Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:5]=2[C:4](=[O:14])[O:3]1.[CH2:16]([NH2:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:16]([NH:22][CH2:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([CH3:15])([CH3:1])[O:3][C:4](=[O:14])[C:5]=2[CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC1(C)OC(=O)c2cc(C=O)ccc2O1
Reactant: CCCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCCNCc1ccc2c(c1)C(=O)OC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carbaldehyde (510 mg, 2.47 mmol) in anhydrous DCE (20 mL) was added n-hexylamine (392 μL, 2.97 mmol), acetic acid (212 μL) and sodium triacetoxyborohydride (786 mg, 3.71 mmol) and the resulting mixture was stirred at rt for 3 hrs. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (20/80)) gave 627 mg (87%) of the title compound. HPLC, Rt: 2.70 min purity: 86.4% ). 1H NMR (CDCl3) δ: 0.85 (t, J=6.8 Hz, 3H), 1.28 (m, 6H), 1.48 (m, 2H), 1.70 (s, 6H), 2.41 (m, 1H), 2.58 (t, J=7.3 Hz, 2H), 3.74 (s, 2H), 6.90 (d, J=8.5 Hz, 1H), 7.53 (dd, J=8.5, 2.3 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:9])[CH3:8].[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)#[N:23]>CN(C)C=O.CC(C)([O-])C.[K+]>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1)[NH:10][C:7](=[O:9])[CH3:8])[CH3:16]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.8 %

Procedure:
To 50 ml of dimethylformamide is added 5.7 g (51 mmoles) of potassium tert-butoxide and 11.1 g (51 mmoles) of diethyl acetamidomalonate and the resulting mixture stirred at 25° for 15 minutes. The solution is then cooled to 10° and a solution of 10.0 g (51 mmoles) of 4-cyanobenzyl bromide, Case, J. Am. Chem. Soc., 47, 1143, (1925) in 40 ml of dimethylformamide is added dropwise over 20 minutes. The mixture is then stirred at 25° for 1 hour after which a further 0.285 g (2.5 mmoles) of potassium tert-butoxide and 0.55 (2.5 mmoles) of diethyl acetamidomalonate are added and stirring continued for 1 hour at 25°. The reaction mixture is then poured into 300 ml of ice water, causing the product to precipitate. Filtration, washing with water and drying yields 10.3 g (31 mmoles, 61%) of N-acetyl-4-cyano-α-(ethoxycarbonyl)phenylalanine ethyl ester, m.p. 160°-163°.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[CH:17]=[O:18])[CH:20]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Reactant: OB(O)c1cccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Temperature: 95 °C
Yield: 47 %

Procedure:
5-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXIV) (1.53 g, 4.30 mmol), pyridine-3-boronic acid (CXXXI) (0.58 g, 4.73 mmol), and potassium phosphate tribasic (1.37 g, 6.45 mmol) was dissolved in 1,4-dioxane (43.0 mL) and water (9.0 mL) Tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.4301 mmol) was added, and the reaction was heated to 95° C. for 2.5 h. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic phase was separated and washed sequentially with water and brine. The material was dried (MgSO4), concentrated, and purified by flash chromatography using a 40 g Thomson normal phase silica gel cartridge (100% hexanes→1:1 EtOAc:hexanes) to afford 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (CXXXII) (0.62 g, 2.02 mmol, 47% yield) as a tan amorphous solid. 1H NMR (DMSO-d6) δ ppm 10.23 (s, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.61 (dd, J=4.8, 1.5 Hz, 1H), 8.39 (d, J=0.98 Hz, 1H), 8.17-8.14 (m, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.95-7.93 (m, 1H), 7.64-7.60 (m, 1H), 6.13 (dd, J=9.4, 2.4 Hz, 1H), 3.93-3.90 (m, 1H), 3.86-3.81 (m, 1H), 2.45-2.41 (m, 1H), 2.11-2.07 (m, 2H), 1.82-1.78 (m, 1H), 1.66-1.62 (m, 2H); ESIMS found for C18H17N3O2 m/z 308 (M+H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[S:3]([O:6][C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])(C)C)=[O:14])[CH2:9][CH:8]=1)(=[O:5])=[O:4].FC(F)(F)C(O)=O.C(N(CC)CC)C.ClC(OC[C:41]1[CH:46]=[CH:45]C=[CH:43][CH:42]=1)=O>ClCCl>[F:21][C:2]([F:1])([F:20])[S:3]([O:6][C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:19]2[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=2)=[O:14])[CH2:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50 mL roundbottom flask, was placed tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (3.5 g, 10.00 mmol). To this was added dichloromethane (20 mL) followed by the addition of trifluoroacetic acid (5 mL). The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. This was followed by the addition of dichloromethane (20 mL). This was followed by the addition of triethylamine (3.03 g, 29.94 mmol). To the mixture was added benzyl chloroformate (2.05 g, 12.02 mmol). The resulting solution was allowed to react overnight at room temperature. The reaction mixture was filtered and the filtrate was concentrated under vacuo. The crude mixture was purified by silica gel chromatography (1:40 EtOAc/petroleum ether) to yield the title compound as a yellow liquid.
Reaction SMILES: CC(C)([O-:4])C.[K+].C[C:8]1([CH3:16])[N:12]([CH2:13][CH2:14][OH:15])[CH2:11][CH2:10][O:9]1.[CH2:17]([CH:20]([CH2:27][CH2:28][CH3:29])[CH2:21][CH2:22][CH2:23]C1CO1)[CH2:18][CH3:19]>C(OCC)C>[OH:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][O:9][CH2:8][CH:16]([OH:4])[CH2:19][CH2:18][CH2:17][CH:20]([CH2:21][CH2:22][CH3:23])[CH2:27][CH2:28][CH3:29]
Reactant: CC1(C)OCCN1CCO
Reactant: CCCC(CCC)CCCC1CO1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCCC(CCC)CCCC(O)COCCNCCO
Temperature: 75 °C
Reaction time: 6 h
Yield: 177.9 %

Procedure:
To a 10 mL Schlenk tube containing potassium tert-butoxide (125 mg, 1 mmol, 0,5 eq.) under nitrogen atmosphere, was added freshly distilled 2,2-dimethyl-3-(2-hydroxyethyl)-oxazolidine (1,4 mL, 10 mmol, d 1,035, 5 eq.) before heating at 75° C. until complete dissolution. To the solution was added slowly 2-(4-propyl-heptyl)-oxirane (0,43 mL, 2 mmol, d 0,856) over 1 h at 75° C. The reaction was stirred at 75° C. After 6 h, the reaction was cooled to room temperature before adding diethyl ether (40 mL). The organic phase was extracted with aqueous hydrochloric acid (1 M, 3×12 mL). Then, a solution of aqueous sodium hydroxide (25%) was added to bring the mixture to pH 14 before extracting it with diethyl ether (4×16 mL). The combined organic phases were dried over sodium sulfate and concentrated to afford the title compound (515 mg, 90% yield). 1H NMR (CDCl3, 400 MHz) d?(ppm): 3,83-3,74 (m, H); 3,67 (t, J=5,2 Hz, 2H); 3,67-3,56 (m, 2H); 3,52 (dd, J=2,7 Hz, J=9,9 Hz, H); 3,30 (dd, J=8,2 Hz, J=9,9 Hz, H); 3,05-2,96 (m, 2H+2H); 1,50-1,15 (m, 15H); 0,87 (t, J=7,0 Hz, 6H). 13C NMR (CDCl3, 129,9 MHz) d?(ppm): 75,9; 70,3; 70,2; 60,9; 51,1; 48,9; 36,9; 36,0 (2C); 33,7; 33,6; 22,7; 19,8 (2C); 14,5 (2C).
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10](C)([O-])[CH3:11].[K+].C(Br)C=C.Cl>CN(C)C=O.O>[CH2:11]([C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:10]=[CH2:9]
Reactant: O=CC1CCCCC1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC1(CO)CCCCC1
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
To a solution of cyclohexane carbaldehyde (2.24 g) in N,N-dimethylformamide (30 mL) were added potassium tert-butoxide (2.70 g) and allyl bromide (4.33 mL) under ice cooling. The solution was stirred under ice cooling for 30 minutes. Water and 1N hydrochloric acid were then added to the solution, and it was extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the resulting residue in ethanol (60 mL) was added sodium borohydride (567 mg) under ice cooling. The solution was stirred at room temperature for 16 hours. Acetic acid was added to the solution, and it was concentrated under reduced pressure. To the resulting residue was added saturated aqueous sodium bicarbonate solution, and it was extracted with diethyl ether. The organic layer was washed in turn with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=4:1) to give the title compound (1.47 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:11]2[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:11]3[CH:16]=[C:15]([CH2:17][CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: CCc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-ethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[CH:3][C:4](=[N:6][OH:7])[NH2:5].[CH:15]([O-])([O-])OCC>B(F)(F)F.CCOCC>[CH3:1][C:2]([C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)=[CH:3][C:4]1[N:5]=[CH:15][O:7][N:6]=1
Reactant: CC(=CC(N)=NO)c1ccc(Cl)cc1
Reactant: CCOC([O-])[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=Cc1ncon1)c1ccc(Cl)cc1

Procedure:
β-Methyl-p-chlorocinnamamidoxime (4.64 g.) was refluxed with ethyl orthoformate (50 ml.) and two drops of boron trifluoride etherate for 45 min. Ethyl orthoformate was removed under reduced pressure and the residual brown oil was dissolved in chloroform (100 ml.) and washed consecutively with 2N-hydrochloric acid (20 ml.), saturated sodium hydrogen carbonate solution (20 ml.), and water (20 ml.). The chloroform solution was evaporated to a brown oil (ca. 4.6 g.) which was chromatographed on silica gel. Elution with benzene gave 3-(β-methyl-p-chlorostyryl)-1,2,4-oxadiazole, 2.90 g. (60%), m.p. 56°-57°, λmax (EtOH) 273 nm (ε 20760) (Found: C 59.95; H, 4.2; Cl, 15.9; N, 12.7. C11H9ClN2O requires C, 59.85; H, 4.1; Cl, 16.1; N, 12.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13]CC)=[O:12])=[C:9]([NH2:16])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1)=[O:5])[CH3:2].[Br:23][C:24]1[CH:39]=[CH:38][C:27]([C:28](Cl)=[N:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]2[N:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:11](=[O:13])[C:10]3[C:6]([C:4]([OH:3])=[O:5])=[N:7][N:8]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:9]=3[N:16]=2)=[CH:38][CH:39]=1.[CH2:1]([O:3][C:4]([C:6]1[C:10]2[C:11](=[O:12])[N:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:28]([C:27]3[CH:38]=[CH:39][C:24]([Br:23])=[CH:25][CH:26]=3)=[N:16][C:9]=2[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: ClC(=Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(N)c1C(=O)OCC
Product: CCOC(=O)c1nn(-c2ccccc2)c2nc(-c3ccc(Br)cc3)n(-c3ccc(Cl)cc3)c(=O)c12
Product: O=C(O)c1nn(-c2ccccc2)c2nc(-c3ccc(Br)cc3)n(-c3ccc(Cl)cc3)c(=O)c12

Procedure:
6-(4-Bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid is prepared from 5-amino-1-phenyl-1H-pyrazole-3,4-dicarboxylic acid diethyl ester and 4-bromo-N-(4-chloro-phenyl)-benzimidoyl chloride by following a similar procedure as described in example 2 except that the reaction mixture is heated at 170° C. in a microwave for 45 min instead of 20 min. the crude product is purified by preparative LC/MS to yield 6-(4-bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid as the major product and 6-(4 bromo-phenyl)-5-(4-chloro-phenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carboxylic acid ethyl ester (example 341) as by product. Example 340: HPLC-MS calculated C24H14BrClN4O3 (M+1+): 520.0. Found: 520.0. Example 341: 1H NMR (CDCl3) δ (ppm) 8.10(d, 2H), 7.50(t, 2H), 7.41(m, 3H), 7.34 (d, 2H), 7.20(d, 2H), 7.09 (d, 2H), 4.52(q, 2H), 1.45(t, 3H). HPLC-MS calculated C26H18BrClN4O3 (M+1+): 549.0. Found: 549.0.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)(C(OCC)=O)C(OCC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C(O)C>[CH2:7]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)(c1ccccc1)c1ccc([N+](=O)[O-])cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cc2ccccc2)nc1
Yield: 70.5 %

Procedure:
1.5 g of diethyl 2-phenyl-2-(5-nitropyridin-2-yl)malonate was dissolved in 50 ml of ethanol. After adding 10 ml of water and 10 ml of conc. sulfuric acid, the mixture was heated under reflux for 8 hours. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluted with ethyl acetate/n- hexane) to thereby give 632 mg of the title compound as reddish brown crystals.
Reaction SMILES: C[Si](OP(=O)=O)(C)C.[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[N:10].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[S:29])[CH:24]=[CH:25][CH:26]=1.[C:33]([O:39][CH2:40][CH2:41][C:42]#[N:43])(=[O:38])[CH2:34][C:35]([CH3:37])=O>O1CCOCC1>[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]2[C:34]([C:33]([O:39][CH2:40][CH2:41][C:42]#[N:43])=[O:38])=[C:35]([CH3:37])[N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:31])[F:32])[CH:22]=3)[C:28](=[S:29])[NH:30]2)=[CH:13][CH:12]=1)#[N:10]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)OP(=O)=O
Solvent: C1COCCO1
Product: CC1=C(C(=O)OCCC#N)C(c2ccc(C#N)cc2)NC(=S)N1c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Under argon, trimethylsilyl polyphosphate (10.6 g) is dissolved in 75.7 ml absolute dioxane. To this solution are added 4-cyanobenzaldehyde (5.95 g, 45.4 mmol), 3-trifluoromethylphenyl thiourea (5 g, 22.7 mmol) and 2-cyanoethyl acetoacetate (6.4 g, 45.4 mmol). The reaction mixture is stirred at 80° C. for 3 hours. After evaporation of the dioxane solvent, the residue is dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, 38% sodium bisulfite solution and saturated sodium chloride solution. After drying with magnesium sulfate and evaporating off the solvent, the residue is dissolved in 15 ml methanol and purified by preparative HPLC (column: Kromasil 100 C 18 5 μm, 30 mm×150 mm; precolumn: Gromsil ODS 4 HE 15 μm, 10 mm×20 mm; flow rate: 66 ml/min; solvent A: acetonitrile, solvent B: water; gradient: 0 min 10% A, 3 min 10% A, 11 min 90% A, 13 min 90% A, 13.2 min 10% A, 15 min 10% A; wavelength: 220 nm; injection volume: approx. 2000 μl; number of injections: 12). The product containing fractions are combined and concentrated in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]C(N)=O)=[C:11]([O:20][CH2:21][O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=[N:28]CCC2)CC1.BrN1C(=O)CCC1=O.[OH-].[K+]>CO.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH2:28])=[C:11]([O:20][CH2:21][O:22][CH3:23])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: COCOc1cc(OCc2ccccc2)ccc1CCC(N)=O
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: COCOc1cc(OCc2ccccc2)ccc1CCN
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a solution of 28.42 g of 3-(4-benzyloxy-2-methoxymethoxyphenyl)propionamide and 40.4 mL of 1,8-diazabicyclo[5.4.0]-7-undecene in 895 mL of methanol was added 16.04 g of N-bromosuccinimide at 65° C. After the mixture was stirred at 65° C. for 15 minutes, to the reaction mixture was added additional 16.04 g of N-bromosuccinimide at 65° C. After being stirred at 65° C. for 15 minutes, the resulted mixture was concentrated under reduced pressure to remove the solvent. To the residue were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give oily product. To a solution of this residue in 242 mL of ethanol was added 67.6 mL of 8 mol/L aqueous potassium hydroxide solution, and the mixture was refluxed for 15 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. To the residue were added 500 mL of ethyl acetate, 50 mL of toluene, and 300 mL of water, and the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel (eluent: hexaneethyl acetate) to give 80.0 g of 2-(4-benzyloxy-2-methoxymethoxyphenyl)ethylamine as a colorless oil.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[C:13]([C:16]1[C:17](=[O:24])[O:18]C(C)=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:14].CI>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[C:13]([C:16]1[C:17](=[O:18])[O:24][C:7]([CH2:5][CH3:6])=[CH:20][C:21]=1[OH:22])(=[O:15])[CH3:14]
Reactant: CC(=O)c1c(O)cc(C)oc1=O
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCc1cc(O)c(C(C)=O)c(=O)o1
Temperature: -10 °C
Yield: 47.1 %

Procedure:
A solution of diisopropylamine (2.6 mL, 18.1 mmol) in anhydrous tetrahydrofuran (5 mL) under argon at −40° C. was treated dropwise with n-butyllithium (7.0 mL, 2.5 M in hexanes). The resulting solution was allowed to warm to −10° C. over 15 minutes. In a separate flask, hexamethylphosphoramide (2 mL) and 3-acetyl-6-methyl-4-hydroxy-2-pyrone (923 mg, 5.49 mmol) were combined and azeotroped to dryness with benzene (3×25 mL) before being dissolved in anhydrous tetrahydrofuran (5 mL). To the LDA solution at −78° C. was added dropwise over 5 minutes the solution of hexamethylphosphoramide and 3-acetyl-6-methyl-4-hydroxy-2-pyrone. The reaction mixture became a solid red/orange mass after the addition was complete and was kept at −78° C. for 40 minutes before methyl iodide (0.38 mL, 6.04 mmol) was added in a single portion. The reaction flask was removed from the cooling bath and swirled vigorously by hand as it warmed to room temperature over 20 minutes. Over this time the solid mass dissipated and became a coarse precipitate. The reaction mixture was poured into 30 mL 1 N hydrochloric acid and organics were extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with 5% aqueous sodium bisulfite and brine (30 mL each), dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (10% ethyl acetate in hexanes+1% acetic acid) to afford 3-acetyl-6-ethyl-4-hydroxy-2-pyrone (471 mg, 47%) as a white solid: LRMS (ES+) m/z [M+H]+. found 183 (Exact mass=182.06). Used without further characterization.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)=[CH2:2].[Li]CCCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:22](=[O:24])[CH3:23])=[N:12][CH:11]=[N:10]2)=[CH:7][CH:8]=1)=[CH2:2]
Reactant: CON(C)C(C)=O
Reactant: C=Cc1ccc(-n2cncn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(-n2ncnc2C(C)=O)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(4-vinyl-phenyl)-1H-[1,2,4]triazole (1 g, 5.8 mmol) in 25 mL of THF, was added n-BuLi (0.37 g, 5.8 mmol) at −78° C. and stirred for 30 min. To this N-methoxy-N-methyl acetamide in THF (0.66 g, 6.4 mmol) was added and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc (3×50 mL). The combined EtOAc layer was washed with brine and dried over sodium sulphate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2, 100-200 mesh, 40% EtOAc in Pet ether) to afford the title compound as an off white solid (280 mg, 23%): mp 97-98° C.; 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.50 (d, 2H), 7.38 (d, 2H), 6.68 (dd, 1H), 5.85 (d, 1H), 5.38 (d, 1H), 2.75 (s, 3H); ESIMS m/z 214.14 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.Cl[S:20]([OH:23])(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[OH-:8].[NH2:1][C:2]1[N:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[C:6]([NH2:9])[N+:7]=1[O:8][S:20]([OH:23])(=[O:22])=[O:21]
Reactant: Nc1cc(NCCc2ccccc2)nc(N)[n+]1[O-]
Reactant: O=S(=O)(O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Nc1cc(NCCc2ccccc2)nc(N)[n+]1OS(=O)(=O)O
Product: [OH-]
Reaction time: 8 h

Procedure:
A mixture of 1.00 gm of 2,4-diamino-6-(benzylmethylamino)pyrimidine-3-oxide, 1.15 grams of chlorosulfonic acid and 2.50 grams of di-isopropylethylamine in 25 mls of chloroform is stirred overnight. The mixture is concentrated in vacuo. The residue is stirred with aqueous sodium bicarbonate, filtered, and washed with ether to give 2,6-diamino-4-(benzylmethylamino)-1-(sulfooxy)-pyrimidinium hydroxide, inner salt.