Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([CH3:14])[CH2:3][O:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][N:6]=1>C1COCC1.CO.[Pd]>[F:1][CH:2]([CH3:14])[CH2:3][O:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CC(F)COc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(F)COc1ncccc1N
Reaction time: 4 h

Procedure:
2-(2-fluoropropoxy)-3-nitropyridine (199.97 mg) was dissolved in a mixture of THF (10 ml) and methanol (5 ml). Pd/C (20 mg) was added and the mixture was hydrogenated at room temperature for 4 h and 3 bar. The mixture was concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11]C)=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[NH2:15][CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19].C(N(CC)CC)C>>[CH2:18]([CH:17]([CH2:20][CH3:21])[CH2:16][NH:15][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)[CH3:19]
Reactant: CCC(CC)CN
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(CC)CC
Product: CCC(CC)CNc1nc(SC)ncc1C(=O)OC
Yield: 102.6 %

Procedure:
Ethyl 4-chloro-2-methylthio-5-pyrimidinecarboxylate (0.40 g, 1.72 mmol) was reacted with 1-amino-2-ethyl butane (0.175 g, 1.72 mmol) and triethylamine (0.60 mL, 4.32 mmol) at ambient temperature for 18 hours. The reaction was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and the concentrated to give the title compound (0.50 g, 98%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:18]=2[N:19]=1.CN.[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:31][NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3cc(OC(F)(F)F)ccc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(OC(F)(F)F)ccc3s1)n2C
Yield: 63.9 %

Procedure:
1-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid methylamide (27 mg) was prepared by following General Procedure F using 1-methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboxylic acid (41 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 423.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[CH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[BrH:34].Br.[NH2:36][CH2:37][C:38]1[O:42][C:41]([C:43]([O:45][C:46]2[CH:55]=[CH:54][C:53]3[C:48](=[CH:49][CH:50]=[C:51]([C:56](=[NH:58])[NH2:57])[CH:52]=3)[CH:47]=2)=[O:44])=[CH:40][CH:39]=1.C1(NC(NC2CCCCC2)=O)CCCCC1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[BrH:34].[C:1]([O:5][C:6]([CH:8]=[CH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:36][CH2:37][C:38]2[O:42][C:41]([C:43]([O:45][C:46]3[CH:55]=[CH:54][C:53]4[C:48](=[CH:49][CH:50]=[C:51]([C:56](=[NH:57])[NH2:58])[CH:52]=4)[CH:47]=3)=[O:44])=[CH:40][CH:39]=2)=[O:16])=[CH:17][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)O)cc1
Reactant: N=C(N)c1ccc2cc(OC(=O)c3ccc(CN)o3)ccc2c1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)NCc2ccc(C(=O)Oc3ccc4cc(C(=N)N)ccc4c3)o2)cc1
Yield: 40.9 %

Procedure:
In 15 ml of pyridine and 4 ml of N,N-dimethylacetamide (hereinafter abbreviated as DMA) were dissolved 2.0 g of 4-(2-t-butoxycarbonylvinyl)benzoic acid and 0.1 g of 4-dimethylaminopyridine (hereinafter abbreviated as DMAP) and the solution was stirred while cooling with ice. Then, 1.99 g of N,N'-dicyclohexylcarbodiimide (hereinafter abbreviated as DCC) was added to the mixture obtained above. The mixture was stirred at the same temperature for 30 minutes and then 3.49 g of 6-amidino-2-naphthyl 5-aminomethylfuran-2-carboxylate dihydrobromide was added thereto. The reaction mixture was stirred for 3 hours while cooling with ice and then overnight at room temperature, and the precipitated N,N'-dicyclohexylurea (hereinafter abbreviated as DCU) was separated by filtration and washed with a small amount of DMA. The filtrate was added dropwise to 800 ml of ether while stirring and cooling with ice. After the precipitate formed had sedimented, the supernatant was removed by decantation, then 400 ml of acetone was added to the residue and the mixture was stirred for 1 hour at room temperature. After repeating the procedure twice, the precipitated crystals were collected by filtration to obtain 1.88 g of the intended product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[OH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1.CCO.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>[OH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(Br)cn1
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: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1ccc(-c2ccc(CO)cc2)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
To a solution of 5-bromopicolinaldehyde (0.7 g, 3.76 mmol) in toluene (8 mL) and EtOH (6 mL) was added (4-(hydroxymethyl)phenyl)boronic acid (0.68 g, 4.516 mmol), 2M Na2CO3 (5.6 mL, 11.3 mmol) and Pd(PPh3)4 (0.2 mg, 0.188 mmol) under argon. The mixture was degassed and heated to 100° C. and stirred for 2 h. After completion of the reaction by monitoring with TLC (60% EtOAc\hexane), the resulting mixture was filtered with Celite® reagent and the filtrate was separated. The filtrate was concentrated, extracted with EtOAc (2×100 mL), washed with water (100 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by a Biotage Isolera® One column purifier (silica gel 100-200μ) using 38% ethyl acetate in hexane to provide a yellow solid (0.6 g, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.14 (d, 1H), 8.306 (dd, 1H), 7.98 (d, 1H), 7.80 (d, 2H), 7.47 (d, 2H), 5.25 (s, 1H), 4.56 (d, 2H); LC-MS: m/z 214.3 [M+H]+.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C@H:11]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:18]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([S:7]([CH2:10][C@H:11]2[N:15]([CH3:18])[C:14](=[O:16])[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)C[C@@H]2CCC(=O)N2C)cc1
Temperature: -70 °C
Yield: 40 %

Procedure:
(5S)-5-(p-Toluenesulphonylmethyl)-2-pyrrolidinone (0.8 g, 3 mmol) was dissolved in dry THF and cooled to −70° C. Lithium diisopropylamide was slowly added and the reaction stirred for 20 minutes before addition of methyl iodide (2 ml, excess). The reaction was allowed to warm to ambient temperature for over 2 hours. The reaction was partitioned between ethyl acetate and water, the organic layer separated, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography eluting from methylene chloride to 5% methanol/95% methylene chloride and the product evaporated to give (5S)-5-(p-toluenesulphonyl-methyl)-1-methyl-2-pyrrolidinone (340 mg, 40%) as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][N:10]=[C:11]=[S:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.C(OCC)(=O)C>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[S:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nccs1
Reactant: S=C=NCCCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCCc1ccccc1)Nc1nccs1
Temperature: 25 °C
Reaction time: 20 h
Yield: 16.5 %

Procedure:
A solution of 3-phenylpropyl isothiocyanate (500 mg, 2.82 mmol) and 2-aminothiazole (300 mg, 3.0 mmol) in N,N-dimethylformamide (10 mL) was heated to 100° C. After 20 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with 1N hydrochloric acid, water (3×), and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by flash chromatography on silica gel (1% ethyl acetate in dichloromethane) and then recrystallized from ethyl acetate to provide 129 mg of the title product. A second crop was recrystallized from 1:1 ethyl acetate/hexanes to provide another 110 mg of the title product. Total yield of the title product: 239 mg (30%) as an off-white solid. A sample was recrystallized again from ethyl acetate:
Reaction SMILES: CS[C:3]([N:7]1[N:11]=[CH:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8]1)=[N:4][CH2:5][CH3:6].[NH:16]1[C:24]2[C:19](=[CH:20][C:21]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1>C(#N)C>[CH2:8]1[C:9]2([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH:10]=[N:11][N:7]1[C:3]([NH:4][CH2:5][CH3:6])=[N:28][S:25]([C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[NH:16][CH:17]=[CH:18]2)(=[O:27])=[O:26]
Reactant: NS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: CCN=C(SC)N1CC2(C=N1)CCCC2
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccc2[nH]ccc2c1)N1CC2(C=N1)CCCC2
Yield: 0 %

Procedure:
100 mg (1 mol equiv.) N-Ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboximidothioic acid methyl ester and 92.5 mg (1.05 mol equiv.) 1H-indole-5-sulfonic acid amide were added to 3 mL acetonitrile. The reaction mixture was refluxed overnight and volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:EtOAc=1:1) afforded 152 mg (87%) 1H-indole-5-sulfonic acid (2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methyleneamide. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.2 Hz, 3H), 1.59-1.79 (m, 8H), 3.43-3.51 (m, 2H), 3.79 (br.s., 2H), 6.63-6.65 (m, 1H), 6.76 (s, 1H), 6.99 (br.s., 1H), 7.30 (t, J=2.8 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.76 (dd, J=8.6, 1.8 Hz, 1H), 8.27 (br.s., 1H), 8.54 (br.s., 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:20])[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([O:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:20])[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc(=O)c(-c2ccc(O)c(O)c2)co1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(=O)c(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)co1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 5-(3,4-dihydroxyphenyl)-4-oxo-4H-pyran-2-carboxylate (3.0 g), anhydrous potassium carbonate (6.0 g) and benzyl bromide (3.0 ml) in dry DMF (30 ml) was stirred at room temperature for 2 hours and then filtered. The filtrate was cooled, acidified with 2 N hydrochloric acid (20 ml) and diluted with water (80 ml). The solid product was recrystallised from ethanol to give ethyl 5-(3,4-dibenzyloxyphenyl)-4-oxo-4H-pyran-2-carboxylate (mp 122°-125° C.).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)([CH3:6])([CH3:5])[CH3:4].[C:17]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[C:3]([O:7][C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]1[CH:15]=[CH:14][N:13]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccc3)cc2)c1

Procedure:
Starting materials: sodium hydride 60% (0.207 g), (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester (compound D1) (0.531 g), 4-biphenylsulphonylchloride (0.834 g). Reaction conditions: −30° C., 10 min; 30° C., 30 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:12](=[O:24])[N:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=[CH:15][C:16]=1Cl.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][C:16]2[CH:15]=[N:14][N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:24])[C:11]=2[Cl:10])=[CH:4][CH:3]=1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Reactant: SCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: O=c1c(Cl)c(SCc2ccc(Cl)cc2)cnn1-c1ccccc1
Yield: 84 %

Procedure:
The reaction of 15.8 g (100 millimoles) of 4-chlorobenzyl mercaptan with 24.1 g (100 millimoles) of 4,5-dichloro-2-phenylpyridazin-3(2H)-one and 10.1 g (100 millimoles) of triethylamine is carried out as described in Method 2 and gives 30.5 g (84%) of a material which is found to be pure by thin-layer chromatography and has a melting point of 154°-155° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:19]OS([O-])=O.[K+]>CO.O>[CH3:8][C:6]1[CH:5]=[C:4]([S:9]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])=[O:19])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2cccc(F)c2C#N)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc(C)cc(S(=O)c2cccc(F)c2C#N)c1
Yield: 47 %

Procedure:
2-[(3,5-Dimethylphenyl)thio]-6-fluorobenzonitrile (Example 18) (1.0 g, 3.9 mmol) was dissolved in 100 ml of methanol. A solution of OXONE®.dagger. (2.63 g, 4.3 mmol) in 15 ml of water was added dropwise with stirring. After stirring 1.5 h, the solid was removed by vacuum filtration and washed with 3×50 ml of methanol. The filtrate was concentrated to dryness and chromatographed on silica get (flash; Hex/EtOAc 2:1) to provide 0.5 g (47%) of 2-[(3,5-dimethylphenyl)sulfinyl]-6-fluorobenzonitrile: mp 146°-147° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[N:11]=[CH:12][N:13]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(O)(=O)C>[CH2:1]([NH:8][C:9]1[N+:26]([O-:35])=[CH:25][N:24]=[C:23]2[C:10]=1[N:11]=[CH:12][N:13]2[C@@H:14]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[C@H:15]1[OH:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NCc4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Solvent: CC(=O)O
Product: [O-][n+]1cnc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.9 %

Procedure:
N6 -Benzyladenosine (25 mg, 70 μmol) and m-chloroperbenzoic acid (38 mg, 220 μmol) were dissolved in 1 ml acetic acid. The resulting solution was stirred at room temperature for 2 days. The solvent was evaporated under a stream of nitrogen, and the residue was dissolved in a minimum of methanol and chromatographed on a silica plate (250μ) using acetonitrile:water, 4:1 (v/v). The UV absorbing band at Rf =0.53 was extracted with methanol to provide 7.3 mg (28% yield) of N6 -benzyladenosine-N1 -oxide. Mass and 1H-NMR spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][S:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl.[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH2:35])[CH3:31]>>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][NH:35][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([S:12](=[O:14])(=[O:13])[NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=2[Cl:1])=[CH:16][CH:17]=1)[CH3:31]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2Cl)cc1
Agent: Cl
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2Cl)cc1

Procedure:
The title compound was prepared from 4-[2-(2-chloro-4-fluoro-phenoxy)-phenylsulfamoyl]-benzoic acid and glycine ethyl ester hydrochloride according to the method described in Example 1.1/d.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:2]=1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH2:60])[CH:55]=[C:54]2[CH3:61]>CN(C=O)C.O.CCOC(C)=O>[F:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH:60][C:13]([C:10]1[CH:11]=[N:12][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:8][CH:9]=1)=[O:15])[CH:55]=[C:54]2[CH3:61]
Reactant: Cc1cn(N)c2ccc(F)cc12
Reactant: O=C(O)c1cnc(-c2cccnc2)nc1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(NC(=O)c2cnc(-c3cccnc3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A solution of 2-pyridin-3-yl-pyrimidine-5-carboxylic acid (664 mg, 2.79 mmol), HCTU (1.27 g, 3.07 mmol), and DIPEA (1.4 mL, 8.02 mmol) in DMF (15 mL) is stirred at rt under N2 for 10 min. 5-fluoro-3-methyl-indol-1-ylamine (491 mg, 2.55 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated in ether (3 times) and methanol to afford 2-pyridin-3-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (375 mg, 42%) as a solid. MS: 348 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 12.10 (s, 1H), 9.61-9.60 (m, 1H), 9.45 (s, 2H), 8.81-8.80 (m, 1H), 8.77 (dt, 1H), 7.64 (dd, 1H), 7.41 (dd, 1H), 7.35 (dd, 1H), 7.32 (s, 1H), 7.03 (td, 1H), 2.27 (s, 3H). IC50=10 nM.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.S(O[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)(C1C=CC(C)=CC=1)(=O)=O>CO>[N:1]1([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][CH:28]([NH:31][C:32]([O:34][CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)=[O:33])[CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: c1c[nH]nn1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N3CCC(NC(=O)OCc4ccccc4)CC3)cc2)cc1
Solvent: CO
Product: O=C(NC1CCN(c2ccc(CCn3ccnn3)cc2)CC1)OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
1,2,3-triazole (3.4 ml, 58.6 mmol) was added to the N-(4-(2-tosyloxyethyl)phenyl)-4-benzyloxycarbonylaminopiperidine (3.0 g, 5.90 mmol) obtained in Example 7(5), followed by stirring at 90° C. for 2 hours. Methanol was added to the reaction mixture. The mixture was refluxed under heat for 1 hour, and then allowed to cool to room temperature. The precipitate was collected by filtration, thereby obtaining N-(4-(2-(1,2,3-triazol-1-yl)-ethyl)-phenyl)-4-benzyloxycarbonylaminopiperidine (1.3 g, 54%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:26])[CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:32](N(C)C)[N:33]([CH3:35])[CH3:34])(C)(C)C.CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:26])[C:15]([C:16]2[CH:25]=[CH:24][C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)=[CH:32][N:33]([CH3:35])[CH3:34])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)Cc2ccc3c(c2)CCCC3)cc1OC
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc3c(c2)CCCC3)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 107.7 %

Procedure:
2.65 g (7.50 mmol) of N-[2-(3,4-dimethoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide, 3.92 g (22.5 mmol) of t-butoxybis (dimethylamino)methane and 30 ml of N,N-dimethylformamide were mixed and stirred at 90° C. for 3 hours and then at 110° C. for 3 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 3.30 g of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].[Cl:12][C:13]1[CH:37]=[CH:36][C:16]([C:17]([NH:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)[CH:21]=2)=[O:18])=[CH:15][C:14]=1I>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[C:22]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)[CH:21]=2)=[O:18])=[CH:36][C:37]=1[C:2]#[C:1][C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(I)c3)cc(C(F)(F)F)c2)cn1
Product: Cc1cn(-c2cc(NC(=O)c3ccc(Cl)c(C#Cc4cnc5cccnn45)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 4-chloro-3-iodo-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The title compound was obtained as a light yellow solid. Mp: 153-154° C.; 1H NMR (300 MHz, CDCl3) δ: 9.35 (1 H, s), 8.48-8.49 (1 H, d, J=3.6 Hz), 8.25 (1 H, s), 8.15 (2 H, brs), 7.89-7.92 (4 H, m), 7.57-7.60 (1 H, d, J=8.4 Hz), 7.37 (1 H, s), 7.12-7.16 (1 H, dd, J=4.2 and 9.3 Hz), 2.27 (3 H, s). HRMS (ESI-TOF+): m/z [M+2H]+2 calcd for C26H18ClF3N6O: 261.0586. found: 261.0584.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](O)([CH2:32][CH3:33])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=3)[CH2:19]2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([SH:42])=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([S:42][C:39]2[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=2)([CH2:32][CH3:33])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:30][CH3:31])=[C:23]([O:28][CH3:29])[CH:24]=3)[CH2:19]2)=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC(O)(CCCCC(=O)N1CCc2cc(OC)c(OC)cc2C1)c1ccc(OC)c(OC)c1
Reactant: Cc1ccc(S)cc1
Product: CCC(CCCCC(=O)N1CCc2cc(OC)c(OC)cc2C1)(Sc1ccc(C)cc1)c1ccc(OC)c(OC)c1
Yield: 58 %

Procedure:
The procedure of Example 60 is repeated using of 2.7 g of 2-[6-(3,4-dimethoxyphenyl)-6-hydroxy-1-oxooctyl]-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline and 1.06 g of p-thiocresol. This affords 1.92 g of the desired product as a white foam.