Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)C(F)(F)C(F)(F)C(F)(F)F.[F:14][C:15]([F:25])([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH2:16][OH:17].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:14][C:15]([F:25])([C:18]([F:23])([F:24])[C:19]([F:20])([F:21])[F:22])[CH2:16][O:17][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(F)(F)C(F)(F)C(F)(F)F
Agent: FC(F)(F)C(F)(F)C(F)(F)C(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)C(F)(F)C(F)(F)F)cc1

Procedure:
For example, to prepare 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane, 2,2,3,3,4,4,4-heptafluorobutanol and p-toluenesulfonyl chloride are reacted to form 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate. Then, N-methylpyrrolidone, lithium chloride, and the 2,2,3,3,4,4,4-heptafluorobutyl-p-toluenesulfonate are reacted to form 1-chloro-2,2,3,3,4,4,4-heptafluorobutane. Finally, chlorine and the 1-chloro-2,2,3,3,4,4,4-heptafluorobutane are reacted to form the 1,1-dichloro-2,2,3,3,4,4,4-heptafluorobutane.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[C:10]([CH:11]=O)=[CH:9][N:8]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[N:7]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.Cl.[NH2:27]O.C([O-])=O.[Na+].O>C(O)=O>[S:1]1[CH:5]=[C:4]([C:6]2[C:10]([C:11]#[N:27])=[CH:9][N:8]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[N:7]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2
Reactant: NO
Reactant: O=Cc1cn(-c2ccc(C(=O)O)cc2)nc1-c1csc2ccccc12
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#Cc1cn(-c2ccc(C(=O)O)cc2)nc1-c1csc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.4 %

Procedure:
A solution of 4-(3-benzo[b]thiophene-3-yl-4-formylpyrazole-1-yl)benzoic acid (0.26 g), hydroxylamine hydrochloride (0.058 g) and sodium formate (0.10 g) in formic acid (5 mL) was heated under reflux for 24 hours. To this reaction mixture was added water at room temperature, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. This obtained residue was dissolved with pyridine (5 mL), to this mixture was added trifluoroacetic anhydride (0.48 g) in a dropwise manner under ice cooling, and this mixture was stirred at room temperature for 5 hours. To this reaction mixture was added 2 mol/L hydrochloric acid, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was washed with n-hexane/diethyl ether=1/1 to give the title compound (0.13 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1.[Cl:24]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[C:23]=1[Cl:24]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21
Reactant: ClCl
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1ccc(N)c2Cl
Temperature: 25 °C

Procedure:
17 g (0.052 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one in 100 ml of glacial acetic acid are treated slowly with a solution of 4 g of chlorine gas in 50 ml of glacial acetic acid. The reaction mixture is stirred at room temperature, evaporated after 60 minutes and the residue is treated with aqueous ammonia and methylene chloride. After extracting the aqueous phase with methylene chloride, the organic extract is dried and evaporated. The crude product is purified by chromatography on 600 g of silica gel with methylene chloride and methylene chloride/ethyl acetate (5:1) as the elution agent. From ethyl acetate/ether/n-hexane there is obtained 7-amino-6-chloro-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 195°-196°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].O[NH:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23]2)=[NH:19].C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23]4)[N:19]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=N)NO)cc2C1
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3ccc4c(c3)CN(C(=O)OC(C)(C)C)C4)no2)cc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.6 %

Procedure:
A mixture of 3,4-diethoxybenzoic acid (0.19 g; 0.904 mmol), a product of Step D (0.25 g; 0.904 mmol) and EDC (0.27 g; 1.4 mmol) in anhydrous DMF (2 ml) was stirred at ˜60° C. for 1 h, then cooled to room temperature and diluted to 20 ml with EtOAc. This was washed with H2O (2×5 ml), brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness. The residue was diluted to 3 ml with anhydrous diglyme and 1M TBAF in THF (0.5 ml) was added and the resulting mixture was stirred at ˜80° C. for 1 h, then solvents were removed in vacuo. The residue was purified by crystallization from MeOH, to give the title compound (0.084 g; 20%) as greyish solid. 1H-NMR (CDCl3) 1.4-1.6 (m, 15H+H2O); 4.14-4.24 (m, 4H); 4.7-4.76 (m, 4H); 6.97 (d, 1H, J=6 Hz); 7.32-7.4 (m, 1H); 7.66 (d, 1H, J=3 Hz); 7.78 (dd, 1H, J=3, 9 Hz); 8.02-8.08 (m, 2H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[OH:12][OH:13]>C(OCC)C>[CH:9]1[CH:10]=[C:2]([C:1]([OH:6])=[O:11])[C:3]([C:4]([O:12][OH:13])=[O:5])=[CH:7][CH:8]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: OO
Solvent: CCOCC
Product: O=C(O)c1ccccc1C(=O)OO
Temperature: 25 °C

Procedure:
To the mixture containing phthalic anhydride (2.22 g, 0.015 mole) and diethyl ether (25 mL), hydrogen peroxide solution (3.4 g; 0.03 moles; as 30% aqueous solution) was added and the reaction mixture was stirred at 25° C. to dissolve the anhydride. The reaction mixture was transferred to a separating funnel, ether layer was separated and aqueous layer was extracted with ether (3×10 mL). Combined ether extracts are dried over sodium sulfate and this solution of monoperphthalic acid was used.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 2.4 g.), conc. hydrochloric acid (1.84 g.), methaol (36 ml.) and tetrahydrofuran (30 ml.) was stirred at 30° l C. for 2 hours. The resultant solution was concentrated in vacuo. Water (60 ml.) was added to the residue and the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-n-hexyloxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.86 g.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:16]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][S:21]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:22])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1cccc(NS(=O)(=O)c2cccnc2)c1
Yield: 104.7 %

Procedure:
A solution of tert-butyl-3-aminobenzoate (100 mg, 0.5 mmol) and pyridine-3-sulfonylchloride (110 mg, 0.5 mmol) in pyridine (5 ml) was heated to 50° C. for 90 min. On cooling, the reaction was diluted with toluene (100 ml) and concentrated in vacuo. This was repeated with further aliquots of toluene until all the pyridine had been removed to afford the title compound as a yellow oil (175 mg). HPLC retention time 4.27 min. Mass spectrum (ES+) m/z 335 (M+H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].N>>[C:1]1([C@@H:7]2[CH2:11][NH:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8]2)[CH2:2][CH:3]=[CH:4][CH2:5][CH:6]=1
Reactant: O=C(O)[C@@H]1C[C@H](c2ccccc2)CN1
Agent: N
Agent: [Li]
Product: O=C(O)[C@@H]1C[C@H](C2=CCC=CC2)CN1

Procedure:
cis-4-Phenyl-L-proline is treated with lithium and ammonia according to the procedure of Example 1 of U.S. Pat. No. 3,485,819 to yield cis-4-(1,4-cyclohexadienyl)-L-proline.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[F:21][C:22]([F:31])([F:30])[C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:28][C:25]4[CH:24]=[C:23]([C:22]([F:31])([F:30])[F:21])[S:27][CH:26]=4)=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2]
Reactant: OCc1csc(C(F)(F)F)c1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.5 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (300 mg), (5-(trifluoromethyl)-3-thienyl)methanol (352 mg) and triphenylphosphine (877 mg) in THF (10 ml) was added bis(2-methoxyethyl) azodicarboxylate (783 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from IPA-IPE to give the title compound (70.0 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].N1C=CN=C1.Cl[Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18]>C1COCC1.CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:9])([CH3:1])[CH2:7][O:8][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18]
Reactant: COC(=O)C(C)(C)CO
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 20 h
Yield: 86.7 %

Procedure:
To a solution of 6.76 mL (53 mmol) of methyl 2,2-dimethyl-3-hydroxypropionate in anhydrous THF/DMF (110 mL, 10/1) are added 4.33 g (63.6 mmol) of imidazole and 11.3 mL (53 mmol) of chlorotriisopropylsilane under nitrogen atmosphere. After stifling at room temperature for 20 h, the reaction mixture is concentrated under reduced pressure and the residue is dissolved in TBME (175 mL). The organic layer is washed with water (30 mL), brine (30 mL), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to afford 13.25 g of 2,2-dimethyl-3-triisopropylsilanyloxy-propionic acid methyl ester as a yellow oil, which is used in the next step without further purification. Yield: 79%; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.01-1.07 (21H, m), 1.18 (6H, s), 3.66 (3H, s), 3.69 (2H, s)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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]>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=2[C:2]2[CH:3]=[C:4]([O:10][C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[CH2:18][CH2:19]1
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Reactant: Cn1cc(Oc2cc(Br)cn(C)c2=O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(Oc2cc(-c3cc(S(C)(=O)=O)ccc3OCC3CC3)cn(C)c2=O)cn1
Temperature: 75 °C
Yield: 74.1 %

Procedure:
A mixture of 5-bromo-1-methyl-3-(1-methylpyrazol-4-yl)oxypyridin-2-one (30 mg, 0.11 mmol), 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (44 mg, 0.16 mmol), Pd(dppf)Cl2 (8 mg) and K3PO4 (57 mg, 0.26 mmol) in dioxane (1.5 mL) and water (200 uL) was purged with nitrogen, capped, and heated to 75° C. for 12 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (35 mg, 78%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.12-0.36 (m, 2H) 0.46-0.61 (m, 2H) 0.99-1.17 (m, 1H) 3.14-3.23 (m, 3H) 3.55-3.60 (m, 3H) 3.75-3.83 (m, 3H) 3.88-3.96 (m, 2H) 7.18-7.32 (m, 2H) 7.32-7.40 (m, 1H) 7.68-7.91 (m, 4H). LCMS (M+H)+=430.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:17]([NH:19][NH2:20])=[O:18]>C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:17]([NH:19][N:20]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:18]
Reactant: NNC(=O)c1cc(Cl)cc(Cl)c1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 100 °C
Yield: 69 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 3,5-dichlorobenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 159 mg of the title compound (69%) as a orange solid in 90% purity by HPLC (Rt: 5.86, 6.66, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([O:1][C:2]2[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)=[O:6])=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 95.7 %

Procedure:
Using 3-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide (2.81 g, 10.0 mmol), 1-fluoro-4-nitrobenzene (1.55 g, 11.0 mmol) and potassium carbonate (1.38 g, 10.0 mmol), and in the same manner as in Example A25(iii), the title compound (3.85 g, 96%) was obtained as a pale-yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:13][NH2:14])[CH:6]=[CH:7][C:8]=1[S:9](=[O:12])(=[O:11])[NH2:10].[F:15][C:16]([F:35])([F:34])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[C:23]([Cl:32])[CH:22]=1)=O>>[Cl:32][C:23]1[CH:22]=[C:21]([C:19]2[N:13]([C:5]3[CH:6]=[CH:7][C:8]([S:9]([NH2:10])(=[O:11])=[O:12])=[C:3]([F:2])[CH:4]=3)[N:14]=[C:17]([C:16]([F:35])([F:15])[F:34])[CH:18]=2)[CH:26]=[CH:25][C:24]=1[C:27]1[O:28][CH:29]=[CH:30][CH:31]=1
Reactant: NNc1ccc(S(N)(=O)=O)c(F)c1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(-c2ccco2)c(Cl)c1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)c(Cl)c2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 60 using 3-fluoro-4-sulfamoylphenylhydrazine hydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and 4,4,4-trifluoro-1-[3-chloro-4-(2-furyl)phenyl]butane-1,3-dione instead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step 2.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[Cl:21])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.Cl[CH2:23][CH:24]=O>CN(C=O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:10]2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]3[CH:23]=[CH:24][N:1]=[C:2]3[C:11]=2[Cl:12])=[C:15]([Cl:21])[CH:16]=1
Reactant: COC(=O)c1cnc(N)c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: O=CCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 80 °C

Procedure:
To a suspension of methyl 6-amino-4-(4-bromo-2-chlorophenylamino)-5-chloronicotinate (966 mg, 2.48 mmol) in 13 ml DMF was added chloroacetaldehyde (50% aq. solution, 0.32 ml, 396 mg, 2.52 mmol) and the mixture was heated in a closed vessel to 80° C. for 3 h. The dark solution was cooled to room temperature and the DMF was removed by vacuum distillation. The residue was dissolved in THF and directly purified by column chromatography (EtOAc/hexanes 10:1+2% TEA) which delivered the desired product (638 mg, 62%). Rf (EtOAc/Hexanes 10:1)=0.4. 1H-NMR (500 MHz, MeOH-D3): δ=9.16 (s, 1H), 7.86-7.85 (d, 1H), 7.54-7.53 (d, 1H), 7.50-7.48 (d, 1H), 7.19-7.17 (dd, 1H), 6.51-6.50 (d, 1H), 3.82 (s, 3H).
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24]>CC(=O)OCC.O>[CH3:24][CH:23]([CH3:25])[CH2:22][CH2:21][O:7][C:4]1[CH:5]=[CH:6][C:1]([OH:8])=[CH:2][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(O)cc1
Temperature: 60 °C

Procedure:
A mixture of benzene-1,4-diol (20.0 g), DMF (100 mL), cesium carbonate (59.2 g) and 1-bromo-3-methyl-butane (13.7 g) was heated to 60° C. for 12 hours. After the mixture reached room temperature, it was distributed between water and EA. The organic phase was washed twice (water), dried (Na2SO4) and concentrated. The residue was purified by chromatography (SiO2; EA/heptane 1:2) to provide the subtitle compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13].S([C:34]#[N:35])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[N:14]1([C:12](=[O:13])[CH2:11][S:10][C:2]2[N:3]([C:34]#[N:35])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(CSc1nc2ccccc2[nH]1)N1CCCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: C1CCOC1
Product: N#Cn1c(SCC(=O)N2CCCc3ccccc32)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
To a solution of compound 16 (0.52 g, 1.6 mmol, 1.0 eq) in 6 mL of dry THF stirred at −78° C. under N2 LiHMDS (1.7 mL, 1.05 eq) was added. The mixture was stirred for 15 min. at −78° C. and then TosCN (306 mg, 1.05 eq. in 1 mL of THF) was added dropwise. The reaction mixture was quickly allowed to warmed up to RT. The reaction mixture was quenched with 10 mL of NH4Cl (sat.), extracted into ethyl acetate, washed with brine and concentrated to give creamy solid. The crude was purified by column chromatography (ethyl acetate/hexanes) to give 79 (330 mg, 59%). MP=153.3-154.2° C. Anal/Calcd. for C19H16H4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20. Found C, 65.59; H, 4.66; N, 16.06, S 9.16.
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20](C(=O)C)[CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.C(=O)([O-])O.[Na+]>C(O)C>[CH:3]1([NH:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH3:21])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)NC2CCCCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CNc1ccc(S(=O)(=O)NC2CCCCCC2)cc1
Yield: 44 %

Procedure:
Ethanol (20 ml) and 1N aqueous sodium hydroxide (20 ml) were added to the obtained white crystal [N-cycloheptyl-4-(N-acetyl-N-methylamino)benzenesulfonamide] (4.72 g, 90%). The obtained mixture was heated under reflux overnight, acidified by the addition of 1N aqueous hydrochloric acid and adjusted to pH 8 with sodium hydrogencarbonate. The resulting mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate and concentrated to precipitate a crystal. This crystal was recovered by filtration and washed with ether to give the title compound as a white crystal (1.92 g, 44%). m.p. (°C.): 111 to 113
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>>[Cl:1][C:2]1[C:3]([C:4]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][CH3:11])=[CH:14][C:15]=2[N+:20]([O-:22])=[O:21])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1ccc(NC(=O)c2cccnc2Cl)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-chloronicotinoyl chloride and 4-methoxy-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 10.76 (s, 1H), 8.78 (d, J=9.3, 1H), 8.58-8.55 (m, 1H), 8.13-8.09 (m, 1H), 7.73 (d, J=3.0, 1H), 7.45-7.40 (m, 1H), 7.34-7.28 (m, 1H0, 3.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(NCC)C.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#[CH:38]>[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.CN(C)C=O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:38]#[C:37][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#Cc1ccccn1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#Cc3ccccn3)c21

Procedure:
A flame-dried flask under an atmosphere of nitrogen gas containing N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Preparation # 15) (0.28 g) is treated with copper (I) iodide (0.01 g), dichlorobis(triphenylphosphine)palladium (II) (0.03 g), dimethylformamide (DMF) (3 mL) and diethylamine (3 mL). The resulting stirring suspension is treated with 2-ethynylpyridine (0.1 mL). After stirring overnight, the suspension is concentrated under reduced pressure and then in vacuo. The residue is adsorbed onto silica gel and is flash column chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product-containing fractions are combined and concentrated under reduced pressure. The resulting material is crystallized from a mixture of methanol:acetonitrile to afford the title compound (0.22 g) as a white solid.