Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]1([CH:24]2[O:28][C:27](=[O:29])[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[C:18]1([CH:24]2[O:28][CH:27]([OH:29])[CH2:26][CH2:25]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCC(c2ccccc2)O1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: OC1CCC(c2ccccc2)O1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
4.1 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise to a solution of 1.0 g of 5-phenyloxolane-2-one in 12 mL of toluene at −60° C., and the obtained mixture was then stirred for 30 minutes. Thereafter, 1 mL of methanol was added to the reaction mixture, and thereafter, 40 mL of a 20% potassium sodium tartrate aqueous solution was then added to the mixture at room temperature. The thus obtained mixture was stirred for 1 hour. Thereafter, the water layer was removed, and the solvent was then distilled away under reduced pressure, so as to obtain 0.98 g of 5-phenyloxolan-2-ol in the form of a colorless oily product.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[S:45]1[CH:49]=[N:48][N:47]=[C:46]1[NH2:50].[H-].[Na+]>CN(C=O)C>[S:45]1[CH:49]=[N:48][N:47]=[C:46]1[NH:50][C:37](=[O:38])[C:36]([NH:35][C:33]([C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:19]3[O:18][C:17]([C:14]4[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=4)=[C:21]([C:22]([NH:23][CH3:24])=[O:25])[C:20]=3[CH:26]=2)[CH:44]=[CH:43][CH:42]=1)=[O:34])([CH3:40])[CH3:41]
Reactant: Nc1nncs1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4nncs4)c3)cc12
Reaction time: 8 h
Yield: 47 %

Procedure:
DIEA (44 μL, 0.253 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (40 mg, 0.084 mmol), 1,3,4-thiadiazol-2-amine (17.05 mg, 0.169 mmol) in DMF (843 μL) at rt. NaH (17 mg, 0.422 mmol) was added, and the slurry became a clear solution after 10 min. It was allowed to stir overnight. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (22 mg, 45%). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.44 (1H, br. s.), 9.14 (1H, br. s.), 8.78 (1 H, br. s.), 8.47-8.57 (1H, m), 8.30 (1H, s), 7.97-8.04 (2H, m), 7.88-7.95 (3 H, m), 7.75-7.84 (2H, m), 7.61 (1H, t, J=7.78 Hz), 7.41 (2H, t), 2.86 (3H, d, J=4.88 Hz), 1.57 (6H, s). LC-MS retention time: 1.57 min; m/z (MH+): 488. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=11.23 min, purity=97%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=10.56 min, purity=96%.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4]COC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[CH3:26][C:27]1[CH:28]=[C:29]([OH:44])[CH:30]=[CH:31][C:32]=1[NH:33][C:34]1[S:35][C:36]([C:39]2[CH:43]=[CH:42][S:41][CH:40]=2)=[CH:37][N:38]=1.Cl.ClCCN(C)C>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:44][C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:34]2[S:35][C:36]([C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)=[CH:37][N:38]=2)=[C:27]([CH3:26])[CH:28]=1
Reactant: Cc1cc(O)ccc1Nc1ncc(-c2ccsc2)s1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: CN(C)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(OCCN(C)C)ccc1Nc1ncc(-c2ccsc2)s1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 3-methyl-4-(5-thiophen-3-yl-thiazol-2-ylamino)-phenol and using (2-chloroethyl)-dimethylamine hydrochloride. The title compound: ES-MS: 360.0 [M+H]+; single peak at tR=2.78 min (System 2); Rf=0.32 (CH2Cl2/MeOH, 75/25).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][OH:17].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>CN(C)C=O.O>[Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][O:17][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCOc1cc(CO)c(Br)c(OCOC)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(COCc2ccccc2)c(Br)c(OCOC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
The above-obtained [2-bromo-3,5-bis(methoxymethoxy)phenyl]methanol (3.5 g, 11 mmol) was dissolved in N,N-dimethylformamide (20 mL) and cooled to 0° C. The obtained solution was added with 60% sodium hydride-oil dispersion (0.59 g, 15 mmol) and benzyl bromide (2.0 mL, 17 mmol), followed by stirring at a room temperature for 1 hour. The reaction mixture was added with methanol and water and extracted with chloroform 3 times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1 to 10/1) to obtain 2-bromo-1-(benzyloxymethyl)-3,5-bis(methoxymethoxy)benzene (3.2 g, 70%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18].C(=O)([O-])[O-].[K+].[K+]>[Cu].O>[CH3:18][C:12]1[CH:11]=[C:16]([CH:15]=[CH:14][CH:13]=1)[O:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1ccccc1
Reactant: Cc1cccc(O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(OCC(=O)c2ccccc2)c1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
A mixture of 50 g (0.324 mol) of 2-chloroacetophenone, 104.8 g (0.97 mol) of m-cresol, 45 g (0.326 mol) of potassium carbonate and 1 g of copper is heated at 120° C. for 16 hours. After cooling it is poured into water and extracted twice with methyl tert-butyl ether (MTB ether). The ether phase is washed five times with concentrated sodium hydroxide solution and then twice with water, dried and concentrated. 67.2 g (92% yield) of 2-(3-methylphenoxy)acetophenone remain as yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([C@H:19]1[CH2:24][C@H:23]([OH:25])[CH2:22][CH2:21][O:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:6]([C@H:19]1[CH2:24][C@H:23]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][CH2:21][O:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCO[C@@H](C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
Methanesulfonyl chloride (0.62 g, 5.41 mmol) in dry methylene chloride (10 ml) was added dropwise to a mixture of trans-2-diphenylmethyl-4-hydroxypyran 3a (0.73 g, 2.70 mmol), triethylamine (0.41 g, 4.06 mmol) in methylene chloride (10 ml) and was cooled to 0° C. After one hour, the reaction was gradually allowed to reach room temperature over a period of four hours. Additional methylene chloride (20 ml) was added to the reaction mixture, and the mixture was washed in turn with saturated aqueous sodium bicarbonate, brine and water, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and purification by flash chromatography gave compound 4a (0.93 g, 99.9% yield) as an oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].Cl[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(O)CC(C)C.Cl[Cu]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14](=[O:15])[CH3:13]
Reactant: O=C(CCl)c1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Product: CC(=O)c1ccccc1Oc1ccc2ccccc2c1

Procedure:
A mixture of 2-naphthol (0.035 mole), 2-chloroacetophenone (0.026 mole), potassium carbonate (0.040 mole) and CuCl (100 mg) in isoamyl alcohol (3 ml) was refluxed overnight. Then the reaction mixture was filtered and the precipitate was washed a few times with ethyl acetate and then the filtrate was washed with a 10% aqueous sodium hydroxide solution and water. The solvent was removed by evaporation under reduced pressure and the residue was distilled under high vacuum to give a pure product in the form of a light yellow liquid.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>C(O)C>[F:12][C:13]([F:20])([F:19])[C:14]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][C:3]1=[O:11])=[O:15]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1Cc2ccccc2N1
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2ccccc2C1C(=O)C(F)(F)F
Reaction time: 1 h
Yield: 57.6 %

Procedure:
Sodium (3.0 g, 0.13 mole) was dissolved in 150 ml of ethanol, and then 13.3 g (0.10 mole) of 2-oxindole was added at room temperature, with stirring. The resulting mixture was cooled in an ice-bath and 18.5 g (0.13 mole) of ethyl 2,2,2-trifluoroacetate was added rapidly with stirring. The cooling bath was removed, and the reaction mixture was heated to the reflux temperature of the solvent and held there for 1 hour. At this point, the reaction mixture was cooled and the bulk of the solvent was removed by evaporation in vacuo. The residue was added to 300 ml of water, to which was then added 100 ml of concentrated hydrochloric acid. The resulting mixture was cooled in an ice-bath and then the solid was collected by filtration. The latter solid was dissolved in ethyl acetate, and the ethyl acetate solution was washed with saturated sodium chloride and then dried using magnesium sulfate. The dried solution was evaporated in vacuo, and the residue was recrystallized from toluene, to give 13.2 g of the title compound as yellow crystals, m.p. 183.5°-184.5° C.
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[CH2:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>CC#N.CCOCC>[F:2][C:3]1([F:8])[CH2:7][CH2:6][N:5]([S:21]([CH:20]=[CH2:19])(=[O:23])=[O:22])[CH2:4]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.6 %

Procedure:
A solution of 3,3-difluoropyrrolidine hydrochloride (0.3 g, 2.1 mmol, Matrix) and DIEA (0.37 mL, 2.1 mmol) in MeCN (5 mL) was stirred at about 50° C. for about 30 min. The reaction was cooled to ambient temperature and concd under reduced pressure. The solid was dissolved in MeCN (2 mL) and a solution of 2-chloroethanesulfonyl chloride (0.22 mL, 2.1 mmol) in Et2O (3 mL) was added at about −78° C. and stirred for about 2 h. To the reaction mixture was added DIEA (0.6 mL, 3.4 mmol) and stirred for about 1 h. The reaction was warmed to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between DCM (5 mL) and water (2×2 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concd under reduced pressure to give crude 3,3-difluoro-1-(vinylsulfonyl)pyrrolidine (0.11 g, 27%) which was used without further purification: LC/MS (Table 1, Method b) Rt=2.04 min; MS m/z: 198 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14]O)=[CH:5][CH:4]=1.O1CCCC1.S(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][CH2:14][C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(-c2oncc2CO)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CSc1ccc(-c2oncc2CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a mixture of 5-(4-methylthiophenyl)-4-isoxazolylmethanol (7.35 g), tetrahydrofuran (20 ml) and toluene (80 ml) was added dropwise thionyl chloride (5.93 g) at 0° C. and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 4-chloromethyl-5-(4-methylthiophenyl)isoxazole (7.70 g, yield 97%) was obtained as crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio) and recrystallized from diethyl ether-hexane to give a colorless prism. melting point: 73–74° C.
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:10]=1.[OH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:11]2[CH:10]=[C:9]([C:35]3[CH:36]=[CH:37][C:32]([CH2:31][OH:30])=[CH:33][CH:34]=3)[CH:21]=[CH:20][C:12]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Nc1ccc(F)cc1
Reactant: OCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(CO)cc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 29.8 %

Procedure:
To toluene 4.0 mL solution of tert-butyl 4-bromo-2-(4-fluoroanilino)benzoate 0.20 g were added ethanol 1.2 mL, water 0.60 mL, 4-(hydroxymethyl)phenylboronic acid 91 mg, sodium hydrogen carbonate 0.12 g and tetrakis(triphenylphosphine)palladium(0) 35 mg at room temperature, and it was heated and refluxed under nitrogen atmosphere for 6 hours. After the reaction mixture was cooled to room temperature, water was added to it. The organic layer was separated and collected, dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=2:1] to give tert-butyl 2-(4-fluoroanilino)-4-(4-(hydroxymethyl)phenyl)benzoate 64 mg of a pale yellow solid.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[C:26]4[NH:29][C:30]([C:32]4[C:33](=[O:47])[N:34]([CH2:38][C:39]5[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=5)[CH:35]=[CH:36][CH:37]=4)=[O:31])=[CH:21][CH:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(Cl)Cl.C[O-].[Na+]>CO>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[CH:24][CH:25]=[C:26]3[NH:29][C:30]([C:32]3[C:33](=[O:47])[N:34]([CH2:38][C:39]4[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=4)[CH:35]=[CH:36][CH:37]=3)=[O:31])=[CH:21][CH:20]=2)=[CH:11]1
Reactant: O=C(Nc1cccc2ccc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)cc12)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cccc2ccc(-c3c[nH]c4ncccc34)cc12)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [7-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-naphthalen-1-yl]-amide (0.035 g, 0.000054 mol;) was dissolved in Methylene chloride (2 g, 0.02 mol;) and 0.5 M of Sodium methoxide in methanol (2 mL) then heated at 80 degrees for 1 hour. LC-MS showed the appearance of product at 1.64 506.91. The crude was concentrated and dissolved in a mixture of methanol and DMSO then directly injected onto the gilson for purification. The pure fractions were combined and concentrated to give the product. ES (+) MS m/e=506.91; (400 MHz, DMSO-d6) δ ppm 5.43 (s, 2H), 6.76 (t, 1H, J=8 Hz), 6.98 (d, 1H, J=8 Hz), 7.08 (m, 1H), 7.25 (m, 1H), 7.36-7.6 (m, 3H), 8.01 (d, 1H, J=8 Hz), 8.14 (s, 1H), 8.27 (m, 2H), 8.35 (m, 2H), 8.49 (s, 1H), 8.60 (m, 1H), 8.80 (d, 1H, J=8 Hz), 12.10 (s. 1H), 12.63 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[Cl:12][Sn]Cl>Cl>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[C:4]([Cl:12])[N:3]=1
Reactant: Cl[Sn]Cl
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Product: Nc1cc(Cl)c(Cl)nc1N

Procedure:
The compounds of the present invention may be prepared as follows. It has been reported that reduction of 2-amino-5-chloro-3-nitropyridine (2) by SnCl2 in concentrated HCl resulted in both reduction of the nitro group to an amino group as well as chlorination of the pyridine ring to give 2,3-diamino-5,6-dichloropyridine (4) as the only isolated product (Israel & Day, J. Org. Chem. 24:1455-1460 (1959)). We found that reduction of 2 under identical conditions as reported gave a mixture of 2,3-diamino-5-chloropyridine (3) and 2,3-diamino-5,6-dichloropyridine (4) in a ratio of 4:1. The mixture could not be separated by crystallization in water. It could be separated by preparative TLC and chromatography. Cyclization of 3 with oxalic acid gave 8-NQX 5 and cyclization of 4 with oxalic acid gave 8-NQX 6. 6,7-dichloro-8-NQX 6 was found to have a Ki of about 200 nM, which is similar to the corresponding 6,7-dichloro-QX. 6-Chloro-8-NQX 5 also was found to be about as active as the corresponding 6-chloro-QX. 6-Bromo-7-methyl-8-NQX (8) was found to have a Ki of about 200 nM. 6-NQX 11 and 6,8-diN-QX 13 also were found to be about as active as QX. ##STR8##
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][O:5][C@@H:4]2[C@H:7]([O:10][C:11]3[NH:12][C:13]4[C:14]([N:28]=3)=[N:15][C:16]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[C:17]([Cl:19])[CH:18]=4)[CH2:8][O:9][C@H:3]12.[CH2:29](N)[CH2:30][NH2:31].C(=S)=S>>[Cl:19][C:17]1[CH:18]=[C:13]2[NH:12][C:11]([O:10][C@H:7]3[C@H:4]4[O:5][CH2:6][C@@H:2]([OH:1])[C@H:3]4[O:9][CH2:8]3)=[N:28][C:14]2=[N:15][C:16]=1[C:20]1[CH:27]=[CH:26][C:23]([C:24]2[NH:31][CH2:30][CH2:29][N:25]=2)=[CH:22][CH:21]=1
Reactant: NCCN
Reactant: N#Cc1ccc(-c2nc3nc(O[C@@H]4CO[C@H]5[C@@H]4OC[C@H]5O)[nH]c3cc2Cl)cc1
Solvent: S=C=S
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(C4=NCCN4)cc3)c(Cl)cc2[nH]1
Temperature: 50 °C

Procedure:
A vial was charged with 4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydro-furo[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]benzonitrile (24.8 mg, 0.062 mmol), ethylenediamine (0.5 ml, 7.46 mmol), and carbon disulfide (5 μl, 0.083 mmol). The reaction mixture was heated to 50° C. for 19 h. The reaction mixture was cooled to room temperature before being concentrated under reduced pressure to 0.1 mL. The concentrated reaction mixture was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 0%-30% acetonitrile/water+0.05% TFA gradient, followed by a 30% acetonitrile/water+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C21H20ClN5O4 441.12 observed m/e: 442.19 (M+H)+ (Rt 0.25/2 min); 1H NMR δ (ppm) (CD3OD): 7.95 (s, 4H), 7.85 (s, 1H), 5.54 (qt, J=5.3 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 4.46 (t, J=5.0 Hz, 1H), 4.26-4.30 (m, 1H), 4.16 (dd, J=5.7 Hz, J=10.3 Hz, 1H), 4.14 (s, 4H), 4.11 (dd, J=4.7 Hz, J=10.2 Hz, 1H), 3.89 (dd, J=6.8 Hz, J=8.1 Hz, 1H), 3.59 (t, J=8.6 Hz, 1H).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][CH:13]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=O.S(Cl)(Cl)=O.[Br:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[C:33]([F:38])[CH:32]=1.N1C=CC=CC=1>ClCCl>[CH:24]1[C:25]2[CH:13]([CH2:12][O:11][C:9]([N:1]3[CH2:8][CH2:7][CH2:6][C@@H:2]3[C:3](=[O:5])[NH:35][C:34]3[CH:36]=[CH:37][C:31]([Br:30])=[CH:32][C:33]=3[F:38])=[O:10])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccc(Br)cc1F)[C@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Fmoc-D-Pro (1.2 g, 3.56 mmol) was suspended in 10 mL dry dichloromethane (DCM), cooled in an ice water bath, and then thionyl chloride (0.78 mL, 10.7 mmol) was added slowly. After addition was complete, the ice water bath was removed and the reaction was stirred at ambient temperature overnight. The solution was concentrated to dryness. The oil was redissolved in 20 mL dry DCM under an Ar atmosphere, and 4-bromo-2-fluoroaniline (0.81 g, 4.3 mmol) was added, followed by dry pyridine (0.87 mL, 10.7 mmol). The mixture was stirred at ambient temperature for 4 hours, then concentrated. The residue was redissolved in 100 mL EtOAc, washed with 1M HCl (3×50 mL), brine (2×50 mL), dried with MgSO4, filtered and concentrated to yield the title product as a sticky oil. (1.8 g, 99%) APCI (AP+): 509.2, 511.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl.C([O-])(=O)C.[Na+]>O.O1CCOCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:17]([CH3:16])(=[O:19])=[O:18])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 81.4 %

Procedure:
To a 25 mL round-bottomed flask was added was added 5-bromo-2-chloropyridin-3-amine (1.50 g, 7.23 mmol, Asymchem, Morrisville, N.C.), pyridine (20.0 mL, 248 mmol) and methanesulfonyl chloride (2.8 mL, 36 mmol). The mixture was stirred at 25° C. for 48 h. The mixture was then concentrated in vacuo and the residue was treated with methanol (30 mL), 1,4-dioxane (30 mL) and potassium carbonate (10 g, 72 mmol) and stirred at 60° C. for 5 h. The mixture was poured into water (300 mL) and acidified to pH 5 using conc HCl. To the solution was added pH 4.8 buffer (100 mL, Teknova, 3 M sodium acetate solution pH adjusted to 4.8) and the solution was extracted with EtOAc (3×100 mL). The combined extracts were washed with water (1×100 mL), brine (100 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (5 to 60% EtOAc/hexane) afforded a semi-solid that was washed with 10% EtOAc/hexane to afford the title compound as a tan solid (1.68 g, 81%). MS (ESI, positive ion) m/z: 285 (M(79Br)+1), 287 (M(81Br)+1).