Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH2:4][CH:5]([CH:16]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[CH3:36])[C:17](=[CH2:28])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:19])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:7])C.C(N(C(C)C)CC)(C)C.IC.[OH-].[K+]>C(#N)C>[F:35][C:31]1[C:30]([CH3:36])=[C:29]([CH:16]([C:17](=[CH2:28])[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[O:19])[C:5](=[CH2:4])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[O:7])[CH:34]=[CH:33][CH:32]=1
Reactant: C=C(C(=O)c1cccc(OC)c1)C(c1cccc(F)c1C)C(CN(C)C)C(=O)c1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CC#N
Product: C=C(C(=O)c1cccc(OC)c1)C(C(=C)C(=O)c1cccc(OC)c1)c1cccc(F)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a stirred solution of crude 2-((dimethylamino)methyl)-3-(3-fluoro-2-methylphenyl)-1,5-bis(3-methoxyphenyl)-4-methylenepentane-1,5-dione (91 g, 186 mmol) in acetonitrile (769 mL) was added diisopropylethylamine (65 mL, 376 mmol) followed by iodomethane (140 mL, 2.24 mol). The mixture was stirred at room temperature for 16 h. To this mixture was added 2 M KOH (307 mL, 614 mmol), and the temperature was raised to 75° C. for 16 h. The mixture was partitioned between dichloromethane and water. The layers were separated and the aqueous phase extracted with 500 mL dichloromethane. The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The residue was treated with 350 mL ether, isolated by filtration, and washed with 2×100 mL of ether. The ether layers were concentrated in vacuum to give 3-(3-fluoro-2-methylphenyl)-1,5-bis(3-methoxyphenyl)-2,4-dimethylenepentane-1,5-dione (63.8 g, 77% yield), (characterized by LCMS and 1H NMR). LRMS (M+H+) m/z=445.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]#[N:7].[C:8](OC)(=[O:16])[C:9]1[C:10](=[CH:12][CH:13]=[CH:14][CH:15]=1)[SH:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8](=[O:16])[N:7]=1
Reactant: COC(=O)c1ccccc1S
Reactant: N#Cc1nccs1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2nccs2)sc2ccccc12
Yield: 71.4 %

Procedure:
1,3-Thiazole-2-carbonitrile (0.32 g, 2.9 mmol) and methyl thiosalicylate (0.98 g, 5.8 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 2 hrs. After cooling, the precipitates were collected by filtration and recrystallized from diisopropyl ether-ethanol to give the titled compound (0.51 g, 70%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2OS(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH2:28]1[CH:32]([OH:33])[CH2:31][NH:30][CH2:29]1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:30]1[CH2:29][CH2:28][CH:32]([OH:33])[CH2:31]1
Reactant: OC1CCNC1
Reactant: COc1ccc2nccc(OS(=O)(=O)C(F)(F)F)c2n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(N3CCC(O)C3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1,1-Trifluoro-methanesulfonic acid 6-methoxy-[1,5]naphthyridin-4-yl ester (20 g, 65 mmol) was dissolved in DMF and treated with triethylamine (12 mL, 84 mmol) and DL-3-pyrrolidinol (7.4 g , 84 mmol.) The reaction mixture was stirred overnight at room temperature. The resulting reaction mixture was diluted with water (200 mL) and stirred for 1 h. The resulting precipitate was filtered off, washed with diethyl ether, and air dried to afford the title compound: LC-MS m/z 246 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH:18]([CH3:20])[CH3:19].[OH-:21].[Na+].[CH2:23]=O.Cl>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:23][OH:21])[CH:18]([CH3:20])[CH3:19]
Reactant: C=O
Reactant: [OH-]
Reactant: CC(C)C1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)C1(CO)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 48 h

Procedure:
To a solution of (1-oxo-2-isopropyl-6,7-dichloro-5-indanyloxy)acetic acid (3.17 g., 0.01 mole) and sodium hydroxide (0.5 g., 0.0125 mole) in water (90 ml.) is added aqueous formaldehyde (1 ml., 0.012 mole). The resulting solution is stirred at 20°-25° C. for 41/2 days and acidified with hydrochloric acid. There is obtained 2.5 g. of (1-oxo-2-hydroxymethyl-2-isopropyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 200°-202° C. after recrystallization from ethanol-water.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:11]1[S:12][C:13]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)([CH3:17])[C:14](=[O:16])[N:15]=1)[CH3:9].[OH-:26].[K+].Cl>CC(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:11]1[S:12][C:13]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH2:23])=[O:26])=[CH:24][CH:25]=2)([CH3:17])[C:14](=[O:16])[N:15]=1)[CH3:9]
Reactant: [OH-]
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1F
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(N)=O)cc2)S1)c1ccccc1F
Temperature: 85 °C
Reaction time: 1 h

Procedure:
The mixture of 4-(2-((S)-1-(2-fluorophenyl)ethylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)benzonitrile (0.080 g, 0.23 mmol) and potassium hydroxide (VWR, 0.17 g, 2.9 mmol) and t-BuOH (2 mL) was gradually heated to 85° C. The solid gradually dissolved and the mixture became a solution. After 1 h, the reaction was added to 2N HCl until the pH was ca. 7-8. The mixture was extracted three times with CH2Cl2, and the combined organic layers was dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography. MS: 372 (M+1), 370 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[CH:8](O)=[O:9]>>[CH:8]([NH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)=[O:9]
Reactant: O=CO
Reactant: Cc1cc(N)no1
Product: Cc1cc(NC=O)no1
Yield: 93.8 %

Procedure:
To 3-amino-5-methylisoxazole (10.0 g), 99% formic acid (47.0 g) is added, and the resultant mixture is refluxed for 1 hour with stirring. The reaction mixture is evaporated under reduced pressure to remove the formic acid. The residue is mixed with icy water (50 ml), and the precipitated crystals are filtered. The crystals are washed with water and dried under reduced pressure to give 3-formylamino-5-methylisoxazole (12.06 g). This substance is recrystallized from methanol to give crystals melting at 130.5° to 131° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:7][CH:8]=1.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:20]=[CH:21][C:22]=1[Cl:23].C(=O)([O-])[O-].[K+].[K+]>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:3][C:4]4[N:5]=[C:6]([CH2:9][N:10]5[CH2:15][CH2:14][O:13][CH2:12][CH2:11]5)[S:7][CH:8]=4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: ClCc1csc(CN2CCOCC2)n1
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(CN2CCOCC2)n1
Temperature: 70 °C
Reaction time: 21 h
Yield: 55.1 %

Procedure:
4-([4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}morpholine hydrochloride (0.024 g, 0.089 mmol) and 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (0.030 g, 0.089 mmol) were suspended in DMP (2 mL) and potassium carbonate (0.062 g, 0.449 mmol) was added. The mixture was stirred at 70° C. for 21 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC to afford the title compound as a colorless solid (0.026 g, 0.049 mmol, 54% yield). 1H NMR (400 MHz; CDCl3): 2.50 (br s, 1H); 2.57-2.64 (m, 4H); 3.75 (t, 4H); 3.84 (s, 2H); 3.96 (s, 3H); 5.28 (s, 2H); 7.09 (s, 1H); 7.31 (s, 1H); 7.37 (s, 1H); 7.43 (d, 1H); 7.60 (dd, 1H); 7.97 (d, 1H); 8.61 (s, 1H); MS (EI) for C24H23Cl2N5O3S: 532 (MH+).
Reaction SMILES: [C:1]([C:3]1([C:6]([OH:8])=O)[CH2:5][CH2:4]1)#[N:2].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Br.[Br:46][C:47]1[N:48]=[C:49]2[C:54]([NH:55][C@H:56]3[C@@H:60]([CH3:61])[CH2:59][NH:58][CH2:57]3)=[C:53]([C:62]([NH2:64])=[O:63])[CH:52]=[N:51][N:50]2[CH:65]=1>C(Cl)Cl>[Br:46][C:47]1[N:48]=[C:49]2[C:54]([NH:55][C@H:56]3[C@@H:60]([CH3:61])[CH2:59][N:58]([C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)=[O:8])[CH2:57]3)=[C:53]([C:62]([NH2:64])=[O:63])[CH:52]=[N:51][N:50]2[CH:65]=1
Reactant: N#CC1(C(=O)O)CC1
Reactant: C[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of 1-cyanocyclopropanecarboxylic acid (0.264 g, 2.380 mmol) in DCM (15.9 ml) were added DIEA (2.079 ml, 11.90 mmol), and BOP (1.263 g, 2.86 mmol). The solution was stirred at room temperature for 10 minutes, and 2-bromo-8-(((3S,4S)-4-methylpyrrolidin-3-yl)amino) imidazo[1,2-b]pyridazine-7-carboxamide, hydrobromide (from Step 2 of Example 1, 1.00 g, 2.380 mmol) was added. The reaction was stirred for 1 hr. After removal of the solvent, the crude product was purified by flash chromatography (ISCO, prepacked silica gel column eluting with 0-5% EtOAc/MeOH over 15 column volumes) to afford 2-bromo-8-(((3S,4S)-1-(1-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-yl)amino)imidazo[1,2-b]pyridazine-7-carboxamide as a white solid, 1.01 g, 2.336 mmol, 98% yield. ESI-MS (Method B): m/z 434.1 ([M+H]+). HPLC (Method B) Rt: 2.505 min.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:13]([NH:15][C@H:16]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@@H:17]([CH3:19])[OH:18])=[O:14])[CH2:11][OH:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CCOCC.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:13]([NH:15][C@H:16]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@@H:17]([CH3:19])[OH:18])=[O:14])[CH2:11][OH:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[F:42][C:43]([C:44]([OH:46])=[O:45])([F:48])[F:47]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Reaction time: 1 h

Procedure:
46.1 g of BOC-Leu-Ser-Thr-OBzl are dissolved in 92.5 ml of 90% strength trifluoroacetic acid and left for 1 hour at 20° C. Thereafter dry ether (925 ml) is added whilst stirring, and the mixture is stirred for one hour at 0° C. and left to stand overnight at -10° C. The resulting precipitate is filtered off, washed three times with dry ether and dried in vacuo over sodium hydroxide. Melting point 168°-171° C.; Rf7 = 0.80 (on silica gel).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH2:20][NH2:21].[N:22]([O-])=O.[Na+]>O.C(O)(=O)C>[CH3:18][C:16]([CH3:19])([OH:17])[CH2:15][N:14]1[C:10]2[C:9]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:20]3[N:21]=[N:22][N:3]=[C:2]3[C:11]=2[N:12]=[CH:13]1
Reactant: O=N[O-]
Reactant: NN
Reactant: CC(C)(O)Cn1cnc2c(Cl)nc3ccccc3c21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(O)Cn1cnc2c1c1ccccc1n1nnnc21

Procedure:
A suspension of 4-chloro-α,α-dimethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (1.0 g, 3.6 mmole, U.S. Pat. No. 4,689,338 Example 189 Part D) in hydrazine (3 mL, 6.9 mmole) was heated on a steam bath for 1 hour then diluted with water. The resulting precipitate was isolated by filtration. The solid was dissolved in a mixture of acetic acid (2 mL) and water (15 mL) then combined with a solution of sodium nitrite (0.5 g) in water. The resulting precipitate was isolated by filtration, washed with water and dried to provide 0.71 g of α,α-dimethyl-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline-6-ethanol as a white solid, m.p. 246-247° C. (shrunk at 230° C.). Analysis: Calculated for C14H14N6O: %C, 59.56; %H, 5.00; %N, 29.77; Found: %C, 59.45; %H, 5.06; %N, 29.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:12]=1.S(Cl)([Cl:32])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15]([Cl:32])=[O:16])[N:12]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CNc2nc(CCC(=O)O)nc3sc4ccccc4c23)cc1Cl
Solvent: ClCCl
Product: COc1ccc(CNc2nc(CCC(=O)Cl)nc3sc4ccccc4c23)cc1Cl

Procedure:
1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]propionic acid and 1.2 equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. The solvent is removed, affording 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]propionyl chloride.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([NH2:21])=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:11]=1)=[O:5])C.Cl.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:4]([C:6]1[C:7]([NH2:21])=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:14]=2)[CH:11]=1)=[O:5]
Reactant: CN
Reactant: CCOC(=O)c1cn2cc(-c3ccccc3)nc2cc1N
Agent: Cl
Product: CNC(=O)c1cn2cc(-c3ccccc3)nc2cc1N
Yield: 60 %

Procedure:
According to the procedure described in step 1 of example 18 7-amino-2-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid ethyl ester was reacted with methylamine hydrochloride to give the title compound as off-white solid (60%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2([C:23]([O:25]C(C)(C)C)=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].Cl.CN(C)CCCN=C=NCC.[OH:42][N:43]1C2C=CC=CC=2N=N1.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1O.CN1CCOCC1>CN(C)C=O>[O:2]1[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[N:52]=[C:1]1[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([C:17]2([C:23]([NH:43][OH:42])=[O:25])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: Nc1ccccc1O
Reactant: CC(C)(C)OC(=O)C1(S(=O)(=O)c2ccc(OCCCC(=O)O)cc2)CCOCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NO)C1(S(=O)(=O)c2ccc(OCCCc3nc4ccccc4o3)cc2)CCOCC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
Part A. To a solution of 4-[[4-(3-carboxypropoxy)phenyl]sulfonyl]tetrahydro-2H-pyran-4-carboxylic acid, 1,1-dimethylethyl ester (3.0 g, 7.0 mmol) in N,N-dimethylformamide (14 mL) was added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.88 g, 9.8 mmol) and 1-hydroxybenzotriazole (1.32 g, 9.8 mmol). The resulting suspension became a clear amber solution after stirring at 50° C. for 1.5 hr. The reaction was then treated with 2-aminophenol (0.76 g, 7.0 mmol), followed by N-methylmorpholine (2.3 mL, 21.0 mmol). The reaction was stirred at 50° C. overnight. After 21 hr, the reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated sodium bicarbonate solution, water, 1:1 solution of water:brine, and brine; dried over sodium sulfate; filtered; and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate/hexanes to afford 2.98 g (82%) of the amide as an amber oil. ESMS m/z=542 [M+Na]+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C1CCCCC1.[CH3:18][CH:19]([SH:23])[CH:20]([SH:22])[CH3:21].C(=O)C1C=CC=CC=1>O>[CH3:21][CH:20]1[CH:19]([CH3:18])[S:23][CH:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:22]1
Reactant: CC(S)C(C)S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Solvent: O=Cc1ccccc1
Product: CC1SC(c2ccccc2)SC1C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Into a 100 ml reaction flask equipped with thermometer, reflux condenser and magnetic stirring bar and hot plate with magnetic stirring apparatus is placed 0.5 grams of para-toluenesulfonic acid, 5.0 ml cyclohexane and 6.1 grams (0.05 moles) of 2,3-butanedithiol. Over a period of 25 minutes, 5.3 grams (0.05 moles) of benzaldehyde is added to the reaction mass with stirring. The reaction mass is then heated to reflux with stirring and refluxed for a period of 9.5 hours while taking off water of reaction. At the end of the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The resulting filtrate is distilled on a Microvigreux column yielding the following three fractions:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH3:40])[CH2:26][CH2:27][N:28]([S:36]([CH3:39])(=[O:38])=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>>[CH3:24][N:25]([CH3:40])[CH2:26][CH2:27][N:28]([C:29]1[CH:30]=[CH:31][C:32]([NH:35]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:33][CH:34]=1)[S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Product: CC/C(Nc1ccc(N(CCN(C)C)S(C)(=O)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:8]/[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][O:12][C:13]2=[O:18].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:27][O-:28].[Na+]>C(OCC)(=O)CC>[O:28]=[C:27]1[C:10]2[C:14]([C:13]([O:12][CH3:11])=[O:18])=[CH:15][CH:16]=[CH:17][C:9]=2[NH:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[O-]
Reactant: O=Cc1ccccc1
Reactant: O=C1OCc2c(/N=C/c3ccccn3)cccc21
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccccn1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.2 %

Procedure:
4-Aminoisobenzofuran-1(3H)-one (600 mg, 4 mmol), picolinaldehyde (856 mg, 8 mmol) and 1 g of MgSO4 were added into 40 mL of dichloromethane and the mixture was stirred under reflux overnight, then the mixture was evaporated under reduced pressure and the residues was dried in vacuum. 476 mg of (E)-4-(pyridin-2-ylmethyleneamino) isobenzofuran-1(3H)-one was obtained. A mixture of (E)-4-(pyridin-2-ylmethyleneamino) isobenzofuran-1(3H)-one (476 mg, 2 mmol), benzaldehyde (212 mg, 2 mmol), sodium methanolate (432 mg, 8 mmol) and ethyl propionate (40 mL) was stirred at room temperature overnight. Then the resulting mixture was evaporated under reduced pressure and extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20:1 to 5:1) to give 30 mg of methyl 4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate; yield 5%. LC-MS (ESI) m/z: 459 (M+1)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[F:17][C:18]1([F:30])[O:22][C:21]2[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:20]=2[O:19]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:27]([C:25]2[CH:24]=[CH:23][C:21]3[O:22][C:18]([F:30])([F:17])[O:19][C:20]=3[CH:26]=2)[OH:28])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccc2c(c1)OC(F)(F)O2
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc3c(c1)OC(F)(F)O3)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 2,2-difluoro-benzo[1,3]dioxol-5-carboxylic acid
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C([O:21][C:22](=O)[C:23](=[O:34])[CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)C>C(O)C>[OH:34][C:23]1[C:22](=[O:21])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:15]([C:14]2[CH:17]=[CH:18][C:11]([CH3:10])=[CH:12][CH:13]=2)[C:24]=1[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1
Reactant: NCCCn1ccnc1
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Solvent: CCO
Product: Cc1ccc(C2C(c3c[nH]c4ccccc34)=C(O)C(=O)N2CCCn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 4-Methyl-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3-(1H-Indol-3-yl)-2-oxo-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [OH:1][C:2]1([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:33])[CH:17]=3)=[CH:14][N:15]=2)[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]1([CH3:10])[CH3:9].Cl.[NH2:35][OH:36]>N1C=CC=CC=1>[OH:36]/[N:35]=[C:4]1/[C:3]([CH3:9])([CH3:10])[C:2]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:33])[CH:17]=3)=[CH:14][N:15]=2)([OH:1])[CH2:7][CH2:6][CH2:5]/1
Reactant: NO
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCCC(=O)C3(C)C)s2)c1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC/C(=N\O)C3(C)C)s2)c1
Temperature: 60 °C
Yield: 96.8 %

Procedure:
A mixture of the product of Step 2 (300 mg, 0.63 mmol) and hydroxylamine hydrochloride (87 mg, 1.26 mmol) in pyridine (3 mL) was heated to 60° C. for 1 h, concentrated, and purified by flash chromatography to afford the title compound (301 mg, 0.61 mmol). MS ESI: [M+H]+ m/z 492.2. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.26 (s, 1H), 8.84 (d, J=4.9, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.48 (s, 1H), 7.29 (d, J=4.9, 1H), 7.16 (s, 1H), 5.97 (s, 1H), 2.82 (m, 1H), 2.33 (s, 3H), 2.24:2.38 (m, 2H), 1.65-1.85 (m, 3H), 1.08 (s, 3H), 1.07 (s, 3H). rhSYK activity=+++