Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(F)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1ccc(F)c(F)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 28.3 %

Procedure:
3,4-difluoroaniline (0.105 mL, 1.06 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (130 mg, 0.27 mmol) using a procedure similar to the one described in Example 3.00 to give 8-(1-(3,4-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (35.0 mg, 28.8%) as a white solid. Mass Spectrum: M+H+ 458. NMR Spectrum: (DMSOd6) 1.50 (d, 3H), 2.70 (s, 3H), 2.94 (s, 3H), 3.50-3.63 (m, 4H), 3.71-3.79 (m, 4H), 4.92-5.01 (m, 1H), 5.60 (s, 1H), 6.25 (d, 1H), 6.46 (ddd, 1H), 6.54 (d, 1H), 7.05 (dd, 1H), 7.54 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:11](=[O:21])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[CH:8][C:9]=1[Br:10])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[Br:10][C:9]1[CH:8]=[C:7]([C:11](=[O:21])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1Br
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1cccc(O)c1)c1cc(Br)c(C(=O)O)s1
Reaction time: 15 h

Procedure:
A mixture of 3-Bromo-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carboxylic acid methyl ester (160 mg, 0.43 mmol), lithium hydroxide monohydrate (180, mg, 4.32 mmol), THF (5 mL) and water (6 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 110 mg (70%). MS m/e 357.7 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Br:17]Br>C(Cl)(Cl)(Cl)Cl>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH2:1][Br:17])=[CH:7][CH:6]=1)([O-:16])=[O:15]
Reactant: BrBr
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
4-Methyl-2'-nitrobiphenyl (from Step A) (2.173 g, 10.2 mmol) was dissolved in CCl4 (100 mL) and heated to reflux with stirring. To this was added a bromine solution [prepared by diluting 11.2 ml (11.2 mmole) of commercial 1.0M solution in CCl14 to a final volume of 40 mL with CCl4 ] dropwise while a 100 W lamp was used to irradiate the refluxing reaction mixture. After completion of addition, the solution was cooled to room temperature, volatiles were removed, and the residue was flash chromatographed over 700 mL SiO2, eluting with 1.5-4.0-10.0% EtOAc/hexane, to afford 2.68 g (90%) of the title compound, 85% pure as indicated by NMR (the remainder being the dibrominated material), but homogeneous on TLC (4/1 hex-EtOAc).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[C:6]([CH2:9][N:10]1[C:14](=[O:15])[C:13](=[CH:16]OCC)[S:12][C:11]1=[S:20])([OH:8])=[O:7]>C(O)C>[C:6]([CH2:9][N:10]1[C:14](=[O:15])[C:13](=[CH:16][NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])[S:12][C:11]1=[S:20])([OH:8])=[O:7]
Reactant: CC(C)CN
Reactant: CCOC=C1SC(=S)N(CC(=O)O)C1=O
Solvent: CCO
Product: CC(C)CNC=C1SC(=S)N(CC(=O)O)C1=O
Yield: 65.6 %

Procedure:
0.74 Gram (0.01 mole) of isobutylamine was added to a mixture of 1.2 g (0.005 mole) of 3-carboxymethyl-5-ethoxymethylidenerhodanine and 10 ml of ethanol, and the resulting mixture was subjected to reaction at a temperature of 50° to 60° C. for 1 hour. The reaction mixture was concentrated and the resulting residue was dried and dissolved into water. The solution was made neutral or weakly acidic with a dilute hydrochloric acid and the formed precipitate was separated by filtration. The precipitate was washed with water, dried and recrystallized from a mixture of ethyl acetate and petroleum ether (4/1 by volume) to give 0.9 g of 3-carboxymethyl-5-isobutylaminomethylidenerhodanine in the form of yellowish red crystal (yield: 64.3%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].[Cl:10][C:11]1[C:12]([O:19][CH3:20])=[C:13]([NH:17][NH2:18])[CH:14]=[CH:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[C:12]([O:19][CH3:20])=[C:13]([N:17]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([F:9])([F:8])[F:1])=[N:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: COc1c(Cl)cccc1NN
Solvent: CCO
Product: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1N
Yield: 24.1 %

Procedure:
To a stirred solution of 4,4,4-trifluoro-3-oxobutanenitrile (1.64 g, 11.96 mmol, 1.0 eq) in ethanol (15 mL) was added (3-chloro-2-methoxyphenyl)hydrazine (2.5 g, 11.96 mmol, 1.0 eq) and the mixture was refluxed for 3 h. Ethanol was evaporated, the mixture diluted with water and extracted with ethyl acetate (300 mL×2), dried (Na2SO4), evaporated again under vacuum. The crude product was purified by CC using EtOAc/PE (1:4) as eluent to get 1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-amine (0.84 g, 24%, yellow oil; TLC system: EtOAc/PE (2:3), Rf: 0.5).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(OC(=O)C)(=O)C.C(OCC)(OCC)OCC>[C:1]([N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:24])[C:18](=[CH:22][O:21][CH2:19][CH3:18])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([F:25])[CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F

Procedure:
A solution of 3.95 g (11.25 mmol) ethyl 4-(1-acetyl-1,2,3,6-tetrahydro-4-pyridyl)-2,5-difluoro-β-oxobenzenepropionate in 25 ml of acetic anhydride and 2.8 ml of trietyl orthoformate was refluxed 1.5 hours. The title compound was isolated as a syrup after evaporation under vacuum in an oil bath at 80° C.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=2[CH3:22])=[C:12]2[C:7]([C:8]([C:23]([F:26])([F:25])[F:24])=[CH:9][CH:10]=[CH:11]2)=[N:6]1.B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:1][C:2]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=2[CH3:22])=[C:12]2[C:7]([C:8]([C:23]([F:26])([F:25])[F:24])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: COc1ccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccc(C)cc2C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: Cc1ccc(Cn2nc3c(C(F)(F)F)cccc3c2-c2ccc(O)cc2C)c(C)c1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of 2-(2,4-Dimethylbenzyl)-3-(4-methoxy-2-methylphenyl)-7-trifluoromethyl-2H-indazole (0.27 g, 0.63 mmol) and tetrabutylammonium iodide (0.7 g, 1.9 mmol) in 10 mL of CH2Cl2 was cooled to −78° C. and treated with boron trichloride 1M in CH2Cl2 (1.9 mL, 1.9 mmol). The reaction mixture was allowed to warm to ambient temperature. The reaction mixture was partitioned with 1N HCl and the organic phase was concentrated in vacuo. The residue was purified by flash chromatography to give 0.18 g of title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]([CH3:15])[NH2:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][N:13]([CH3:15])[NH:14][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)Nc1ccc([N+](=O)[O-])c(N)c1
Temperature: 125 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (20 g, 116 mmol), N,N-dimethyl-hydrazine (44 mL, 580 mmol) and anhydrous potassium carbonate (17.6 g, 128 mmol) in N,N-dimethylacetamide (50 ml) were stirred at 125° C. under nitrogen for 3 days Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured onto cold water (400 mL), stirred vigorously and incubated at 4° C. overnight. The resulting brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. This was then slurried in diethyl ether, filtered, washed with additional diethyl ether, dried to afford 5-(N′,N′-Dimethyl-hydrazino)-2-nitro-phenylamine (10.7 g, 47% yield) as a yellow solid. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2N)([C:10]#[CH:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.N([O-])=O.[Na+]>O>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([C:10](=[CH2:11])[C:14]3[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=3[O:12]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C#CC1(Oc2ccc(F)cc2N)CCN(C(C)=O)CC1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: C=C1c2cc(F)ccc2OC12CCN(C(C)=O)CC2
Reaction time: 0.46 h
Yield: 25.7 %

Procedure:
A stirred suspension of 19.4 g of 1-N-acetyl-4-(2-amino-4-fluorophenoxy)-4-ethynylpiperidine, 91 ml of water and 6.9 ml of hydrochloric acid was heated at reflux until the starting material dissolved. The mixture was then cooled to below 10°. To the mixture was added slowly, dropwise, 7.6 ml of concentrated hydrochloric acid at a rate such that the temperature did not exceed 10°. To the mixture was then added dropwise a solution of 5.09 g of sodium nitrite in 11 ml water, maintaining the temperature below 10°. The mixture was stirred at 5°-10° for 25-30 min and subsequently filtered into 145 ml of 30% hypophosphorous acid. The mixture was allowed to stand overnight in a cold room and at room temperature for 8 hr. The mixture was diluted with water, extracted twice with ether, washed with saturate sodium chloride solution and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was evaporated. The residue was filtered through 200 g of alumina and eluted with 600 ml of ether. Evaporation of solvent provided an oil, which crystallized on standing to yield 4.72 g (25.7%) of product, mp 114°-116°.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].O[C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:8][CH:7]=1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CC1C=CC=CC=1C>[Cl:4][C:1]([C:15]1[CH:16]=[CH:17][C:12]([C:10]([C:9]2[CH:18]=[CH:19][CH:6]=[CH:7][CH:8]=2)=[O:11])=[CH:13][CH:14]=1)=[O:2]
Reactant: O=C(Cl)Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
A total of 3.4 kg of phosgene was passed through a solution of 4 kg of 4-hydroxybenzophenone and 190 g of benzyltrimethylammonium chloride in 11.4 kg of o-xylene over a period of 5 hours, during which time the internal temperature was raised from 95° to 120° C. The introduction of phosgene was then stopped, and stirring was continued for 30 minutes at 115° C. Before the product was worked up, the excess phosgene was expelled with nitrogen. The salt (catalyst) which precipitated toward the end of the reaction was filtered off, and the solvent was removed by distillation. There were obtained 4.9 kg (93%) of yellowish 4-chloroformylbenzophenone having a melting point of 67°-72° C. This crude product having a Cl content of 12.69% (theory=13.60%) was used unpurified as starting material for subsequent reactions.
Reaction SMILES: C([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]1([C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14]1)[CH2:8][CH2:7]2)(O)=O.[N-:20]=[N+]=[N-].[Na+].[OH-].[Na+]>OS(O)(=O)=O>[NH2:20][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]1([C:17](=[O:18])[NH:16][C:15](=[O:19])[NH:14]1)[CH2:8][CH2:7]2
Reactant: O=C1NC(=O)C2(CCc3cc(C(=O)O)ccc3C2)N1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2c(c1)CCC1(C2)NC(=O)NC1=O
Temperature: 50 °C

Procedure:
A stirred mixture of (±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione (described in Intermediate 1) (1.50 g, 5.76 mmol), and sodium azide (749 mg, 11.53 mmol) in conc. H2SO4 (30 mL) was heated to 50° C. for 2 h, then allowed to cool to ambient temperature. The mixture was adjusted to pH 8 by addition of 6 N aqueous NaOH and concentrated in vacuo to precipitate a solid. The precipitate was collected by filtration and washed extensively with H2O. Drying in vacuo afforded the title compound as a light brown solid. MS: m/z=232 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([O:23]C)=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[C:21]([OH:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)cc2C(=O)O)CC1
Temperature: 50 °C
Yield: 93.3 %

Procedure:
4-(4-Fluoro-2-methoxycarbonyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (5.5 g, 16.2 mmol) is dissolved in THF (40 mL) and 1 M aqueous LiOH (33 mL) is added at room temperature. The solution is warmed to 50° C. for 3 h. THF is removed under reduced pressure and the aqueous part is washed with 50% EtOAc in hexane. The aqueous part is acidified with 1 M aqueous HCl followed by extraction with EtOAc (3×50 mL). Combined organic layer is dried over anhydrous MgSO4 and concentrated under reduced pressure to afford 4-(2-carboxy-4-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a solid (4.9 g, 98%).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:16])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+]>O>[CH2:6]([O:5][CH2:4][CH:3]1[CH2:2][O:16]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCOCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCOCC1CO1
Temperature: 40 °C
Yield: 67 %

Procedure:
To the crude 1-chloro-3-decyloxy-2-propanol prepared as described above and cooled to 40° C. was added NaOH (50% aqueous, 176 g, 2.2 mole) and water (44 g). The temperature rose to 50° C., then the mixture was heated to 85° C.-90° C. for three hours. Analysis by GC showed the crude product contained 11% unreacted alcohol and 75% of the expected epoxide. Water (200 ml) was added to dissolve precipitated salt. The aqueous phase was separated (pH 14) and the organic phase washed with 5% NaCl solution to pH 7-8 (2 ×400 ml). The crude product (435 g, 102%) was fractionally distilled at 12 mmHg to yield 286 g of (decyloxy)methyloxirane (67% overall based on epichlorohydrin). GC showed the product was 97% pure.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[N:14]2[C:15](=[O:27])[C:16](=[O:26])[NH:17][C:18]3[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].F[B-](F)(F)F.[O:33]=[N+:34]=[O:35]>ClCCl>[CH2:6]([O:5][P:4]([CH:9]1[N:14]2[C:15](=[O:27])[C:16](=[O:26])[NH:17][C:18]3[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[C:21]([N+:34]([O-:35])=[O:33])=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: O=[N+]=O
Reactant: CCOP(=O)(OCC)C1CCc2cc(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCc2c([N+](=O)[O-])c(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Reaction time: 15 h
Yield: 52.1 %

Procedure:
812 mg of 9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester is dissolved in 15 ml of dichloromethane and mixed with 531 mg of nitronium tetrafluoroborate at room temperature. It is stirred for 15 hours and concentrated by evaporation. The residue is taken up in ethyl acetate and washed with 5% sodium bicarbonate solution. After column chromatography, 470 mg of 8-nitro-9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester of melting point 254° C. is obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25](S(C)(=O)=O)[N:24]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([CH2:6][C:7]2[C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[N:9][CH:10]=[CH:11][CH:12]=2)[N:24]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cc1cccnc1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(OC)nc(Cc2cccnc2NC(=O)OC(C)(C)C)n1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (19.2 ml of a 2.5M solution in hexane) was added dropwise to a stirred suspension of the product of stage (a) above (5.0 g) in dry tetrahydrofuran (100 ml) under nitrogen at -70° C. The mixture was stirred at -70° C. for 20 minutes and then at 5° C. for 3 hours. It was then cooled to -70° C. and treated with 4,6-dimethoxy-2-methylsulfonylpyrimidine (5.42 g), and the mixture was stirred at -70° C. for 1 hour, then at room temperature overnight. Saturated ammonium chloride solution (500 ml) was added, and the mixture was extracted with ethyl acetate (2×100 ml). The combined extracts were washed with saturated sodium chloride solution (50 ml), dried and evaporated to give an orange oil which was triturated with hexane to give 5.35 g of the desired product as a pale yellow solid, mp 89°-92° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][C:22]1N(C)N=NN=1.ClC1[C:38](=[O:39])C2C(=CC=CC=2)C(=O)C=1NC1C=CC(S(NC2C=C(C)C=CC=2)(=O)=O)=C(OC)C=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][CH2:38][OH:39]
Reactant: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: COc1cc(NC2=C(Cl)C(=O)c3ccccc3C2=O)ccc1S(=O)(=O)Nc1cccc(C)c1
Product: O=S(=O)(Nc1cc(SCCO)c(O)c2ccccc12)c1cccs1

Procedure:
5.2.53 N-(4-hydroxy-3-(2-hydroxyethylthio)naphthalen-1-yl)thiophene-2-sulfonamide (14k) was prepared according to the procedure for 14d except using N-(3-(2-hydroxyethylthio)-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13k), which, after purification via flash chromatography (Hex/EtOAc), afforded the title compound 20.3 mg (53.1%) as a grey solid, m.p.: ° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([C:2]2[CH:3]=[C:4]([C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=4[F:22])[N:12]=[N:13][CH:14]=3)[CH:5]=[CH:6][C:7]=2[F:8])[C:29]=1[C:30]#[N:31]
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Reactant: CC1(C)OB(c2cccc(F)c2C#N)OC1(C)C
Product: N#Cc1c(F)cccc1-c1cc(-c2cnnc(-c3ccc(F)cc3F)n2)ccc1F

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine was coupled to 6-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile by the method of Example 12 to give 3,2′-difluoro-5′-[3-(2,4-difluorophenyl)-[1,2,4]triazin-5-yl]biphenyl-2-carbonitrile as a yellow solid: δH (400 MHz, CDCl3) 6.99-7.11 (2H, m), 7.32-7.40 (2H, m), 7.47 (1H, t, J 9.2 Hz), 7.70-7.76 (1H, m), 8.30-8.40 (3H, m), 9.66 (1H, s); m/z(ES+) 407.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[CH3:21][C:22](N)([CH3:25])[CH2:23][NH2:24].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:9])[C:18]3=[N:20][C:22]([CH3:25])([CH3:21])[CH2:23][N:24]3[C:10](=[O:17])[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]2=3)=[CH:6][CH:7]=1
Reactant: CC(C)(N)CN
Reactant: NC(=O)C1(c2ccc(Cl)cc2)OC(=O)c2ncccc21
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CN2C(=O)c3ncccc3C(O)(c3ccc(Cl)cc3)C2=N1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A mixture of 3-(4-chlorobenzoyl)-2-pyridinecarboxylic acid (13 g), potassium cyanide (4.56 g), and acetic acid (30 mL) was heated at 120-125 C. in a sealed pressure bottle for 48 h. After cooling to ambient temperature, the mixture was poured into ice water. The precipitated solid was dissolved in ethyl acetate, washed with sodium bicarbonate saturated solution then with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was treated with ether. The formed solid was collected by filtration and dried to give 10.2 g of 5-(4-chlorophenyl)-7-oxo-5,7-dihydrofuro[3,4-b]pyridine-5-carboxamide. A mixture of 5-(4-chlorophenyl)-7-oxo-5,7-dihydrofuro[3,4-b]pyridine-5-carboxamide (5 g), 2-methyl-1,2-diamino propane (6.3 g), and toluene (80 mL) was heated at reflux for 18 h in a flask equipped with a water separator. The mixture was cooled to ambient temperature. The precipitated material was collected by filtration and dried to give the title compound (2.4 g), m.p. 257-260° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 4-tert-Butyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR: δ 1.29 (s, 9H), 2.94 (s, 3 H), 7.42-7.46 (m, 3H), 7.51 (d, J=8.8 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.62 (d, J=7.2 Hz, 1 H), 7.66 (d, J=6.8 Hz, 1H), 7.74 (d, J=8.0 Hz, 1 H), 8.1 (bs, 1H). MS: M/z 443.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.C1(P(=[CH:34][C:35]([O:37][CH3:38])=[O:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:34]/[C:35]([O:37][CH3:38])=[O:36])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Product: COC(=O)/C=C/c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.3 %

Procedure:
Added to a solution of 8.68 g (0.044 mol) of 3,4,5-trimethoxybenzaldehyde in 50 ml of methanol were 15.0 g (0.044 mol) of methyl (triphenylphosphoranylidene)acetate, followed by stirring at room temperature for 18 hours. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (silica gel: "MERCK #9385", eluent: 1:1 mixed solvent of ethyl acetate and hexane), whereby 11.24 g of the title compound were obtained as a colorless solid (quantitative yield).