Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:5](=O)[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)(=[O:3])[CH3:2].[C:12](=[O:15])([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[C:1]([C:4]1[C:12](=[O:15])[N:8]([CH2:9][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7](=[O:10])[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c(=O)[nH]c1=O
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cn(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O
Reaction time: 0.33 h
Yield: 79.9 %

Procedure:
A suspension of 5-acetyluracil (3.1 g, 20 mmol), and potassium carbonate (6.9 g, 50 mmol) in DMF (75 ml) was stirred for 20 min. Then benzyl bromide (6.0 ml, 50 mmol) was added. The resulting mixture was stirred for 8 h at room temperature. DMF was distilled under vacuum. The residue was purified by column (dichloromethane:methanol 40:1). The appropriate fraction was concentrated and crystallized from ethanol to afford 5.34 g of a white solid. Yield was 79.8%. Mp. 92-93° C. 1HNMR (CDCl3): 8.23 (s, 1H), 7.29-7.49 (m, 10H), 5.17 (s, 2H), 5.01 (s, 2H), 2.62 (s, 3H). 13CNMR (CDCl3): 194.5, 160.7, 151.0, 148.4, 136.2, 134.4, 129.2, 129.0, 128.9, 128.5, 128.2, 127.8, 112.2, 53.4, 44.9, 30.7. FAB-HRMS: [M+H]+ calcd. for C20H19N2O3 335.1396, found 335.1412.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([NH2:16])=[N:6][CH:5]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([NH:16][C:24](=[O:26])[CH3:25])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(N)c(C#C[Si](C)(C)C)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cnc(NC(C)=O)c(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-amino-5-trimethylsilanylethynyl-nicotinic acid methyl ester (6.05 g, 24.4 mmol) and pyridine (4 mL, 49.4 mmol) in dichloromethane (80 mL) was added acetyl chloride (2.6 mL, 35.6 mmol) at 0° C. The mixture was allowed to warm up to 25° C. and stirred for 12 h. The reaction mixture was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to afford 6-acetylamino-5-trimethylsilanylethynyl nicotinic acid methyl ester which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1(O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]1[O:10]C)([O-:3])=[O:2].CN([CH:16]=[O:17])C.N#N.Br[CH:21]([CH3:23])[CH3:22]>>[CH:21]([O:10][C:5]1[C:6]([O:17][CH3:16])=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:23])[CH3:22]
Reactant: CN(C)C=O
Reactant: CC(C)Br
Reactant: COC1C=CC=CC1(O)[N+](=O)[O-]
Agent: N#N
Product: COc1cccc([N+](=O)[O-])c1OC(C)C
Temperature: 55 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of 2-nitroguaiacol (Thompson, M. J.; Zeegerers, P. J. Tetrahedron, 1990, 46, 2661; 0.5062 g; 3 mmol) in anhydrous DMF (5 ml) K2CO3 (0.41 g; 3 mmol) was added and resulting mixture was stirred for 15 min under reduced pressure and saturated with N2. To it, 2-bromopropane (1 ml; 10.6 mmol) was added and the reaction flask was sealed with septum and stirred overnight at 55° C. After evaporation of DMF under reduced pressure the residue was partitioned between diethyl ether (20 ml) and water (10 ml). The organic phase was washed with 2% aq. KOH (5 ml), brine, dried over anhydrous MgSO4, filtered off and filtrate evaporated to dryness. The residue was dissolved in small volume of CH2Cl2 and filtered through short column with SiO2, which was eluded with fresh CH2Cl2. The combined filtrates were evaporated to dryness under reduced pressure to give 2-isopropoxy-3-methoxynitrobenzene (0.62 g; 98% yield) as creamy syrup. 1H-NMR (CDCl3) 1.26 (d, 6H, J=6.17 Hz); 3.87 (s, 3H); 4.61 (m, 1H, J=6.17 Hz); 7.06 (m, 2H); 7.26 (m, 1H). This was dissolved in ethanol (30 ml) and the resulting mixture was degassed under reduced pressure. To it 10% Pd on carbon (0.22 g) was added and the mixture was saturated with H2 and stirred for 5 h under the balloon pressure of H2. The catalyst was removed by filtration through Celite. The filtrate was evaporated to dryness to give the title compound (0.702 g; 92.5% yield) as colourless oil. 1H-NMR (CDCl3) 1.28 (d, 6H, J=6.19 Hz); 3.7 broad s, 2H); 3.79 (s, 3H); 4.45 (m, 1H, J=6.19 Hz); 6.2-6.78 (m, 2H); 6.8(m, 1H).
Reaction SMILES: C([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([S:23]([Cl:26])(=[O:25])=[O:24])[C:19]([O:21][CH3:22])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=O)C.[CH3:27][NH:28][CH3:29]>>[ClH:26].[ClH:26].[CH3:22][O:21][C:19]1[C:18]([S:23](=[O:25])(=[O:24])[N:28]([CH3:29])[CH3:27])=[CH:17][C:8]2[CH:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[CH:20]=1
Reactant: CNC
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)C(c1ccccc1)CN(C(C)=O)CC2
Product: COc1cc2c(cc1S(=O)(=O)N(C)C)C(c1ccccc1)CNCC2
Product: Cl

Procedure:
Reacting 3-acetyl-8-chlorosulfonyl-7-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine with dimethylamine and then with refluxing hydrochloric acid gives 7-methoxy-8-(N,N-dimethylsulfamoyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. Treating this methoxy compound with refluxing hydrobromic acid gives 7-hydroxy-8-(N,N-dimethylsulfamoyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][NH:10][C:9]2=O)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2c([N+](=O)[O-])cccc12
Product: O=[N+]([O-])c1cccc2c(Cl)ncnc12

Procedure:
A solution of 8-nitroquinazolin-4(3H)-one (Intermediate-7, step-1, 300 mg, 1.57 mmol) in POCl3 (3 mL) was heated at reflux for 2 h. Then the reaction mixture was concentrated and dried to afford 4-chloro-8-nitroquinazoline which was used for the next step without further purification. Then NaH (263 mg, 11.54 mmol, 95%) was added to EtOH (2 mL) at 0° C. and stirred at that temperature for 15 minutes before it was added to a solution of 4-chloro-8-nitroquinazoline in THF (2 mL) at 0° C. Then the reaction mixture was stirred at rt for 4 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 200 mg of the title product. MS (m/z): 220.23 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:24][CH2:25][C@@H:26]([O:29][C@@H:30]([N:33]2[C:39](=[O:40])[NH:38][C:36](=[O:37])[CH:35]=[CH:34]2)[CH2:31][OH:32])[CH2:27][OH:28])([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.N1C(=O)CC[C@H]1C(O)=O.[C:57](Cl)(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CCO.C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]([O:24][CH2:25][C@@H:26]([O:29][C@@H:30]([N:33]2[C:39](=[O:40])[NH:38][C:36](=[O:37])[CH:35]=[CH:34]2)[CH2:31][O:32][C:57]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:64])[CH2:27][OH:28])([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C(OC[C@H](CO)O[C@H](CO)n2ccc(=O)[nH]c2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(OC[C@H](CO)O[C@H](COC(=O)c2ccccc2)n2ccc(=O)[nH]c2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Nucleoside 102-U (3.01 g, 5.50 mmol) was coevaporated with an. toluene (15 mL). The resulting residue was dissolved in an. DCM (150 mL) along with an. Pyr. (4.4 mL) and the mixture was cooled to −70° C. Benzoyl chloride (700 μL, 6 mmol) was slowly added to the reaction mixture and stirred for 1 h at −70° C. EtOH (5 mL) was added to the solution and subsequently allowed to reach rt. The reaction mixture was washed with sat. aq. NaHCO3 (3×100 mL) and brine (100 mL). The combined aqueous phase was back extracted with CH2Cl2 (100 mL). The organic phases were combined and evaporated. The resulting residue was purified by column chromatography (3.5% MeOH in DCM) affording the product 103-U as a white foam after evaporation of the solvents.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C>>[N:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:6]/[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccccc1/C=C/c1ccncc1
Temperature: 0 °C
Yield: 99.1 %

Procedure:
To 15.1 g of 2-nitrobenzaldehvde was added 9.3 g of 4-picoline followed by addition of 5 ml of acetic anhydride and the mixture was refluxed for 12 hours. This reaction mixture was poured in ice-water, made basic with 2N--NaOH, and extracted with chloroform. The extract was dehydrated over anhydrous magnesium sulfate and the solvent was evaporated off to provide 22.40 g of (E)-2-[2-(4-pyridyl)ethenyl]-1-nitrobenzene. This product was treated as in Reference Example 2 (2) to provide the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:21])[CH:9]=1)([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[N:27][C:28](Cl)=[N:29][CH:30]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Br:24][C:25]1[CH:26]=[N:27][C:28]([NH:21][CH2:20][C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=2[C:8]2[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=2[O:22][CH3:23])=[N:29][CH:30]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
C-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (3.47 g) is dissolved in dioxane (50 ml), and thereto are added 5-bromo-2-chloropyrimidine (5.30 g) and N,N-diisopropylethylamine (5.74 ml) and the mixture is stirred at 100° C. for 2 hours and a half. The reaction solution is allowed to cool to room temperature, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=50:1→22:3) to give (5-bromo-pyrimidin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (4.82 g). MS (m/z): 482/480 [M+H]+
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][CH:6]([F:22])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([CH:17]=[C:18]([F:21])[CH2:19][OH:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:20][CH2:19][C:18]([F:21])=[CH:17][C:14]1([C:11]2[CH:10]=[CH:9][C:8]([O:7][CH:6]([F:5])[F:22])=[CH:13][CH:12]=2)[CH2:16][CH2:15]1)(=[O:3])[CH3:2]
Reactant: OCC(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Yield: 99 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.92 ml), 1-(4-difluoromethoxyphenyl)-1-(2-fluoro-3-hydroxyprop-1-enyl)cyclopropane Example 16) (0.49 g), benzene (24 ml) and pyridine (0.2 ml) to yield the title compound (0.55 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([I:9])=[CH:4][C:3]=1[Cl:10].[OH:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:16]2[CH:17]=[C:12]([OH:11])[CH:13]=[CH:14][CH:15]=2)=[C:5]([I:9])[CH:4]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Clc1cc(I)c(I)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1cccc(-c2cc(Cl)c(Cl)cc2I)c1
Temperature: 25 °C
Yield: 21.9 %

Procedure:
A mixture of 1,2-dichloro-4,5-diiodobenzene (1.5 g, 3.76 mmol), 3-hydroxyphenylboronic acid (0.52 g, 3.76 mmol), Na2CO3 (1.99 g, 18.8 mmol) and Pd(PPh3)4 (0.35 g, 0.30 mmol), in 1,4-dioxane (10 mL) and water (2 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (300 mg, 22% yield). ESI-MS m/z: 362.9 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: NCCCO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(F)cc2F)cc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(F)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
4-(2,4-Difluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (0.15 g, 0.5 mmol) was dissolved in a mixture of anhydrous THF (20 ml) and anhydrous DMF (2 ml). CDI (0.18 g, 1.1 mmol) was added and the solution stirred at RT for 2 h. 3-Amino-1-propanol (0.16 g, 2.2 mmol) was then added and the solution stirred for a further 15 h. The solvent was removed under reduced pressure and the residue partitioned between 2% MeOH/EtOAc and water. The organic fraction was washed with water ×2, NaHCO3, brine, dried (Na2SO4) and concentrated to give crude 4-(2,4-difluoroanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide. Further purification by flash chromatography on silica gel (5% MeOH/CH2Cl2) afforded 4-(2,4-difluoroanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (0.12 g, 68%) as a cream solid; m.p. (EtOAc/Hexane) 129-132° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.84 (br s, 1H), 8.36 (t, J=5.4 Hz, 1H), 8.22 (s, 1H), 7.51-7.37 (m, 2H), 7.16-7.10 (m, 1H), 5.32 (d, J=1.1 Hz, 1H), 4.47 (t, J=4.9 Hz, 1H), 3.47 (dd, J=11.5, 6.2 Hz, 2H), 3.35 (s, 3H), 3.27 (dd, J=12.7, 6.8 Hz, 2H), 1.67 (p, J=6.7 Hz, 2H). LCMS (ACPI−) 336 (100%). Anal. Calcd for C16H17F2N3O3.0.25 H2O: C, 56.2; H, 5.2; N, 12.3. Found C, 56.4; H, 5.3; N, 12.5.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][N:17]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:12]([O:14]C)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.O.Cl>[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][N:17]([C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[C:12]([OH:14])=[O:13])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C(CN(Cc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CN(Cc1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
Lithium hydroxide (62.4 mg) was added to a solution of the product of step (b) (1.0 g) in tetrahydrofuran/water (30 ml). The resulting solution was stirred at room temperature for 4 hours, diluted with 1N HCl (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colourless foam (990 mg). NMR δH (360 MHz, CDCl3) 1.44 (9H, s), 3,49 (2H, m), 4.51 (3H, m), 5.17 (2H, m), 5.79 (1H, br s), 7.20-7.42 (8H, m). m/e (CI+) 497 (MH+).
Reaction SMILES: B(F)(F)F.[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][O:13]2)=[CH:8][CH:7]=1.C(C(C1C=[CH:36][C:35]([OH:38])=CC=1O)=O)C1C=CC=CC=1.C1([C:46](CC2C=CC=CC=2)=[O:47])C=CC=CC=1>>[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([C:46]([O:38][CH2:35][CH3:36])=[O:47])[O:13]2)=[CH:8][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1O
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Agent: FB(F)F
Product: CCOC(=O)c1oc2cc(O)ccc2c(=O)c1-c1ccccc1

Procedure:
Deoxybenzoins undergo α-keto formylation, intramolecular acetal formation, and a facile dehydration to give the pyrone ring C and hence, the isoflavones as shown in Scheme 1, Step 2 and below. Substituted deoxybenzoins were synthesized by reacting appropriate substituted phenyl acetic acids with properly substituted resorcinols in the presence of BF3. The starting material (7-hydroxy isoflavone, compound 1) for the synthesis of the 7-O-substituted isoflavones was prepared by cyclization of 2,4-dihydroxyphenyl benzyl ketone (Aldrich Chemical Co. Milwaukee, Wis.) as described by WO 91/15483, and shown in steps 2 and 3 of scheme 1, and further described in Gao et al. (2003) Bioorganic & Medicinal Chemistry, in press. 7-Hydroxy-2-ethoxycarbonylisoflavone (compound 20) was prepared by cyclization of the corresponding deoxybenzoin in the presence of an appropriate formyl equivalent as shown in Li, D. Y.; Gao, Z. J.; Ji, Q. E. Synthesis of isoflavones derivatives (I)-7-methoxy-3′-N, N-dialkylaminomethyl-4′-hydroxy isoflavones (Chinese J. Med. Chem. 1991, 1 (2), 38-42). The 2-carboxy derivatives (compounds 16, 21, and 22) were obtained by hydrolyzing their respective ethyl esters. The 4′-amino derivatives (compounds 32 and 33) were prepared by reducing their corresponding 4′-nitro derivatives (compounds 27 and 28) under the condition set forth in WO 91/15483, and Li, D. Y.; Gao, Z. J.; Ji, Q. E. Synthesis of isoflavones derivatives (I)-7-methoxy-3′-N, N-dialkylaminomethyl-4′-hydroxy isoflavones. Chinese J. Med. Chem. 1991, 1 (2), 38-42. Full explanations of the syntheses are set forth below. All compounds synthesized were purified by Sephadex-LH-20 and/or silica gel columns. Products were identified by 1HNMR, 13C-NMR, MS, and elemental analyses. Purity of all compounds prepared in this study was greater than 97.8% as judged by HPLC with UV detection at 254 mn. Molecular weights, melting points, molecular formulae, and elemental analysis data of these analogs are included in EXAMPLE IV, below.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[N+]([O-])=O>CN(C)C=O.O.C(O)(=O)C>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:22]([O:21][CH3:20])=[CH:27][C:26]=1[N+:28]([O-:30])=[O:29]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCOc1cc(OC)c([N+](=O)[O-])cc1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A mixture of 12.7 g (0.0525 mole) of hexadecylalcohol and 2.50 g of a 55% by weight oily suspension of sodium hydride (0.057 mole) in 100 ml of dimethylformamide was stirred for 1 h at 50° C. (formation of foam). Thereafter 11.4 g (0.05 mole) of 1,4-dimethoxy-2,5-dinitrobenzene prepared as illustrated hereinbefore was added and the mixture was stirred for 1 h at 50° C. The mixture was poured in 500 ml of water and 10 ml of acetic acid. The precipitate which was formed, was filtered off and washed with water, dried and recrystallized from methanol. Yield: 60%; melting point: 71° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][C@H:35]1[C@H:40]2[CH2:41][C@H:37]([CH:38]=[CH:39]2)[C@H:36]1[C:42]([NH2:44])=[O:43]>>[NH2:44][C:42]([C@@H:36]1[C@@H:37]2[CH2:41][C@@H:40]([CH:39]=[CH:38]2)[C@@H:35]1[NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:31]1[CH:30]=[CH:29][C:28]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)=[O:7])=[O:18])=[O:43]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NC(=O)[C@H]1[C@@H](N)[C@@H]2C=C[C@H]1C2
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N[C@@H]2[C@H](C(N)=O)[C@H]3C=C[C@@H]2C3)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide, the title compound was obtained in 78% purity by HPLC. MS(ESI+): m/z=473.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[CH:13](=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH2:9][N+:10]([O-:12])=[O:11])[C@H:14]([CH:15]([CH3:17])[CH3:16])[CH:13]=[O:18])=[CH:6][CH:7]=1
Reactant: CC(C)CC=O
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccc(Br)cc1

Procedure:
The title compound was prepared from (E)-1-bromo-4-(2-nitrovinyl)benzene and isovaleraldehyde according to general procedure. The enantiomeric excess was determined by HPLC with Chiralpak AD-H column at 254 nm (2-propanol:hexane=10:90), 1 mL/min, tmajor=7.6 min, tminor=7.2 min, the diastereomeric ratio was determined by 1H NMR. [α]D20=−30.2 (c=0.27, CHCl3);
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:19]O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:19])=[O:6]
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1C
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(C)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution of 3,4-dimethyl-2-nitrobenzoic acid (13 g) and thionyl chloride (11.8 g) in toluene (100 ml) was refluxed for 4 h. The reaction mixture was cooled at 0° C., treated with methanol (15 ml) and the solvent was removed under vacuum. The reaction mixture was treated water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 3,4-dimethyl-2-nitrobenzoate (10 g). 1H-NMR (400 MHz, CDCl3): 2.19 (s, 3H), 2.38 (s, 3H), 3.87 (s, 3H), 7.25 (d, 1H), 7.79 (d, 1H).