Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:3]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.[CH3:31][S:32]SC.CCOCC>CCCCC.C1COCC1>[F:1][C:2]1[N:3]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:4]=[C:5]([S:32][CH3:31])[N:6]=1
Reactant: CSSC
Reactant: Fc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-1-triphenylmethylimidazole (0.328 g.) and t-butyl lithium (1.0 ml. of a 2M solution in pentane) in THF (3 ml.) was stirred at -78° for 2 hours. Dimethyl disulphide (0.18 ml.) was added and the mixture was stirred for 0.5 hours at -78° then at -15° for 1 hour. Ether was added and the organic layer washed to neutrality with water and finally with brine. The solution was dried and the solvent evaporated to give 2-fluoro-4-methylthio-1-triphenylmethylimidazole (0.368 g.), m.p. 142°-143°.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:22][OH:23])[CH:7]=[C:8]([C:12]3[N:13]=[CH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31]1([C:37]#[CH:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CN(C)C=O.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.[Cu](I)I>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([C:8]2[O:9][C:10]3[C:5]([C:6](=[N:22][OH:23])[CH:7]=2)=[CH:4][CH:3]=[C:2]([C:38]#[C:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:11]=3)[N:13]=1
Reactant: C#Cc1ccccc1
Reactant: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#Cc3ccccc3)ccc12
Temperature: 90 °C
Yield: 13.2 %

Procedure:
A solution of 7-bromo-2-isoquinolin-3-yl-chromen-4-one oxime (52 mg, 0.142 mmol), trans-dichlorobis(triphenylphosphine)palladium (10 mg, 0.014 mmol), copper iodide (5.3 mg, 0.028 mmol) in dimethylformamide (3 ml) was degassed with argon for 10 min and then treated with triethylamine (30 μl, 0.213 mmol) and phenyl acetylene (19 μl, 0.170 mmol). The solution was warmed to 90° C. for 18 hours and then poured onto a 0.5N aqueous solution of hydrogen chloride, extracted with ethyl acetate and purified by preparative HPLC (gradient 25-10% Water/acetonitrile+0.05% trifluoroacetic acid) to yield 2-isoquinolin-3-yl-7-phenylethynyl-chromen-4-one oxime (7.3 mg, 13%) as a yellow solid and a 80/20 mixture of Z/E oxime isomers.
Reaction SMILES: [O:1]=[C:2]([N:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:3]NC(=O)C1C=CC(C(=O)C)=CC=1.[C:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)(=[O:33])[CH3:32].CC[N:45](C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[O:1]=[C:2]([N:16]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C:41]1[CH:42]=[C:34]([C:31](=[O:33])[CH3:32])[CH:35]=[CH:36][C:37]=1[C:38]([NH2:45])=[O:39]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)c1ccc(C(=O)NCC(=O)N(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C(N)=O)c(CC(=O)N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
N-{2-Oxo-2-{di(phenylmethyl)amino}ethyl}-4-acetylbenzamide: To a solution of 4-acetylbenzoic acid (1.21 g, 7.37 mmol) in DMF (35 mL) was added successively the product of the preceding section (b) (2.03 g, 7.0 mmol), DIPEA (4.3 mL, 24.5 mmol) and BOP.PF6 (3.25 g, 7.37 mmol). The resulting solution was stirred at room temperature for 2 h, then diluted with EtOAc, washed serially with H2O, 4N aqueous HCl, saturated NaHCO3, and brine, dried (MgSO4) and concentrated under reduced pressure to give N {2-oxo-2-{di(phenylmethyl)amino}ethyl}-4-acetylbenzamide (2.70 g, 99% yield) as a light yellow foam: 1H NMR (400 MHz, DMSO-d6) 8 8.89 (t, 1H, J=5.7 Hz), 8.05 (d, 2H, J=8.4 Hz), 8.00 (d, 2H, J=8.4 Hz), 7.24-7.44 (m, 10 H), 4.61 (s, 2H), 4.51 (s, 2H), 4.25(d, 2H, J=5.7 Hz), 2.52 (s, 3H); MS (FAB) m/z 401 (MH)+. This product was used as such in the next reaction (section (d)).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]([OH:6])=O.N1[CH:19]=[CH:18]N=C1.C(Cl)(=O)C.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]1=[O:33].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[CH3:18][C:19]1[N:25]([CH:26]2[CH2:31][CH2:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[C:4](=[O:6])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][C:7]=2[C:11]([F:14])([F:13])[F:12])[N:1]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: c1c[nH]cn1
Reactant: Nc1cccc(C(F)(F)F)c1C(=O)O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC(=O)Cl
Solvent: CC#N
Solvent: O
Product: Cc1nc2cccc(C(F)(F)F)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a stirred mixture of 2-amino-6-(trifluoromethyl)benzoic acid (3.0 g, 15 mmol) and imidazole (1.2 g, 18 mmol) in acetonitrile (30 mL), was added acetyl chloride (1.3 mL, 18 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.4 g, 15 mmol), imidazole (2.2 g, 32 mmol) and triphenyl phosphite (4.6 mL, 18 mmol) and heated to reflux for 22 hours. To the mixture, was added water (100 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50 mL) to give 3-(2-methyl-4-oxo-5-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (2.02 g, 51% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.84 min (99.9%); mp: 268-270° C.; 1H NMR (DMSO-d6) δ 2.14-2.22 (m, 1H, CHH), 2.55-2.70 (m, 5H, CH3, 2CHH), 2.76-2.92 (m, 1H, CHH), 5.29 (dd, J=6, 11 Hz, 1H, NCH), 7.89-7.98 (m, 3H, Ar), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.45, 23.27, 30.43, 56.74, 117.19, 123.19 (q, JC-F=273 Hz), 125.75 (q, JC-F=7 Hz), 126.42 (q, JC-F=32 Hz), 132.05, 133.97, 149.12, 156.58, 157.59, 169.19, 172.48; LCMS: MH=340; Anal Calcd for C15H12N3O3F3+1 H2O: C, 50.43; H, 3.95; N, 11.76; F, 15.95. Found: C, 50.26; H, 3.82; N, 11.66; F, 15.71.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH:12]([CH3:22])[CH2:13][N:14]2[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Br)(Br)[Br:25]>N1C=CC=CC=1>[Br:25][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH:12]([CH3:22])[CH2:13][N:14]1[CH2:19][CH:18]([CH3:20])[O:17][CH:16]([CH3:21])[CH2:15]1
Reactant: CC1CN(CC(C)C(O)c2ccc(C(C)(C)C)cc2)CC(C)O1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Product: CC1CN(CC(C)C(Br)c2ccc(C(C)(C)C)cc2)CC(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 200.5 %

Procedure:
21.6 g (0.07 mole) of 1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-1-propanol (obtained according to Example 2) were dissolved in 250 ml of petroleum ether with 1.9 ml of pyridine and a solution of 2.9 ml (0.03 mole) of phosphorus tribromide in 50 ml of petroleum ether was added dropwise at -5° to -10° C. The mixture was subsequently stirred at room temperature for 3 hours and the precipitate was filtered off, washed with petroleum ether and dissolved in chloroform. The chloroform phase was washed with sodium bicarbonated solution, dried over sodium sulphate and concentrated in vacuo. 23 g (88% of theory) of 1-bromo-1-(p-tert.-butyl-phenyl)-2-methyl-3-(2,6-dimethylmorpholin-4-yl)-propane were obtained as a viscous oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].[H][H].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[C:12]([C:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:13]
Reactant: CCOC(=O)CBr
Reactant: [H][H]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
4.3 g of sodium hydride as a 60% dispersion in oil are added to a solution of 10 g of 3,4-dichlorophenylacetonitrile in 50 ml of THF and the mixture is stirred until the evolution of hydrogen has ceased. It is cooled to 0° C. and a solution of 18 g of ethyl bromoacetate in 50 ml of THF is added dropwise. The mixture is allowed to return to RT and stirred overnight. It is evaporated to dryness, the residue is taken up with ether and the mixture is washed with a buffer solution of pH 2 and dried over MgSO4. The residue is chromatographed on silica using a DCM/AcOEt mixture (80/20; v/v) as the eluent to give 15 g of the expected compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:15][C:14](=[O:23])[C:13]=2[CH:24]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[ClH:1].[CH:18]1([C:16]2[O:17][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:29]4[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]4)=[CH:24][C:13]=3[C:14](=[O:23])[CH:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: OC1CCNCC1
Reactant: O=c1cc(C2CCCC2)oc2ccc(OCCCCCCCl)cc12
Product: Cl
Product: O=c1cc(C2CCCC2)oc2ccc(OCCCCCCN3CCC(O)CC3)cc12

Procedure:
The reaction between 6-(6-chlorohexoxy)-2-cyclopentyl-4H-1-benzopyran-4-one and 4-hydroxypiperidine was carried out in a manner similar to that of Example 3: mp 125°-126° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (700 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (520 mg, yield: 79%). This was recrystallized from ethanol-water. Melting point: 177–178° C.
Reaction SMILES: O1C=CC([NH:6][CH2:7][C:8]#[N:9])=C1.C(N(CC)CC)C.Cl.[C:18](Cl)(=O)[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1>>[CH2:18]([NH:9][CH:8]([C:28]1[CH:27]=[CH:31][O:30][CH:29]=1)[C:7]#[N:6])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: N#CCNc1ccoc1
Reactant: O=C(Cl)c1cccnc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#CC(NCc1cccnc1)c1ccoc1
Reaction time: 1 h

Procedure:
2.3 g of the α-(3-furyl)aminoacetonitrile and 4.1 g of triethylamine were dissolved in 100 ml of THF. Then 3.6 g of nicotinic acid chloride hydrochloride was added thereto under ice-cooling. The obtained mixture was stirred for one hour and then at room temperature for six hours. After filtering the solid matter thus formed, the solvent was distilled off. The obtained oily substance was purified by column chromatography to thereby give 2.7 g of α-(nicotinylamino)-(3-furyl) acetonitrile in the form of crystals.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([C:11]1[S:49][C:14]2[N:15]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:36][C:35]=3[F:48])[C:16](=[O:32])[N:17]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=3)=[O:22])[C:18](=[O:19])[C:13]=2[CH:12]=1)[CH3:10].[N:50]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([C:11]1[S:49][C:14]2[N:15]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[C:46]4[NH:50][C:4](=[O:7])[O:5][N:47]=4)=[CH:36][C:35]=3[F:48])[C:16](=[O:32])[N:17]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=3)=[O:22])[C:18](=[O:19])[C:13]=2[CH:12]=1)[CH3:10]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(F)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3F)c2s1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(F)c3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3F)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A mixture of hydroxylammonium chloride (1.31 g), sodium hydrogencarbonate (1.98 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(3-fluoro-4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.9 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (40 mL), N,N′-carbonyldiimidazole (0.3 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To the obtained residue were added 20% sulfuric acid (10 mL) and ethanol (20 ml), and the mixture was stirred at 100° C. for 1 hr, and extracted with chloroform and water. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.5 g, 51%).
Reaction SMILES: CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:12])=O.[CH2:15]([N:22]1[CH2:31][CH2:30][CH:29]2[C:24](=[N:25][C:26]([S:33][CH3:34])=[N:27][C:28]2=O)[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH2:15]([N:22]1[CH2:31][CH2:30][C:29]2[C:28]([Cl:12])=[N:27][C:26]([S:33][CH3:34])=[N:25][C:24]=2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSC1=NC(=O)C2CCN(Cc3ccccc3)CC2=N1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Solvent: ClCCCl
Product: CSc1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
N,N-Dimethylaniline (3.2 g, 26.6 mmol) and phosphorus oxychloride (32.6 g, 213 mmol) were added to the solution of 7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4(4aH)-one (7.6 g, 26.6 mmol) in 1,2-dichloroethane (20 mL, anhydrous) and were stirred in a preheated oil bath at 90° C. for 1 hr. Reaction mixture was poured into ice, neutralized by solid sodium carbonate, extracted by ethyl acetate and dried over sodium sulfate. Solvent was removed in vacuo and light brown oil residue was used directly in the next step.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:12]/[C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[NH2:25][CH:26]([CH3:29])[CH2:27][OH:28]>C1(C)C=CC=CC=1>[OH:28][CH2:27][CH:26]([NH:25][C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:12]/[C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])[CH3:29]
Reactant: CCOC(=O)c1cnc(/C=C/c2c(-c3ccccc3)noc2C)s1
Reactant: CC(N)CO
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ncc(C(=O)NC(C)CO)s1
Reaction time: 15 h
Yield: 78.2 %

Procedure:
To a stirred solution of 2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid ethyl ester (30 mg, 0.09 mmol) in toluene (0.5 mL) was added rac-2-amino-1-propanol (9 mg, 0.12 mmol) and TBD (4 mg, 0.03 mmol). After 15 h, the reaction mixture was concentrated in vacuo then purified by chromatography (silica, 0 to 3% methanol in dichloromethane) to give the title compound (26 mg, 80%) as a white solid. MS: m/e=370.0 [M+H]+.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.CN1C(=O)N(C)CCC1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:21]=1.CI>C1COCC1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([CH3:2])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:22][CH:21]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COc1ccc(CC(C)C(=O)OC(C)(C)C)cc1
Agent: [Li+]
Solvent: CI
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COc1ccc(CC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
An oven dried flask was charged with THF (40 mL) under nitrogen and cooled to −78° C. and 2M LDA in THF (7.19 mL, 14.38 mmol) was added dropwise followed by DMPU (8 mL, 5.75 mmol). Tert-butyl 3-(4-methoxyphenyl)-2-methylpropanoate (1.44 g, 5.75 mmol) was added by cannula in THF (4×5 mL), and the reaction was stirred at −78° C. for 1 hr. Methyl iodide (1.079 mL, 17.26 mmol) was added dropwise, and the reaction was stirred 30 minutes at −78° C. and then warmed to room temperature for 1 hr. The reaction was quenched with water (40 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with 1N HCl (2×30 mL) and brine (2×30 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 60% ethyl acetate/hexanes) afforded tert-butyl 3-(4-methoxyphenyl)-2,2-dimethylpropanoate. 1H NMR (CDCl3, 500 MHz) δ 7.07 (d, J=8.5 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 3.78 (s, 3H), 2.76 (s, 2H), 1.43 (s, 9H), 1.11 (s, 6H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4]O.[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:1]1[CH2:3][C@@H:2]1[CH2:4][N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC[C@H]1CO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Temperature: 0 °C
Reaction time: 48 h
Yield: 73.9 %

Procedure:
To a cold solution of (S)-1-oxiranylmethanol (5 g, 67.5 mmol) and phthalimide (9.9 g, 67.3 mmol) in tetrahydrofuran (200 mL) in ice bath was added triphenylphosphine (17.9 g, 68.2 mmol) and diethyl azodicarboxylate (12.3 g, 70.6 mmol). The mixture was stirred at 0° C. for 2 h and at ambient temperature for 48 h. The mixture was concentrated under vacuum, and the oily residue was purified by flash silica column chromatography, yielding the desired product (10.1 g) as pale yellow solid: Rf=0.51 in 1:1 EtOAc/hexane. 1H-NMR (CDCl3, 300 MHz): δ (ppm) 7.76-7.64 (m, 2H), 7.63-7.60 (m, 2H), 3.9-3.8 (dd, 1H), 3.70-3.65 (dd, 1H), 3.15 (m, 1H), 2.70-2.67 (dd, 1H), 2.58-2.55 (dd, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[C:14]([NH:22][OH:23])([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15].Cl>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:22]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[O-:23])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:2]
Reactant: CC(C)(C)CC(C)(C)NO
Reactant: CCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: CO
Product: CCOc1cc(C=[N+]([O-])C(C)(C)CC(C)(C)C)ccc1OC
Yield: 60 %

Procedure:
A solution of 3-ethoxy-4methoxybenzaldehyde, N-tert-octylhydroxylamine and catalytic amount of HCl in methanol was refluxed for 90 hrs with molecular sieves in a soxhlet for waster removal. The title compound was obtained in 60.0% yield as white powder, m.p. 77.5° C. (Rf =0.40 on a silica gel plate using hexanes:EtOAc, 3:2, v:v, as an eluant).
Reaction SMILES: [C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O.N1CCOCC1.Cl>O.C(O)C>[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=[CH:2][C:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])=[O:3]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(=O)C1C(=O)CCC1=O
Agent: Cl
Solvent: CCO
Solvent: C1COCCN1
Solvent: O
Product: COc1ccc(C=CC(=O)C2C(=O)CCC2=O)cc1O

Procedure:
2-Acetyl-1,3-cyclopentanedione (3.83 g.) was treated with 5.0 g. of 3-hydroxy-4-methoxybenzaldehyde in 120 ml. of ethanol in the presence of 5 ml. of morpholine under reflux for 5 hours. After cooling, the reaction mixture was poured into 200 ml. of water containing 8 ml. of conc. hydrochloric acid. Deposited crystals were separated by filtration, washed with water and ethanol successively, and dried. 2-(3-Hydroxy-4-methoxycinnamoyl)-1,3-cyclopentanedione (5.46 g.) was obtained, in the form of yellow crystals which showed mp. 137°-139° C. after recrystallisation from a mixed solvent of ethanol and dioxane.