO)c2)n1
Solvent: CC#N
Product: OCc1cccc(-n2ncc(NC(=S)NCC(F)(F)F)n2)c1
Reaction time: 8 h

Procedure:
A mixture of this sample of unpurified 4-amino-2-(3-hydroxymethylphenyl)-1,2,3-triazole, 2,2,2-trifluoroethylisothiocyanate (0.202 g.) and acetonitrile (5 ml.) was kept at room temperature overnight. The mixture was evaporated to leave a residue of unpurified 4-[3-(2,2,2-trifluoroethyl)thioureido]-2-(3-hydroxymethylphenyl)-1,2,3-triazole which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1SCc1ccccc1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A solution of the product of Example 2A (7.72 g, 31.26 mmol), sodium carbonate (3.31 g, 31.26 mmol) and benzyl mercaptan (3.90 mL, 30.21 mmol) in absolute ethanol (50 mL) was stirred at reflux for 6 hours, cooled to 25° C. and added to water (200 mL). The precipitate was collected by filtration, washed with water and dried to give the title compound (10.71 g, 98%). 1H NMR (300 MHz, CDCl3): δ 8.26 (d, J=9.19 Hz, 1 H), 7.36 (m, 10 H), 6.91 (d, J=2.57 Hz, 1 H), 6.78 (dd, J=9.19, 2.57 Hz, 1 H), 5.06 (s, 2 H), 4.12 (s, 2 H).
Reaction SMILES: ClCCCl.C[Al](C)C.[CH2:9]([SH:11])[CH3:10].[CH:12]([O:15][N:16]=[C:17]([C:27]([O:29]C)=O)[C:18]([N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)=[N:19][O:20][CH3:21])([CH3:14])[CH3:13]>C(OC(C)C)(C)C.O>[CH:12]([O:15][N:16]=[C:17]([C:18](=[N:19][O:20][CH3:21])[N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)[C:27](=[O:29])[S:11][CH2:9][CH3:10])([CH3:13])[CH3:14]
Reactant: CON=C(C(=NOC(C)C)C(=O)OC)n1cncn1
Reactant: CCS
Agent: C[Al](C)C
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: ClCCCl
Product: CCSC(=O)C(=NOC(C)C)C(=NOC)n1cncn1
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To 8 ml of 1,2-dichloroethane was added 7.5 ml (7.5 mmol) of a trimethylaluminum (1 mol/l) hexane solution. Thereinto was drop-wise added 0.47 g (7.5 mmol) of ethanethiol at room temperature, followed by stirring for 30 minutes. To this mixed solution was added, at room temperature, a 1,2-dichloroethane solution containing 0.50 g (1.9 mmol) of the 1-(2-isopropoxyimino-2-methoxycarbonyl-1-methoxyiminoethyl)-1H-1,2,4-triazole produced in Example 12, followed by stirring for 1.5 hours. The reaction mixture was diluted with isopropyl ether. Thereto was added a small amount of water, followed by stirring. The resulting precipitate was removed by filtration. The solvent was distilled off. The resulting residue was purified by silica gel column chromatography (elutant:ethyl acetate/hexane=1/2) to obtain 0.56 g (yield: 98%) of a title compound as a yellow oily matter.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:19])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=2)[CH2:9][CH2:8][NH:7]1.CO.Cl>C(O)(C)C>[ClH:1].[CH3:2][O:3][C:4](=[O:19])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)CC1NCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COC(=O)CC1NCCc2ccc(N)cc21
Reaction time: 2 h
Yield: 112.9 %

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline-1-acetic acid methyl ester hydrochloride (3.08 g, 10.7 mmol) in a solution of methanol (170 ml) and saturated hydrogen chloride in isopropanol (12 ml) was added 10% Pd--C (0.5 g). The reaction mixture was hydrogenated on a Parr Hydrogenator for 2 h at 50 psi. After the catalyst was removed by filtration, the solvent was concentrated to about 1/5 the volume. Isopropanol (70 ml) was added and the precipitate was collected to afford the title compound as a pale yellow solid (3.10 g, 98%), m.p. 245-6° C. (dec.).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:40]1C=CC=CC=1.[N:46](C(OC(C)C)=O)=[N:47]C(OC(C)C)=O>C1(C)C=CC=CC=1.[Zn](N=[N+]=[N-])N=[N+]=[N-]>[N:40]([CH2:1][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1)=[N+:46]=[N-:47]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: c1ccncc1
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(C=O)cc2n1
Agent: [N-]=[N+]=N[Zn]N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccccc2)c2ccc(CN=[N+]=[N-])cc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7-formyl-4-phenylquinoline-2-carbonitrile (520 mg, 2.0 mmol) in toluene (12 mL) was added triphenylphosphine (1.05 g, 4.0 mmol), Zn(N3)2.2 pyridine (461 mg, 1.5 mmol) and diisopropyl azodicarboxylate (787 μL, 4.0 mmol). The mixture was stirred at room temperature for 3 h, concentrated and purified on silica gel (eluting with EtOAc/hexanes, 3:7) to give the title compound. MS (+ESI): 286 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:22])[C:19]=1[O:20][CH3:21])[CH2:15][NH2:16].C([O-])(=O)C.[NH4+]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:22])[C:19]=1[O:20][CH3:21])[CH2:15][NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COc1c(F)cc(CN)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1c(F)cc(CNc2ccccc2[N+](=O)[O-])cc1F
Yield: 100 %

Procedure:
A mixture of 2-fluoronitrobenzene (0.82 g, 5.8 mmole), 3,5-difluoro-4-methoxybenzylamine, (3.0 g, 17.3 mmole) and ammonium acetate (0.5 g) was reacted substantially as described in 1C above to yield 1.7 g, (100%) of the title compound as orange crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:9][Si:10]([CH3:14])([CH3:13])[C:11]#[CH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([C:12]#[C:11][Si:10]([CH3:14])([CH3:13])[CH3:9])=[CH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C#C[Si](C)(C)C)cn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 2.0 g (11.6 mmol) 5-bromo-2-methyl-pyridine and 2.3 mL (16.3 mmol) 1-trimethylsilyl-ethyne using 68 mg (0.36 mmol) CuI, 305 mg (1.2 mmol) triphenylphosphine, 213 mg (0.30 mmol) PdCl2(PPh3)2 and 18 mL (127 mmol) triethylamine in 18 mL dry THF. For the work-up the reaction mixture is diluted with ethyl acetate, the organic phase is extracted with water and brine. The product is purified by chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 1.5 g (68%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:18][NH2:19].O>CCO>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH3:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 18 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (1 g, 7.3 mmol) in EtOH (10 mL) was added Na2CO3 (1.3 g, 12.3 mmol) and MeNH2 at 18° C. The mixture was stirred for 16 hours at 18° C. after which TLC analysis showed the reaction was complete. The reaction mixture was then concentrated to get the crude material which was treated with water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to get yield the crude product which was purified by crystallized with ethanol to give the desired product (780 mg, 55.7%) as a yellow solid. LCMS (m/z): 188.1 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:18]=3[N:19]=2)[CH:11]=[C:10]([Cl:25])[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:25][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([O:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:18]=3[N:19]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Oc2nc3cc(Cl)ccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Cl)cc(Oc2nc3cc(Cl)ccc3s2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.5 %

Procedure:
To [3-chloro-5-(5-chloro-benzothiazol-2-yloxy)-phenyl]-carbamic acid tert-butyl ester (263, 1.17 g, 2.85 mmol) was added trifluoroacetic acid. The mixture was stirred at ambient temperature for 5 h, at which time TLC showed there was no starting material remained. The mixture was concentrated to dryness under reduced pressure, dissolved in EtOAc. The organic solution was washed with 1N NaOH, washed twice with a brine solution, dried over Na2SO4 and concentrated. The residue was purified by chromatography with CH2Cl2 to give 785 mg of product. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J=8.6 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 6.62 (t, J=1.9 Hz, 1H), 6.58 (t, J=1.8 Hz, 1H), 6.50 (t, J=1.9 Hz, 1H), 5.81 (s, 2H). MS (EI): m/z 311 (M+H).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7]Br.[C:9]([O-:12])(=[O:11])[CH3:10].[K+].O>CC(C)=O>[C:9]([O:12][CH2:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[Cl:1])(=[O:11])[CH3:10]
Reactant: CC(=O)[O-]
Reactant: Clc1sccc1CBr
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCc1ccsc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Methylthiophene (19.63 g) was dissolved in acetonitrile (100 ml), and sulfuryl chloride (16.64 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour, stirred under reflux for another 1 hour, then cooled to room temperature, and 10% aqueous sodium thiosulfate (200 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-chloro-3-methylthiophene (21.52 g). A mixture of 2-chloro-3-methylthiophene (3.53 g), N-bromosuccinimide (4.73 g), 2,2'-azobis(isobutyronitrile) (0.87 g) and carbon tetrachloride (25 ml) was stirred under reflux for 4 hours. The mixture was cooled to room temperature and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-chloro-3-bromomethylthiophene. A suspension of the crude product of 2-chloro-3-bromomethylthiophene and potassium acetate (9.82 g) in acetone (50 ml) was stirred at room temperature for 48 hours. The mixture was poured into water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-acetoxymethyl-2-chlorothiophene. This crude product was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and 1N aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at room temperature for 30 minutes. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-hydroxymethyl-2-chlorothiophene (3.22 g). 3-Hydroxymethyl-2-chlorothiophene (3.16 g) was dissolved in methylene chloride (50 ml), and manganese dioxide (9.66 g) was added. The mixture was stirred at room temperature for 15 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-chloro-3-thiophenecarbaldehyde (3.16 g). The crude product of 2-chloro-3-thiophenecarbaldehyde was dissolved in acetonitrile (20 ml), and sodium dihydrogen phosphate (0.67 g) in water (10 ml) and 30% aqueous hydrogen peroxide (2.6 ml) were added. Further, sodium chlorite (3.41 g) in water (30 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhdrous magnesium sulfate to give 2-chloro-3-thiophenecarboxylic acid (1.92 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:11][CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CCOC(=O)/C=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)/C=C/COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A mixture of 3-fluoro-6-nitrophenol (200 g, 1.27 mol), anhydrous K2CO3 (202 g, 1.46 mol) and NMP (1.2 L) under nitrogen atmosphere was stirred at 25° C. for 30 min. Ethyl 4-bromocrotonate (80% tech., 252 mL, 1464 mmol) was added during 2-3 min to the obtained red suspension and the resulting mixture was stirred over night at ambient temperature. The yellowish suspension was then poured into ice-water (8.0 L) under stirring. After stirring for 1 h the solids were filtered off, washed with water (5×1.0 L), heptane (4×0.50 L) and then dried over night at 50° C. in vacuo affording the title compound (332 g, 1.20 mmol, 98% w/w, 95% yield).
Reaction SMILES: [C:1](=[O:6])([O:4]C)[O:2][CH3:3].[CH3:7][N:8]([CH3:10])[CH3:9].[CH3:11]O>>[CH3:3][O:2][C:1](=[O:4])[O-:6].[CH3:7][N+:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CN(C)C
Reactant: CO
Reactant: COC(=O)OC
Product: COC(=O)[O-]
Product: C[N+](C)(C)C
Temperature: 140 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To a 1.5 L autoclave equipped with a stirrer and a heating means were added 90 g (1.0 mol) of dimethyl carbonate, 59 g (1.0 mol) of trimethyl amine and 510 g (15 mol) of methanol. Stirring was initiated after the autoclave was sealed. The autoclave was heat to 140° C., and pressure was 1.5 MPa. The reaction was kept at 140° C. for 4 h. Then the reaction mixture was cooled to 50° C. and discharged into a 1 L three-necked flask. Part of methanol was removed from the solution of tetramethylammonium methyl-carbonate in methanol thus obtained under vacuum, and then the solution was cooled to ambient temperature. White crystal precipitated out. The crystal was filtrated, oven dried and recrystallized from methanol, to give 119.5 g of tetramethylammonium methyl-carbonate having a purity of 99.2% as measured by chromatography. The yield was 80.2%.