Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:53][O:54][C:55](=[O:74])[C@@H:56]([NH2:73])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][C:65]2[CH:70]=[CH:69][N:68]=[C:67]([CH3:71])[C:66]=2[CH3:72])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:73][C@H:56]([C:55]([O:54][CH3:53])=[O:74])[CH2:57][C:58]2[CH:59]=[CH:60][C:61]([O:64][C:65]3[CH:70]=[CH:69][N:68]=[C:67]([CH3:71])[C:66]=3[CH3:72])=[CH:62][CH:63]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccc(Oc2ccnc(C)c2C)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Temperature: 0 °C

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (80 mg) was taken up in 2 mL of anhydrous DCM and EDCI (34 mg), HOBT (25 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride (50 mg) were added and stirred for minutes. The reaction mixture was cooled to 0° C. and DIEA (85 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, it was purified by column chromatography (silica gel; 1:3 ethyl acetate/hexanes to 4% MeOH in 1:1 ethyl acetate/hexanes) (70 mg). LCMS (m/z): 869.
Reaction SMILES: [Mg].C(COCCOCCOC)CCC.II.BrCCBr.[CH:21]1([CH3:31])[CH2:26][CH2:25][CH:24]([CH:27]([CH3:29])[CH3:28])[CH:23](Cl)[CH2:22]1.[C:32](=[O:34])=[O:33]>>[CH:21]1([CH3:31])[CH2:26][CH2:25][CH:24]([CH:27]([CH3:29])[CH3:28])[CH:23]([C:32]([OH:34])=[O:33])[CH2:22]1
Reactant: O=C=O
Reactant: CC1CCC(C(C)C)C(Cl)C1
Agent: CCCCCOCCOCCOC
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Product: CC1CCC(C(C)C)C(C(=O)O)C1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Magnesium (37 g, 50 mesh), butyl diglyme (600 g), and iodine (0.1 g) were added under nitrogen to a 1-liter flask equipped with agitation, addition funnel, off-set adaptor for thermometer, gas addition tube, and condenser. The mixture was stirred for 30 min. at 90° C., and then 1,2,-dibromo ethane (2 cc) was slowly added. p-Menth-3-yl chloride (200 g) was then added at a rate of 50 g/hr (0.32 mole/hr). After approximately ½ of the p-menth-3-yl chloride was added, carbon dioxide was concurrently added by bubbling the carbon dioxide into the mixture at a rate of 15.91 g/hr (0.36 mole/hr), and at a temperature of 90° C. Addition of the carbon dioxide was continued at a temperature of 90° C. until 30 min. after all of the p-menth-3-yl chloride was added. After carbonation was complete, the resultant mixture was hydrolyzed with aqueous hydrochloric acid (1:1 hydrochloric acid/water), and the resultant oil layer was neutralized with trisodium phosphate. VPC analysis showed a yield of 93.18% by weight of p-menthane-3-carboxylic acid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][C:12]([OH:17])([CH3:16])[CH2:13][CH2:14]O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[C:1]([O:9][CH2:10][CH2:11][C:12]([OH:17])([CH3:16])[CH2:13][CH2:14][Br:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(CCO)CCOC(=O)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(CCBr)CCOC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.5 %

Procedure:
To a solution of 3,5-dihydroxy-3-methylpentyl benzoate (1.0 g) and carbon tetrabromide (2.78 g) in tetrahydrofuran (30 mL) was added dropwise a solution of triphenylphosphine (2.20 g) in tetrahydrofuran (10 mL) under ice-cooling. After stirring at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=9:1→6:4) to give the title compound (979 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]O)=[CH:4][N:3]=1.[Br:14]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.[OH-].[Na+]>C(#N)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][Br:14])=[CH:4][N:3]=1
Reactant: Nc1ncc2ncn(CCO)c2n1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Nc1ncc2ncn(CCBr)c2n1
Temperature: 35 °C
Reaction time: 5 h

Procedure:
17.92 g (0.1 mole) of 2-amino-9-(2-hydroxyethyl)purine was completely dissolved in 400 ml of acetonitrile, to which 84.42 g (0.20 mole) of dibromotriphenylphosphine was then added. The mixture was stirred for 5 hours at a temperature of 30-40° C. After completion of the reaction, 300 ml of water was added to the reaction product. The resulting solution was neutralized with aqueous sodium hydroxide solution and extracted four times with 500 ml portions of a mixed solution of chloroform and methanol (4:1). The organic layer was collected, and dried with anhydrous magnesium sulfate, followed by filtration and washing. The resulting filtrate was concentrated under reduced pressure, and crystallized from chloroform, 22.03 g (91%) of white 2-amino-9-(2-bromoethyl)purine.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][NH2:4].[Cl:6][C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15](Cl)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1>C(N(CC)CC)C>[Cl:6][C:7]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:4][CH2:3][CH:2]([CH3:5])[CH3:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: CC(C)CN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Product: CC(C)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
2-Methylpropylamine (0.5 mL) was added to a suspension of 2,4-dichloro-3-nitroquinoline (1 g) and triethylamine (15 mL) at 40° C. over a period of 40 min. The solution was then heated at 70° C. for 1 h. The triethylamine and 2-methylpropylamine were removed by distillation and the residue was slurried for 1 h in aqueous 1N HCl. The solid product 2-chloro-N-(2-methylpropyl)-3-nitro-4-quinolinamine was collected by filtration, washed with water and recrystallized from petroleum ether.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:25]=[C:16]3[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][N:15]3[N:14]=2)=[CH:9][CH:8]=1.CN(C)[CH:28]=[O:29]>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:25]([CH:28]=[O:29])=[C:16]3[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:22])[F:24])=[CH:20][N:15]3[N:14]=2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)nn2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 94 %

Procedure:
To a cold (0° C.) solution of phosphorus oxychloride (8.0 mL, 86 mmol) in N,N-dimethylformamide (160 mL) was added 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridine (11.0 g, 39.3 mmol). The reaction mixture was stirred at room temperature for 72 hours, then quenched with ice water. The solid precipitate was collected on a filter to provide 2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (11.4 g, 94%) as a white solid. Rf 0.45 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 8.92 (s, 1H), 8.53 (d, 1H), 7.80 (m, 2H), 7.70 (d, 1H), 7.27 (t, 2H); 19F NMR (CDCl3) δ −62.62, −110.62; MS m/z 307 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][OH:14])[O:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].ClC1C=CC(O[CH2:22][C:23]#[N:24])=CC=1.CC(C)([O-])C.[K+].Cl>CN(C=O)C.O>[OH:14][CH2:13][CH:10]1[CH2:11][O:12][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[C:15]([CH2:22][C:23]#[N:24])[C:8]=2[O:9]1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c([N+](=O)[O-])ccc2c1OC(CO)CO2
Temperature: -2.5 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of racemic (7-nitro-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanol (1.00 g, 4.73 mmol) and 4-chlorophenoxyacetonitrile (827 mg, 4.94 mmol) in DMF (12 mL) was added dropwise to a solution of potassium tert-butoxide (2.12 g, 18.9 mmol) in DMF (20 mL) at −5-0° C. After the addition was complete (7 minutes), the reaction mixture was stirred for 1 hour at −5-0° C. The reaction mixture was acidified with 1 N HCl before drowning into water (200 mL). The mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with 1N NaOH (3×50 mL) to remove most of the 4-chlorophenol. After removal of solvent, the residue was purified by flash chromatography on silica gel, gradient elution using 2:3, 1:1, 3:2, 100:0 ethyl acetate/hexane, to give 139 mg, 14% recovered starting material and 804 mg, 68% yield of the title compound as a solid. 1H NMR (CDCl3) δ 7.77 (1H, d, J=9.12 Hz); 7.01 (1H, d, J=9.12 Hz); 4.50-4.40 (2H, m); 4.30-3.91 (5H, m); 2.25-2.21 (1H, m). 13C NMR (CDCl3) δ 148.07, 141.71, 141.55, 119.44, 117.07, 116.96, 115.71, 74.36, 65.31, 61.18, 14.89.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:13])=[C:4]([Cl:12])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[C:3]([Cl:13])=[C:4]([Cl:12])[C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([Cl:16])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)c1Cl
Reaction time: 1.25 h

Procedure:
The desired tetrachlorobenzoyl chloride is prepared by reacting the tetrachlorobenzoic acid with thionyl chloride. A six fold molar excess of thionyl chloride is slowly added to the acid. This mixture is heated to reflux and held at this temperature for 1.25 hours. The solution is then cooled and the excess thionyl chloride vacuum distilled off. The solution is further distilled under vacuum to yield the pure tetrachlorobenzoyl chloride in 92-93% yield.
Reaction SMILES: [C:1]1([C@H:7]2[O:12][C@@H:11](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([O-:27])(=[S:26])[CH3:25].[Na+].C1C=CC=CC=1>CN(C)C=O>[C:24]([S:26][C@@H:11]1[CH2:10][CH2:9][O:8][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:12]1)(=[O:27])[CH3:25]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCO[C@@H](c3ccccc3)O2)cc1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)S[C@@H]1CCO[C@@H](c2ccccc2)O1
Temperature: 117.5 °C
Yield: 43.5 %

Procedure:
In 200 ml of dimethylformamide were dissolved 29.0 g (86.8 mmol) of cis-2-phenyl-4-(p-toluenesulfonyloxy)-1,3-dioxane and 17.0 g (149 mmol) of sodium thioacetate, and the solution was heated at 115 to 120° C. under a nitrogen atmosphere for 1 hour. After cooling, benzene was added to the reaction mixture and the mixture was washed with water, followed by evaporation of the solvent. The thus obtained brown residue was subjected to column chromatography using silica gel and the fractions eluted with a mixed solvent of benzene-hexane (2:1) were collected, followed by recrystallization from a mixed solvent of benzene-hexane to obtain 8.99 g (yield: 43%) of the title compound having a melting point of 95 to 96° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]2=O)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[H][H]>[Pd].CC(O)=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COC(=O)C1CCc2ccc(OC)cc2C1=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CCc2ccc(OC)cc2C1
Yield: 70.4 %

Procedure:
A slurry of methyl 7-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (6.0 g, 26 mmol) and 10% palladium on carbon (100 mg) in AcOH (120 mL), and concentrated sulfuric acid (780 μL) was allowed to stir under 30 psi of hydrogen for 2.5 h. The reaction mixture was diluted with chloroform, and filtered through Celite. The filtrate was washed with water (5×), dried over Na2SO4 and evaporated. The residue was purified by filtration through a pad of silica, to give methyl 7-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylate as an oil (4.03 g, 71%). 1H NMR (300 MHz, CD3OD): δ 6.94 (d, 1H), 6.67-6.62 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 2.94-2.91 (m, 2H), 2.78-2.70 (m, 3H), and 2.18-2.09 (m, 1H), and 1.86-1.73 (m, 1H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:21][C:12]2=[C:13]3[N:18]([N:19]=[C:11]2[CH2:10]1)[CH:17]=[C:16]([CH3:20])[CH:15]=[N:14]3)=O)(C)(C)C.CCO>CC(O)=O>[ClH:1].[CH3:20][C:16]1[CH:15]=[N:14][C:13]2[N:18]([N:19]=[C:11]3[CH2:10][NH:9][CH2:21][C:12]3=2)[CH:17]=1
Reactant: Cc1cnc2c3c(nn2c1)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cnc2c3c(nn2c1)CNC3
Temperature: 25 °C
Reaction time: 28 h
Yield: 65.1 %

Procedure:
Aq. 32% HCl (1.61 mL; 16.4 mmol; 3 eq.) was added to a solution of 6-methyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (1.5 g; 5.47 mmol; 1 eq.) in AcOH (7.5 mL) and the resulting mixture was stirred at room temperature for 28 hours then poured dropwise into EtOH (40 mL) under vigorous stirring. The precipitate was filtered off, washed with EtOH then MTBE and dried to afford the title compound (0.75 g, 65%) as a white solid. 1H NMR (DMSO-d6) δ 10.50 (s, 2H), 9.06-9.02 (m, 1H), 8.51 (d, J=2.1 Hz, 1H), 4.55-4.52 (m, 4H), 2.33 (s, 3H). HPLC (max plot) 100.0%; Rt 4.36 min.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](O)=[O:14])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[N:63]=[C:62]([NH2:64])[N:61]=[C:60]([NH:65][C:66]3[CH:71]=[CH:70][C:69]([O:72][C:73]4[CH:78]=[CH:77][N:76]=[C:75]([C:79]([F:82])([F:81])[F:80])[CH:74]=4)=[CH:68][CH:67]=3)[CH:59]=2)=[CH:54][CH:53]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C(=O)C.CS(C)=O.CCOC(C)=O.CO>[NH2:8][CH:12]([CH2:13][OH:14])[C:11]([NH:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH:65][C:66]3[CH:71]=[CH:70][C:69]([O:72][C:73]4[CH:78]=[CH:77][N:76]=[C:75]([C:79]([F:81])([F:82])[F:80])[CH:74]=4)=[CH:68][CH:67]=3)[N:61]=[C:62]([NH2:64])[N:63]=2)=[CH:54][CH:53]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)COC1(C)C
Reactant: Nc1ccc(-c2cc(Nc3ccc(Oc4ccnc(C(F)(F)F)c4)cc3)nc(N)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc(C(F)(F)F)c3)cc2)cc(-c2ccc(NC(=O)C(N)CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
To a solution of (4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidine-4-carboxylic acid (0.56 g, 2.3 mmol) in dry N,N-dimethylacetamide (10 mL) was added HATU (0.11 g, 2.87 mmol) and DIEA (0.742 g, 5.75 mmol). After the reaction solution was stirred at rt for 1 h, 6-(4-aminophenyl)-N4-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine (Example 165, 0.84 g, 1.92 mmol) was added. The solution was stirred for an additional 24 h at rt and separated by preparative HPLC to afford a solid intermediate, which was treated with methanol (10 mL) and concentrated HCl (0.5 mL) for 12 h at rt. The resulting mixture was diluted with DMSO and purified by HPLC to give a solid. The solid was stirred with saturated sodium bicarbonate and EtOAc for 2 h. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to afford 0.433 g (43%) of pure product. 1H NMR (DMSO-d6) δ 9.34 (s, 1H), 8.59 (d, 1H), 7.88 (m, 4H), 7.76 (d, 2H), 7.37 (s, 1H), 7.16 (m, 3H), 6.45 (s, 1H), 6.36 (s, 2H), 4.88 (t, 1H), 3.56 (m, 2H), 3.39 (m, 1H); MS ES 526 (M+H)+calcd 526.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)(=[O:3])[CH3:2]
Reactant: Nc1cccnc1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.6 %

Procedure:
To a stirred solution of 200 mg (0.7 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (10 mL), 3-aminopyridine (0.098 mg, 1.04 mmol) was added portionwise. The resulting mixture was stirred at room temperature for five hours. The solvent was evaporated and the residue purified by column chromatography (silica gel, dichloromethane/methanol 97:3) to yield the title compound (60 mg, 26% yield).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:4]3[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: OC1CCCNC1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCCC(O)C3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3-hydroxypiperidine (0.198 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH—CHCl3) to afford the title compound E23 as an off-white solid (0.06 g, 21%). mp 100-102° C.; HPLC: Hichrom RPB (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 5.5); solvent B=CH3CN], Gradient elution program: T/% B=0/20, 10/20, 25/80, 40/80, 55/60, 65/20, 70/20; 270 nm, Rt 41.95 min, 98.43% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [C:1]1([C:7]2[N:14]3[C:10]([S:11][CH:12]=[CH:13]3)=[N:9][C:8]=2[C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]1([C:7]2[N:14]3[C:10]([S:11][CH:12]=[CH:13]3)=[N:9][C:8]=2[C:15]2[CH:16]=[CH:17][C:18]([CH2:19][OH:20])=[CH:23][CH:24]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2nc3sccn3c2-c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2nc3sccn3c2-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
0.12 g (0.36 mM) of methyl 4-(5-phenylimidazo[2,1-b][1,3]thiazol-6-yl)benzoate is dissolved in 8 mL of dry THF. To this is added lithium aluminum hydride (5 eq) at 0° C. The reaction mixture is brought to RT and stirred for 2 h. It is then quenched with sat. solution of sodium sulphate and filtered. The filtrate is evaporated and extracted in ethyl acetate. The organic layer is dried and concentrated to obtain the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:32])([F:31])[CH2:29][OH:30].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>C(OCC)(=O)C>[CH3:19][O:18][C:16]([C:10]1[C:9]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:14][CH:13]=[C:12]([O:30][CH2:29][C:28]([F:32])([F:31])[F:27])[N:11]=1)=[O:17]
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1nc(OCC(F)(F)F)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate (500 mg, 1.16 mmol), 2,2,2-trifluoroethanol (84 μl, 1.16 mmol), cesium carbonate (415 mg, 1.27 mmol) and dry DMSO (5 ml) was stirred at r.t. for 3 h. The reaction mixture was poured into ethyl acetate (100 ml) and extracted with saturated sodium bicarbonate (aqueous solution). The organic layer was washed with water and brine and the aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried, evaporated and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as white solid (456 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl>[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][N:40]([C:13]([C:12]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:9][O:10][C:11]=3[CH3:16])=[O:15])[CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3,4-dichlorophenyl)piperazine (425 mg, 1.84 mmol), a white solid required compound (587 mg, 1.35 mmol, 74%) was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[N:21]=[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[O:19][C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:7]=1.[Cl-].[NH4+:28].N.O>C(O)C>[NH2:28][C:2]1[C:3]2[N:21]=[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[O:19][C:4]=2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1ccc(CCNc2nc(Cl)c3nc(-c4ccco4)oc3n2)cc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CCNc2nc(N)c3nc(-c4ccco4)oc3n2)cc1
Temperature: 100 °C
Yield: 48.5 %

Procedure:
7-chloro-2-(2-furyl)-5-[2-(4-methoxyphenyl)ethyl]amino-oxazolo[5,4-d]pyrimidine (0.5 g) and ammonium chloride (0.1 g) were added to a saturated solution of ammonia in ethanol (20 ml) and sealed in a Caries tube. The sealed tube was then heated at 100° C. for 18 hours. The cooled reaction mixture was poured into water (200 ml) and the resultant precipitate removed by filtration. The solid was recrystallised from methanol to afford 7-amino-2-(2-furyl)-5-[2-(4-methoxyphenyl)ethyl]amino-oxazolo[5,4-d]pyrimidine (0.23 g, 48.6%), m.p. 194°-196° C.; microanalysis, found: C, 61.5; H, 4.8; N, 19.5%; C18H17N5O3 requires: C, 61.5; H, 4.9; N, 19.9%; NMR (DMSO-d6); 2.76(t,2H ArCH2), 3.44(brq 2H, CH2NH), 3.72(s, 3H, OMe), 6.70(m, 1 H furyl-H), 6.28(brs, 1H NH), 6.84(d, 2H, ArH), 7.13(complex, 5H ArH, NH2 furyl-H), 7.89(m, 1H, furyl-H); m/e [M+H]+ 352.