Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([NH2:29])[N:21]=2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[Cl:15].[NH:30]([CH2:32][C:33](O)=[O:34])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[NH2:29][C:22]1[N:21]=[C:20]([NH:19][CH2:18][CH2:17][NH:16][C:5]2[N:6]=[C:7]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=3[Cl:15])[C:2]([NH:1][C:33](=[O:34])[CH2:32][NH:30][CH3:31])=[N:3][CH:4]=2)[CH:25]=[CH:24][C:23]=1[N+:26]([O-:28])=[O:27]
Reactant: CNCC(=O)O
Reactant: Nc1nc(NCCNc2cnc(N)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNCC(=O)Nc1ncc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of [5-amino-6-(2,4-dichlorophenyl)pyrazin-2-yl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine (30 mg, 0.068 mmol) in THF (2 ml) were added sarcosine (26 mg, 0.138 mmol), HBTU (104.5 mg, 0.2756 mmol) and DIPEA (60 μl) and stirred overnight at 80° C. The mixture was cooled down to room temperature, concentrated and taken in ethyl acetate and water. The layers were separated and the organic layer was washed with water and brine, dried, concentrated and purified to afford the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([NH2:11])=[CH:4][N:3]=1
Reactant: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnc(N)c(N)c1
Yield: 98.2 %

Procedure:
5 g 2-Amino-3,5-dinitropyridine in a mixture of 66 ml methanol and 33 ml THF were hydrogenated over 800 mg 10% palladium on charcoal at room temperature and atmospheric pressure. After the calculated amount of hydrogen was consumed, the catalyst was filtered off and the filtrate was concentrated under vacuum yielding 3.31 g of the crude product which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:18]=[CH:17]3)[CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.[NH4+].[Cl-]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:18]=[CH:17]3)[CH:10]([NH:12][S:39]([CH:36]2[CH2:38][CH2:37]2)(=[O:41])=[O:40])[CH3:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(Oc2ccc3c(cnn3-c3ccccn3)c2)C(C)N)cn1
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(Oc2ccc3c(cnn3-c3ccccn3)c2)C(C)NS(=O)(=O)C2CC2)cn1
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-[6-methoxypyridin-3-yl]-1-[1-(pyridin-2-yl)indazol-5-yl]oxypropan-2-amine (50 mg, 130 μmol) in dichloromethane (5 mL) was added triethylamine (44 μl), followed by cyclopropane sulfonic acid chloride (28 mg, 200 μmol) and DMAP (1.6 mg, 13 μmol).The stirring was continued for 20 min at room temp The reaction mixture was poured into sat. NH4Cl solution and extracted with dichloromethane then the solvent was removed i.vac., and the product purified by chromatography on silica gel. Yield 24 mg as a racemic mixture of two diastereomeres (37%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1Cl
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(Cl)cc3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,4-dichloro-phenyl)-acrylic acid.
Reaction SMILES: [Br:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:5]2[O:6][CH2:7][C:8](=O)[N:9]([CH:10]([CH3:16])[C:11](OCC)=[O:12])[C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.O.[NH2:47][NH2:48]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21])[O:6][CH2:7][C:8]1[N:9]2[CH:10]([CH3:16])[C:11](=[O:12])[NH:47][N:48]=1
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(C(F)(F)F)c(Br)cc21
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Temperature: 25 °C
Yield: 18.4 %

Procedure:
A mixture of ethyl 2-(6-bromo-3-oxo-7-(trifluoromethyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)propanoate (7.7 g, 19.44 mmol) and Lawesson reagent (8.65 g, 21.38 mmol) in toluene (20 mL) was heated at reflux for 1 h. The reaction mixture was cooled to ambient temperature, hydrazine hydrate (4.98 g, 155 mmol) was added and the reaction mixture was heated at 80° C. for 1 h. The reaction mixture was cooled to ambient temperature and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 16-33% EtOAc in petroleum ether) to give 6-bromo-4-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as white solid (1.30 g, 18%). 1H NMR (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 7.66 (s, 1H), 7.34 (s, 1H), 4.88 (q, J=6.8 Hz, 1H), 4.72 (d, J=13.2 Hz, 1H), 4.64 (d, J=13.2 Hz, 1H), 1.30 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:22][CH2:23][CH2:24][C:25]([NH:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:26]
Reactant: O=C(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(N)cccc3c2C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3c(NC(=O)CCCl)cccc3c2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (4.62 g, 16.08 mmol) in benzene (100 mL) was added a catalytic amount of DMAP. An inert atmosphere was created and chloropropionyl chloride (2)(1.68 mL) was added dropwise to the reaction mixture. After stirring at room temperature for 20 min, the reaction mixture was transferred to a separatory funnel containing 50% solution of sodium bicarbonate and was extracted with CH2Cl2 (3×250 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo to give tert-butyl 6-[(3-chloropropanoyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as a white solid in 99% yield: 1H NMR (DMSO, 500 MHz) δ 1.38–1.53 (m, 9H), 2.75–2.99 (m, 2H), 3.65–3.78 (m, 4H), 3.88–3.97 (m, 2H), 4.53 (brs, 2H), 6.88–6.96 (m, 1H), 7.15–7.22 (m, 1H), 7.31–7.37 (m, 1H), 9.72 (brs, 1H), 10.44 (brs, 1H) ppm.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].O1CCOCC1>Cl>[C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCN(C(=O)OC(C)(C)C)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)OC1CCNc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 8-acetoxy-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (Step 1) (190 mg, 0.426 mmol) in 4M HCl in dioxane (dry) (2.665 ml, 10.66 mmol) was left to stir at room temperature for 1 hour, under an atmosphere of nitrogen. The mixture was concentrated in vacuo and the crude product was purified by chromatography on silica eluting with EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C:16]([O-:18])=[O:17])C(C)=CC=CC=1O.[K+].C(=O)=O>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([C:16]([OH:18])=[O:17])=[CH:3][CH:2]=1
Reactant: Cc1cccc(O)c1C(=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1ccc(O)cc1
Yield: 73.2 %

Procedure:
A pressure vessel was charged with 4.70 g of phenol, 25.57 g of potassium meta cresolate being in a dry powder form and 56 g of NeoSK 1400. With stirring, reaction was carried out at a carbon dioxide pressure of 9 kg/cm2 (G) and at 320° C. for one hour. An analysis of the reaction mixture after conversion to acid form showed a para-hydroxybenzoic acid yield of 73.2% on the basis of phenol.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.[OH-].[Na+].[Na+].[Cl-]>O>[CH3:10][N:11]1[CH2:16][CH2:15][C:14]2[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[C:13]=2[CH2:12]1
Reactant: NNc1ccccc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN1CCc2[nH]c3ccccc3c2C1
Temperature: 55 °C
Yield: 75.3 %

Procedure:
To a suspension of phenylhydrazine (5.4 g) in 75 mL water was added slowly 4.2 mL of 12 N HCl, followed by addition of 1-methylpiperidin-4-one (6.7 g). Additional 16 g of 12N HCl was added and the reaction mixture was heated at 55° C. for 2 days. After cooling in a ice-water bath, 10 N NaOH solution was added slowly until pH>12.20 g of NaCl was added to the mixture and the reaction mixture was extracted with 2×100 mL of CH2Cl2. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was swished from EtOAc to give 7 g of the title compounds as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=O)=[C:6]([NH2:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.NC1C(N=O)=C(N)N=C(NCCC2C=CC=CC=2)N=1.NC1C(N=O)=C(N)N=C(NCCC2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47](OC)C=2)N=1.NC1C(N=O)=C(N)N=C(NCCC2C=CC(OC)=CC=2)N=1.C1(CCNC2N=C(N)C(N)=C(N)N=2)C=CC=CC=1.COC1C=C(CCNC2N=C(N)C(N)=C(N)N=2)C=CC=1OC.CC1C=CC(CCNC2N=C(N)C(N)=C(N)N=2)=CC=1>>[NH2:1][C:2]1[NH:3][C:4]([S:11][CH3:12])=[N:5][C:6]2[C:7]=1[N:8]=[C:47]([C:48]1[O:51][CH:52]=[CH:50][CH:49]=1)[N:10]=2
Reactant: COc1ccc(CCNc2nc(N)c(N=O)c(N)n2)cc1OC
Reactant: CSc1nc(N)c(N=O)c(N)n1
Agent: COc1ccc(CCNc2nc(N)c(N)c(N)n2)cc1OC
Agent: COc1ccc(CCNc2nc(N)c(N=O)c(N)n2)cc1
Agent: Cc1ccc(CCNc2nc(N)c(N)c(N)n2)cc1
Product: CSc1nc2nc(-c3ccco3)nc-2c(N)[nH]1

Procedure:
The starting materials for Examples 10, 11, 12 were prepared as described in Example 5 starting from 4,6-diamino-2-methylthio-5-nitrosopyrimidine. 4,6-diamino-2-(2-phenylethyl)amino-5-nitrosopyrimidine; m/e [M+H]30 259; 4,6-diamino-2-[2-(3,4-dimethyoxyphenyl)ethyl]amino-5-nitrosopyrimidine m/e [M+H]+ 319; 4,6-diamino-2-[2-(4-methoxyphenyl)ethyl]amino-5-nitrosopyrimidine; 2-(2-phenylethyl)amino-4,5,6-triaminopyrimidine; m/e [M+H]+ 245; 2-[2-(3,4-dimethoxyphenyl)ethyl]amino-4,5,6-triaminopyrimidine; m/e [M+H]+ 305; and 2-[2-(4-methylphenyl)ethyl]amino-4,5,6-triaminopyrimidine; m/e [M+H]+ 258.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([C:19]1[C:20]([N:28]=[CH:29][N:30]([CH3:32])C)=[N:21][C:22]([CH2:25][CH2:26][CH3:27])=[CH:23][CH:24]=1)#N>C(O)(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[C:2]([NH:1][C:32]2[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH3:27])=[N:21][C:20]=3[N:28]=[CH:29][N:30]=2)[CH:7]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: CCCc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 130 °C

Procedure:
The product from Example 6c (49 mg 0.231 mmol) and the product from Example 128A (50 mg, 0.231 mmol) were dissolved in acetic acid (1 mL) and heated to 130° C. for 1.5 hours. After cooling to room temperature a solid in the acetic acid solvent appeared which was collected by filtration to provide the title compound as an acetic acid salt (77 mg, 68%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 0.96 (t, J=7.4 Hz, 3H), 1.80 (m, 2H), 1.88 (s, 6H), 2.40 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 6.74 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.1 Hz, 1H), 7.03 (m, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.22 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 8.53 (s, 1H), 8.78 (d, J=8.5 Hz, 1H); MS (ESI)+ m/z 403 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH:6](=O)[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>C(O)C.CN(C)C=O>[C:17]([C:16]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)(=[O:18])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=Cc1ccccc1O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C(c1ccccc1)c1cc2ccccc2o1
Temperature: 80 °C
Yield: 34.1 %

Procedure:
To a solution of sodium ethoxide prepared from 28 g sodium metal and 500 ml absolute ethanol was added 122 g (1 mole) salicylaldehyde and 200 ml dimethylformamide. The mixture was heated to 80° C. Then 200 g (1 mole) alpha-bromoacetophenone was added in small portions. The mixture was stirred at reflux for 1.5 hours after which the ethanol was distilled. The residue was cooled and partitioned between 750 ml water and 750 ml ethyl acetate. The organic layer was washed twice with 400 ml portions of 1N sodium hydroxide, water (2×300 ml), dried (Na2SO4), concentrated to one-third volume, filtered to remove precipitated product which was washed with ethyl ether to yield 75.8 g of 2-benzoylbenzo(b)furan as pink crystals, m.p. 88°-90° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][CH:1]([Br:5])[Br:2])=[CH:39][CH:40]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Carbon tetrabromide (78.1 g, 235.6 mmole) and triphenylphosphine (123.5 g, 471.2 mmole) were combined in 460 ml dichloromethane in a flame dried 1000 ml three neck round bottom flask under nitrogen at 0° C. The mixture was stirred 1 hour at 0° C. and was treated portionwise with 4-benzyloxybenzaldehyde (25 g, 117.8 mmole). The reaction was stirred 30 minutes at 0° C. and was washed successively with 1×100 ml water and 1×100 ml saturated sodium chloride. The organics were dried over magnesium sulfate and were poured into 3 liters hexane. The supernatant was collected and the residue was dissolved in a minimum amount of dichloromethane. This solution was also poured into 3 liters hexane and the process was repeated one more time. The combined supernatants were filtered through a 125 ml plug of silica gel (230-400 mesh) in a 600 ml coarse filter funnel. The plug was washed with 1 liter 15% ethyl acetate/hexane and the combined eluents were concentrated in vacuo to provide 38.2 g (89%) of 2-(4-Benzyloxyphenyl)-1,1-dibromo-ethane as a white solid. Melting Point: 97°-98° C. The dibromo-olefin (20 g, 54.3 mmole) was dissolved in 200 ml dry tetrahydrofuran in a flame dried 500 ml three neck round bottom flask under nitrogen. The solution was cooled to -78° C. and was treated slowly dropwise with butyllithium (70 ml, 108.6 mmole). The reaction was stirred 1 h at -78° C. followed by 1 hour at 0° C. The mixture was cooled to -78° C. and was treated with methyl-chloroformate (4.6 ml, 60 mmole). The reaction mixture was stirred for 20 minutes at -78° C. and then for 1.5 hours at 0° C. The reaction was quenched with 1×100 ml 1:1 saturated ammonium chloride/saturated sodium chloride. The layers were separated and the aqueous layer was washed with 2×100 ml diethyl ether. The combined organics were dried over magnesium sulfate and were concentrated in vacuo to a red oil. The oil was crystallized and then recrystallized from hexane to provide 9.2 g (75%) of methyl-4-benzyloxyphenylpropiolate as orange tinged flakes. Melting Point: 78° C.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[N:15]=[C:14]([S:16][CH3:17])[CH:13]=[N:12][CH:11]=1>C(Cl)(Cl)Cl>[NH2:9][C:10]1[C:11]([Br:8])=[N:12][CH:13]=[C:14]([S:16][CH3:17])[N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1cncc(N)n1
Solvent: ClC(Cl)Cl
Product: CSc1cnc(Br)c(N)n1

Procedure:
NBS (3.28 G, 18.4 MMOL) WAS SLOWLY ADDED TO A STIRRED SOLUTION OF 6-AMINO-2-METHYLTHIOPYRAZINE (2.6 G, 18.4 MMOL) IN CHLOROFORM (100 ML). AFTER 1 H THE REACTION MIXTURE WAS PARTITIONED BETWEEN 10% SODIUM METABISULFITE SOLUTION AND CHLOROFORM. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO. THE CRUDE PRODUCT WAS PURIFIED BY FLASH COLUMN CHROMATOGRAPHY ON SILICA GEL (20% ETHYL ACETATE/HEXANES) TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID: 1H NMR (CDCL3): Δ 2.49 (S, 3H), 4.97 (BR S, 2H), 7.59 (S, 1H).
Reaction SMILES: II.[BH4-].[Na+].[CH2:5]([N:12]1[C:17](=O)[CH:16]2[CH:14]([CH2:15]2)[C:13]1=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[OH-].[Na+]>C1COCC1>[CH2:5]([N:12]1[CH2:13][CH:14]2[CH:16]([CH2:15]2)[CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1C2CC2C(=O)N1Cc1ccccc1
Agent: Cl
Agent: II
Agent: [BH4-]
Solvent: C1CCOC1
Product: c1ccc(CN2CC3CC3C2)cc1
Temperature: 0 °C

Procedure:
A solution of iodine (2.27 g) in THF (27.9 mL) was added dropwise to a mixture of sodium borohydride (818 mg) in dry THF (45 mL) at 0° C. over the course of 40 min. Subsequently, at this temperature, a solution of 3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione (750 mg) in THF (11.1 mL) was added dropwise. The reaction mixture was then heated under reflux for 6 h. The mixture was cooled to 0° C. and 3N HCl was cautiously added. The reaction solution was then neutralized with 2N sodium hydroxide solution. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuo. The crude product was purified by preparative HPLC. The product with the molecular weight of 173.12 (C12H15N) was obtained in this way; MS (ESI): 174 (M+H+).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:12])[N:6]([CH2:8][C:9](O)=[O:10])[CH3:7])([CH3:3])[CH3:2]>O.Cl>[CH:1]([N:4]1[C:9](=[O:10])[CH2:8][N:6]([CH3:7])[C:5]1=[O:12])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)N(C)CC(=O)O
Agent: Cl
Solvent: O
Product: CC(C)N1C(=O)CN(C)C1=O
Yield: 100.3 %

Procedure:
A mixture of 14.9 g of (3-isopropyl-1-methylureido)acetic acid in 50 ml of water and 50 ml of concentrated hydrochloric acid was refluxed for 2 h. On cooling the mixture was diluted with water and extracted with ethyl acetate to give 13.4 g of a colourless oil. Mass spectrum (EI) m/z 156 M+.
Reaction SMILES: [Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1.[CH3:16][C:17]1[C:26]([CH3:27])=[C:25]2[C:20]([CH2:21][CH2:22][C:23]([CH2:29][CH2:30][CH2:31][CH:32]([CH2:34][CH2:35][CH2:36][CH:37]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH3:38])[CH3:33])([CH3:28])[O:24]2)=[C:19]([CH3:45])[C:18]=1O.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH3:27][C:26]1[C:17]([CH3:16])=[C:18]([O:12][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH:2]([Br:1])[CH2:14][Br:15])=[CH:10][N:9]=2)=[O:13])[C:19]([CH3:45])=[C:20]2[CH2:21][CH2:22][C:23]([CH2:29][CH2:30][CH2:31][CH:32]([CH2:34][CH2:35][CH2:36][CH:37]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH3:38])[CH3:33])([CH3:28])[O:24][C:25]=12
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C)c2c(c(C)c1OC(=O)c1ccc(CCC(Br)CBr)cn1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reaction time: 3 h
Yield: 81 %

Procedure:
2.42 g of 5-(3,4-dibromobutyl)picolinic acid, 2.15 g of dl-α-tocopherol and 4.0 ml of triethylamine were dissolved in 15 ml of methylene chloride, and with stirring under ice cooling, a solution of 1.0 ml of phosphorus oxychloride in 5 ml of methylene chloride was added dropwise. The reaction was performed at this temperature for 3 hours. The reaction mixture was washed with 2 N hydrochloric acid, and then with water, and dried. Then, methylene chloride was distilled off. The residue was chromatographed on a column of silica gel using benzene/ethyl acetate (4:1) as an eluent to give 3.03 g of dl-α-tocopheryl 5-(3,4-dibromobutyl)picolinate as a slightly yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[C:12](=[O:25])[CH:13]=[C:14]([C:20]([O:22]CC)=[O:21])[O:15]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+:32].[Na+]>C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[C:12](=[O:25])[CH:13]=[C:14]([C:20]([O-:22])=[O:21])[O:15]3)=[CH:26][CH:27]=1.[Na+:32]
Reactant: CCOC(=O)c1cc(=O)c2c(OCCOc3ccc(N)cc3)cccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(OCCOc2cccc3oc(C(=O)[O-])cc(=O)c23)cc1
Yield: 204.2 %

Procedure:
A solution of ethyl 5-[2-(4-aminophenoxy)ethoxy]chromone-2-carboxylate (3.4g.) in 95% ethanol (250ml.) was boiled, to which was added at once an aqueous solution (20ml.) of sodium carbonate (0.5g.) under heating. The resultant mixture was refluxed for 2 hours. After cooling, the ethanol was evaporated under reduced pressure. The residue was recrystallized from 80% aqueous ethanol to give brown scaly crystals (3.5g.) of sodium 5-[2-(4-aminophenoxy)ethoxy]chromone-2-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Cl)([O-:3])=[O:2].[I-].[K+].[Cl:14][C:15]1[CH:16]=[C:17]([S:22][C:23]2[NH:27][C:26]([CH2:28][O:29]CC3C=CC(OC)=CC=3)=[N:25][C:24]=2[CH:39]([CH3:41])[CH3:40])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)C.CN(C)C=O>[Cl:21][C:19]1[CH:18]=[C:17]([S:22][C:23]2[N:27]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[N+:1]([O-:3])=[O:2])[C:26]([CH2:28][OH:29])=[N:25][C:24]=2[CH:39]([CH3:41])[CH3:40])[CH:16]=[C:15]([Cl:14])[CH:20]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)[nH]2)cc1
Reactant: O=[N+]([O-])c1ccccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)c1nc(CO)n(Cc2ccccc2[N+](=O)[O-])c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.1 %

Procedure:
To dimethylformamide was added 237 mg of o-nitrobenzyl chloride and 228 mg of potassium iodide under ice-cooling, the mixture was allowed to warm up to room temperature and stirred for 20 minutes. Then, 400 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (101b) was added, followed by addition of 152 mg of potassium carbonate. Then, the mixture was warmed up to 50° C., and allowed to react for 6 hours. After completion of the reaction, the mixture was diluted with water, extracted with diethyl ether, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To thus-obtained oil were added 10 ml of ethanol and 20 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, extracted with ethyl acetate, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crystals were washed with diethyl ether, filtered, and 195 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1-(o-nitrobenzyl)-1H-imidazole (103c) was obtained (yield 47%). mp 160-166° C.