Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCCCCCCCCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCCCCCCC=C[Sn](CCCC)(CCCC)CCCC
Temperature: 50 °C
Yield: 95.8 %

Procedure:
A solution of 1-dodecyne (50.0 g), tributyltinhydride (109.4 g), and azobisisobutyronitrile (100 mg) was stirred at 95° C. for 3 hrs. The reaction mixture was cooled to 50° C. and evaporated. The residue was filtered through a column of silica, using hexane as the eluent. The appropriate fractions were collected and evaporated. The residue was dried under vacuum to give 131.7 g (96.0%) of tri-n-butyl-1-dodecenylstannane.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:45]I>ClCCl.CCOCC>[I:45][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7][CH2:6]2
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(CO)ccc21
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1CCCc2cc(CI)ccc21
Reaction time: 0.33 h

Procedure:
To a solution of (R)-tert-butyl 6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (415.5 mg, 1.5 mmol) in dichloromethane/ether (1:1, 30 mL) at room temperature were added triphenylphosphine (590 mg, 2.25 mmol) and imidazole (153 mg, 2.25 mmol). To this stirred solution was then added iodine (571 mg, 2.25 mmol). After stirring for 20 min, the reaction was quenched with 10% Na2S2O3 (15 mL) until it became a clear two-phase solution. The aqueous phase was extracted with ether. The combined organic phase was dried over Na2SO4, filtered, and evaporated to dryness. Flash chromatography (SiO2, hexane/CH2Cl2=3:1 to pure CH2Cl2) afforded the title compound as a white solid. B. Preparation of (R)-tert-butyl 6-(2-(1,3-dithian-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)[CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:2]1.[CH2:39](I)[CH3:40].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:39]([N:13]([CH2:12][CH:11]([NH:23][C:24](=[O:38])[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH3:40]
Reactant: CCI
Reactant: COc1ccccc1CNCC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1OC)CC(Cc1c[nH]c2ccccc12)NC(=O)CN1CCN(c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a room temperature solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.41 g, 0.80 mmole) in 5 ml of anhydrous N,N-dimethylformamide were added ethyl iodide (120 μl, 1.5 mmoles) and potassium carbonate (120 mg, 0.87 mmole). This mixture was then heated to 50° C. and maintained at that temperature for about 4 hours after which it was stirred at room temperature for about 16 hours. The N,N-dimethylformamide was then removed under reduced pressure. The product was partitioned between ethyl acetate and water, and then washed with brine, before drying over sodium sulfate. The solvents were removed in vacuo. Preparative thin layer chromatography provided 360 mg of the title product as a yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>[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.C(NC(C)C)(C)C>[CH3:29][Si:30]([CH3:32])([CH3:31])[C:33]#[C:34][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(C)cc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: Cc1cc(C)cc(C#C[Si](C)(C)C)c1
Temperature: 75 °C

Procedure:
A solution of 5-bromo-m-xylene (19.4 g, 105 mmol) and diisopropylamine (100 mL) was degassed with argon and kept under an argon atmosphere. CuI (2.07 g, 10.7 mmol), PPh3 (4.06 g, 15.3 mmol) and Pd(PPh3)2Cl2 (2.09 g, 2.92 mmol) were added followed by addition of trimethylsilylacetylene (12.3 g, 18 mL, 125 mmol). The reaction was heated to 75° C. for 2 h giving a dark brown viscous mixture. Additional trimethylsilylacetylene (6.15 g, 9 mL, 63 mmol), PPh3 (2.04 g, 7.78 mmol), CuI (1.05 g, 5.51 mmol) and Pd(PPh3)2Cl2 (1.62 g, 2.31 mmol) were added and then the reaction was heated to 80° C. for 4 h. After cooling the reaction to room temperature, hexanes (300 mL) was added and the solution was filtered through celite. The hexane layer was washed with 1N HCl (600 mL), brine (300 mL), dried (Na2SO4), and concentrated to give crude 1-trimethylsilyl-2-(3,5-dimethylphenyl)-acetylene which was used for the next step.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: Clc1ccccn1
Reactant: C[C@@H]1CNCCN1
Solvent: Cc1ccccc1C
Product: C[C@@H]1CN(c2ccccn2)CCN1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40.3 %

Procedure:
To a solution of (R)-2-methyl piperazine (6.6 g, 0.066 mol) in xylene (100 mL) at 140° C. under nitrogen was added 2-chloro pyridine (4 g, 0.035 mol) slowly over a period of 1 h. The heating was continued for additional 12 h and cooled to RT. The solvent was removed under reduced pressure and the resulting residue was purified by chromatography using chloroform methanol (8/2) as eluent to afford the title product as a liquid (2.5 g, 40%). TLC-Chloroform/MeOH (8/2); Rf=0.2. HPLC purity: 97%.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:6]([C@H:9]([C@H:12]([CH3:14])[OH:13])[O:10][CH3:11])[O:7][CH3:8])[CH:4]=[O:5].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C@@H:3]1[C@H:6]([O:7][CH3:8])[C@@H:9]([O:10][CH3:11])[C@H:12]([CH3:14])[O:13][C@H:4]1[O:5][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22]
Reactant: CO[C@H]([C@@H](OC)[C@H](C=O)OC)[C@H](C)O
Reactant: O=C1CCC(=O)N1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON2C(=O)CCC2=O)[C@@H]1OC
Reaction time: 4 h
Yield: 51.8 %

Procedure:
To a stirred solution of 2,3,4-tri-O-methyl-L-rhamnose (6.5 g, 31.5 mmol) and N-hydroxysuccinimide (5.4 g, 47 mmol) in 50 mL of benzene was added 50 mg (cat) of p-toluenesulfonic acid. The solution was heated to reflux and water was collected using a Dean-Stark trap. After 4 h, the solution was cooled and the supernatant toluene layer was separated from a small amount of insoluble gum. The organic layer was washed with 20 mL of saturated NaHCO3 solution, then dried over MgSO4 and concentrated to a solid. Recrystallization from ether-hexanes gave 4.95 g (52%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH2:1][Br:13]
Reactant: COc1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc([N+](=O)[O-])c1CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.0 g (18 mmol) of 2-methyl-3-nitroanisole was dissolved in 500 ml of carbon tetrachloride. The resultant solution was added with 6.4 g (36 mmol) of N-bromosuccinimide, and the mixture was subjected to irradiation of light emitted from an infrared lamp of 375 W (manufactured by Toshiba) for 3 hours at the reflux temperature. The mixture was then cooled to a room temperature. Succinimide precipitated in the mixture was separated by filtration, and the obtained filtrate was condensed under reduced pressure to obtain a crude product of 2-methoxy-6-nitrobenzyl bromide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:7]=[C:6]([O:14][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of 1-bromo-2,5-difluoro-4-nitrobenzene (2.56 g, 0.011 mmol) in methanol (20 mL) was added a 25% sodium methoxide in methanol solution (2.5 mL). The mixture was stirred at room temperature for 1.5 hours. The reaction was then concentrated, re-dissolved in EtOAc and washed with water. The aqueous wash was back-extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (2.65 g, 99%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][C:7]=12)#[N:2].[H][H]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[N:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][C:7]=12
Reactant: N#Cc1cnn2c1[nH]c(=O)c1ccccc12
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cnn2c1[nH]c(=O)c1ccccc12

Procedure:
A suspension of 1.5 g of 3-cyano-4H-pyrazolo[1,5-a]quinazolin-5-one in 150 mL of 20% ammonia in methanol was shaken with 15 g of aqueous Raney nickel at ambient temperature under 60 psi of hydrogen for 70 minutes. The suspension was diluted with 150 mL of methanol and warmed to dissolve the precipitated product. Filtration through a nylon membrane and concentration of the filtrate yielded the title compound. MS (ESI) m/z 198 (M+H—NH3)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=1)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:1]1([C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:10][CH3:11])=[CH:13][CH:14]=2)=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)C#Cc1ccc(CC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(c1ccc(CC)cc1)n1cnc2ccccc21
Temperature: 100 °C

Procedure:
To a solution of benzimidazole (118 mg, 1.00 mmol) in DMF (3 mL) was added ethyl 3-(4-ethylphenyl)-2-propynoate (202 mg, 1.00 mmol) and potassium carbonate (152 mg, 1.10 mmol). This suspension was heated to 100° C. for 48 hours, then cooled to room temperature, and evaporated in vacuo. The residue was partitioned between water and dichloromethane, and the separated aqueous layer extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (96:4) to afford (in order of elution), ethyl (2Z)-3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate, mixed fractions, and ethyl (2E)-3-(1H-benzimidazol-1-yl)-3-(4-ethylphenyl)-2-propenoate.
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([CH3:40])([CH3:39])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]3[CH:23]=[CH:24][C:25]([C:27]4[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=4)=[CH:26][C:16]=3[N:15]=2)=[C:10]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH:9]=1)C.[OH-].[Na+]>O1CCOCC1.O>[NH2:33][C:30]1[N:29]=[CH:28][C:27]([C:25]2[CH:24]=[CH:23][C:17]3[N:18]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([CH3:39])([CH3:40])[C:4]([OH:41])=[O:3])=[CH:9][C:10]=4[N:34]4[CH:38]=[N:37][CH:36]=[N:35]4)=[N:15][C:16]=3[CH:26]=2)=[CH:32][N:31]=1
Reactant: CCOC(=O)C(C)(C)COc1ccc(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c(-n2cncn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(COc1ccc(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c(-n2cncn2)c1)C(=O)O
Temperature: 65 °C
Reaction time: 144 h
Yield: 70.4 %

Procedure:
To a solution of 3-{4-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzoimidazol-2-yl]-3-[1,2,4]triazol-1-yl-phenoxy}-2,2-dimethyl-propionic acid ethyl ester (example 66) (95 mg, 0.17 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) is added 3 M NaOH solution (0.17 mL, 0.52 mmol) at room temperature. The solution is stirred at 65° C. for 6 days. The solution is concentrated and the residue is re-dissolved in H2O (5 mL). The pH of the solution is adjusted to 5 with 12N HCl solution. The milky solution is extracted with EtOAc (3×10 mL). The combined organic layer is dried with MgSO4 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (63 mg, 70%). LCMS (ESMS): m/z: 527.40 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.Cl>C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Br)cn1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 4-chloro-3-nitrobenzoyl chloride (22.0 g, 0.1 mol) and 2-amino-5-bromopyridine (17.3 g, 0.1 mol) in toluene (250 mL) was refluxed for 4 hours, allowing gaseous HCl to escape the reaction vessel through an open, water cooled condenser. The reaction mixture was cooled to room temperature, diluted with hexanes (200 mL) and filtered to give the title compound (33.9 g, 95%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])=[CH:11][CH:10]=1)(=[O:8])=[O:7])=[O:4].C(N(CC)CC)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(#N)C>[C:34]([NH:1][CH2:2][C:3]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])=[CH:13][CH:14]=1)(=[O:8])=[O:7])=[O:4])(=[O:36])[CH3:35]
Reactant: Cc1onc(-c2ccccc2)c1-c1ccc(S(=O)(=O)NC(=O)CN)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)NCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2C)cc1
Reaction time: 2 h
Yield: 72.1 %

Procedure:
The 2-amino-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide (Example 79)(4.08 g, 10.9 mmol) was mixed in acetonitrile at room temperature. Triethylamine (3.03 g, 30.0 mmol) and acetic anhydride (1.23 g, 12.1 mmol) were added and the heterogeneous solution was stirred for 2 hours. The solution was vacuum filtered through a pad of diatomaceous earth and solvent was removed at reduced pressure. Water was added and the solution was stirred for 30 minutes. White crystals formed, were collected by vacuum filtration and dried to afford the desired product as a white solid (3.25 g, 78%): mp 218.2-219.3° C. 1H NMR (CD3OD/300 MHz) 8.01 (d, 2H, J=8.2 Hz), 7.42-7.36 (m, 7H), 3.85 (s, 2H), 2.50 (s, 3H), 1.95 (s, 3H). FABLRMS m/z 414 (M+H). Anal. Calc'd for C20H19N3O5S: C, 58.10; H, 4.63; N, 10.16. Found: C, 58.18; H, 4.66; N, 10.14.
Reaction SMILES: [F:1][C:2]1[C:7](Cl)=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C([Mg:16][Br:17])(C)C>>[F:1][C:2]1[C:7]([Mg:16][Br:17])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: CC(C)[Mg]Br
Reactant: Fc1c(F)c(F)c(Cl)c(F)c1F
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F

Procedure:
The process according to claim 6 wherein the step (a) pentafluorochlorobenzene is reacted with isopropylmagnesium bromide in a mole ratio range from about 1:1 to 2:1 in a dialkyl ether solvent to provide pentafluorophenylmagnesium bromide.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH2:30].CCN(C(C)C)C(C)C>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH:30][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: COc1ccccc1CCN
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CCNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-(2-methoxy-phenyl)-ethylamine and DIEA to give 2-[2-(2-methoxy-phenyl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)=[O:4].[Se](=O)=[O:20]>O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH:17]=[O:20])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)=[O:4]
Reactant: O=[Se]=O
Reactant: Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Solvent: O
Product: O=Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Reaction time: 8 h
Yield: 18 %

Procedure:
In a 25 ml. round-bottomed flask equipped with a magnetic bar, water-cooled reflux condenser, and argon-filled balloon, 7-chloroacetamido-2-methylquinoline-5,8-dione (28) (prepared as described in Example 28) (0.529 g., 2 mmol), selenium dioxide (0.255 g., 2.3 mmol), 12 ml of dried, distilled 1,4-dioxane, and 0.25 ml. of water were stirred and slowly heated to reflux over a two-hour period. The reaction was monitored by TLC and allowed to go to completion (29.5 hours). The selenium was allowed to settle, and the supernatant solution was pipetted off and filtered. 1,4-Dioxane (10 ml.) was added to the residue, stirred and refluxed for five minutes. The entire mixture was filtered and the selenium was washed with dichloromethane (10 ml.). All filtrates were combined and stored at 4EC overnight. Solid precipitate from the chilled mixture was filtered yielding 0.0985 g. of crude product (yield of 18%). This was purified by recrystallization from ethyl acetate/dichloromethane. The original remaining filtrate was diluted with 50 ml of dichloromethane and washed with 3% sodium bicarbonate solution (2×50 ml.). The aqueous layer was then extracted with dichloromethane (2×20 ml.) The organic layers were dried with magnesium sulfate and rotoevaporated to give a dark orange solid. The product was dried under vacuum overnight and 0.2941 g. of product was obtained (yield of 52%, total 70%). This product could be further purified by flash chromatography and recrystallization from ethyl acetate/dichloromethane: mp 190-192EC; 1H NMR (CDCl3)*4.26 (2H, s, C-7NHCOCH2Cl), 8.04 (1H, s, C-6H), 8.33 (1H, d, J=8.1 Hz, C-3H), 8.62 (1H, d, J=8.1 Hz, C-4H), 9.54 (1H, br. s, C-7NH), 10.28 (1H, s, C-2CHO); IR (KBr) vmax 3310, 3089, 2950, 2852, 1731, 1720, 1678, 1644, 1521, 1118 cm−1; EIMS, m/e (relative intensity) 278/280 (M+, 2.7/1, 95), 243 (33), 229 (33), 215 (55), 202 (base), 175 (61), 146 (17); HRMS, m/e for C14H9ClN2O3 calculated 278.009435, found 278.008764; analysis for C14H9ClN2O3 calculated C, 51.72; H, 2.53; Cl, 12.72; N, 10.05; Found C, 51.81; H, 2.9; Cl, 12.79; N. 9.86.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH][nH]c(=O)c2cc(Br)ccc12
Product: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 24.3 %

Procedure:
A mixture of 6-bromo-2,3-dihydro-phthalazine-1,4-dione (42.8 g, 178 mmol) in POCl3 (300 mL) was heated at reflux for 3 h. The mixture was allowed to cool and concentrated. The residue was taken up in EtOAc (400 mL) and water (200 mL), and neutralized with sodium bicarbonate. The layers were separated, aqueous layer was extracted with EtOAc (3×200 mL), and combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in dioxane (300 mL) and 2N NaOH (250 mL). The mixture was heated at 50° C. for 30 min, poured into water (3 L), and stirred for 15 min. Solid was filtered and dried in vacuum at room temperature to give title compound as a greenish solid (12.0 g, 24.3%). M/z (M+1)=259.32.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[S:22][C:23]([Cl:26])=[CH:24][CH:25]=1.Cl>O1CCCC1>[Cl:26][C:23]1[S:22][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:25][CH:24]=1
Reactant: ClCc1cnoc1-c1ccc(Cl)s1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1cnoc1-c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a solution of diethyl malonate (10.1 g) in tetrahydrofuran (60 ml) was gradually added sodium hydride (60%, oil, 2.29 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(5-chloro-2-thienyl)isoxazole (6.70 g) in tetrahydrofuran (60 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was acidified by pouring into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was dissolved in a mixture of 6N hydrochloric acid (80 ml) and acetic acid (120 ml). The mixture was heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate to give a colorless prism (4.95 g, yield 67%) of 3-[5-(5-chloro-2-thienyl)-4-isoxazolyl]propionic acid. melting point: 138–139° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]1[O:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21][CH:22]([N:24]([CH3:31])[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH3:23])=[CH:20][C:14]=2[O:13]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:10][CH2:11][CH:12]1[O:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21][CH:22]([N:24]([CH3:31])[C:25](=[O:30])[C:26]([F:28])([F:27])[F:29])[CH3:23])=[CH:20][C:14]=2[O:13]1
Reactant: [H][H]
Reactant: CC(Cc1ccc2c(c1)OC(CNC(=O)OCc1ccccc1)O2)N(C)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(Cc1ccc2c(c1)OC(CN)O2)N(C)C(=O)C(F)(F)F
Reaction time: 4 h
Yield: 87.9 %

Procedure:
To a solution of 150 mg (0.33 mmol) of 1I in 10 ml of methanol was added 24 mg of 10% Pd—C, and the mixture was hydrogenated for 4 hours at room temperature under atmospheric pressure using a hydrogen filled balloon. The reaction mixture was filtered through CELITE and the residue was washed with 20 mL of methanol. The filtrates were combined and concentrated to dryness under reduced pressure. The residue was purified by silica gel flash column chromatography using 10% methanol in ethyl acetate to give 95 mg (0.29 mmol, 86%) of 1J as a colorless oil (M+H, 319).