Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH2:43]C)[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:45]([P:54](=[O:61])([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:59]([O:58][P:54](/[CH:45]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)([O:55][CH2:56][CH3:57])=[O:61])[CH3:60]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OCC)c(C)o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)c1
Reaction time: 3 h
Yield: 77 %

Procedure:
To a mixture of ethyl (3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-ethoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (2.0 g), tetraethyl methylenediphosphonate (1.07 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.16 g) at room temperature, and the mixture was stirred at the same temperature for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as a colorless oil from a fraction eluted with ethyl acetate-hexane (9:1, v/v) (1.87 g, yield 77%).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]2[O:24][CH2:23]2)=[CH:16][CH:15]=1>O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH:22]([OH:24])[CH2:23][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:18][CH:19]=1
Reactant: c1c[nH]cn1
Reactant: Brc1ccc(CCC2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CCc1ccc(Br)cc1)Cn1ccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a sample of pure sodium hydride (1.60 g, 66.58 mmol, 1.4 equiv) under a N2 atmosphere was added DMF (40 mL). The mixture was cooled to 0° C. and imidazole (4.86 g, 71.34 mmol, 1.5 equiv) was added in many small portions over 1 h. Stirring was continued for an additional 0.5 h at 0° C. To the mixture was added dropwise the neat epoxide 12a (10.80 g, 47.56 mmol, 1 equiv); the epoxide container was rinsed with DMF (10 mL) and the rinse solution was added to the reaction mixture. The mixture was stirred at 0° C. for 0.5 h and then at rt for 24 h. Monitoring by TLC (silica gel, EtOAc) confirmed the completion of the reaction. Water (20 mL) was added, the mixture cooled to 0° C., and more water (200 mL) was added without stirring. After 1 h at 0° C. an additional 100 mL of water were added. The white solid was removed by filtration and washed with water (3×250 mL), and then with hexanes (200 mL). High-vacuum drying gave the imidazole-alcohol 13a (11.80 g, 39.98 mmol, 84%) as a white solid: mp 121-122° C., Rf=0.08 (ethyl acetate); 1H NMR (400 MHz, CDCl3): δ 1.68-1.82 (m, 2H), 2.68-2.76 (m, 1H), 2.82-2.89 (m, 1H), 3.75-3.94 (m, 3H), 6.80 (s, 1H), 6.84 (s, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.31 (s, 1H), 7.40 (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 31.3, 36.0, 54.1, 69.5, 119.9, 128.5, 130.4, 131.6, 140.6; HRMS (EI) Calcd. for C13H15BrN2O: 294.0368 (M+). Found: 294.0375.
Reaction SMILES: B#B.[C:3]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7].O1C=CN=B1.Cl>C1COCC1.CCOCC.CO>[O:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C@@H:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)c1ccco1
Agent: B#B
Agent: Cl
Agent: b1ncco1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CCCC[C@H](O)c1ccco1
Temperature: 10 °C
Yield: 70 %

Procedure:
10.4 mmol (10.4 mL) of diborane (1 M solution in THF) was added dropwise in a period of 10 m at room temperature to a solution of 2-valeryl furan (2.62 g, 17.2 mmol) and 1.68 mmol (4.2 mL) of (3aR)-1,3,3-triphenyl pyrrolidino [1,2-c] [1,3,2] oxazaborole (see E. J. Corey et al. J. Am. Chem. Soc. 1987, 109, 7925-26, 0.4M solution in THF) in 25 mL THF. The reaction mixture was stirred for 20 m and was cooled to 10° C. 6 mL methanol was cautiously added and followed by adding 62 mg HCl (by weight) in ether. Stirred for 0.5 h, white solid was precipitated out. The cloudy mixture was poured into 100 mL ether and 100 mL water. The organic layer was separated, washed with saturated sodium bicarbonate, water, brine, dried and filtered. The filtrate was evaporated to an yellowish oil which was chromatographed eluting with 10 % ethyl acetate in hexane to obtain 70% of the product. [α]25D =-13°, 60% ee by Mosher' ester analysis.
Reaction SMILES: O[Li].O.O.C([O:9][C:10]([C:12]1([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:38])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]2([C:31]([O:33]CCCC)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])CCC>CCO>[C:31]([C:26]1([CH2:25][CH2:24][CH2:23][CH2:22][C:21](=[O:38])[CH2:20][CH2:19][CH2:18][CH2:17][C:12]2([C:10]([OH:11])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:27][CH2:28][CH2:29][CH2:30]1)([OH:33])=[O:32]
Reactant: CCCCOC(=O)C1(CCCCC(=O)CCCCC2(C(=O)OCCCC)CCCC2)CCCC1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: O=C(CCCCC1(C(=O)O)CCCC1)CCCCC1(C(=O)O)CCCC1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
LiOH.H2O (3.21 g, 76.4 mmol) and H2O (40 mL) were added to a solution of butyl 1-9-[1-(butoxycarbonyl)cyclopentyl]-5-oxononyl-1-cyclopentanecarboxylate (7.25 g, 15.0 mmol) in EtOH (120 mL) and the resulting mixture was stirred at reflux temperature for 25 h, allowed to cool to rt and concentrated in vacuo to a smaller volume. H2O (100 mL) was added and the resulting mixture was extracted with Et2O (25 mL), acidified with aqueous HCl (6 M, 15 mL) and extracted with Et2O (3×50 mL). The latter organic layers were combined, dried (Na2SO4, to avoid loss of material, a minimal amount of Na2SO4 was used, with the desiccant becoming a white, oily paste. The organic layer was decanted from the desiccant.) and evaporated in vacuo to give 1-[9-(1-carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic acid (5.46 g, 95% pure by 1H NMR, 94%, mp=99-103° C.) as a white solid. An analytical sample was obtained after recrystallization from iPr2O/heptane. mp=104-106° C. 1H NMR (CDCl3): δ=2.39 (t, J=6.9 Hz, 4H), 2.18-2.10 (m, 4H), 1.69-141 (m, 20H), 1.27-1.14 (m, 4H). 13C NMR (CDCl3): δ=211.1, 184.6 (2×), 53.9 (2×), 42.5 (2×), 39.0 (2×), 35.9 (4×), 25.7 (2×), 24.9 (4×), 24.0 (2×). Anal. calcd for C21H34O5: C, 68.82; H, 9.35. found: C, 68.78; H, 9.47.
Reaction SMILES: Br[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][O:10][C:6]=2[C:5]([OH:17])=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:3]=1.[CH3:23][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[OH:17][C:5]1[C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[C:2]([CH3:23])=[N:3][C:4]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1nc(Br)c2c(-c3ccccc3)noc2c1O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2c(-c3ccccc3)noc2c1O
Temperature: 125 °C
Yield: 33.3 %

Procedure:
A nitrogen flushed flask was charged with ethyl 4-bromo-7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (150 mg, 0.413 mmol), DMF (2 mL), tetramethylstannane (0.17 mL, 1.24 mmol), and Pd(PPh3)2Cl2 (58 mg, 0.083 mmol). The mixture was heated in an oil bath (bath temperature=120-130° C.) for 2 hours. After the reaction mixture was cooled to room temperature, it was purified by flash chromatography (0-30% EtOAc/hexanes) to afford 41 mg of the title compound. MS: (+) m/z 299.43 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[OH-].[K+]>O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 67.8 %

Procedure:
A mixture of 0.5 mole each of p-nitrochlorobenzene (79.0 g), p-hydroxyanisole (62.0 g), and potassium hydroxide (33.0 g, 86% pure), in 100 ml water was heated at 140° C. for about 3.5 hours. The resulting solid, collected by filtration, had a melting point of 100°-107° C. Reactants were further removed from the crude product by steam distillation, and the remaining solid was washed with copious amounts of water to afford a brown, granular mass of 4-methoxy-4'-nitrodiphenyl ether (83 g, 68% yield).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([N:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([O:9]C)=[O:8]>CO>[Cl:3][C:4]1[C:5]([N:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:21])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)N(C)c1c(C(=O)OC)ccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N(C)c1c(C(=O)O)ccc(Cl)c1Cl
Yield: 108 %

Procedure:
Sodium hydroxide solution (2M, 44.6 ml) was added dropwise during 5 minutes to a stirred solution of methyl 3,4-dichloro-2-(N-methyl-N-ethoxycarbonylamino)benzoate (9.1g) in methanol. After 0.5 hours the methanol was evaporated, the residue diluted (water), washed (ether), acidified with potassium bisulphate and extracted (ethyl acetate). The extract was dried (magnesium sulphate) and evaporated to give 3,4-dichloro-2-(N-methyl-ethoxycarbonylamino)benzoic acid (9.38 g) as a brown oil, NMR 1.2(m,3H), 3.1(s,3H), 4.0(m,2H), 7.4(m,1H), 7.9(m,1).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1nc(Br)cs1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: OCc1nc(-c2ccccc2OCc2ccccc2)cs1
Temperature: 90 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a mixed solution of the compound (900 mg, 4.6 mmol) obtained in Example 30a, 2-benzyloxyphenylboronic acid (1.3 g, 5.6 mmol) and 2M aqueous sodium carbonate solution (2.8 mL, 5.6 mmol) in 1,2-dimethoxyethane-ethanol (v/v=3/1, 12 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (380 mg, 0.46 mmol), and the mixture was stirred at 90° C. overnight. The resulting salt was filtered and removed, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=60/40) to give the title compound (1.2 g, 88%) as colorless crystals.
Reaction SMILES: FC1C=CC(CN2C[CH2:11][N:10]3[C:13](=O)[CH:14]=[C:15](O)[C:16](O)=[C:9]3C2=O)=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:42]=[CH:43][C:44]=1[F:45])[CH2:27][N:28]1[CH2:33][CH2:32][N:31]2[C:34](=[O:40])[CH:35]=[C:36]([OH:39])[C:37]([OH:38])=[C:30]2[C:29]1=[O:41]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:42]=[CH:43][C:44]=1[F:45])[CH2:27][N:28]1[CH2:33][CH2:32][N:31]2[C:34](=[O:40])[C:35]([CH2:11][N:10]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:9]3)=[C:36]([OH:39])[C:37]([OH:38])=[C:30]2[C:29]1=[O:41]
Reactant: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccc(F)c(Cl)c1
Reactant: O=C1c2c(O)c(O)cc(=O)n2CCN1Cc1ccc(F)cc1
Product: O=C1c2c(O)c(O)c(CN3CCCCC3)c(=O)n2CCN1Cc1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared using a procedure similar to that described in Example 11, except that 2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione was substituted with 2-(3-chloro4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCOc1cccc(C=O)c1
Temperature: 57 °C
Yield: 101.1 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (5.0 g, 41 mmol) in N,N-dimethylformamide (100 mL) was added bromo-2-(2-methoxyethoxy)ethane (6.0 mL, 45 mmol) followed by addition of solid potassium carbonate (17 g, 122 mmol). The resulting slurry was heated under nitrogen at 57° C. for 19 h. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with methanol and the filtrate was reduced in vacuo to ˜50 mL and poured into water (200 mL). The solution was acidified to pH˜4 with hydrochloric acid (1 M) and extracted with ethyl acetate (3×150 mL). The combined organic layer was washed with aqueous copper sulphate (75 mL), water (100 mL) and brine (100 mL), dried over sodium sulphate, filtered and concentrated in vacuo to a viscous oil. The oil was dried in vacuo to give 9,3 g (99% yield) of the title compound as a tan oil. 1HNMR (300 MHz, DMSO-d6, TFA-d) δ 9.98 (s, 1H), 7.51 (m, 2H), 7.44 (s, 1H), 7.30 (m, 1H), 4.18 (t J=5 Hz, 2H), 3.76 (t, J=5 Hz, 2H), 3.60 (t, J=5 Hz, 2H), 3.46 (t, J=5 Hz, 2H), 3.25 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][CH2:12][NH:11]2)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26](Br)=[O:27].[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]1([CH:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][CH2:12][N:11]2[CH2:25][C:26]([NH:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(c1ccccc1)C1NCCc2cc(OC)c(OC)cc21
Reactant: NCc1ccccc1
Reactant: O=C(Br)CBr
Product: CCC(c1ccccc1)C1c2cc(OC)c(OC)cc2CCN1CC(=O)NCc1ccccc1

Procedure:
prepared by reaction of 1-(1-Phenyl-propyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with benzylamine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:18])([F:17])[CH2:13][C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH2:13][C:12]([F:18])([F:17])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)CC(F)(F)F
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (10.0114 g; 56.5520 mmoles) and 3,3,3-trifluoro-propionic acid (7.5 mL; 84.9 mmoles) were combined with 6N HCl (20 mL; 120 mmoles) and heated to 108° C. for 18 hrs. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and water (200 mL), then sodium bicarbonate (15.15 g; 180.3 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×60 mL). The extracts were combined, washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid. A sample of the crude brown solid was purified by column chromatography (SiO2; 100% CH2Cl2) to yield the title compound as a light brown solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1)[CH3:2].ClN1C(=O)CCC1=O.[F:20][C:21]([F:39])([F:38])[C:22]1[CH:23]=[C:24]([C:32]([C:34]([F:37])([F:36])[F:35])=[CH2:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C(=O)([O-])O.[K+]>CN(C)C=O.O>[F:20][C:21]([F:38])([F:39])[C:22]1[CH:23]=[C:24]([C:32]2([C:34]([F:37])([F:36])[F:35])[O:9][N:8]=[C:7]([C:6]3[CH:10]=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:33]2)[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1
Reactant: CCc1ccc(C=NO)cc1
Reactant: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Reaction time: 14 h

Procedure:
To a solution of 1.49 g of 4-ethylbenzaldoxime in 10 mL of N,N-dimethylformamide, 1.60 g of N-chlorosuccinimide was added and the resultant mixture was stirred at room temperature for 2 hours. Next, to the reaction mixture, 3.00 g of 3,5-bis(trifluoromethyl)-1-(1-trifluoromethylethenyl)benzene and 3.00 g of potassium hydrogen carbonate were added and the stirring of the resultant reaction mixture was continued at room temperature further for 14 hours. After the completion of the reaction, 10 mL of water was added to the reaction mixture and the resultant reaction mixture was extracted with ethyl acetate (50 mL×1). The organic phase was washed with 20 mL of water and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure. To the resultant residue, hexane was added and a deposited crystal was filtered off to obtain 3.00 g of the objective substance as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccnc(Cl)c1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-chloropyridin-4-amine (1.0 g, 7.78 mmol, 1.00 equiv) and N,N-Diisopropylethylamine (1.0 mL) in dichloromethane (30.0 mL). This was followed by the addition of a solution of 3-(trifluoromethyl)benzoyl chloride (2.6 g, crude) in dichloromethane (5.0 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0˜1:2). This resulted in 2.2 g (92%) of N-(2-chloropyridin-4-yl)-3-(trifluoromethyl)benzamide as a light-yellow syrup
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH3:12])=O)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15]>C(O)C.C(O)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[N:15][N:14]([CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: CN(N)c1ccccc1
Reactant: CON=C(C(C)=O)C(=O)N(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CON=C(C(=O)N(C)C)C(C)=NN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.1 %

Procedure:
1.0 g (5.8 mmol) of 2-methoxyimino-N,N-dimethylacetoacetamide was dissolved in 15 ml of ethanol and 0.5 ml of acetic acid, and 0.78 g (6.4 mmol) of N-methyl-N-phenylhydrazine was added and the mixture was stirred for 24 hours at room temperature. After distilling the solvent of water was added and the mixture was extracted three times with 20 ml of diethylether. After washing with a dilute hydrochloric acid, water and a saturated aqueous sodium chloride, the mixture was dried over with anhydrous magnesium sulfate, and the solvent was distilled of, and finally the residue thus obtained was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 1.38 g (yield: 86%) of 2-methoxyimino-N,N-dimethy-3-(N-methyl-N-phenylhydrazono)butyramide as a yellow oil.
Reaction SMILES: [Br-].[C:2]1(=[O:34])[N:6]([CH2:7][CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:5](=[O:29])[C:4]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:3]12.[Cl:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O.CC(C)([O-])C.[K+].O>O1CCCC1>[Cl:35][C:36]1[CH:37]=[C:38](/[CH:39]=[CH:9]\[CH2:8][CH2:7][N:6]2[C:2](=[O:34])[C:3]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:4]3[C:5]2=[O:29])[CH:41]=[CH:42][CH:43]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: O=C1c2ccccc2C(=O)N1CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CC/C=C\c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
A mixture of 3-phthalimidopropyltriphenylphosphonium bromide (15.1 g) and 3-chlorobenzaldehyde (4.0 g, Aldrich, U.S.A.) in tetrahydrofuran (150 mL) was cooled to −78° C. in a dry ice/acetone bath. Potassium tert-butoxide (3.2 g) was added and the mixture was stirred for 20 min, then allowed to warm to 0° C. After four hours, the solution was poured into 200 mL water and extracted three times with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate, and reduced in vacuo. The residue was dissolved in 200 mL of a 1:1 mixture of ethyl acetate/hexanes, and filtered through a short silica gel plug to remove the triphenylphosphine oxide byproduct. Evaporation of the filtrate yielded 5.7 g of cis-N-[4-(3-chlorophenyl)-but-3-enyl]-phthalimide in a 10:1 ratio of cis:trans isomers.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36]Cl.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=2)[N:3]=1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3ccccn3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 75.4 mg (0.46 mmol) of 2-picolyl chloride hydrochloride are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 104 mg (81% of theory) of product.