Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:3]([OH:9])([CH2:5][C:6]([OH:8])=[O:7])=[O:4])[CH3:2].[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4:30]>C1(C)C=CC=CC=1>[Ti+4:30].[CH2:1]([P:3]([OH:9])([CH2:5][C:6]([O-:8])=[O:7])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][C:6]([O-:8])=[O:7])([OH:9])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][C:6]([O-:8])=[O:7])([OH:9])=[O:4])[CH3:2].[CH2:1]([P:3]([CH2:5][C:6]([O-:8])=[O:7])([OH:9])=[O:4])[CH3:2]
Reactant: CCP(=O)(O)CC(=O)O
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Product: CCP(=O)(O)CC(=O)[O-]
Yield: 102.4 %

Procedure:
152 g (1 mol) of 2-(ethylhydroxyphosphinyl)acetic acid (produced as in Example 11) and 170 g of titanium tetrabutoxide are refluxed in 500 ml of toluene for 40 hours. The resulting butanol is distilled off from time to time with proportions of toluene. The solution formed is subsequently freed of solvent to leave 167 g (96% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid titanium salt.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=1.CI>C(#N)C>[CH3:1][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([F:17])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 5 h

Procedure:
A 2 L round bottom flask equipped with a stir bar and reflux condenser was charged with acetonitrile (1 L), K2CO3 (263 g, 1.9 mol) and 4-hydroxy-2-fluoro-1-nitrobenzene (100 g, 0.64 mol). Methyl iodide (271 g, 1.9 mol) was added to the reaction mixture and heated at reflux temperatures with vigorous stirring for 5 h. The acetonitrile was removed and ethyl acetate (1 L) and H2O (700 mL) were added. The heterogeneous mixture was transferred to a reparatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×200 mL). The organic phases were combined and washed with H2O (2×500 mL), brine (500 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the desired product as a slightly yellow solid (107 g, 98%).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5].[CH3:19]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>CCOCC>[CH3:19][O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5]
Reactant: CN(C)C=O
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To α-hydroxyimino-2-phenoxyphenylacetonitrile (a mixture of E- and Z-isomers) (1.19 g, 0.005 mole) were added dried dimethylformamide (10 ml) and potassium carbonate (0.90 g, 0.006 mole), and methyl iodide (0.78 g, 0.0055 mole) was added dropwise to the mixture under ice cooling, followed by stirring at room temperature for 4 hours. After completion of the reaction, ether (150 ml) was added, followed by washing twice with water (100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-methoxyimino-2-phenoxyphenylacetonitrile (1.06 g, yield: 84.0%) as a colorless oil.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br>CC#N>[Br:13][CH2:14][CH2:15][CH2:16][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCCCBr
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OCCCBr
Temperature: 25 °C

Procedure:
To a solution of N-hydroxyphthalimide (2.0 g) and 1,3-dibromopropane (2.49 ml) in 50 ml of dry CH3CN was added diisorpopylethylamine (4.27 ml). The mixture was stirred at room temperature. After 4 hours the volatiles were removed in vacuo. The residue was triturated with Et2O to provide 2.53 g of while solid, homogeneous by TLC.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C1COCC1.CCO.O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:6])=[CH:7][C:8]=1[F:9]
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cc(F)c(Br)cc1N
Temperature: 95 °C
Yield: 81.4 %

Procedure:
To a solution of 4-bromo-5-fluoro-2-nitroaniline (1.0 g, 4.3 mmol) in THF (9.0 mL), EtOH (9.0 mL) and H2O (3 mL) was added iron powder (1.2 g, 21.3 mmol) and ammonium chloride (0.34 g, 6.4 mmol), and the mixture was heated at 95° C. for 4 hours. The cooled mixture was diluted with EtOH, filtered through diatomaceous earth until no further color came through the filter, and concentrated. The residue was dissolved in EtOAc, washed with H2O, brine, dried (Na2SO4), filtered and concentrated. Hexane was added and the resulting solid collected by filtration to give the title compound (710 mg, 3.5 mmol, 81%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.OC1C=CC=CN=1.[F:18][C:19]1[CH:24]=[C:23](F)[C:22]([F:26])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:23]2[CH:24]=[C:19]([F:18])[C:20]([N+:27]([O-:29])=[O:28])=[CH:21][C:22]=2[F:26])[CH:7]=[CH:6][N:5]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: Oc1ccnc(Cl)c1
Agent: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
Sodium hydride (60% by weight in mineral oil) (3.08 g, 77 mmol) was placed in a 500 mL round bottom flask flushed with argon. DMF (140 mL) was added and the mixture was cooled in an ice bath. 2-Chloro-4-hydroxypyridine (7.68 g, 59.3 mmol) was then added slowly over 45 minutes. After addition of the hydroxypyridine was complete 2,4,5-trifluoronitrobenzene (10.5 g, 59.3 mmol) was added as a solution in DMF (29 mL). The mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to remove the majority of DMF in the mixture, and was then partitioned between ethyl acetate (300 mL) and 10% aqueous lithium chloride (150 mL). A precipitate formed which was removed via suction filtration and then the layers were separated. The organic layer was washed with additional 10% aqueous lithium chloride (2×150 mL), saturated aqueous sodium bicarbonate (150 mL) and brine (150 mL). The organic layer was dried over magnesium sulfate and evaporated to yield a dark red solid which was purified by silica gel chromatography (10 to 30% ethyl acetate/hexane) to give 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (13.56 g, 80% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.45 (dd, 1H), 8.39 (d, 1H), 7.87 (dd, 1H), 7.39 (d, 1H), 7.24 (dd, 1H); MS (ESI) m/z: 287.0 (M+H+).
Reaction SMILES: [FH:1].C(=O)=O.CC(C)=O.[CH3:9][O:10][C:11]1[C:12]([N+:19]([O-:21])=[O:20])=[CH:13][C:14]([CH3:18])=[C:15]([CH:17]=1)N.N([O-])=O.[Na+]>N1C=CC=CC=1>[F:1][C:15]1[CH:17]=[C:11]([O:10][CH3:9])[C:12]([N+:19]([O-:21])=[O:20])=[CH:13][C:14]=1[CH3:18]
Reactant: COc1cc(N)c(C)cc1[N+](=O)[O-]
Reactant: F
Agent: O=C=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: COc1cc(F)c(C)cc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
Hydrogen fluoride (70%) in pyridine (47.4 ml, 0.48 mol) in a plastic separatory funnel was added dropwise over 20 min. to pyridine (16 mL) in a plastic bottle at −78° C. (dry ice/acetone bath) under nitrogen. Note: reaction was exothermic. After the addition was complete, the reaction was stirred for 10 min. at −78° C. 5-Methoxy-2-methyl-4-nitroaniline (9.11 g, 0.05 mol) was then added and the reaction mixture was stirred for an additional 10 min. at −78° C. Sodium nitrite (5.8 g, 0.08 mol) was then added and the reaction mixture was stirred an additional 10 min. at −78° C. The reaction mixture was allowed to warm to RT and then heated to 60° C. for 2 h. The reaction mixture was then allowed to cool to RT and an ice/water mixture (300 mL) was added. The resultant precipitates were collected by vacuum filtration, washed with water and dried under vacuum. The solid product was recrystallized from methylcyclohexane to give yellow crystals as the title product (5.8 g, 63%).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].S(=O)(=O)(O)[OH:11].C1(C)C=CC=CC=1.N>C(O)(C)(C)C.O>[CH3:9][C:8]1[C:3]([C:1]([NH2:2])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cccnc1C#N
Agent: N
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccnc1C(N)=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Suspend 2-cyano-3-methyl pyridine (400 g) in t-butanol (800 mL) and heat to 70° C. Add concentrated sulphuric acid (400 mL) dropwise over 45 minutes. Maintain the temperature at 75° C., until the reaction is complete, and for an additional 30 minutes. Dilute the mixture with water (400 mL), charge with toluene (600 mL) and bring to pH 10 with concentrated aqueous ammonia. Maintain the temperature at 50°-55° C. during the work up. Separate the toluene phase, and reextract the aqueous layer. Combine toluene phases and wash with water. Remove the toluene to yield the title compound N-(1,1-dimethylethyl-(3-methyl-2-pyridine carboxamide, as an oil, from which solid product is crystallized. (Yield 97%, as determined by an internal standard assay with gas chromatography).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH2:11][C@H:10]1[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][Si](C=[N+]=[N-])(C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C:13]([C:15]([O:17][CH3:27])=[O:16])=[CH:12][CH2:11][C@@H:10]1[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C(=O)O)=CC[C@H]1c1cc(F)c(F)cc1F
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1=CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 39 %

Procedure:
Alternative resolution procedure: A solution of Example 39A (510 mg) was dissolved in methanol (1 mL) and CH2Cl2 (1 mL), and then (trimethylsilyl)diazomethane solution (0.4 mL, 2M in ether) was added. After ten minutes, acetic acid (0.2 mL) was added. The resultant solution was concentrated in vacuo and partitioned between ethyl acetate and bicarb. The organic extract was washed with brine and dried over sodium sulfate. The crude material was deprotected using the procedure of Step B in Example 20D; and the product was partitioned between sodium bicarbonate and ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. The crude product (410 mg) was dissolved in 30 ml of ethanol. 420 mg (0.8 eq) of dibenzoyl (D)-tartaric acid was added, and the mixture was stirred until homogeneous. The resultant solution was allowed to stand overnight and the crystalline product was collected by filtration (yield 39%, ee>98%). The crystalline solid was dissolved in tetrahydrofuran (10 mL). Then, di-tert-butyl dicarbonate (1.1 eq.) and saturated sodium bicarbonate solution (5 mL) were added. After thirty minutes, the reaction mixture was concentrated and subjected to column chromatography (eluting with 20% ethyl acetate/hexane) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:18]3[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][NH:15][C:14](=O)[C:13]=3[CH:12]=[CH:11]2)=[CH:5][CH:4]=1.P(Cl)([Cl:34])(OC1C=CC=CC=1)=O.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[Cl:34][C:14]1[C:13]2[CH:12]=[CH:11][N:10]([CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:18]=2[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][N:15]=1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: CCOC(=O)c1c[nH]c(=O)c2ccn(Cc3ccc(OC)cc3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cnc(Cl)c2ccn(Cc3ccc(OC)cc3)c12

Procedure:
Ethyl 1-{[4-(methyloxy)phenyl]methyl}-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (2.90 g) and phenyl dichlorophosphate (18 ml) were heated at 180° C. under argon for 30 minutes. The reaction mixture was allowed to cool, poured onto iced water, and neutralised to pH7 using solid sodium bicarbonate. To the reaction mixture was added ethyl acetate and the insoluble material was filtered off. The aqueous was separated and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a clear oil (2.0 g).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13].C([O-])(O)=O.[Na+].C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]([NH:15][CH2:14][CH2:12][OH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCCO)OCc1ccccc1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Benzylchloroformate (44.95 kg, 263.5 mol, 1.0 eq.) was added over a 2 hour period at room temperature to a solution of ethanolamine (16.1 kg, 263.5 mol, 1.0 eq.) in water (34 gal). After stirring for 30 minutes, this was added to a cold (5-10° C.) solution of NaHCO3 (33.2 kg, 395.25 mol, 1.5 eq) in H2O (330 L) over a 30 min period and then allowed to stir at room temperature overnight. Ethyl acetate (22 gal) was added, the layers separated, and the aqueous layer extracted again with 22 gal. ethyl acetate. The combined organic extracts were concentrated under vacuum to a volume of 10 gal, and the remainder displaced with isopropyl ether. The resulting slurry was stirred and cooled to +10° C. for 2 hours, then filtered. The solids were washed with isopropyl ether and vacuum dried to give the title compound(39.1 kg, 71.1%). mp 61-63° C. NMR (300 MHz, d6-DMSO): δ=7.50-7.37 (m, 5H), 7.37-7.16 (m, 1H), 5.05 (s, 2H), 4.70-4.63 (m, 1H), 3.46-3.37 (m, 2H), 3.13-3.03 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[ClH:12].[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: Cc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(CCl)cn1
Product: Cl
Temperature: 65 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
(6-Methylpyridin-3-yl)methanol (8.54 g, 69.34 mmol) was dissolved in toluene (0.5M, 125 mL). Thionyl chloride (10.12 mL, 138.7 mmol) was added dropwise, during which a white solid began to precipitate out of solution. The mixture was heated to 65° C. and stirred for 1 hour. The mixture was concentrated, shaken in ether and collected by filtration to provide 5-(chloromethyl)-2-methylpyridine hydrochloride (11.3 g, 92% yield) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][N:21]([CH2:32][CH2:33]O)[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:33][CH2:32][N:21]([CH2:20][CH2:19][OH:18])[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: Cc1ccc(S(=O)(=O)N(CCO)CCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)OCCN(CCO)S(=O)(=O)c3ccc(C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 5.0 g, 21.7 mmol), N,N-bis(2-hydroxyethyl)-p-toluenesulfonamide (16.89 g, 65.1 mmol) and N,N-dimethylaminopyridine (DMAP, 0.530 g, 4.34 mmol) in CH2Cl2 (250 mL) and DMF (3 mL) at room temperature was added 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDAC, 4.99 g, 26.05 mmol). The reaction mixture was stirred overnight at room temperature, and then partitioned between CH2Cl2 and HCl (1N). The aqueous layer was washed with CH2Cl2 and the combined organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAC/hexane (1:1) to give the title compound as a thick oil (7.15 g, 15.16 mmol, 70% yield): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.6 Hz, 2H), 7.66 (m, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.40 (dd, J=1.7, 8.5 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.18 (dd, J=2.5, 8.8 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 4.28 (m, 2H), 3.95 (s, 3H), 3.88 (q, J=7.2 Hz, 1H), 3.38 (m, 2H), 3.09 (t, J=5.1 Hz, 2H), 2.44 (s, 3H), 2.18 (t, J=6.0 Hz, 1H), 1.61 (d, J=7.2 Hz, 3H). Mass spectrum (API-TIS) m/z 472 (MH+), 489 (M+18+).
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.O1C=CC=C1C=CC(O)=O.[CH:36]1([N:42]=[C:43]=[N:44][CH:45]2[CH2:50][CH2:49][CH2:48]CC2)CCCCC1>O1CCCC1>[CH3:1][N:42]([C:43]1[CH:48]=[CH:49][CH:50]=[CH:45][N:44]=1)[CH3:36]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: O=C(O)C=Cc1ccco1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 500 mg of radicicol, 568 mg of 2-furanacrylic acid, 15 ml of dry tetrahydrofuran, 707 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 746 mg of the title compound were obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:24]>C1COCC1.CN1CCCN(C)C1=O>[CH3:24][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]([C:14]=23)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: Cn1c(-c2ccccc2)c2c3c(cccc31)C(=O)NCC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of compound 12 (51.3 mg, 0.20 mmol) in THF (1 mL) and 0.1 mL 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was cooled with an ice/water bath and treated dropwise with a suspension of NaH (0.45 mmol) in THF (0.5 mL). The yellow mixture was allowed to stir at 0° C. for 10 min., and was treated dropwise with a 1M solution of iodomethane in THF (0.22 mL, 0.22 mmol). The mixture was allowed to warm to ambient temperature and stirred for 30 min. The reaction was quenched at 0° C. with saturated aqueous NH4Cl, and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 1-5% MeOH in CH2Cl2) to yield 18 as a white solid, 44.9 mg (81%). mp 254-256° C. (dec.); 1H NMR (DMSO-d6) δ 2.88 (m, 2H), 3.40 (m, 2H), 3.74 (s, 3H), 7.34 (t, 1H, J=7.7 Hz), 7.56 (m, 5H), 7.73 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=7.7 Hz), 8.15 (bt, 1H); Anal. (C18H16N2O.0.75 H2O) C, H, N.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.[NH2:25][CH:26]([CH2:30][CH3:31])[CH2:27][O:28][CH3:29]>C(OC(=O)C)C.CCCCCC.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:29][O:28][CH2:27][CH:26]([N:25]1[C:2]2[C:11]3[N:10]=[CH:9][CH:8]=[C:7]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=4[CH3:20])[C:6]=3[N:5]=[C:4]([C:21]3[C:13]([CH3:14])=[CH:12][C:7]([CH3:8])=[CH:6][C:11]=3[CH3:2])[C:3]=2[CH:22]=[CH:23]1)[CH2:30][CH3:31]
Reactant: Cc1cc(C)c(-c2ccnc3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Reactant: CCC(N)COC
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCC(COC)n1ccc2c(-c3c(C)cc(C)cc3C)nc3c(-c4c(C)cc(C)cc4C)ccnc3c21
Reaction time: 8 h

Procedure:
A solution of 4-chloro-3-(2-chloroethyl)-8-mesityl-2-methyl[1,5]naphthyridine (200 mg, 0.557 mmol) in 2-amino-1-methoxybutane (2.0 mL) was stirred at 200° C. for four hours in a sealed tube. After overnight, the residue was purified by silica gel column chromatography (30-50% ethylacetate/hexane) Activated manganese dioxide (290 mg, 3.24 mmol) was added to a solution of the resulting product (130 mg, 0.33 mmol) in toluene (20 mL) and the mixture was heated under reflux for one day. After filtering through Celite, the mixture was evaporated. The residue was purified by silica gel column chromatography-(10% ethyl acetate/hexane), to give the title compound (108 mg) as white crystals.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=CC(OCC)=O)C=CC=CC=1.O1C=CC=C1C=O.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1/[CH:38]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1COCC1.C(O)C.[Pd]>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)/C=C/c1ccco1
Agent: [Pd]
Agent: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: O=Cc1ccco1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccco1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 2-triphenylphosphoranylideneacetate (34.84 g, 100 mmol, 1 eq) and furan-2-carbaldehyde (9609 mg, 100 mmol, 1 eq) in anhydrous THF (200 ml) was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure and the residue triturated with ether to produce a brown solution and a precipitate. The solid was filtered, washed and removed. The filtrate was then evaporated. The product was purified by column chromatography on silica eluting with 0-20% ethyl acetate in hexanes. The desired fractions were evaporated to yield a cis/trans mixture of ethyl (E)-3-(2-furyl)prop-2-enoate as a pale yellow oil (NMR suggested mainly trans product) (15.5 g, 93%). b) A cis/trans mixture of ethyl (E)-3-(2-furyl)prop-2-enoate (15.5 g, 93.27 mmol, 1 eq) was stirred in ethanol (120 ml) containing 10% palladium on charcoal (775 mg, 5% by w). The reaction mixture was stirred under hydrogen for 4 h. A further quantity of 10% Pd/C (775 mg, 5% by w) was added. The reaction was stirred under hydrogen for an additional 95 mins. The reaction was filtered and evaporated under reduced pressure. The crude product was purified by silica column chromatography eluting with 20% ethyl acetate in hexanes. The desired fractions were evaporated under reduced pressure and ethyl 3-(2-furyl)propanoate was obtained as a clear oil (3.69 g, 24% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:13]>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([Cl:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: CO
Product: CC(C)(C)c1ccc(O)c(Cl)c1
Temperature: 25 °C

Procedure:
4-tert-Butyl-phenol (2.64 g, 17.5 mmol) was dissolved in 1M solution of SO2Cl2 in DCM (17.5 mL, 17.5 mmol) and MeOH (0.71 mL, 17.5 mmol) was added. The reaction was stirred at rt and monitored for progression. Additional 1M SO2Cl2/DCM (10 mL) and MeOH (0.36 mL) were added. The reaction mixture was concentrated in vacuo to yield the target compound. Calculated mass=186. Observed mass=187