Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:18])=[O:17])[CH:8]=2)[NH:3]1.[Br:32][C:33]1[CH:66]=[CH:65][C:36]([CH2:37]N2C3C(=CC(S(N4CCCC4COC4C=CC=CC=4)(=O)=O)=CC=3)C(=O)C2=O)=[CH:35][CH:34]=1>>[Br:32][C:33]1[CH:66]=[CH:65][C:36]([CH2:37][N:3]2[C:4]3[C:9](=[CH:8][C:7]([S:16]([N:19]4[CH2:23][CH2:22][CH2:21][CH:20]4[CH2:24][O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)(=[O:17])=[O:18])=[CH:6][CH:5]=3)[C:10](=[C:11]([C:12]#[N:13])[C:14]#[N:15])[C:2]2=[O:1])=[CH:35][CH:34]=1
Reactant: N#CC(C#N)=C1C(=O)Nc2ccc(S(=O)(=O)N3CCCC3COc3ccccc3)cc21
Reactant: O=C1C(=O)N(Cc2ccc(Br)cc2)c2ccc(S(=O)(=O)N3CCCC3COc3ccccc3)cc21
Product: N#CC(C#N)=C1C(=O)N(Cc2ccc(Br)cc2)c2ccc(S(=O)(=O)N3CCCC3COc3ccccc3)cc21
Yield: 86 %

Procedure:
2-[1-(4-Bromo-benzyl)-2-oxo-5-(2-phenoxymethyl-pyrrolidine-1-sulfonyl)-1,2-dihydro-indol-3-yl-idene]-malononitrile (27d) was prepared according to the same procedure for compound 26 except using 25d, to afford 52 mg (86%) of 27d as a purple solid, mp 237.0° C. (decomp). 1H NMR (300 MHz, CDCl3) δ 8.46 (s, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.20-7.13 (m, 4H), 6.90 (t, J=7.5 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 6.68 (d, J=7.8 Hz, 2H), 4.84 (m, 2H), 4.06 (m, 2H), 3.97 (m, 1H), 3.46 (m, 2H), 2.08-1.86 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[C:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:19]=3)=[N:15][CH:16]=2)[CH2:10][CH2:9]1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)[N:32]=1.C(N(C(C)C)CC)(C)C>CC#N>[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[CH:24]=[C:25]3[CH2:30][CH2:29][N:28]([C:38]([NH:37][C:33]4[N:32]=[N:31][CH:36]=[CH:35][CH:34]=4)=[O:39])[CH2:27][CH2:26]3)=[N:15][CH:16]=2)[CH2:10][CH2:9]1
Reactant: C(=C1CCNCC1)c1cccc(Oc2ccc(C3CC3)cn2)c1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C4CC4)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.8 %

Procedure:
To a solution of 5-cyclopropyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine trifluoroacetate (0.972 g, 3.17 mmol) in CH3CN (10 mL) was added phenyl pyridazin-3-ylcarbamate (0.751 g, 3.49 mmol) followed by diisopropylethylamine (2.76 mL, 15.9 mmol). The reaction was stirred at room temperature for 3 d. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (0-15% EtOH/CH2Cl2) to afford the title compound as a white foam (1.19 g). Recrystallization from hot diisopropyl ether with a few drops of methanol afforded the title compound as an off-white solid (0.857 g, 63% yield). MS (APCI 10V) AP+2 428.09; 1H NMR (400 MHz, CDCl3) δ ppm 0.61-0.67 (m, 2H) 0.93-0.99 (m, 2H) 1.82-1.90 (m, 1H) 2.45 (t, 2H) 2.59 (t, 2H) 3.54 (t, 2H) 3.64 (t, 2H) 6.39 (s, 1H) 6.79-6.82 (m, 1H) 6.92-6.96 (m, 1H) 6.96-7.01 (m, 2H) 7.30-7.35 (m, 2H) 7.38-7.42 (m, 1H) 7.73 (br. s., 1H) 8.01 (d, 1H) 8.29 (d, 1H) 8.82 (d, 1H).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([C:32]([CH3:41])([CH3:40])[C:33]([O:35]C(C)(C)C)=[O:34])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([C:32]([CH3:41])([CH3:40])[C:33]([OH:35])=[O:34])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:30][CH3:31])=[C:27]([F:29])[CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)C(=O)OC(C)(C)C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)(C)C(=O)O)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
Tert-butyl 2-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2-methylpropanoate (25 mg, 0.035 mmol) was dissolved in TFA (344 μL), trifluoromethanesulfonic acid (15.48 mg, 0.103 mmol) was added, and the resulding mixture was stirred at 80° C. for 4 h. The reaction mixture was subsequently concentrated in vacuo and the residue was taken up in 100 mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0% to 100% EtOAc/hexanes) gave impure product which was further purified by preparatory TLC (2 plates; silica gel). TLC plates were loaded with the impure material and eluted in 10% MeOH/DCM to give the title compound (70% yield) following extraction of the product-containing bands with methanol, filtration, and concentration in vacuo. 1H NMR (400 MHz, d4-MeOH) δ 9.00 (d, J=2.74 Hz, 1H) 8.58 (s, 1H) 8.39 (d, J=2.54 Hz, 1H) 8.16-8.24 (m, 2H) 4.01 (s, 3H) 2.52 (s, 3H) 1.59 (s, 6H). m/z (ESI, +ve) 414.0 (M+H)+. m/z (ESI, +ve ion) 414.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[N:29]1([CH2:35][CH2:36][OH:37])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([N:32]1[CH2:33][CH2:34][N:29]([CH2:35][CH2:36][OH:37])[CH2:30][CH2:31]1)=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: OCCN1CCNCC1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)N2CCN(CCO)CC2)c(=O)n(C)c1=O

Procedure:
Example 44 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and 2-(piperazin-1-yl)ethanol. 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 2 H) 6.95 (t, J=8.0 Hz, 1 H) 4.17 (br, 1 H) 3.86 (br, 3 H) 3.54 (br, 5 H) 3.33 (br, 1 H) 3.28 (br, 5 H) 3.10 (br, 2 H) 2.37 (br, 1 H). [M+H] calc'd for C19H23FIN5O4, 532; found, 532.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1>[C:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C)cc1
Yield: 90.6 %

Procedure:
Into a reaction flask equipped with a stirrer and thermometer was charged 216 grams (2.0 moles) of p-cresol, 225 grams (2.2 moles) of acetic anhydride and 500 milliliters of pyridine and the resulting reaction mixture was then heated to a temperature of 50° C.-55° C. After completion of the reaction, work-up and distillation at reduced pressure, 272 grams of p-methylphenyl acetate was obtained (91 percent of theoretical). The nuclear magnetic resonance (NMR) spectrum was consistent with the chemical structure.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([NH2:22])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[C:8]#[N:9])[CH:2]=[CH2:3].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[CH2:1]([O:4][C:5]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[C:11]([NH:22][S:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:10]=[C:7]([C:8]#[N:9])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCOc1cc(C#N)cc(N)c1Oc1cccc(OC)c1
Product: C=CCOc1cc(C#N)cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1cccc(OC)c1

Procedure:
Analogously to Example 143e), from 3-allyloxy-5-amino-4-(3-methoxy-phenoxy)-benzonitrile by coupling with 4-tert-butylbenzenesulphonyl chloride there was obtained N-[3-allyloxy-5-cyano-2-(3-methoxy-phenoxy)-phenyl]-4-tert-butyl-benzenesulphonamide as a crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[C:19]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2CO)cc1-c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(Cc3ccccc3)cc2C=O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
A mixture of {1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-phenylbenzyl)oxy]-1H-pyrazol-4-yl}methanol (0.20 g), activated manganese dioxide (0.60 g) and tetrahydrofuran (10 mL) was stirred at room temperature for 5 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-phenylbenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.19 g, yield 95%). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 122-123° C.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([S:11][CH3:12])[N:4]=1)=[O:2].[BH4-].[Na+].N1C=CN=C1.[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>CO.C(OCC)(=O)C.CN(C)C=O.O>[CH3:12][S:11][C:5]1[N:4]=[C:3]([CH2:1][O:2][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CSc1nc(C=O)ccc1C#N
Agent: [BH4-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CSc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C#N
Yield: 91 %

Procedure:
To a solution of 6-formyl-2-(methylthio)nicotinonitrile (1.0 g, 5.6 mmol) in methanol (10 ml) was slowly added sodium borohydride at 0° C. with stirring, and the resulting mixture was stirred at the same temperature for 10 minutes. After evaporating the solvent in vacuo, the residue obtained was diluted with ethyl acetate, poured into water (20 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. Subsequently, to a solution of the residue obtained and imidazole (0.76 g, 11 mmol) in N,N-dimethylformamide (6 ml) was added triisopropylsilyl chloride (1.3 ml, 6.2 mmol) with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, the reaction mixture was poured into water (20 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 3:97) as the eluent to afford the title compound (1.7 g) in a yield of 91% as a colourless oily product.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[N+:17]([O-])=O)=[CH:5][CH:4]=1)=[CH2:2].[Sn](Cl)Cl.Cl.[OH-].[K+]>C(O)C.O1CCCC1>[CH:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[NH2:17])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=Cc1ccc(Oc2ccc(N)cc2N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
1-[4-Vinylphenoxy]-2,4-dinitrobenzene (9.0 g, 31 mmol) was dissolved in 100 ml ethanol/tetrahydrofuran (1:1). In succession, tin(II)chloride (70.9, 310 mmol), and 10N HCl (37.7 ml, 377 mmol) were added. The solution was stirred at room temperature 16 h. The reaction mixture was poured into a separatory funnel containing 150 ml ice-cold water followed by the addition of 20% KOH (ice-cold, 629 g). The mixture was extracted with ether (3×100 ml). The combined organic phases were washed with water (3×100 ml) and brine, dried with solid MgSO4 and concentrated. Column chromotography yielded 4.5 g product. The product was crystallized from 40% ethyl acetate in hexane. 1H NMR (CDCl3): 7.32 (d, 2H, J=8.5 Hz), 6.88 (d, 2H, J=8.6 Hz), 6.73 (d, 1H, J=8.3 Hz), 6.66 (dd, 1H, J=17.3, 11.9 Hz), 6.15 (d, 1H, J=2.9 Hz), 6.08 (dd, 1H, J=2.4, 8.2 Hz), 5.61 (dd, 1H, J=17.6 Hz, 0.8 Hz), 5.14 (d, 1H, J=10.9 Hz), 4.38 (br s, 4H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[C:12]([NH2:35])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1>C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:36])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:35][C:1](=[O:4])[CH:2]=[CH2:3]
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1N(C)CCN(C)C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A solution of acryloyl chloride (0.354 mL, 4.35 mmol) in CH2Cl2 (5 mL) was added dropwise to a mixture of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 125, 1.9 g, 4.35 mmol) in CH2Cl2 (100 mL), which was cooled in an ice/water bath. The resulting mixture was stirred for 1 h and then washed with sat. NaHCO3. The resulting organic solution was dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (1.069 g, 50%) as an oil which crystallised on standing to give a cream crystalline solid. Some later fractions from the FCC which had a brown colour were concentrated and re-chromatographed to give more of the title compound (334 mg, 16%) as a pale brown oil which crystallised on standing to give a tan-coloured crystalline solid. Total yield: 1.403 g, 66%; 1H NMR: 1.69-1.77 (2H, m), 1.88-1.97 (2H, m), 2.21 (6H, s), 2.29 (2H, t), 2.71 (3H, s), 2.88 (2H, t), 3.02 (2H, t), 3.84 (3H, s), 4.09 (2H, t), 5.74 (1H, dd), 6.24 (1H, dd), 6.40 (1H, dd), 6.97-7.02 (2H, m), 7.87 (1H, s), 8.13 (1H, s), 8.31 (1H, d), 8.85 (1H, s), 10.08 (1H, s); m/z: ES+ MH+ 491.34.
Reaction SMILES: [C:1]1([C:7](=[N:16][NH2:17])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:20][C:21](=O)[CH2:22][N+:23]([O-:25])=[O:24])C.N1CCCCC1>C1C=CC=CC=1>[N+:23]([C:22]1[C:21](=[O:20])[NH:17][N:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: NN=C(C(=O)c1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: O=c1[nH]nc(-c2ccccc2)c(-c2ccccc2)c1[N+](=O)[O-]

Procedure:
8.96 g (0.040 mole) of benzilmonohydrazone, 5.3 g (0.040 mole) of ethylnitroacetate and 4.8 g (0.056 mole) of piperidine in 100 mL of benzene were heated in a round bottom flask with a Dean-Stark trap and condenser for 24 hrs.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:18][CH:19]([CH2:23][CH2:24][Cl:25])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[Cl:25][CH2:24][CH2:23][CH:19]([CH3:18])[C:20]([NH:10][C:8]1[O:7][N:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:9]=1)=[O:21]
Reactant: CC(CCCl)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)on1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)no1

Procedure:
To a stirred solution of 7 g of 3-(1,1-dimethylethyl)-5-aminoisoxazole dissolved in 50 ml ethyl acetate was added 5.05 g of triethylamine at room temperature. As the solution continued to stir, 8 g of 2-methyl-4-chlorobutyric acid chloride was added to the reaction mixture over a 15 minute period. The reaction was allowed to stir for about 3 days and the precipitated triethylamine hydrochloride salt was collected by filtration and washed with ethyl acetate. The solvent was evaporated from the filtrate under reduced pressure and the residue was recrystallized from diethyl ether to afford 4-chloro-N-[3-(1,1-dimethylethyl)-5-isoxazolyl]-2-methylbutanamide as a solid. mp 135°-137° C.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[C@H:5]([CH2:6][O:7][C@@H:8]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.C([N-]C(C)C)(C)C.[Li+].[C:24]([O:28][C:29]([N:31]1[CH2:37][C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C@H:32]1[CH:33]=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].C(O)(=O)C>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[CH2:37][C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C@H:32]1[CH:33]([OH:34])[CH:3]1[C:2](=[O:1])[N:9]2[C@H:5]([CH2:6][O:7][C@@H:8]2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CC[C@H]2CO[C@H](c3ccccc3)N12
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)C1C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Reaction time: 0.5 h
Yield: 11.3 %

Procedure:
To a solution of (2R, 5S)-8-oxo-2-phenyl-3-oxa-1-azabicyclo[3.3.0]octane (50 g, 246 mmol, J. Org. Chem., 51, 3140 (1986)) in tetrahydrofuran (1500 ml), lithium diisopropylamide (2M tetrahydrofuran-heptane solution, 147.6 ml, 295.2 mmol) was dropwise added at -78° C., and the reaction solution was stirred at the same temperature for 30 minutes. A solution of (2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxyprolinal (61.0 g, 245.9 mmol) in tetrahydrofuran (400 ml) was dropwise added thereto, and the reaction solution was stirred at the same temperature for 30 minutes. Acetic acid (17.6 ml, 307.5 mmol) was dropwise added to the reaction solution. Then, the dry ice bath was removed and the reaction mixture solution was stirred for 30 minutes. To the reaction solution, ethyl acetate and 5% sodium hydrogen carbonate aqueous solution were added and the solution mixture was subjected to liquid separation and the aqueous layer was extracted with ethyl acetate. The organic layers were put together and washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. Ethyl acetate and n-hexane were added to the residue and the precipitated crystal was collected by filtration to obtain (2R, 5S)-7-[[(2S, 4R)-N-tert-butoxycarbonyl-4-(tert-butyldimethylsiloxy)pyrrolidin-2-yl](hydroxy)methyl]-8-oxo-2-phenyl-3-oxa-1azabicyclo[3.3.01octane diastereomer A (14.0 g, yield: 11.3%). The filtrate was concentrated to obtain an oily diastereomer mixture (114.7 g, yield: 87.5%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)[S:7][CH:8]=2)[CH2:3][CH2:2]1.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1.C([O-])(=O)C.[Na+]>COCCOC>[CH:1]1([C:4]2[N:5]=[C:6](/[CH:9]=[CH:10]/[C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:14]=[CH:15][CH:16]=3)[S:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CC3)cs2)c1
Reactant: O=C1CCC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)CCC(=O)Nc1cccc(/C=C/c2nc(C3CC3)cs2)c1
Yield: 40.9 %

Procedure:
A mixture of 2.5 g (10 mmol) of (E)-3-[2-[4-(cyclopropyl)-2-thiazolyl]ethenyl]benzeneamine prepared as in example 1 as above, 1.5 g (15 mol) of succinic anhydride, 1.64 g (20 mmol) of anhydrous sodium acetate and 200 ml of 1,2-dimethoxyethane was stirred and heated under reflux for 2 hr. The reaction mixture was cooled and concentrated in vacuo. The residue was heated on the steam bath with 200 ml of water for 0.5 hr. The solid was collected and recrystallized from ethanol to give 1.4 g of (E)-4-[[3-[2-(4-cyclopropyl-2-thiazolyl)-ethenyl]phenyl]amino]-4-oxobutanoic acid, mp 177°-179° dec, as off-white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([C:19](=O)[CH3:20])[CH:18]=1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:9]/[N:10]=[C:19](/[C:17]1[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=1[OH:22])\[CH3:20])=[O:8]
Reactant: NNC(=O)c1cncc(Cl)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cncc(Cl)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 35.3 %

Procedure:
5-Chloronicotinohydrazide (30 mg, 0.175 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (29.8 mg, 0.175 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (20 mg). 1H NMR (400 MHz, acetone-d6): δ 9.06 (s, 1H), 8.77 (s, 1H), 8.37 (s, 1H), 7.62 (d, 1H, J=2.8 Hz), 7.31 (dd, 1H, J=2.0 & 8.4 Hz), 6.95 (d, 1H, J=8.8 Hz), 2.58 (s, 3H). ESI-MS: 324.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][CH:9]([CH2:13][NH2:14])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:30])[O:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:12]2[O:11][CH2:10][CH:9]([CH2:13][NH:14][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH:24]=[CH:25][C:26](=[O:30])[O:27][C:28]=4[CH:29]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Reactant: COc1cccc2c1OCC(CN)O2
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2c1OCC(CNCCCOc1ccc3ccc(=O)oc3c1)O2
Yield: 24.4 %

Procedure:
2,3-Dihydro-5-methoxy-1,4-benzodioxin-2-methanamine (1.29 g, 6.61 mmole), 7-(3-chloropropoxy)coumarin (1.59 g, 6.7 mmole), diisopropylethylamine (2.5 ml, 14.35 mmole) and sodium iodide (4.96 g, 33.1 mmole) were combined in 75 ml of DMF and heated at 80°-100° C. for 3 days under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on silica gel using 30% ethyl acetate/dichloromethane as eluant. The product-containing fractions (Rf=0.25 on silica gel tlc with 2.5% methanol/dichloromethane) were combined and concentrated in vacuum and the residue (0.68 g) redissolved in dichloromethane and boiled on a hot plate, the dichloromethane gradually being replaced with isopropanol. 2N HCl/isopropanol (4 ml) was added and the title compound was collected by filtration and dried in vacuum at 80° C. The procedure yielded 0.64 g of white solid, monohydrochloride, m.p. 202°-204° C.