Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:4][CH:3]=1.[O-:28][C:29]#[N:30].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH:19]1([C:15]2[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12](=[O:27])[N:11]3[C:16]=2[C:17]([CH3:18])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:29]([NH2:30])=[O:28])=[CH:7][CH:6]=2)[CH:9]=[CH:10]3)[CH2:21][CH2:20]1
Reactant: N#C[O-]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)ccn2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(N)=O)cc3)ccn2c1=O
Reaction time: 3 h
Yield: 87.7 %

Procedure:
54 mg of ethyl 8-(4-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 2) was dissolved in a mixture of 3 ml of acetic acid and 2 ml of water. 2 ml of an aqueous solution of 19 mg of sodium cyanate was added to the obtained solution at 35° C. and they were stirred at that temperature for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 53 mg of ethyl 1-cyclopropyl-9-methyl-4-oxo-8-(4-ureidophenyl)-4H-quinolizine-3-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C([N-]C(C)C)(C)C.[Li+].[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[CH:28]=[CH2:29]>O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]([F:18])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:29][CH2:28][C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: CCOC(=O)C(F)N1C(=O)c2ccccc2C1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(CCC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 2-(1,3-dioxoisoindolin-2-yl)-2-fluoroacetate (0.80 g, 3.2 mmol) in tetrahydrofuran (30 mL) is added lithium diisopropylamide (1.7 mL, 3.4 mmol, 2 M) at -78° C. After 30 minutes, t-butyl acrylate (0.42 g, 3.2 mmol) is added to the mixture which is allowed to reach room temperature. The solvent is removed in vacuo and the residue stirred with methylene chloride (50 mL) and water (30 mL) for 10 min. The organic layer is washed with brine (30 mL), and dried over sodium sulfate. The solvent is removed in vacuo to give tert-butyl 4-(1,3-dioxoisoindolin-2-yl)-4-fluoro-4-ethoxycarbonylbutanoate which is further purified by column chromatography.
Reaction SMILES: [CH:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[C:12]12[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:17]C(=O)O[C:13]2=[O:14].O>CN(C=O)C>[NH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[C:13]([NH:9][C:8]1[CH:7]=[CH:6][C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[CH:11][CH:10]=1)=[O:14]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCC(C)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
4-sec-butyl aniline (B) (1.49 g, 10.0 mmol) was added to a solution of isatoic anhydride (A) (1.63 g, 10.0 mmol) in anhydrous DMF (40 mL) and the reaction mixture was stirred at 115° C. for 16 hours under nitrogen. It was then cooled to room temperature and poured into water (200 mL), and extracted with ethyl acetate (200 mL). The organic phase was washed with water (100 mL), 10% aqueous NaOH solution (100 mL), water (100 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 2-amino-N-(4-sec-butylphenyl)benzamide (C) as a brown solid. Yield: 1.27 g (47%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][NH2:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:23][O:22][CH3:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.334 g, 1.21 mmol) in DCM (25.0 mL) were added O-methylhydroxylamine 97 (0.193 g, 2.31 mmol), 1-hydroxybenzotriazole (0.25 g, 1.85 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 g, 1.82 mmol) and 4-di(methylamino)pyridine (0.34 g, 2.78 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue, which was subjected to chromatography to give (2S,5R)-6-(benzyloxy)-N-methoxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 98 (0.17 g, 46%) as a white foam.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:26]([S:30](Cl)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]>>[CH2:26]([S:30]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:32])=[O:31])[CH2:27][CH2:28][CH3:29]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CCCCS(=O)(=O)Cl
Product: CCCCS(=O)(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 10.4 μL (0.11 mmol) 1-butanesulfonyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[CH2:27][C:28]1[C:36]2[O:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:33][C:32]=2[CH:31]=[CH:30][CH:29]=1.C(OCC)(=O)C>CS(C)=O>[CH3:3][O:4][C:5](=[O:25])[C@H:6]([CH2:15][C:16]1[CH:17]=[C:18]([CH3:24])[C:19]([O:23][CH2:27][C:28]2[C:36]3[O:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[N:33][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[C:20]([CH3:22])[CH:21]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COC(=O)[C@H](Cc1cc(C)c(O)c(C)c1)NC(=O)OC(C)(C)C
Reactant: ClCc1cccc2nc(-c3ccccc3)oc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)[C@H](Cc1cc(C)c(OCc2cccc3nc(-c4ccccc4)oc23)c(C)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
60% Sodium hydride (20 mg, 0.495 mmol) was added to a solution of N-t-butoxycarbonyl-3,5-dimethyl-L-tyrosine methyl ester (160 mg, 0.495 mmol) in dimethyl sulfoxide (2 ml) at 18° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of 7-chloromethyl-2-phenylbenzoxazole (241 mg, 0.990 mmol) in dimethyl sulfoxide (3 ml) and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was poured into a mixture of ice water and ethyl acetate and then extracted with ethyl acetate. The extract was washed with water and saturated saline solution in turn and dried. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4) to give N-t-butoxycarbonyl-3,5-dimethyl-O-[(2-phenyl)benzoxazol-7-yl]methyl-L-tyrosine methyl ester (185 mg, 70%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].[C:19](Cl)(=[O:21])[CH3:20]>>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16])[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Product: CC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
Prepared from 4-(2-dimethylamino-ethyl-amino)-1,3-dinitrobenzene and acetyl chloride
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.C1C([C@H]([O:58][C@@H:59]2[O:64][C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)C#N)=CC=C(O)C=1.[OH:71][C:72]1[CH:77]=[CH:76][C:75]([CH2:78][CH:79]=[N:80]O)=[CH:74][CH:73]=1>>[NH2:80][C@H:79]([C:59]([OH:64])=[O:58])[CH2:78][C:75]1[CH:76]=[CH:77][C:72]([OH:71])=[CH:73][CH:74]=1
Reactant: ON=CCc1ccc(O)cc1
Reactant: N#C[C@@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)c1ccc(O)cc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The complete reaction mixtures contain: 3 μl of isolated, recombinant P450TYR (6 pmol, heterologously expressed in E. coli and isolated as in Halkier et al, Arch. Biochem. Biophys. 322: 369-377, 1995), 10 μl of isolated and dialyzed P450OX (approximately 0.4 pmol), 5 μl of NADPH-P450 oxidoreductase (0.075 U), 1 μl of partially purified UDPG glucosyl transferase from Sorghum, 5 μl of DLPC (10 mg/ml in 50 mM Kpi (pH7)), 0.25 μl of [U-14C]-tyrosine (0.05 μCi/mmol, 443 mCi/mmol, Amersham), 3 μl of UDPG (33 mg/ml in 50 mM Kpi (pH7)), and 3 μl of castanospermin (2 mM in 50 mM Kpi (pH7)). The components are mixed by repeated suspension and if necessary the final volume adjusted to 30 μl by the use of 50 mM Kpi (pH7). The enzyme reaction is initiated with 1 μl of NADPH (25 mg/ml). Dhurrin is also synthesized via reconstitution of P450OX with p-hydroxyphenylacetaldehyde oxime (leaving out P450TYR and tyrosine from the reaction mixtures any additional components being unchanged.). These assays contain either 0.5 μl of [U-14C]-p-hydroxyphenylacetaldehyd oxime (0.014 μCi/μl, 394 mCi/mmol) or 3 μl of unlabelled p-hydroxyphenylacetaldehyde oxime (20 mM) as substrate for P450OX. In the latter case the radioactive label is 1 μl of [U-14C]-UDPG (0.025 μCi/μl, 287 mCi/mmol, Amersham). All reaction mixtures are prepared as duplicates. After incubation for 1 h at 30° C. each set of reaction mixtures is applied to TLC sheets. The first set of reaction mixtures is analyzed using the ethyl acetate/toluene solvent as in example 4.5. The second set of reaction mixtures is analyzed using a solvent system consisting of ethyl acetate/acetone/dichloromethane/methanol/water (20/15/6/5/4, v/v/v/v/v) in order to achieve separation of the hydrophilic product dhurrin from tyrosine and from the hydrophobic intermediates. Radiolabelled substrates and products are visualized using the STORM 840-phosphorimager.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH:14]([CH2:16][CH2:17][CH3:18])[CH3:15]>C(O)C>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([CH:14]([CH3:15])[CH2:16][CH2:17][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CCCC(C)Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCC(C)C(C(=O)OCC)C(=O)OCC
Yield: 67.4 %

Procedure:
Sodium metal (5.24 g, 0.23 g atm) was reacted with 25 mL of absolute ethanol. To this solution was added dropwise, with stirring, diethyl malonate (36.0 mL, 0.24 mol). The solution was heated to reflux and 2-bromopentane (29.0 mL, 0.23 mol) was added dropwise. After refluxing overnight, the reaction was cooled and the ethanol removed on a rotovap. The product was washed with water, dried with MgSO4 and fractionally distilled to give 35.7 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4]([CH2:7][CH:8]=1)(=[O:6])=[O:5].[OH-].[Na+].[CH:11](Cl)(Cl)Cl>>[CH3:11][C:2]1[CH:1]=[CH:8][CH2:7][S:4](=[O:5])(=[O:6])[CH:3]=1
Reactant: CC1=CCS(=O)(=O)C1
Reactant: ClC(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1=CS(=O)(=O)CC=C1

Procedure:
5-Methyl-2H-thiopyran-1,1-dioxide is prepared in three steps from 3-methyl-3-sulfolene using the method of Gaoni, J. Org. Chem., 46 (1981) 4502. Thus, 3-methyl-3-sulfolene is first reacted with chloroform and aqueous sodium hydroxide in the presence of a quaternary ammonium salt to give the dichlorocarbene adduct. Partial dehalogenation with lithium aluminum hydride in tetrahydrofuran gives the chlorocyclopropane. Finally, base-catalyzed ring expansion with lithium diisopropylamide gives the desired thiopyran dioxide compound (see Scheme 1, above).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(=[O:5])=[O:4].O.[NH2:23][NH2:24]>C(O)C>[CH3:1][N:2]([CH3:21])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10](=[N:23][NH2:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:5])=[O:4]
Reactant: NN
Reactant: CN(C)S(=O)(=O)Nc1cccc(C(=O)c2ccccc2)c1
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)Nc1cccc(C(=NN)c2ccccc2)c1
Yield: 109 %

Procedure:
A solution of 3-[N-(dimethylaminosulfonyl)amino]-benzophenone (200 mg) and hydrazine hydrate (100 mg) in ethanol (4 ml) is refluxed for 17.5 hours. The reaction mixture is concentrated in vacuum and the residue is basified with aqueous sodium hydrogencarbonate and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of silica gel, which is eluted with 3% methanol and methylene chloride. The eluate is concentrated in vacuum to give 3-[N-(dimethylaminosulfonyl)-amino]benzophenone hydrazone(228 mg) as an oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Cl)(C)C.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>C(OCC)C.C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[B:14]([OH:19])[OH:15]
Reactant: Ic1ccccc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of 1,2-diiodobenzene (0.102 g, 3.08 mmol) in 60 mL of a mixture of THF and diethylether (Et2O) (1:1) was added dropwise at −78° C. isopropylmagnesium chloride (2 M in THF, 1.54 mL, 3.08 mmol). After the mixture was stirred for 2 h at that temperature, B(OiPr)3 (1.74 g 2.12 mL, 9.24 mmol) was added. The solution was warmed to room temperature overnight; then 40 mL of HCl (10%) was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times). Drying over Na2SO4, evaporation and purification by flash chromatography gave 0.62 g of the pure product (82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[S:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:10]2[S:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([Cl:15])[N:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1sc(Nc2cccc(Br)c2)nc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.6 %

Procedure:
A solution of 8.6 g (0.05 mol) of 3-bromoaniline in 100 ml of dimethylformamide is added dropwise to a solution of 12.0 g (0.06 mol) of 2,4-dichloro-5-nitrothiazole in 100 ml of dimethylformamide at 0° C. to 5° C. in the course of about 2 hours and the mixture is subsequently stirred at the same temperature for a further 4 hours. It is then stirred into 1,000 ml of ice-water and the precipitate is filtered off, washed with water and dried. To remove excess 2,4-dichloro-5-nitrothiazole, the product is stirred in 80 ml of petroleum ether at room temperature, filtered off, washed with petroleum ether and dried. 16.0 g (95.7% of theory) of 2-(3-bromophenylamino)-4-chloro-5-nitrothiazole of melting point 191° C. to 192° C. (decomposition) are thus obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:19][NH2:20]>CN(C=O)C>[CH3:19][N:20]1[CH:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][C:9](=[O:18])[CH2:10][CH:11]1[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1
Reactant: CN
Reactant: O=C(/C=C/c1ccncc1)/C=C/c1ccncc1
Solvent: CN(C)C=O
Product: CN1C(c2ccncc2)CC(=O)CC1c1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
A suspension of (1E,4E)-1,5-di(pyridin-4-yl)penta-1,4-dien-3-one (1 g, 3.2 mmol) in DMF (10 mL) was treated with N-methylamine (40% in H2O, 2.8 mL, 32 mmol) at 0° C. The solution was warmed up to ambient temperature and stirred for 6 h at RT. The reaction mixture was poured into ice-water and the resulting precipitate was filtered. The aqueous solution was extracted with DCM and the combined organic layers were dried with MgSO4, filtered and evaporated in vacuo. The crude product was purified by flash-chromatography (CH2Cl2/MeOH 9:1) to obtain NW-B591 as a bright yellow solid (417 mg, 48%) (note: mixture of cis/trans isomers in a ratio of 4:1). mp: 103-106° C. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.65 (dd, 4J=4.5 Hz, 3J=1.5 Hz, 4 H, HAr), 7.42 (dd, 3J=4.5 Hz, 4J=1.6 Hz, 4 H, HAr), 3.51 (dd, 3J=12.0 Hz, J=3.2 Hz, 2 H, CH2), 2.82-2.68 (m, 2 H, CH), 2.57-2.46 (m, 2 H, CH2), 1.89 (s, 3 H, CH3). Signals of the minor isomer: 8.65-8.60 (m, 4 H, HAr), 7.25 (dd, 3J=4.7 Hz, 4J=1.5 Hz, 4 H, HAr), 4.13 (t, 3J=6.0 Hz, 2 H, CH), 2.96-2.86 (m, 2 H, CH2), 2.86 (ddd, J=7.9, J=6.0 Hz, J=1.2 Hz, 2 H, CH2), 2.19 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3) δ (ppm): 204.3 (C), 151.6 (C), 150.4 (CH), 122.2 (CH), 68.9 (CH), 49.6 (CH2), 41.1 (CH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=2)[C:5]([C:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=2)[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1
Reactant: CC(C)c1cccc(OCc2cc(Br)ccc2C(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1cccc(OCc2cc(Br)ccc2C(=O)O)c1
Reaction time: 8 h

Procedure:
Add 23.79 gm. (0.0655 mole) of 5-bromo-α-(3-isopropylphenoxy)-o-toluate to a solution of 5.24 gm. (0.1310 mole) of sodium hydroxide in 35 ml. of water and 315 ml. of methanol. Heat at reflux for 3 hours. Remove the methanol under vacuum and dilute the residual solution with 300 ml. of water. Extract with ether. Separate the aqueous layer and acidify with concentrated hydrochloric acid to the Congo Red end point. Extract the resulting oil into ether, wash with water and dry over magnesium sulfate. Remove the solvent under vacuum and allow the resulting oil (21.33 gm.) to stand overnight. Wash the solids formed with petroleum ether to obtain the title compound [yield 10.94 gm., m.p. 103°-122° C., pmr (CDCl3) 1.20(6H,d,(CH3)2CH--), 2.82(1H,m, (CH3)2CH--), 5.47(2H,s,CH2O--), 9.18 (1H, broad s, COOH)].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: ClCc1ccccn1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(Cc4ccccn4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A2 (0.12 mmol, 50 mg), 2-chloromethyl-pyridine (0.12 mmol, 20 mg) and triethylamine (0.63 mmol, 88 μL) were dissolved in DMF and microwaved at 80° C. for 10 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo provided Compound A5 pure as a yellow solid (27 mg, 47%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.09 (s, 1H), 8.51 (m, 1H), 8.32 (s, 1H), 7.89 (d, 2H), 7.78 (d, 2H), 7.60 (t, 1H), 7.36 (m, 1H), 7.13 (t, 1H), 5.40 (m, 1H), 3.65 (m, 2H), 3.07 (s, 3H), 2.72 (m, 2H), 2.45 (m, 2H), 2.02 (m, 2H), 1.91 (m, 2H). LCMS (ESI), m/z 484.5 (M+H+, 100%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:30]([O-])([N+]([O-])=O)=[O:31]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:30]=[O:31])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 81.9 %

Procedure:
3.5 g of 1-(2-chloroethyl)-3-n-pentyl-3-D-glucopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 3.1 g of 1-(2-chloroethyl)-1-nitroso-3-n-pentyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.O>CN(C=O)C>[Si:18]([O:1][CH2:2][C:3]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cc(Br)ccc1OCCN1CCCC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 76 %

Procedure:
To a solution of (500 mg, 1.67 mmol) 1-[2-(2-hydroxymethyl-4-bromophenoxy)ethyl]pyrrolidine (Part A) in 5.5 mL of anhydrous DMF was added 377 mg of t-butyldimethylsilyl chloride followed by addition of 113 mg of imidazole. The reaction mixture was stirred at room temperature for 30 h. To the reaction was added 6 mL of water. The mixture was extracted with EtOAc (3×60 mL). The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was azeotroped with xylenes to remove any DMF present. Purification by flash chromatography (silica gel, 3% to 4% [10% conc NH4OH in MeOH]/CH2Cl2) afforded 528 mg (1.27 mmol, 77%) of a yellow oil.