Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[SH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:35](I)[CH3:36]>>[CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:35][CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Cc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 4-benzyl-3-mercapto-5-sulfamylbenzoic acid (1.0 g), sodium hydrogen carbonate (0.3 g), sodium dithionite (0.3 g), ethyl iodide (1.0 ml) and saturated sodium hydrogen carbonate solution (8 ml) is stirred at 70° C for 3 hours. After cooling, the precipitated sodium 4-benzyl-3-ethylthio-5-sulfamylbenzoate is collected by filtration and washed with a minor amount of icecold water. After drying, the sodium salt is dissolved in hot water (10 ml), and the solution is clarified by the filtration hot in the presence of decolorizing carbon. The solution is acidified with conc. hydrochloric acid (0.5 ml) to precipitate the 4-benzyl-3-ethylthio-5-sulfamylbenzoic acid. The acid is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, the compound is obtained with a melting point of 234° -235° C.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].Cl[C:9]1[CH:10]=[C:11]([CH3:19])[C:12]2[N:13]([C:15]([NH2:18])=[N:16][N:17]=2)[N:14]=1.[O-]CC.[Na+].O>C(O)C>[CH2:3]([O:4][C:9]1[CH:10]=[C:11]([CH3:19])[C:12]2[N:13]([C:15]([NH2:18])=[N:16][N:17]=2)[N:14]=1)[CH3:2]
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Reactant: O=C(O)C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C)c2nnc(N)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine trifluoroacetate (W2.002b; 50 mg) was dissolved in ethanol (3.5 ml) while stirring at RT. Thereafter, sodium ethoxide was added dropwise while cooling with ice (25 mg dissolved in 1.5 ml of ethanol). After stirring at RT for 2.5 h, the mixture was heated to 60° C. and, after 2.5 h, a further equivalent of sodium ethoxide solution was added. After standing overnight, the mixture was heated again to 60° C., two further equivalents of sodium ethoxide solution were added and the mixture was stirred for 4 h. Subsequently, the mixture was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 27 mg of the title compound were obtained. LC-MS rt: 0.67 min [M+H]+: 194.1 (met. a)
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:8][CH:7]1[C:6](=[O:9])[NH:5][C:4]2=[O:10].[Cl:11][CH2:12][CH2:13][CH2:14][CH:15](I)CCCC.O>CN(C)C=O>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][N:5]1[C:6](=[O:9])[CH:7]2[CH:3]([CH2:8]2)[C:4]1=[O:10]
Reactant: CCCCC(I)CCCCl
Reactant: O=C1NC(=O)C2CC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C2CC2C(=O)N1CCCCCl
Reaction time: 48 h

Procedure:
Sodium hydride (0.11 g, 60% dispersion in oil) was added to a stirred solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.5 g) and 1-chloro-4-iodooctane (0.98 g) in dry dimethylformamide (50 ml) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred for 48 hours and water (50 ml) was then added dropwise. The aqueous mixture was extracted with dichloromethane (2×200 ml) and the combined organic extracts were then washed with water (2×400 ml), dried (MgSO4) and evaporated in vacuo to give an oil. The oil was purified by chromatography on silica (80 g) using 1:1 ethyl acetate/hexane as eluant to give the title compound as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7]=2[CH:14]=1.[Mg]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Agent: [Mg]
Solvent: CO
Product: COc1ccc2c(c1)CC(C(=O)O)O2
Reaction time: 2 h
Yield: 65.1 %

Procedure:
To a suspension of 5-methoxy-benzofuran-2-carboxylic acid (14 g, 72.8 mmol) in MeOH (600 ml) was added magnesium turnings (10.6 g, 437 mmol) and the mixture was vigorously mechanically stirred for 2 hr keeping the temperature below 30° C. After 2 hr, further magnesium was added (10.6 g, 437 mmol) and the mixture stirred a further 4 hr again maintaining the temperature below 30° C. After 6 hr. the mixture was concentrated to ˜100 ml and distilled H2O (600 ml) was added and the pH adjusted to 1-2 with 1N sulfuric acid. The crude mixture was extracted with EtOAc (2×300 ml) and the combined extracts washed with H2O (200 ml). The combined organic phase was dried with Na2SO4, filtered and evaporated to afford yellowish solid, which was recrystallised from hot toluene (100 ml) to afford white crystals (9.2 g, 47.4 mmol, 65%) Mp. 98-100° C., MS: m/e=194.1 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(C(=O)O)c2)CC1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(C(=O)O)c2)CC1
Yield: 43.8 %

Procedure:
The mixture of 9 g of 2-nitro-5-(4-methylpiperazino)benzoic acid, 20 mL of cyclohexene and 3.5 g of Pd/C (10%) is heated under reflux conditions in 120 mL of ethanol for 6 hours. The hot reaction mixture is filtered through celite filter. The filtrate is evaporated to obtain 3.5 g of the title compound. m.p.: 212° C.
Reaction SMILES: ClC(OCC)=O.[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH:14][C:15](O)=[O:16])[CH:8]=1.N1C=CC=C(C=O)C=1.C(O)(=O)CC(O)=O>O1CCCC1.C(N(CC)CC)C>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH:14][CH2:15][OH:16])[CH:8]=1
Reactant: O=C(O)C=Cc1cccnc1
Agent: CCOC(=O)Cl
Agent: O=C(O)CC(=O)O
Agent: O=Cc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCC=Cc1cccnc1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (1.4 ml) and ethyl chloroformate (0.94 ml) were added in succession to a stirred suspension of 3-(3-pyridyl)propenoic acid [1.49 g; prepared from pyridine-3-carbaldehyde and malonic acid using the general method described in Organic Synthesis, Coll, Vol. 4, 1963, 730] in tetrahydrofuran (40 ml) which had been cooled to -15° C. The mixture was stirred at this temperature for 30 minutes and then filtered. The filtrate was added over 15 minutes to a stirred solution of sodium borohydride (0.94 g) in water (8 ml) which had been cooled in an ice-bath. The mixture was stirred at ambient temperature for 3 hours then partitioned between diethyl ether and a dilute aqueous sodium hydroxide solution. The aqueous layer was extracted with diethyl ether and ethyl acetate. The combined organic extracts were washed with a saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated. The residue was purified by column chromatography eluting with toluene/ethyl acetate (1/1 v/v) to give 3-(3-pyridyl)prop-2-en-1-ol as an oil (0.84 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([C:11](=[N:21][OH:22])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:5]=1F.[H-].[Na+]>CN(C=O)C.O.C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:22][N:21]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=3)[C:6]=2[CH:7]=[CH:8][C:9]=1[Cl:10])=[O:24]
Reactant: CCc1ccc(NC(=NO)c2ccc(Cl)c(C(=O)OC)c2F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Nc2noc3c(C(=O)OC)c(Cl)ccc23)cc1
Reaction time: 0.33 h

Procedure:
To a solution of methyl-6-chloro-3-(N-(4-ethylphenyl)-N′-hydroxycarbamimidoyl)-2-fluorobenzoate (225 mg, 641 μmol) in DMF (6.4 ml) chilled to 0° C. was added NaH (17 mg, 706 μmol) in one portion. The yellow solution evolved gas and immediately turned a dark orange color. After 20 min, the mixture was diluted with H2O and DCM, the layers were separated and the aqueous layer was extracted with DCM (2×). The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated to provide the title compound as a light brown solid, which was used for the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8]1.[BH4-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8]1
Reactant: O=C1CCC(c2ccccn2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@H]1CC[C@@H](c2ccccn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 3-(2-pyridyl)cyclopentan-1-one (3.17 g, 19.7 mmol) in MeOH (80 ml) was added portionwise NaBH4 (745 mg. 19.7 mmol) at 0° C., and stirred for 2 h at room temperature. The reaction mixture was poured into ice-water and then extracted with EtOAc. The organic layer was dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/1→1/3) to yield cis-3-(2-pyridyl)cyclopentanol (1.90 g, 59%) as colorless oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].[OH-].[Na+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>O.C(OCC)C>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:8]2[CH:15]=[CH:16][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8.8 g of 4-(4-nitrophenoxy)-butaneamine hydrochloride (Example 34) in 200 ml of water is treated successively with 9 ml of 10N NaOH, and a solution of 7.5 g of 4-methylbenzenesulfonyl chloride in 200 ml of diethylether. The reaction is stirred at room temperature for 3 hours, the precipitate collected, washed with water and diethylether, and air dried. Recrystallization from 50% aqueous ethanol gives the desired product as a solid, m.p. 87°-88° C.; yield, 1.2 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][CH2:11][CH2:10][S:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].Cl.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.[OH-].[Na+].O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:11][CH2:10][S:9][C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCCCC1
Reactant: O=[N+]([O-])c1ccc2c(c1)SCCN2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)SCCN2CCN1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.8 %

Procedure:
A mixture of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (1 g, 5.10 mmol), 1-(2-chloroethyl)piperidine hydrochloride (1.876 g, 10.19 mmol), and tetrabutylammonium bromide (0.082 g, 0.255 mmol) in dichloromethane (10 mL) and 50% NaOH solution (10 mL) was stirred at room temperature overnight (16 hours). The mixture was diluted with dichloromethane (5 mL) and water (20 mL), and the mixture was then transferred to a separatory funnel. The organic layer was removed, and the aqueous layer was extracted in dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The red crude material was subjected to column chromatography on silica gel using the Biotage purification system (80 g silicycle column; solvent gradient: dichloromethane 3CV, ramp to 6:94 (2M NH3 in methanol):CH2Cl2 over 15CV; 254 nm monitoring wavelength; flow=45 mL/minute), to give an orange solid (0.937 g, 59.8%). 1H-NMR (DMSO-d6) δ 7.85-7.81 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 3.82-3.79 (m, 2H), 3.58 (t, J=6.9 Hz, 2H), 3.08-3.04 (m, 2H), 2.50-2.45 (m, 2H), 2.44-2.34 (m, 4H), 1.49-1.46 (m, 4H), 1.40-1.37 (m, 2H); ESI-MS (m/z, %): 308 (MH+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([C:29]#[N:30])[N:14]2[C:19]([NH:20][CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:18][C:17]([CH3:28])=[N:16][C:15]=12.[ClH:31].C(=O)([O-])O.[Na+].Cl.C(OCC)(=O)C>C(O)C.C(OCC)(=O)C>[ClH:31].[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[N:14]3[C:19](=[CH:18][C:17]([CH3:28])=[N:16][C:15]=13)[N:20]([CH:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[C:29]2=[NH:30]
Reactant: CCCC(CCC)Nc1cc(C)nc2c(-c3ccc(C(C)C)cc3Br)cc(C#N)n12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCC(CCC)n1c(=N)c2cc(-c3ccc(C(C)C)cc3Br)c3nc(C)cc1n32
Temperature: 50 °C

Procedure:
To a suspension of 8-(2-bromo-4-isopropyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (321 mg) in ethanol (1.5 mL) was added conc. HCl (0.75 mL) and heated for 50° C. for 3 hours. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude product. To a solution of the crude product in ethyl acetate (2 mL) and ethanol (0.2 mL) was added 4M HCl/ethyl acetate (0.25 mL) under ice-cooling and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to provide 4-(2-bromo-4-isopropyl-phenyl)-6-methyl-1-(1-propyl-butyl)-1H-1,5,7b-triaza-cyclopenta[cd]inden-2-ylideneamine hydrochloride (350 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>S(Cl)(Cl)=O>[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[NH:14][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=1[Cl:1])#[N:18]
Reactant: N#Cc1ccccc1N
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Solvent: O=S(Cl)Cl
Product: N#Cc1ccccc1NC(=O)c1ccc([N+](=O)[O-])cc1Cl
Yield: 29.1 %

Procedure:
A solution of 2-chloro-4-nitrobenzoic acid (6.00 g, 29.8 mmol) in thionyl chloride (20 ml) was heated at reflux for 2.5 hours. The reaction was cooled, the excess thionyl chloride was evaporated in vacuo and the residue was azeotroped with toluene (2×25 ml). The residue was taken up in toluene (35 ml), 2-aminobenzonitrile (1.75 g, 14.8 mmol) was added and the reaction heated at reflux for 2 hours. The reaction was cooled, the solvent was removed in vacuo and the residue was absorbed onto silica gel. Purification by flash chromatography on silica gel, eluting with dichloromethane, yielded N-(2-cyanophenyl)-2-chloro-4-nitrobenzamide (1.30 g, 27% yield) as a pale yellow solid:
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH:23]C(C)(C)C)[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[CH:2]=[CH2:3].FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[C:15]3[N:22]=[C:21]([NH2:23])[S:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][C:10]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[CH:2]=[CH2:3]
Reactant: C=CCn1ccnc1-c1sc(-c2ncnc3sc(NC(C)(C)C)nc23)cc1-c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCn1ccnc1-c1sc(-c2ncnc3sc(N)nc23)cc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A mixture of 7-[5-(1-allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-2-thienyl]-N-(tert-butyl)[1,3]thiazolo[5,4-d]pyrimidin-2-amine (480 mg, 0.886 mmol), trifluoroacetic Acid (2.0 mL) and DCM (6.0 mL) was stirred at rt. After being stirred for 30 min, trifluoromethanesulfonic acid (0.118 mL, 1.33 mmol) was added to the mixture. The mixture was stirred at rt for 49 hours and then the solvent was removed in vacuo. To the residue, sat. NaHCO3 and EtOAc were added. After being stirred for 30 min, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was crystallized from EtOAc and Hexane to yield the title compound (352.9 mg, 82%) as a pale yellow solid. LCMS: (AA) ES+ 485, 487. NMR (400 MHz, d6-DMSO) δ: 8.66 (s, 1H), 8.55 (s, 1H), 8.43 (bs, 2H), 7.74 (d, J=2.0 Hz, 1H), 7.41 (dd, J=8.3, 2.3 Hz, 1H), 7.23-7.20 (m, 2H), 7.02 (d, J=1.3 Hz, 1H), 5.68-5.59 (m, 1H), 5.08-5.05 (m, 1H), 4.85-4.80 (m, 1H), 4.35 (d, J=5.5 Hz, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][C:22](=[O:38])[N:23]2[C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37].CI.Cl[C:42]1C=CC=CC=1C1C=C(O)C=C2C=1C=CC(=O)N2C1C(Cl)=CC=CC=1Cl>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]2[C:19]=1[CH2:20][CH:21]([CH3:42])[C:22](=[O:38])[N:23]2[C:30]1[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: O=c1ccc2c(-c3ccccc3Cl)cc(O)cc2n1-c1c(Cl)cccc1Cl
Reactant: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)C(C)C2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 1 mL of THF at −78° C. was added 130 μL of a 1M solution of lithium bis(trimethylsilyl)amide in THF, then a solution of 50 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-methoxyquinolin-2(1H)-one (INTERMEDIATE 6) in 2 mL of THF dropwise. The mixture was stirred for 30 min at −78° C.; then 57 mg of methyl iodide was added dropwise. The mixture was stirred 10 min at −78° C., then removed from the bath and allowed to warm to rt. The reaction was quenched by addition of 100 μL of MeOH, then poured into 10 mL of water and extracted with 2×10 mL of CH2Cl2. The combined organics were washed with 10 mL of brine, dried (MgSO4), and concentrated. The residue was purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-acetone, to yield a 1:1.5 mixture of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-hydroxyquinolin-2(1H)-one and the title compound. Mass spectrum (ESI) 446 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].NCCC[CH:18]([NH:22][CH3:23])[CH2:19][CH2:20][NH2:21]>CCOCC>[NH2:8][CH2:5][CH2:4][CH2:3][N:22]([CH3:23])[CH2:18][CH2:19][CH2:20][NH:21][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N+:9]=[N-:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CNC(CCN)CCCN
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOCC
Product: CN(CCCN)CCCNc1ccc(N=[N+]=[N-])cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
The reaction was carried out in the dark. A solution of 4-fluoro-3-nitrophenyl azide (0.91 g, 5.0 mmol, Sigma) in 10 ml dry ether was added dropwise with stirring to a solution of 3.2 ml of N-(3-aminopropyl-N-methyl-1,3-propanediamine (10 mmol, Aldrich) in 20 ml dry ether and the mixture was stirred for 30 min. The reaction was monitored using TLC (alumina, elution with methanol). The solvent was removed and the red oil was dissolved in 25 ml water, 25 ml 1.0M HaOH and then extracted into ethyl acetate (2×50 ml). The organic phase was dried over MgSO4 and the solvent then removed in vacuum. TLC: (I) alumina, eluted with methanol, Rf=0.43 (II) silica gel, elution with 1:9 AcOH/H2O, Rf between Rf=0.23 and Rf=0.55. 1H NMR (CDCl3 /TMS) δ: 1.45 (2H, broad s, NH), 1.64 (2H, m, CH2), 1.87 (2H, p, J=6.52 Hz, CH2), 2.25 (3H, s, CH3), 2.43 (2H, t, CH2), 2.47 (2H, t, J=6.46 Hz, CH2), 2.73 (2H, t, J=6.89 Hz, CH2), 3.37 (2H, m, J=6.61 Hz, CH2), 6.89 (1H, d, J=9.23 Hz, ArH), 7.10 (1H, dd, J=2.73, 9.20 Hz, ArH), 7.79 (1H, d, J=2.74 Hz, ArH), 8.47 (1H, m, NH). 13C NMR (CDCl3 /TMS) δ: 143.123 (Q), 131.24 (Q), 127.91 (CH), 127.16 (Q), 115.73 (CH), 115.44 (CH), 55.70 (CH2), 55.40 (CH2), 42.03 (CH2), 41.90 (CH3), 40.50 (CH2), 30.94 (CH2), 26.20 (CH2).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[CH2:7][CH:6]3[CH2:21][O:22][CH2:23][CH2:24][N:5]3[C:4]=2[N:3]=1.[NH:25]1[C:33]2[C:28](=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:25]1[C:33]2[C:28](=[C:29]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH2:12][C:13]5[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=5)[C:16]#[N:17])[CH2:7][CH:6]5[CH2:21][O:22][CH2:23][CH2:24][N:5]5[C:4]=4[N:3]=3)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: N#Cc1cccc(CN2CC3COCCN3c3nc(Cl)ncc32)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: N#Cc1cccc(CN2CC3COCCN3c3nc(-c4cccc5[nH]ccc45)ncc32)c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 3 using 3-((2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)methyl)benzonitrile (PREPARATION x14, 59 mg, 0.173 mmol), PdCl2(dppf) (6.32 mg, 8.63 μmol) and 1H-indol-4-ylboronic acid (55.6 mg, 0.345 mmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.16-3.32 (m, 3H), 3.55-3.66 (m, 2H), 3.92-4.06 (m, 2H), 4.07-4.16 (m, 1H), 4.57-4.78 (m, 3H), 6.96-7.07 (m, 1H), 7.20-7.32 (m, 1H), 7.40-7.48 (m, 1H), 7.52-7.69 (m, 4H), 7.71-7.84 (m, 2H), 7.85-7.93 (m, 1H), 11.45-11.59 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C25H22N6O, 423.19. found 423.3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[N+:18]([CH2:20]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:19]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:11][CH:20]=[N:18][CH:19]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ncc(-c2ccc3c(c2)OCO3)o1
Temperature: 70 °C
Yield: 81.6 %

Procedure:
To a stirred solution of benzo[1,3]dioxole-5-carbaldehyde (657 mg, 4.83 mmol) in methanol (15 mL) was added potassium carbonate (786 mg, 5.69 mmol, 1.3 equiv) and 1-isocyanomethanesulfonyl-4-methyl-benzene (863 mg, 4.38 mmol, 1 equiv). The resulting solution was heated to 70° C. under a nitrogen atmosphere for 3 hours, cooled to ambient temperature, and concentrated in vacuo. The residue was partitioned between methylene chloride and water, and the aqueous layer was extracted three times with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography (30% ethyl acetate in hexanes) provided 5-benzo[1,3]dioxol-5-yl-oxazole (676 mg, 82%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8](O)=[O:9])[CH3:2].C(=O)(O)[O-].[Na+].C=O.[ClH:18]>O.O1CCOCC1.C(O)C>[ClH:18].[CH2:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][OH:9])[CH3:2]
Reactant: CCc1nc[nH]c1C(=O)O
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CCc1nc[nH]c1CO

Procedure:
To a solution of 1.4 g (0.01 mol) of 4-ethylimidazole-5-carboxylic acid dissolved in a mixed solvent of 10 ml of water and 5 ml of 1,4-dioxane are successively added 2.52 g (0.03 mol) of sodium bicarbonate and 2 g of paraformaldehyde. The mixture is heated at 60°-70° C. for 4 hours. After completion of the reaction, the reaction mixture is concentrated to dryness, and the residue is extracted with acetone. The acetone extract is concentrated to give a viscous oil. The viscous oil is dissolved in ethanol, and dry HCl gas is passed to yield 4-ethyl-5-hydroxymethylimidazole hydrochloride as a crystal, m.p.138°-142° C.