Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH:26]1([NH:32][C:33](=[O:36])[CH2:34]Cl)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>CN(C)C=O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[C:4](=[O:3])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]3[O:13][CH2:34][C:33]([NH:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:36])=[N:15]2)=[CH:20][CH:19]=1
Reactant: O=C(CCl)NC1CCCCC1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)NC3CCCCC3)nc2n1
Temperature: 80 °C
Yield: 10.1 %

Procedure:
An oily suspension (50% by weight; 2.1 g) of sodium hydride is added at a temperature in the region of 0° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (12.3 g) in anhydrous dimethylformamide (150 cc). The suspension obtained is stirred for 45 minutes at a temperature in the region of 0° C., N-(cyclohexyl)chloroacetamide (7.7 g) is then added and the mixture is heated to 80° C. for 18 hours. After being cooled, the reaction mixture is poured into water (700 cc) and the precipitate obtained is separated by filtration, washed with water and dried in the air. The solid obtained is purified by chromatography on silica (0.063-0.2 mm; 220 g) contained in a column 4 cm in diameter (eluant: methylene chloride), collecting 50-cc fractions. Fractions 41 to 60 are combined and concentrated to dryness under reduced pressure (2.7 kPa). By recrystallization of the residue obtained in acetonitrile, [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]-N-cyclohexylacetamide (1.8 g), m.p. 175° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[C:18]([NH:21][C:22]1[CH:31]=[CH:30][C:25]([S:26](Cl)(=[O:28])=[O:27])=[CH:24][CH:23]=1)(=[O:20])[CH3:19].Cl>N1C=CC=CC=1>[C:18]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([S:26]([NH:13][C:12]2[CH:14]=[CH:15][C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:16])([F:17])[F:1])=[CH:10][CH:11]=2)(=[O:28])=[O:27])=[CH:30][CH:31]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)cc1
Reaction time: 2 h

Procedure:
To 8.5 g (36 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)aniline in 30 ml pyridine, add 7.8 g (30 mmole) N-acetylsulfanilyl chloride. Stir 2 hours, pour onto ice and acidify with concentrated HCl. Extract with Et2O, and wash this with 1N NaOH. Acidify the aqueous layer, extract with Et2O and dry and concentrate. Recrystallize from Et2O-hexane to give the product; m.p. 198°-200° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[N:10]=1)(C)C.[OH-].[NH4+]>Br>[CH2:2]([O:5][C:6](=[O:21])[CH2:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[N:10]=1)[CH3:1]
Reactant: COc1ccc2nc(CCC(=O)OC(C)(C)C)ccc2c1
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)CCc1ccc2cc(O)ccc2n1
Yield: 75.5 %

Procedure:
A mixture of 1.25 g (4.42 mmol) of 6-methoxy-2-quinolinepropanoic acid 1,1-dimethylethyl ester from the preceding example, and 10 mL of 48% hydrobromic acid solution was heated at reflux for 23 hr then poured onto crushed ice. Concentrated ammonium hydroxide solution was added slowly until the solution became neutral at which point it was concentrated to dryness under reduced pressure. To the residue was added 500 mL of ethanol followed by 20 mL of acetyl chloride and the resulting mixture was stirred at reflux for 17 hr. Most of ethanol was removed under reduced pressure, 150 mL of saturated aqueous sodium bicarbonate and 60 mL of water were added, and the mixture was worked-up with ethyl acetate in the usual manner. The crude product was flash chromatographed on 110 g of silica gel, eluting with hexane-ethyl acetate (3:1) to give 0.819 g (75.5%) of the title compound as a white solid, mp 126.5°-127.5° C.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12.CN(C)C=O.[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38](O)=[O:39])=[O:36]>C(N(CC)CC)C>[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[O:39])=[O:36]
Reactant: O=C(O)CS(=O)CC(F)(F)F
Reactant: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1

Procedure:
A suspension of 4.0 g. (0.01 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml. of dry dimethylformamide is treated with 2 ml. of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol. of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
Methyl 3-hydroxyisoxazole-5-carboxylate (5.18 g, 36.2 mmol) was dissolved in acetone (90 mL) and treated with potassium carbonate (10.21 g, 73.8 mmol) at reflux for 1 hour. At that time, benzyl bromide (6.5 mL, 54.3 mmol) was added, and the mixture was heated at reflux for an additional 3 hours. The reaction mixture was removed from the oil bath and stirred at room temperature for 18 hours. The mixture was filtered and concentrated in vacuo leaving a yellow oil. The oil was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) which gave the title compound as a light yellow solid (5.0 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.[N:19]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)=[C:20]=[O:21]>ClCCl>[C:15]([O:14][C:12]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([NH:11][C:20]([NH:19][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)=[O:21])=[CH:7][CH:6]=2)[C:2]([NH2:1])=[N:3]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(N)ccc21
Reactant: COc1cccc(CCN=C=O)c1
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)Nc2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)c1
Yield: 54.8 %

Procedure:
6.1 700 mg of tert-butyl 3,5-diaminoindazole-1-carboxylate (3.1 mmol) and 532 mg of 1-(2-isocyanatoethyl)-3-methoxybenzene (3.0 mmol) are stirred at RT for 24 hours in 10 ml of dichloromethane. The reaction mixture is washed with water, the organic phase is separated off, dried and evaporated. Purification of the residue by column chromatography (eluent:ethyl acetate) gives 700 mg of tert-butyl-3-amino-5-{3-[2-(3-methoxyphenyl)ethyl]ureido}indazole-1-carboxylate (53%), MS-FAB (M+H+)=426.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])(=O)C.[NH4+]>CN(C=O)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:20])=[CH:9][CH:8]=2)[CH2:23]/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:12])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: BrCC=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C/C=C/c2ccccc2)C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To methyl-4-[2-(4-fluorophenyl)-2-oxoethyl]benzoate(0.48 g, 1.76 mmol) in DMF (5 ml) at 0° C. was added NaH (0.05 g), 2.08 mmol). After a period of 0.5 h, a solution of cinnamyl bromide (0.35 g) in DMF (5 ml) was added to the reaction mixture. The reaction mixture was stirred at r.t. for 1 hour. Ammonium acetate saturated solution (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed with brine and dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography using hexane/ethyl acetate 30% to give 0.43 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[C:28]1(B(O)O)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([F:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: OB(O)C1=CCCCC1
Reactant: COC(=O)c1sc(Br)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](F)CC1

Procedure:
Nitrogen was bubbled through a solution of 5-bromo-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (20 mg, 0.043 mmol) and cyclohexen-1-ylboronic acid (13 mg, 0.103 mmol) in 2M Na2CO3 (1.3 mL) and DME (2.6 mL) for 6 min. Pd(PPh3)4 (4.4 mg) was added and the mixture was refluxed for 1 h and 30 min. It was cooled, diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated. The crude was purified by chromatography over silica gel (hexane: EtOAc-9:1 and 4:1 as eluents) yielding pure 5-cyclohex-1-enyl-3-[(cis-4-fluoro-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (10 mg, 50%).
Reaction SMILES: P(O[CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[C:30]3[N:29]=[C:27]([NH2:28])[NH:26][C:24](=O)[C:23]=3[N:22]=[CH:21]2)[CH2:17][C@@H:16]1[OH:31])(OP(OP(O)(O)=O)(O)=O)(=O)O.[P:32]([O:44]C[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C[C@@H]1O)([O:35][P:36]([O:39][P:40]([OH:43])([OH:42])=[O:41])([OH:38])=[O:37])(=[O:34])[OH:33]>>[CH:27]1[N:29]=[C:30]2[N:20]([C@@H:18]3[O:19][C@H:15]([CH2:14][O:43][P:40]([O:39][P:36]([O:35][P:32]([OH:44])([OH:34])=[O:33])([OH:38])=[O:37])([OH:42])=[O:41])[C@@H:16]([OH:31])[CH2:17]3)[CH:21]=[N:22][C:23]2=[C:24]([NH2:26])[N:28]=1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)n1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O2)c(=O)[nH]1
Product: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O1

Procedure:
200 nM dGTP; 200 nM dCTP;
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[CH:36]=[CH:35][C:34]2[C:33](=[O:37])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:38])[C:25]=2[CH:24]=1>>[CH:24]1[C:25]2[C:26](=[O:38])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33](=[O:37])[C:34]=2[CH:35]=[CH:36][C:23]=1[CH2:22][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc3c(c2)C(=O)c2ccccc2C3=O)c1
Yield: 32.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-chloromethyl anthraquinone were reacted by the same way with the example 1 to obtain the titled compound (165 mg, yield: 32.2%).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][N:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:17].FC(F)(F)C(O)=O>O>[O:17]=[C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[N:13][CH:12]=2)[N:7]1[CH2:6][CH:2]=[O:1]
Reactant: O=c1ccc2cnccc2n1CC1OCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=CCn1c(=O)ccc2cnccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 0.60 g of 1-(1,3-dioxolan-2-ylmethyl)-1,6-naphthyridin-2(1H)-one, 6 mL of a 90% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at room temperature for 12 hours. Thereto was added 1.0 mL of water, and the mixture was stirred for 1 hour, and stirred at 55 to 75° C. for 3 hours 30 minutes. The solvent was distilled off under reduced pressure, thereto were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the mixture was stirred at room temperature for 1 hour 30 minutes. The organic layer was then separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain (2-oxo-1,6-naphthyridin-1(2H)-yl)acetaldehyde.
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:15][C:16]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([CH:15]=[CH2:16])[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C=Cc1c(C)c(Cl)cc(C(C)=O)c1OC
Temperature: 80 °C

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (2.6 g, 9.5 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.9 mL, 11 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (400 mg, 0.5 mmol) and potassium carbonate (4.0 g, 29 mmol) in 1,4-dioxane (60 mL), and water (30 mL). The resulting mixture was heated at 80° C. for 3 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. Purification on a silica gel using ethyl acetate in hexanes (0-20%) gave the desired compound, 2.0 g, 94%. LCMS calculated for C12H14ClO2 (M+H)+: m/z=225.1; found: 225.1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[C:10]3[CH:11]=[CH:12][N:13]=[CH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:4][C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl.O>O1CCOCC1>[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34]([C:4]2[C:3]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[CH:2][N:7]=[N:6][C:5]=2[NH:8][C:9]2[C:10]3[CH:11]=[CH:12][N:13]=[CH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(Nc3cccc4cnccc34)nnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-c2cnnc(Nc3cccc4cnccc34)c2-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
To a mixture of Example 30 (0.08 g, 0.2 mmol) and 4-trifluoromethylphenylboronic acid (0.057 g, 0.3 mmol) in anhydrous dioxane (2 ml) was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (0.007 g, 0.009 mmol) and saturated aqueous sodium carbonate solution (0.3 ml). The mixture was irradiated in a microwave reactor at 170° C. for 10 minutes, allowed to cool to room temperature and poured onto a mixture of chloroform/water (30 ml/10 ml). The phases were separated and the aqueous phase was extracted two times more with chloroform. The combined organic layers were washed with brine, dried over sodium sulfate and adsorbed onto silica gel. Purification by flash column chromatography (ethyl acetate) yielded the title compound (35 mg, 34%) as a yellow solid. m/z (ES+) 511 (M+H+).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[N-:10]=[N+:11]=[N-:12].[Na+].Cl>CN(C=O)C>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:12][N:11]=[N:10][N:8]=2)=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nnn[nH]2)cc1
Temperature: 135 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
A solution of 10.0 grams (0.085 mole) of para-toluonitrile in 160 mL of DMF was stirred and 5.6 grams (0.085 mole) of sodium azide was added. Upon completion of addition, the reaction mixture was warmed to 135° C. where it stirred for three hours. The reaction mixture was then cooled and poured into 200 mL of stirred, cold aqueous 1N hydrochloric acid. Upon completion of addition, the mixture was stirred for five minutes and filtered to collect a white solid. The solid was dried for 16 hours in a vacuum oven at 35-40° C., yielding 7.1 grams of the subject compound. The reaction was repeated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH2:14][NH:15]S(C2C=CC(C)=CC=2)(=O)=O)/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(OI(OC(=O)C)C1C=CC=CC=1)(=O)C.II.C([O-])([O-])=O.[K+].[K+]>ClCCCl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[N:15]2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1ccc(Br)cc1)CNS(=O)(=O)c1ccc(C)cc1
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: II
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2cc(Br)ccc2c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 15.6 %

Procedure:
A solution of 820 mg (1.93 mmol) of methyl (2E)-3-(4-bromophenyl)-2-({[(4-methylphenyl)sulfonyl]amino}methyl)-2-propenoate, 995 mg (3.09 mmol) of bis(acetyloxy)(phenyl)-λ3-iodane and 490 mg (1.93 mmol) of iodine in 35 mL of 1,2-dichloroethane were stirred at 70° C. for 30 min. The solvent was evaporated and the residue taken up in 25 mL DMF and 1.07 g (7.73 mmol) of K2CO3 was added. The mixture was stirred at 120° C. for 6 hr. EtOAc was added and the organics were washed with three portions of H2O then brine. The solution was then concentrated and the residue purified by silica gel chromatography (40 g of silica gel eluting with 0-40% EtOAc in hexanes over 45 minutes) to give 80 mg (16%) of methyl 7-bromo-3-quinolinecarboxylate as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 9.34 (s, 1H), 8.81 (s, 1H), 8.35 (s, 1H), 7.80 (d, J=9 Hz, 1H), 7.73 (d, J=9 Hz, 1H), 4.02 (s, 3H). ESI-LCMS m/z 267 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccccn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(=C1CCNCC1)c1cccc(Oc2ccccn2)c1
Reaction time: 3 h

Procedure:
A solution of tert-butyl-4-(3-(pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.483 g) in dichloromethane (2.5 mL, 0.53 M) was treated with trifluoroacetic acid (2.5 mL). The reaction was allowed to stir for 3 hours, then concentrated to give an oil. The oil was used without purification. 0.652 g, quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:11]3[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.CS(N1C2C(=CC=CC=2)C=N1)(=O)=O.[CH3:33][S:34]([C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][N:38]=1)(=[O:36])=[O:35]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:11]3[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[C:7]([CH2:9][N:39]3[C:40]4[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:37]([S:34]([CH3:33])(=[O:35])=[O:36])=[N:38]3)=[N:8][C:4]=2[CH:3]=1
Reactant: ClCc1nc2cc(Cl)ccc2n1-c1ccc(Cl)nc1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Agent: CS(=O)(=O)n1ncc2ccccc21
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2-c2ccc(Cl)nc2)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 3-1 by using 5-chloro-2-chloromethyl-1-(6-chloro-pyridin-3-yl)-1H-benzoimidazole and methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCCCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[F:35])[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CCOC(OCC)OCC
Solvent: NC1CCCCC1
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3F)c2ncn1C1CCCCC1
Yield: 57.9 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), cyclohexylamine (0.128 ml, 0.92 mmol), and acetic acid (0.1 ml) were used to give 76 mg (0.23 mmol, 57.9% yield) of the title compound.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[P:10]([O:15]C)([O:13][CH3:14])[O:11][CH3:12]>>[CH3:9][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[P:10]([O:13][CH3:14])(=[O:15])[O:11][CH3:12]
Reactant: Cc1cc(C)cc(C)c1
Reactant: COP(OC)OC
Product: COP(=O)(OC)c1c(C)cc(C)cc1C

Procedure:
After electrolysis, the electrolyte contains 15.8% by area of product and also 26.1% by area of mesitylene and 13.1% by area of trimethyl phosphite. The crude electrolyte is worked up by being concentrated on a rotary evaporator. The conducting salt is precipitated from the residue by means of ethyl acetate and is recovered by filtration. Fractional distillation gives 141 g of dimethyl 2,4,6-trimethylbenzenephosphonate, corresponding to a material yield of 31% and a current efficiency of 26%.