Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([Sn](CCCC)(CCCC)CCCC)[N:38]=1.N#N>CN(C=O)C.[Cu]I.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>[Cl:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[O:15][C:14]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=5)=[N:13][N:12]=4)[CH:9]=3)[N:4]([S:26]([C:29]3[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=3)(=[O:27])=[O:28])[CH:3]=2)[N:38]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccc(Cl)n1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3nccc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 80 °C
Yield: 52.4 %

Procedure:
A solution of 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (3.0 g, 5.20 mmol) and 4-chloro-2-(tributylstannyl)pyrimidine (2.5 g, 6.00 mmol) in DMF was bubbled with N2 for 15 min. To the above mixture was added CuI (476 mg; 2.50 mmol) and Pd(PPh3)4 (577 mg, 0.52 mmol) and N2 gas was bubbled for another 15 min. The reaction was heated at 80° C. for 1 h. The reaction was quenched with H2O and the resulting precipitate was filtered, washed with H2O and dried. The crude material was purified with silica gel chromatography (eluting with 30% EtOAc in Hex) to give 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (1.6 g, 53.3%). MS (ESI, pos. ion) m/z: 586.6 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 8.96 (s, 1H), 8.91 (d, J=4 Hz, 1H), 8.62 (s, 1H), 8.35 (m, 1H), 8.17 (d, J=8 Hz, 1H), 8.10 (d, J=8 Hz, 2H), 7.91 (d, J=8 Hz, 1H), 7.65-7.62 (m, 2H), 7.45-7.43 (m, 6H), 7.33 (d, J=8 Hz, 2H), 6.90 (d, J=8 Hz, 2H), 4.38 (d, J=5.6 Hz, 2H), 3.72 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([F:18])=[C:4]([F:17])[C:5]([F:16])=[C:6]2[C:11]=1[C:10]([F:12])=[C:9](F)[C:8]([F:14])=[C:7]2[F:15].[OH-].[K+].C([OH:25])(C)(C)C>O>[F:1][C:2]1[C:3]([F:18])=[C:4]([F:17])[C:5]([F:16])=[C:6]2[C:11]=1[C:10]([F:12])=[C:9]([OH:25])[C:8]([F:14])=[C:7]2[F:15]
Reactant: CC(C)(C)O
Reactant: Fc1c(F)c(F)c2c(F)c(F)c(F)c(F)c2c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Oc1c(F)c(F)c2c(F)c(F)c(F)c(F)c2c1F
Reaction time: 3.5 h
Yield: 72 %

Procedure:
For about 3.5 hours, a mixture of 25 g octafluoronaphthalene (PCR Inc.; Gainesville, Fla.), 12 g KOH, and 100 mL tertiary butyl alcohol was refluxed. Water was added, and the tertiary butyl alcohol was distilled from the reaction mixture. The residue remaining in the flask was acidified with HCl and the aqueous mixture was extracted three times with 75 mL dichloromethane. The combined extracts were washed twice with 150 mL distilled water, dried over MgSO4, and rotary evaporated to yield a semi-crystalline solid. Recrystallization from hot hexanes gave 18 g heptafluoro-2-naphthol (72% yield) as slightly tan colored crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[K+].[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15])([O-:10])=[O:9].Cl.[Na+].[Cl-]>C(#N)C.O>[N+:8]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:15])([O-:10])=[O:9]
Reactant: NCC(=O)O
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)CNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 90 %

Procedure:
Glycine (20 g, 266 mmol) was added to water (200 mL), followed by potassium hydroxide (20 g, 357 mmol) and cooled to 0° C. in an ice bath. To this solution was added 3-nitrobenzoyl chloride (20 g, 108 mmol) in acetonitrile (20 mL) drop-wise over a 10 minute period. After the reaction was complete (3-4 hours) concentrated hydrochloric acid was added until pH=2 followed by saturated aqueous NaCl (75 mL). The product was filtered, washed with water and air dried (22 g, 90% yield). 1H-NMR (d6 -DMSO) δ 3.92 (d, 2H, J=6.1), 7.9 (t, 1H, J=7.9), 8.3 (t, 1H, J=5.6), 8.35 (m, 2H), 8.69 (s, 1H), 9.25 (t, 1H, J=7.2 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:7](=[O:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:5]2.[C-:28]#[N:29].[K+]>CN(P(N(C)C)(N(C)C)=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>[O:15]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:28]#[N:29])=[CH:10][C:9]=2[C:11]([F:14])([F:12])[F:13])[CH2:5][N:6]1[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=1
Reactant: [C-]#N
Reactant: O=C1c2c(cc(Cl)cc2C(F)(F)F)CN1Cc1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1cc2c(c(C(F)(F)F)c1)C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
A mixture of 5-chloro-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.123 g, 0.3 mmol), Pd(PPh3)4 (0.035 g, 0.03 mmol), KCN (0.057 g, 0.88 mmol), and KI (0.125 g, 0.75 mmol) in HMPA (3 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate afforded 1-Oxo-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-1H-isoindole-5-carbonitrile (0.112 g, 93%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.39 (s, 2H), 4.72 (s, 2H), 7.22 (d, 2H), 7.37 (d, 2H), 7.89 (s, 1H), 8.06 (s, 1H) GC-MS: m/z 400 (M)+, 379 (M−21)+.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].O.[NH2:11][NH2:12]>C(O)(=O)C.O>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[NH:12][N:11]=1)[CH3:1]
Reactant: CCC(=O)CC(=O)CC
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(CC)[nH]n1
Yield: 91.7 %

Procedure:
A solution of 3,5-heptanedione (2.4 g, 18.8 mmol) and hydrazine hydrate (1.0 g, 19.0 mmol) and acetic acid (1 drop) in water (10 mL) was heated to reflux for 1 h. The reaction mixture was then cooled in an ice bath to form a white precipitate. The precipitate was then filtered, dissolved in chloroform and dried over MgSO4. The resulting reaction was concentrated under reduced pressure to provide 2.14 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1>>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:18]2[CH:19]=[N:14][CH:15]=[N:16][CH:17]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc(OC)c(C=O)cc1Br
Reactant: OB(O)c1cncnc1
Product: COc1cc(OC)c(-c2cncnc2)cc1C=O
Yield: 98 %

Procedure:
Ex-31A: 2,4-Dimethoxy-5-pyrimidin-5-yl-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and pyrimidine-5-boronic acid in a similar manner as described in Ex-3A, 98% yield. 1H-NMR (CDCl3) δ 10.37 (s, 1H), 9.15 (s, 1H), 8.87 (s, 2H) 7.86 (s, 1H), 6.57 (s, 1H), 4.03 (s, 3H), 3.96 (s, 3H).
Reaction SMILES: [CH2:1]([S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[NH2:25][NH2:26]>CO>[CH2:1]([S:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:25][NH2:26])=[O:15])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NN
Reactant: CCCCCCCCSc1ccc(C(=O)OC)cc1C(F)(F)F
Solvent: O
Solvent: CO
Product: CCCCCCCCSc1ccc(C(=O)NN)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The crude methyl 4-(octylthio)-3-(trifluoromethyl)benzoate was dissolved in 2 mL of MeOH and treated with 2 mL of hydrazine hydrate. The reaction mixture was left to stir at 80° C. for 1 hour, poured into ice-water. The solid was filtered, washed with H2O and dried under vacuum to provide the 4-(octylthio)-3-(trifluoromethyl)benzohydrazide 3a as a yellow solid. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.69 min with gradient 10-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=349.3; 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.13 (d, 1H, J=1.6 Hz), 8.03 (dd, 1H, J=8.2 Hz, J=1.6 Hz), 7.67 (d, 1H, J=8.8 Hz), 4.59 (s, 2H), 3.13 (t, 2H, J=7.2 Hz), 1.61 (pentet, 2H, J=6.8 Hz), 1.44-1.36 (m, 2H), 1.30-1.20 (m, 8H), 0.85 (t, 3H, J=6.8 Hz).
Reaction SMILES: [F-].[Cs+].[F:3][C:4]1[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:7](I)=[C:8]([OH:10])[CH:9]=1.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1)CCC>CN(C)C=O.C(OCC)(=O)C.O.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.[Cu]I>[F:3][C:4]1[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:7]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)=[C:8]([OH:10])[CH:9]=1
Reactant: Oc1cc(F)c(C(F)(F)F)cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(F)c(C(F)(F)F)cc1-c1ccnnc1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 62.5 %

Procedure:
Cesium fluoride (570 mg, 3.8 mmol), tetrakis(triphenylphosphine)palladium(0) (220 mg, 0.19 mmol), and copper(I) iodide (72 mg, 0.38 mmol) were added to a solution of 5-fluoro-2-iodo-4-(trifluoromethyl)phenol (Preparation 8, 579 mg, 1.89 mmol) and 4-(tributylstannyl)pyridazine (770 mg, 2.1 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was heated at 45° C. under an atmosphere of argon. After 1.5 hours, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate and water, and filtered through diatomaceous earth. The layers were separated, and the organic layer was washed with water, aqueous lithium chloride, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in dichloromethane, concentrated onto diatomaceous earth, and purified by automated silica gel flash chromatography (100% dichloromethane to 10% methanol in dichloromethane gradient elution) to afford the title compound as a tan solid (305 mg).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.[CH2:12]([OH:15])[CH:13]=[CH2:14].C(=O)([O-])O.[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([CH2:14][CH2:13][CH:12]=[O:15])=[CH:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: C=CCO
Reactant: CC(C)Nc1ccc(I)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Nc1ccc(CCC=O)cn1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A mixture of 1.80 g (6.87 mmol) of (5-iodopyridin-2-yl)isopropylamine, 1.40 mL (10.7 mmol) of prop-2-en-1-ol, 1.39 g (16.49 mmol) of sodium hydrogen carbonate, 1.72 g (6.18 mmol) of tetrabutylammonium chloride, and 46 mg (0.20 mmol) of palladium (II) acetate in 10 mL of DMF was stirred under argon for 20 hours at 50° C. The reaction mixture was diluted with water and EtOAc, the organic phase was separated off, washed several times with water, and dried over magnesium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, PE/EtOAc 1:1). Yield: 300 mg (23% of theoretical); ClIH16N2O (M=192.258); calc.: molpeak (M+H)+:193; found: molpeak (M+H)+:193; HPLC-MS: 3.58 minutes (method G).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH2:20]>C(O)(C)C>[ClH:2].[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][CH:4]=[C:3]2[NH:20][C:19]1[CH:21]=[C:22]([OH:26])[C:23]([CH3:25])=[CH:24][C:18]=1[F:17]
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2nccc(Nc3cc(O)c(C)cc3F)c2cc1OC
Yield: 28.6 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline hydrochloride (360 mg, 1.4 mmol), (prepared as described for the starting material in Example 2), and 2-fluoro-5-hydroxy-4-methylaniline (212 mg 1.5 mmol), (prepared as described for the starting material in Example 1), in isopropanol (15 ml) was heated at reflux for 3 hours. The mixture was allowed to cool and the solid product was collected by filtration, washed with acetone and dried to give 6,7-dimethoxy-4-(2-fluoro-5-hydroxy-4-methylanilino)quinoline hydrochloride (146 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]2[CH2:64][N:54]3[C:55](=[O:63])[NH:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][C:62]=4[C:53]3=[N:52][CH2:51]2)=[CH:46][CH:45]=1>CN(C=O)C>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]2[CH2:64][N:54]3[C:55](=[O:63])[NH:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][C:62]=4[C:53]3=[N:52][CH2:51]2)=[CH:46][CH:45]=1)=[O:9]
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: Cc1ccoc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccoc1C(=O)Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
A mixture of 3-methyl-furan-2-carboxylic acid (3.7 mg, 0.029 mmol), N,N-diisopropylethylamine (0.025 mL, 0.145 mmol), and HBTU (13.2 mg, 0.035 mmol) in 0.8 mL DMF was stirred at rt for 10 minutes, then 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (7.6 mg, 0.026 mmol) added and the reaction continued at rt. After 40 min, a spatula tip of 3-methyl-furan-2-carboxylic acid and HBTU was added, the reaction briefly warmed to approximately 60° C. several times, then allowed to cool to rt. At 1.25 hours the reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed on a prep plate eluting with 15% MeOH/CHCl3. The obtained solid was then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated to give the title compound as an off-white solid (7.6 mg, 86%). 1H NMR (CD3OD/CDCl3 mixture) δ: 8.03 (dd, J=7.9, 1.2 Hz, 1H), 7.65-7.71 (m, 2H), 7.43-7.52 (m, 2H), 7.26-7.32 (m, 2H), 7.14 (ddd, J=8.1, 7.2, 1.2 Hz, 1H), 7.00-7.05 (m, 1H), 6.45 (d, J=1.5 Hz, 1H), 4.45 (ddd, J=13.0, 4.4, 2.8 Hz, 1H), 3.83-3.91 (m, 1H), 3.59-3.70 (m, 2H), 3.04-3.16 (m, 1H), 2.42 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[NH:8][CH:7]=[C:6]([C:9]([OH:11])=[O:10])[C:4](=[O:5])[CH:3]=1.C(=O)([O-])[O-].[Ca+2].[I:17]Cl.S(=O)(O)[O-].[Na+]>CN(C)C=O>[I:17][C:3]1[C:4](=[O:5])[C:6]([C:9]([OH:11])=[O:10])=[CH:7][NH:8][C:2]=1[CH3:1]
Reactant: ClI
Reactant: Cc1cc(=O)c(C(=O)O)c[nH]1
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: Cc1[nH]cc(C(=O)O)c(=O)c1I
Temperature: 0 °C
Yield: 86 %

Procedure:
To 6-methyl-4-(1H)-pyridone-3-carboxylic acid (prepared according to the procedure described in J. Org. Chem., 1972, 37, 1145-1148) (10.0 g, 65.4 mmol) and calcium carbonate (6.55 g, 65.4 mmol) in N,N-dimethylformamide (100 ml) was added iodine monochloride (21.2 g, 130.8 mmol) in N,N-dimethylformamide (20 ml). After 6 hours sodium bisulfite solution (30 ml) was added and the solution poured into ice water (500 ml). The precipitate was collected by filtration washing with water and methanol to give a cream coloured solid (15.7 g, 86%). 1H NMR (250 MHz, DMSO-d6) δ15.42 (1H, br s), 13.33 (1H, br s), 8.50 (1H, s), 2.60 (3H, s); MS (ES+) m/z 280 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.Cl>ClCCl.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:18][CH:19]([CH3:21])[CH3:20])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)CC1(c2ccc(F)cc2)OC(=O)c2ccncc21
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CC1(c2ccc(F)cc2)OC(=O)C2=C1CNCC2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 53.2 %

Procedure:
To a solution of 3-(4-fluorophenyl)-3-isobutylfuro[3,4-c]pyridin-1(3H)-one (296 mg, 1.04 mmol) in dichloromethane (5 mL) at 0° C. was added 1 N HCl in diethyl ether. The reaction mixture was stirred at 0° C. for 40 min., then filtered and the precipitated hydrochloride salt dried in high vacuo for 1 hour. The precipitate was re-dissolved in ethanol (10 mL), PtO2 (40 mg) was added, and the reaction mixture was hydrogenated at 40 psi for 30 min. The mixture was filtered through a pad of diatomaceous earth, the filtrate concentrated in vacuo. The residue was re-dissolved in dichloromethane (50 mL) and stirred with sat. NaHCO3 soln. for 20 min., then dried (MgSO4) and concentrated. The residue was purified by column chromatography (4 g, SiO2, 0 to 2.5% methanol in dichloromethane) to provide 3-(4-fluorophenyl)-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (160 mg, 53%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.83-0.98 (m, 6H), 1.56 (br. s., 1H), 1.65 (ddd, J=13.37, 6.59, 5.27 Hz, 1H), 1.72-1.81 (m, 1H), 2.15-2.38 (m, 3H), 2.84-3.05 (m, 2H), 3.34-3.50 (m, 1H), 3.58-3.73 (m, 1H), 7.00-7.12 (m, 2H), 7.27-7.34 (m, 2H); MS m/z 290 (M+H)+, 288 (M−H)−.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[O:14][CH2:13][CH2:12][O:6]1
Reactant: O=C(CCCCl)c1cccs1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: ClCCCC1(c2cccs2)OCCO1
Yield: 97.3 %

Procedure:
Add 4-chloro-1-thiophen-2-yl-butan-1-one (10 g, 53 mmol), ethylene glycol (8.14 g, 131.2 mmol) and p-toluene sulfonic acid (362 mg, 1.6 mmol) to benzene (150 mL) and heat at reflux for 16 h under a water trap. Cool the reaction to RT and wash with 1 N NaOH solution (100 mL) and brine (150 mL). Dry (sodium sulfate) and concentrate to give the title product as a dark oil (12 g, 97%).
Reaction SMILES: [Na+].[Na+].[CH:3]([C:5]1[O:9][C:8]([S:10]([O-:13])(=[O:12])=[O:11])=[CH:7][C:6]=1[S:14]([O-:17])(=[O:16])=[O:15])=O.[CH:18]([NH:21][OH:22])([CH3:20])[CH3:19].[Na][Na]>>[CH:18]([N+:21]([O-:22])=[CH:3][C:5]1[O:9][C:8]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:7][C:6]=1[S:14]([OH:17])(=[O:16])=[O:15])([CH3:20])[CH3:19]
Reactant: CC(C)NO
Reactant: O=Cc1oc(S(=O)(=O)[O-])cc1S(=O)(=O)[O-]
Agent: [Na+]
Agent: [Na][Na]
Product: CC(C)[N+]([O-])=Cc1oc(S(=O)(=O)O)cc1S(=O)(=O)O

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2,4-disulfonic acid disodium salt and N-isopropylhydroxylamine, the title compound could be prepared as the disodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=1)=S.[NH2:24][C:25]1[NH:29][N:28]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:26]=1.Cl.C(N=C=NCCCN(C)C)C>C1COCC1.O.C(OC(C)C)(=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][NH:5]/[C:6](/[NH:24][C:25]1[NH:29][N:28]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:26]=1)=[N:8]/[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([F:17])[CH:11]=1
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Reactant: O=C(NC(=S)NCc1ccc(F)cc1Cl)c1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(/N=C(/NCc1ccc(F)cc1Cl)Nc1cc(C(F)(F)F)n[nH]1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
N-((2-Chloro-4-fluorobenzyl)carbamothioyl)-3,4-difluorobenzamide (98.0 g, 273 mmol) and 5-amino-3-trifluoromethylpyrazole (41.3 g, 273 mmol) were dissolved in THF (546 mL). N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (57.6 g, 300 mmol) was added and the reaction was stirred at room temperature for 1 h and then heated to 40° C. for 15 h. The crude mixture was diluted with water (500 mL) and isopropyl acetate (500 mL). The organic layer was washed with brine (500 mL), dried over sodium sulfate, and concentrated. The residue was diluted with isopropyl acetate (1.3 L) and heated to 65° C. for 1 hour. The solution was allowed to cool to room temperature, filtered and the filtrate was concentrated. The residue was heated to 70° C. in acetonitrile (900 mL) and then allowed to cool to room temperature. The resulting suspension was filtered, rinsed with acetonitrile (200 mL) and dried in vacuo at 60° C. to afford 55 g (43%) of (Z)—N-(((2-chloro-4-fluorobenzyl)amino)((3-(trifluoromethyl)-1H-pyrazol-5-yl)amino)methylene)-3,4-difluorobenzamide as a white solid. 1HNMR (400 MHz, MeOH-d4) δ 7.95 (bs, 2H), 7.50 (t, 1H, J=7.2 Hz), 7.26 (m, 2H), 7.06 (t, 1H, J=7.5 Hz), 6.56 (s, 1H), 4.84 (s, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>C1C=CC=CC=1.C(N(CC)CC)C>[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:16])=[CH:13][CH:12]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CSCC[C@H](NC(=O)c1ccc(N)cc1)C(=O)O

Procedure:
In an Erlenmeyer flask, 1.35 g of para-aminobenzoic acid chloride are dissolved in 20 ml benzene in the presence of 2.8 ml triethylamine. 1.49 g L-methionine is added progressively and the resultant mixture is filtered. After evaporation of the filtrate to dryness under vacuum (15 mm Hg), the residue is dissolved in N hydrochloric acid and extracted with chloroform. The chloroformic solution is successively washed with several ml of 10% aqueous HKCO3 solution and with water. It is then collected, dried over magnesium sulfate and evaporated. The product obtained is precipitated in cyclohexane and filtered. After recrystallization in a (1:1) mixture of 95 alcohol-water, 1.95 g of white crystals are isolated. M.p.: 172° C.