Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[O:6])=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1F
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(Cl)cc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 2-fluorobenzoic acid (1.00 g, 7.14 mmol), thionyl chloride (3 mL, 41.1 mmol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the pump. Chlorobenzene (5 mL, 50 mmol) and aluminum trichloride (1.050 g, 7.85 mmol) were added to the reaction mixture. The reaction mixture turned yellow in color on addition of AlCl3. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc. HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [CH3:1][N:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3Cl)[CH:17]=2)=[O:15])[CH2:10]1)[C:3]([CH:5]1[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:26][C:27]1[NH:28][C:29]2[C:34]([CH:35]=1)=[CH:33][C:32]([NH2:36])=[CH:31][CH:30]=2>>[CH3:1][N:2]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[NH:36][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:26])=[CH:35]4)[CH:17]=2)=[O:15])[CH2:10]1)[C:3]([CH:5]1[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C(=O)C1CCC1)C1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC(N(C)C(=O)C6CCC6)C5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from (+/−)-cyclobutane carboxylic acid methyl-{1-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-pyrrolidin-3-yl}-amide and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 488 (MH+); HPLC Rf: 4.84 min.; HPLC purity 95%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)#[N:2].CN([C:15]([O:19][N:20]1N=NC2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl.O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:20]([O:19][CH3:15])[CH3:21])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a stirred solution of 4-cyanobenzoic acid (5.0 g, 34.0 mmol) in DCM (75 mL) were added HATU (19.40 g, 51.0 mmol), N-methoxy, N-methylamine (4.90 g, 51.0 mmol) and TEA (14.30 mL, 102.0 mmol) at RT under a nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3×100 mL). The combined organic extracts were washed with water (60 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to afford 4-cyano-N-methoxy-N-methylbenzamide (6.2 g, 96%) as a yellow color oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:72]1[S:76][CH:75]=[N:74][CH:73]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[S:76]1[C:72]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[CH:22][N:21]=3)[CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:73][N:74]=[CH:75]1
Reactant: Brc1cncs1
Reactant: COC(=O)c1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Temperature: 90 °C
Yield: 72 %

Procedure:
To a flask containing the product of Step 2 (391 mg, 0.92 mmol), dicyclohexyl[2′,4′,6′-tri(propan-2-yl)biphenyl-2-yl]phosphane (44 mg, 0.092 mmol), Pd2(dba)3 (42 mg, 0.046 mmol), cesium carbonate (602 mg, 1.85 mmol) was added a solution of 5-bromothiazole in a degassed mixture of dioxane (8.4 mL) and water (840 μL). The solution was evacuated and then purged with argon 5 times and then heated at 90° C. overnight. The reaction was cooled, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield methyl 3-(1,3-thiazol-5-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}benzoate (254 mg, 0.67 mmol, 72% yield). MS ESI: [M+H]+ m/z 381.0.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[C:10](I)=[N:9]1)=O)(C)(C)C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[NH:8][N:9]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2ccc([N+](=O)[O-])cc21
Reactant: OB(O)c1ccccc1Cl
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(-c3ccccc3Cl)n[nH]c2c1
Temperature: 110 °C
Reaction time: 36 h
Yield: 215.1 %

Procedure:
To a solution of 3-Iodo-6-nitro-indazole-1-carboxylic acid tert-butyl ester (5.83 g, 14.98 mmol) in 200 mL toluene was added 2-chlorophenyl boronic acid (4.48 g, 28.46 mmol), K3PO4 (7.82 g), Pd2(dba)3 (41.53 mg) and 2-(dicyclohexylphosphino)-2′-methylbiphenyl) (436.68 mg). The reaction mixture was heated to 110° C. and stirred at this temperature for 36 hours. The reaction mixture was cooled and partitioned between water and EtOAc. The orgaic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to give 8.82 g of crude 3-(2-Chloro-phenyl)-6-nitro-1H-indazole, MS (M+H)=275.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:15]2[C:10]3=[C:11]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[CH:13][CH:14]=2.C1C(=O)N([Br:30])C(=O)C1.O>C(Cl)Cl.C(#N)C>[Br:30][C:18]1[CH:19]=[CH:20][C:21]2[N:9]3[C:8]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[C:2]([CH3:22])([CH3:1])[C:15]4[C:10]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:16]=2[CH:17]=1
Reactant: CC1(C)c2ccccc2-n2c3ccccc3c3cccc1c32
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cccc1c32
Reaction time: 4 h

Procedure:
6.3 g (22.2 mmol) of 8,8-dimethylindolo[3,2,1-de]acridine are initially introduced in 150 ml of CH2Cl2. A solution of 3.9 g (22.3 mmol) of NBS in 100 ml of acetonitrile is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane, and the solid is isolated.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C@H:12](O)[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:11]([C@@H:12]([N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@@H](O)c1cc2ccc(F)cc2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](c1cc2ccc(F)cc2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a mixture of (R)-1-(2-chloro-7-fluoroquinolin-3-yl)ethanol (3.03 g, 13.4 mmol), phthalimide (2.37 g, 1.20 eq) and PPh3 (4.23 g, 1.20 eq) in THF (70 mL) was added DIAD (3.13 mL, 1.20 eq) dropwise at 0° C. The mixture was then stirred at rt overnight before partitioning between EtOAc (200 mL) and water (200 mL). The organic layer was separated, washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (DCM) to give a white foam of (S)-2-(1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (3.8 g, 80%). Mass Spectrum (ESI) m/e=355 (M+1).
Reaction SMILES: CN1CCOCC1.[C:8]([C:10]1[CH:27]=[CH:26][C:13]([O:14][CH2:15][CH:16]([NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21])[CH3:17])=[CH:12][CH:11]=1)#[N:9].[CH:28]1[CH:33]=[CH:32][C:31]([O:34][C:35](Cl)=[S:36])=[CH:30][CH:29]=1.O>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH:16]([NH:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:23])[CH3:24])[NH:21][C:35]([O:34][C:31]2[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH3:17])=[CH:26][CH:27]=1)#[N:9]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](N)C(C)C
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CC(COc1ccc(C#N)cc1)NC(=O)[C@@H](NC(=S)Oc1ccccc1)C(C)C
Temperature: 25 °C
Yield: 73 %

Procedure:
0.4 g of N-methyhnorpholine was added to a suspension containing 1.1 g of N1 -[2-(4-cyanophenoxy)-1-methylethyl]-L-valinamide suspended in 40 ml of methylene chloride, at -15° C. After 0.7 g of phenyl chlorothionoformate was added to the mixture at -15° C., the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 1.2 g of the desired product in the form of a yellow glutinous substance (yield: 75%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:36]1[NH:41][CH2:40][CH2:39][N:38]2[C:42](=[O:45])[CH2:43][CH2:44][C@@H:37]12.C(=O)([O-])[O-].[K+].[K+].[NH4+].[Cl-]>CS(C)=O>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([CH3:17])[C:18]2[CH:19]=[N:20][C:21]([N:41]3[CH2:40][CH2:39][N:38]4[C:42](=[O:45])[CH2:43][CH2:44][C@H:37]4[CH2:36]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1CC[C@H]2CNCCN12
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccccc1-c1cc(N2CCN3C(=O)CC[C@H]3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 56.2 %

Procedure:
A 8 ml sealed vial was charged with 100 mg (0.161 mmoles) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577), 67 mg (0.483 mmol) of (8aS)-hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one (WO 2003/066635), 44.5 mg (0.322 mmol) of potassium carbonate; the reagents were dissolved in 0.8 ml of DMSO. The reaction mixture was heated at 180° C. for 36-48 hrs and then added to a saturated NH4Cl solution and back extracted with DCM; the crude material was purified on SPE cartridge (Silica) eluting with a gradient from cyclohexane/ethyl acetate 9:1, to ethyl acetate 100% and affording 56 mg of the title compound as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:15])[CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:12][CH2:13]2)=[C:4]([CH3:15])[CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: Cc1cc(Cl)ccc1C1(O)CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: Cc1cc(Cl)ccc1C1(O)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 42.4 %

Procedure:
To a solution of the 4-(4-chloro-2-methyl-phenyl)-piperidin-4-ol (0.160 g, 0.71 mmol) in isopropanol was added 2,6-lutidine (0.24 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.221 g, 0.59 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.130 g, 36%). 1H-NMR (CDCl3): δ 1.57 (s, 6H), 1.92 (d, 2H), 2.30 (t, 2H), 2.49 (s, 3H), 2.48–2.63 (m, 2H), 2.74–3.11 (m, 6H), 3.40 (s, 1H), 5.21 (bs, 2H), 6.09 (t, 1H), 6.75 (d, 1H), 7.06 (d, 1H), 7.08 (s, 1H), 7.20(d, 2H), 7.22–7.36 (m, 1H), 7.57 (d, 1H), 8.36 (dd, 1H). ESI-MS m/z: 519 (M+1), retention time 1.61.
Reaction SMILES: [F:1][CH2:2][C:3]([NH2:11])([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:19](Cl)(=[O:29])[C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22](Cl)=[O:23].C1(=O)NC(=O)C2=CC=CC1=C2>ClCCl>[F:1][CH2:2][C:3]([N:11]1[C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]2[C:19]1=[O:29])([CH2:8][CH:9]=[CH2:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=CCC(N)(CF)C(=O)OC
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: O=C1NC(=O)c2cccc1c2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(CF)(C(=O)OC)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of methyl 2-fluoromethyl-2-amino-4-pentenoate (2.10 g, 13 mmol) and triethylamine (3 g) in dry dichloromethane, phthaloyl dichloride (2.37 g, 11.7 mmol) is added with ice cooling. After stirring overnight, at room temperature, the solution is washed with water and 1 N HCl. Drying and removal of solvent by evaporation gives a residue, consisting mainly of the iso-phthalimide. The residue is dissolved in dry dichloromethane, two equivalents of triethylamine are added, and the mixture is refluxed overnight. Work-up as described above gives the title compound as an oil (3.0 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:29](C([Sn])=C(CCCC)CCCC)[CH2:30]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.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>[CH3:1][C:2]1[C:3]([CH:29]=[CH2:30])=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)c1cc(Cc2ccc(C)nc2)c(C)c(C)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(C)nc2)c(C)c1C
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a solution of methyl 3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.76 g) in DMF (16.0 mL) were added tributylvinyltin (0.87 g), bis(triphenylphosphine)palladium(II) dichloride (0.06 g) and lithium chloride (0.57 g), and the mixture was stirred at 90° C. for 1.5 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.50 g).
Reaction SMILES: [C:1]([S:4][C:5]1[C:12]([F:13])=[C:11]([F:14])[C:8]([CH:9]=[O:10])=[C:7]([F:15])[C:6]=1[F:16])(=[O:3])[CH3:2].C([O-])(=S)C.C([O-])(=S)C.[K+].SC1C(F)=C(F)C(C=O)=C(F)C=1F.C(Cl)[Cl:40]>>[C:1]([Cl:40])(=[O:3])[CH3:2].[C:1]([S:4][C:5]1[C:12]([F:13])=[C:11]([F:14])[C:8]([CH:9]=[O:10])=[C:7]([F:15])[C:6]=1[F:16])(=[O:3])[CH3:2]
Reactant: ClCCl
Agent: CC(=O)Sc1c(F)c(F)c(C=O)c(F)c1F
Agent: CC([O-])=S
Agent: O=Cc1c(F)c(F)c(S)c(F)c1F
Product: CC(=O)Cl

Procedure:
The next target aldehyde was 4-(S-acetylthio)-2,3,5,6-tetrafluorobenzaldehyde (9) (FIG. 35). The fluorine atom in the para position of pentafluorobenzenes is known to be very reactive toward nucleophilic substitution. Indeed, pentafluorophenyl-substituted porphyrins were recently reported to undergo fluoro-substitution by alkyl thiols (Shaw et al. (1999) Tetrahedron Lett. 40: 1595–1596; Shaw et al. (1999) Tetrahedron Lett. 40: 7585–7586). This result encouraged us to attempt a similar substitution of pentafluorobenzaldehyde with thioacetate using conditions resembling those used in the reaction of potassium thioacetate with benzyl halides. After a vigorous reaction we found that the substrate had vanished, and the only product was a very polar substance which bound at the origin of TLC (silica, CH2Cl2). We surmised that the latter molecule might be the anion of 4-mercapto-2,3,5,6-tetrafluorobenzaldehyde (formed by thioester cleavage following nucleophilic substitution), and upon treatment with acetyl chloride the desired aldehyde 9 was obtained in 69% yield after chromatography.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:13][C:12]([C:27]([C:33]([F:36])([F:35])[F:34])([C:29]([F:32])([F:31])[F:30])[OH:28])=[N:11]1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][N:24]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:25][CH2:26]3)=[CH:19][CH:20]=2)[CH2:13][C:12]([C:27]([C:29]([F:30])([F:32])[F:31])([C:33]([F:34])([F:35])[F:36])[OH:28])=[N:11]1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(N3CCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 405, triethylamine (23.0 uL, 0.17 mmol) and methanesulfonyl chloride (5.0 uL, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:32])[N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Br:31])[CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([C:33]([OH:35])=[O:34])[CH2:12]1)=O)C1C=CC=CC=1.C(OCC)(=O)C.C(O)CCC.C(OCC)(=O)C.O>Br.C(O)(=O)C>[Br:31][C:27]1[CH:26]=[C:25]([N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:17]([N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]2[C:33]([OH:35])=[O:34])=[O:32])[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)N(c1ccccc1)c1cccc(Br)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCO
Product: O=C(O)[C@@H]1CNCCN1C(=O)N(c1ccccc1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 2.13 g (3 96 mmole) portion of (S)-4-(benzyloxycarbonyl)-1-[N-(3-bromophenyl-N-phenylcarbamoyl]piperazine-2-carboxylic acid (from Step B) was dissolved in 40 ml of 30% HBr in acetic acid. After stirring for 1 hour at 25° C., the solution was flushed with nitrogen to remove the excess of HBr. Concentration in vacuo gave an oily residue which was partitioned between 100 ml of methylene chloride and 100 ml of water. The stirred slurry was neutralized to pH 7 with 10% NaOH solution. After a brief stirring the entire mixture was filtered to collect 1.50 g (3.71 mmole, 94%) of white solid which was homogeneous by TLC (5:1:1:1 ethyl acetate-n-butyl alcohol-ethyl acetate-water Rf =0.33).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:21]([O:24][CH2:25][CH2:26]Br)(=[O:23])[CH3:22]>CN(C)C=O.O.CCOCC>[C:7]([NH:6][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:22][C:21]([O:24][CH2:25][CH3:26])=[O:23])(=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OCCBr
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CN(NC(=O)c1ccccc1)C(C)(C)C
Yield: 9.4 %

Procedure:
N'-t-butyl-N-benzoylhydrazine (2.0 g), powdered potassium carbonate (5 g) and bromoethyl acetate (1.6 g) were stirred in dimethylformamide (20 ml) at 60° C. for 14 hours. The reaction mixture was diluted with water and ether, and the organic layer was separated. The organic layer was washed several times with water, dried over magnesium sulfate and rotavapped to afford an oil. Chromatographic purification gave the pure oil product (0.25 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:12]1[C:11]([Cl:10])=[CH:29][C:15]2[CH:16]=[C:17]([C:24]([OH:26])=[O:25])[CH:18]([C:20]([F:22])([F:23])[F:21])[O:19][C:14]=2[CH:13]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(Cl)cc1Br
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)cc3Br)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2-bromo-4-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 223.6-225.6° C. 1H NMR (acetone-d6/300 MHz) 7.89 (s, 1H), 7.83 (d, 1H, J=2.6 Hz), 7.73 (s, 1H), 7.52 (dd, 1H, J=8.7 Hz, 2.4 Hz), 7.25 (d, 1H, J=8.9 Hz), 6.55 (s, 1H), 5.83 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=7.2 Hz) FABLRMS m/z 481 (M−H). ESHRMS m/z 480.8856 (M−H, Calc'd 480.8857). Anal. Calc'd for C17H8BrCl2F3O4: C, 42.18; H, 1.67; Br, 16.51; Cl, 14.65. Found: C, 42.15; H, 1.54; Br, 16.56; Cl, 14.39.