Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:8][CH2:9][C:10]([CH3:12])=C)([CH3:7])[C:3]([O:5][CH3:6])=[O:4].N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:7][C:2]([O:8][CH2:9][C:10](=[O:22])[CH3:12])([CH3:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(C)COC(C)(C)C(=O)OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(C)(C)OCC(C)=O
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of the product of Step 1 (1.73 g, 10 mmol) in 1,4-dioxane (75 mL) and water (25 mL) was added osmium tetroxide (4 wt % in water, 0.392 mL, 0.05 mmol), 2,6-lutidine (2.329 mL, 20 mmol), and sodium periodate (8.56 g, 40 mmol). After stirring for 14 hours, a large amount of white precipitate had built up. The reaction mixture was then partitioned between diethyl ether (100 mL) and water (25 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to provide methyl 2-methyl-2-(2-oxopropoxy)propanoate as a brown oil (1.74 g, 10 mmol), which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 4.02 (s, 2H), 3.73 (s, 3H), 2.22 (s, 3H), 1.48 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:7](I)=[N:6][CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:7]([C:17]2[CH2:22][CH2:21][CH2:20][C:19](=[O:23])[CH:18]=2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Reactant: Fc1nccnc1I
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C1C=C(c2nccnc2F)CCC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-Fluoro-3-iodopyrazine (2.5 g, 11.16 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (3.10 g, 13.95 mmol), and sodium carbonate (3.55 g, 33.5 mmol) were suspended in DME (20 ml) and distilled water (5 ml). Argon was bubbled through the resulting mixture for 3 minutes, and dichlorobis(triphenylphosphino)palladium (ii) (0.431 g, 0.614 mmol) was added. The resulting mixture was stirred at 80° C. for 16 hours, the reaction was cooled to RT, and water (200 ml) was added. The resulting mixture was concentrated under reduced pressure and was extracted with EtOAc (3×200 ml). The combined organic layers were washed with brine and dried over sodium sulfate. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0% to 20% EtOAc in hexanes) afforded 3-(3-fluoropyrazin-2-yl)cyclohex-2-enone as a light yellow solid. MS (ESI, pos. ion) m/z: 193.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]3[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: N#Cc1ccc(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: O
Solvent: COCCOC
Product: N#Cc1ccc(-c2ccc3c(c2)CCC3=O)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a stirred solution of 5-bromo-1-indanone (0.40 g, 1.90 mmol) and 4-cyanophenyl boronic acid (0.36 g, 2.47 mmol) in glyme (17 mL) was added a solution of sodium carbonate (0.60 g, 5.70 mmol) in water (3 mL) and tetrakis(triphenylphosphine)palladium (0) (0.11 g, 0.10 mmol). The resulting solution was heated to reflux for 2.5 hours. The solution was cooled to room temperature and partitioned between a saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate in hexane) and triturated with ether to give 4-(1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile as a white solid (0.35 g, 79%). MS (ESI) m/z 234.0936; HRMS: calcd for C16H11NO+H+, 234.09134; found (ESI, [M+H]+), 234.0936.
Reaction SMILES: O1CCOCC1.[CH3:7][C:8]1[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:10](=[O:17])[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1.C(OC(=O)C)(=O)C.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]=O>C(=O)(O)[O-].[Na+]>[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:9]1[C:10](=[O:17])[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:8]1[CH:7]=[CH:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1ccccc1-n1c(C)nc2ccsc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccccc1-n1c(C=Cc2ccccn2)nc2ccsc2c1=O
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To a mixture of fused zinc chloride (2.13 g, 15.6 mmol) and dioxane (75 mL), 2-methyl-3-(2-methylphenyl)-3H-thieno[3,2-d]pyrimidin-4-one (2.0 g, 7.81 mmol, preparation 2), and acetic anhydride (2.2 mL, 23.4 mmol) was added 2-pyridine carboxaldehyde (2.2 mL, 23.4 mmol). The reaction was refluxed 1.5 hours, cooled to ambient temperature, and diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and brine, dried over sodium sulfate and concentrated to leave a dark residue. This material was flash chromatographed on silica gel (45×125 mm). Elution with 20% ethyl acetate/hexane removed an unweighed impurity. Continued elution with 40% ethyl acetate/hexane gave a sticky yellow foam. The foam was triturated with 5% ethyl acetate/hexane to yield 1.9 g (70%) of 3-(2-methyl-phenyl)-2-[2-pyrid-2-yl-vinyl]-3H-thieno[3,2-d]pyrimidin-4-one as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=O)[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1.CCOC(C)=O>C1(C)C=CC=CC=1.C1CCCCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[S:45])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=O)cc2)CCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=S)cc2)CCC1
Yield: 185.6 %

Procedure:
To a solution of {1-[4-(4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (30 mg, 0.0642 mmol) in toluene (3 mL) was added Lawesson's reagent (2,4-bis-(4-methoxy-phenyl)-[1,3,2,4]dithiadiphosphetane 2,4-disulfide) (15.6 mg, 0.039 mmol). The reaction mixture was heated at reflux for 3 hours. The cooled mixture was subjected to flash chromatography (SiO2, 20% EtOAc in cyclohexane). A second chromatography (SiO2, 3% EtOAc in toluene) afforded the title compound (35 mg). LCMS (Method A): RT=5.08 min, [M+H]+=484.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:3]=1[C:4]#N.[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.[OH:23]S(O)(=O)=O>C1COCC1.CCOCC>[NH2:1][C:2]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:3]=1[C:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:23]
Reactant: O=S(=O)(O)O
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1cc2c(cc1N)OCO2
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc2c(cc1C(=O)Cc1ccccc1)OCO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 52 %

Procedure:
To a stirred solution of 1.5 g (10.0 mmol) of 2-amino-4,5-methylenedioxy-benzonitrile in THF (40 mL) was added CuBr (50 mg, 0.34 mmol) and benzylmagnesium chloride (40 mL, 1.0 M solution in Et2O). The reaction mixture was refluxed for 12 h. After cooling to 25° C., H2O (5 mL) was added followed by 15% H2SO4 (15 mL). After stirring for 14 h, ether (50 mL) was added. Organic layer was separated. Aqueous layer was extracted with ether (2×50 mL). The combined organic layer was dried and evaporated. Following chromatography (silica gel, CHCl3), 1.2 g (52%) of the title compound was obtained. IR (CHCl3) 1675 cm−1 MS m/z 255 (M+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.C(N(CC)CC)C>CC(C)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][S:36]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)(=[O:38])=[O:37])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2nc3ccc(O)cc3n2Cc2ccccc2)cc1OC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3n2Cc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
A stirred solution of 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-ol (141 mg) and 4-fluoro-benzenesulfonyl chloride (190 mg) in acetone (8 ml) was treated with triethylamine (258 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give 4-fluoro-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (157 mg) as a yellow solid. Mass spectrum: 534 [M+H]+, retention time: 3.7 minutes.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([Sn](C)(C)C)=[CH:3][CH:2]=1.Br[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[C:15]([C:14]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:13]=1[C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)#[N:16]
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of p-tolyltrimethyltin (389 mg, 1.525 retool) in dry toluene (5 mL) under N2 was added 2-bromo-5-ni tro-benzonitrile (276 mg, 1.22 mmol) and Pd(PPh3)4 (176 mg; 10 mol %). The reaction was stirred at reflux under N2 for 24 hours and then cooled to room temperature. The mixture was diluted with EtOAc and the solid was removed by filtration through a pad of celite. The liltrate was concentrated in vacuo and the residue was purified by flash chromatography on a silica column eluting with Hex/EtOAc (10:1) to afford 214 mg (74%) of the titled compound as a slightly yellow solid. 1H NMR (300 MMz, CDCl3) δ 2.42 (s, 3H), 7.32 (d, 2H), 7.48 (d, 2H), 7.69 (d, 1H), 8.45 (dd, 1H), 8.61 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]2[N:5]([CH3:6])[CH2:4][CH2:3][N:2]2[CH3:1])=[CH:11][CH:10]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CNCCNC
Solvent: c1ccccc1
Product: COc1ccc(C2N(C)CCN2C)cc1

Procedure:
Benzene (20 ml) and N,N'-dimethylethylenediamine (1.56 ml, 14.7 mmol) were added to 4-methoxybenzaldehyde (2 g, 14.7 mmol), and the m tture was refluxed under heating for 5 hours while removing the generated water. Benzene was evaporated to give a crude product of 2-(4-methoxyphenyl)-1,3-dimethylimidazolidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:11])[CH2:9][CH3:10])=[N:6][CH:7]=1.[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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:11][CH:8]([C:5]1[N:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1)[CH2:9][CH3:10]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCC(O)c1ccc(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: Cc1ccccc1
Solvent: CCO
Product: CCC(O)c1ccc(-c2ccc(C#N)cc2)cn1
Temperature: 80 °C
Yield: 45.6 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)propan-1-ol (0.3 g, 1.38 mmol) in toluene (8 mL) and ethanol (4 mL) was added 4-cyano phenyl boronic acid (0.244 g, 1.6 mmol) and a 2 M solution of aq. Na2CO3. The reaction mixture degassed with argon, Pd(PPh3)4 (0.08 g, 0.069 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and heated to 80° C. for 4 h. The reaction mixture was evaporated under vacuum to remove ethanol, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (100 mL), dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by a Biotage Isolera® One column (using 15% ethyl acetate and hexane) to give 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzonitrile (0.15 g, 45.45% yield). 1H NMR (400 MHz DMSO-d6): δ 8.78 (s, 1H), 7.89 (dd, 1H), 7.78 (d, 2H); 7.69 (d, 2H), 7.39 (d, 1H), 4.77 (t, 1H), 3.90 (s, 1H), 1.91-1.81 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:18])=[C:16]([CH3:17])[C:3]=12.CC(C)([O-])C.[Na+].[Cl:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>CN(C=O)C.C(OCC)(=O)C.O>[Br:18][C:15]1[S:14][C:4]2=[N:5][C:6]([CH3:13])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:1][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)(=[O:34])=[O:33])=[C:3]2[C:16]=1[CH3:17]
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(C)c2c1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2sc(Br)c(C)c2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.7 %

Procedure:
To a stirred solution of ethyl 4-amino-2-bromo-3,6-dimethylthieno[2,3-b]pyridine-5-carboxylate (Description 31) (500 mg, 1.519 mmol) in DMF (10 mL) was added sodium tert-butoxide (365 mg, 3.80 mmol) and 3-chlorobenzenesulfonyl chloride (0.428 mL, 3.04 mmol). The whole mixture was stirred at RT under nitrogen for ca. 1.5 h. The reaction mixture was then diluted with ethyl acetate (ca. 30 mL) and water (ca. 50 mL). The organic phase was separated and the aqueous phase re-extracted with ethyl acetate (ca. 30 mL×2). The combined organic phase was dried over Na2SO4 and the solvent concentrated in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-50% ethyl acetate in cyclohexane, to give the title compound (350 mg). LCMS (A) m/z: 504/506 [M+1]+, Rt 1.59 min (acidic).
Reaction SMILES: C(O)=O.CC(O[C:8]([CH3:10])=O)=O.[N+:11]([C:14]1[CH:23]=[C:22]2[C:17](C[CH2:19][NH:20][CH2:21]2)=[CH:16][CH:15]=1)([O-:13])=[O:12].Cl>C1COCC1.CO>[CH3:19][N:20]1[CH2:10][CH2:8][C:17]2[C:22](=[CH:23][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)[CH2:21]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O=CO
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 1311 %

Procedure:
Formic acid (9.4 mL, 250 mmol) was added dropwise to Ac2O (19 mL, 202 mmol) at 0° C. The solution was stirred at 50° C. for 45 min, then cooled to −18° C., diluted with THF (100 mL) and a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline [(a) Tercel, M.; et al., J. Med. Chem. 1996, 39, 1084-1094; (b) Zhu, Z., et al., J. Med. Chem. 2003, 46, 831-837] (251) (13.8 g, 5.0 mmol) in THF (100 mL) was added and stirred at −15 to −18° C. for 30 min. The solution was warmed to 20° C., the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3×250 mL), dried and the solvent evaporated. The residue was dissolved in THF (200 mL), cooled to 10° C. and BH3-DMS solution (10 M, 19.4 mL, 194 mmol) was added. The solution was stirred at 20° C. for 1 h, diluted with MeOH (30 mL) and acidified with HCl solution (1 M, 45 mL). The solution was stirred at 40° C. for 15 min, the solvent evaporated and the residue partitioned between saturated aqueous NaHCO3 solution (250 mL) and EtOAc (250 mL). The aqueous fraction was extracted with EtOAc (3×250 mL), dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give isoquinoline 252 (12.6 g, 85%) as an orange solid: 1H NMR δ 8.09 (dd, J=8.4, 2.3 Hz, 1H, H-6), 7.95 (d, J=2.3 Hz, 1H, H-8), 7.37 (d, J=8.4 Hz, 1H, H-5), 4.27 (d, J=16.1 Hz, 1H, H-1), 3.94 (d, J=16.1 Hz, 1H, H-1), 3.23-3.34 (m, 2H, CH2), 2.99-3.18 (m, 2H, CH2), 2.17 (s, 3H, NCH3); MS (APCI) m/z 193 (MH+, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH3:11])#[CH:2].[Cl:12][C:13]1[C:14]([C:20]#[N:21])=[N:15][CH:16]=[C:17](Cl)[CH:18]=1.C(N(CC)CC)C.CN(C=O)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[Cl:12][C:13]1[C:14]([C:20]#[N:21])=[N:15][CH:16]=[C:17]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=2[CH3:11])[CH:18]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C#Cc1ccc(OC)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(C#Cc2cnc(C#N)c(Cl)c2)c(C)c1
Temperature: 60 °C

Procedure:
To a round bottom flask capped with septa was added 1-ethynyl-4-methoxy-2-methylbenzene (commercially available, 1.1 equiv.), 3,5-dichloropicolinonitrile (commercially available, 1 equiv.), triethylamine (5 equiv.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.05 equiv.) and bis(triphenylphosphine)dichloro-palladium(II) (0.05 equiv.) were added. The septum was replaced with a refluxing condenser and the flask was heated at 60° C. overnight under nitrogen atmosphere. Upon completion of the reaction as monitored by TLC, the content of the flask was loaded onto a large silica gel column pretreated with hexanes. Flash chromatography (silica gel, hexanes:EtOAc (1:4%)) afforded 3-chloro-5-((4-methoxy-2-methylphenyl)ethynyl)picolinonitrile.
Reaction SMILES: N1C=CC=CC=1.[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)#[N:20]>ClCCl.C(N(CC)CC)C>[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][N:16]([S:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][CH:25]=3)(=[O:29])=[O:28])[CH2:17][CH2:18]2)=[CH:9][CH:8]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.6 %

Procedure:
Pyridine (1 ml) was added to a solution of 1-(4-pyridyl)piperazine (0.33 g) in dry dichloromethane (20 ml) and triethylamine (1 ml) at 5° C. The reaction mixture was treated with 4-cyanobenzenesulphonyl chloride (0.40 g). The reaction mixture was then stirred under argon for 4 hours allowing to warm to room temperature. The dichloromethane solvent was removed by evaporation and the residual pyridine solution poured into aqueous sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic extracts were then washed with aqueous sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to yield a pale cream solid which was then recrystallised from ethyl acetate isohexane to give 1-(4-pyridyl)-4-(4-cyanophenylsulphonyl)piperazine (0.31 g) as a solid. m.p. 212-213° C.; microanalysis, found: C, 58.8; H, 4.9; N, 17.1%; C16H16N4O2S requires: C, 8.5: H, 4.91; N, 17.1%; NMR: (CDCl3) 3.18(t,4H), 3.44(t,4H), 6.62(dd,2H), 7.88(q,4H), 8.30(dd,2H); MS: m/z 329 (MH)+.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])=[CH:38][CH:37]=1
Reactant: CN(C[C@@H](N)c1ccc(Cl)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)cc1

Procedure:
Compound 45 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-chloro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [357 (M+H)].
Reaction SMILES: [C:1]1([S-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].Cl[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].ClC1C=CC(C)=CC=1[N+]([O-])=O>>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH3:17]
Reactant: CCc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [S-]c1ccccc1
Agent: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Product: CCc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1

Procedure:
Sodium thiophenolate was reacted with 1-Chloro-4-ethyl-2-nitro-benzene according to the procedure from Example 5H substituting 1-Chloro-4-ethyl-2-nitro-benzene for 4-chloro-3-nitrotoluene to provide 4-Ethyl-2-nitro-1-phenylsulfanyl-benzene which was reduced according to the procedure from Example 5I to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:16][C:17]1[CH:18]=[C:19]([C:23]2[N:24]=[C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[S:26][CH:27]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Cc1cccc(-c2csc(N3CCNCC3)n2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2csc(N3CCN(C(=O)Nc4cccnc4)CC3)n2)c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 35.2 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (229 mg, 0.848 mmol), 1-[4-(3-methylphenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.771 mmol) and diisopropylethylamine (0.269 ml, 1.54 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 20 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 103 mg (35.1%) of the desired product as a solid. mp 157-158° C.