Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>CC(N(C)C)=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Yield: 15 %

Procedure:
A solution of 2-chloro-5-trifluoromethyl-pyridine (2.45 g, 13.50 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.24 g, 16.19 mmol, 1.2 equiv; commercially available) in DMAc (12 mL) was heated by microwave irradiation to 155° C. for 6 h. A solution of 1 M NaOH (100 mL) was added and the reaction mixture extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (4:1→1:1) to yield 0.69 g (15%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.31-1.47 (m, 2H), 1.40 (s, 9H), 1.92-1.98 (m, 2H), 2.81-2.92 (m, 2H), 3.72-3.83 (m, 1H), 3.97-4.03 (m, 2H), 4.77 (d, J=8.1 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 7.62 (dd, J=8.8 Hz, J=2.2 Hz, 1H), 8.25 (br s, 1H). 13C NMR (75 MHz, CDCl3): δ 27.45, 31.17, 41.64, 47.51, 78.72, 105.86, 114.65 (q, J=32.8 Hz), 123.58 (q, J=268.6 Hz), 133.26, 145.15, 153.76, 158.36. 19F NMR (282 MHz, CDCl3): δ-61.22. MS (ISP): 346.1 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:37])([F:36])[C:7]1[CH:8]=[C:9]([C@H:17]2[O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[C:33]([I:34])=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[C@H:18]2[CH3:35])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1>C(O)(=O)C.C([O-])(O)=O.[Na+]>[F:37][C:6]([F:5])([F:36])[C:7]1[CH:8]=[C:9]([C@H:17]2[O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[C:33]([I:34])=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]=4[N+:1]([O-:4])=[O:2])[CH:25]=3)[C@H:18]2[CH3:35])[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2ccccc2cc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2cccc([N+](=O)[O-])c2cc1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Fuming nitric acid was added dropwise to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-iodo-2-naphthyl)methyl]-4-methyl-1,3-oxazolidin-2-one (synthesized from INTERMEDIATE 16 using a method analogous to that described in EXAMPLE 1, Step E) in acetic acid at room temperature. The reaction was stirred at room temperature for 3 h. The reaction was diluted with saturated NaHCO3 (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product as a mixture of product isomers. The main isomer was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-iodo-5-nitro-2-naphthyl)methyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.11 (20% EtOAc/hexanes). LCMS calc.=625.0; found=624.6 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 9.20 (s, 1H); 8.28 (dd, J=1.0, 7.7 Hz, 1H); 8.10 (d, J=8.2 Hz, 1H); 7.93 (s, 1H); 7.89 (s, 1H); 7.81 (s, 2H); 7.61 (t, J=7.9 Hz, 1H); 5.82 (d, J=7.9 Hz, 1H); 4.98 (d, J=15.9 Hz, 1H); 4.48 (d, J=15.9 Hz, 1H); 4.21-4.15 (m, 1H); 0.84 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]2[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]([CH3:16])=[N:3]1.Br[CH2:18][C:19]([N:21]([CH:30]([CH3:32])[CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(Cl)Cl>[CH:30]([N:21]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:19](=[O:20])[CH2:18][NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[C:4]([CH3:16])=[N:3][N:2]([CH3:1])[C:6]=1[CH3:7])([CH3:31])[CH3:32]
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: Cc1nn(C)c(C)c1Nc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2ccccc2Nc2c(C)nn(C)c2C)C(C)C)cc1
Temperature: 80 °C
Yield: 80.7 %

Procedure:
To a solution of N-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-benzene-1,2-diamine (7.56 g, 35.0 mmol) and 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (7.18 g, 38.5 mmol) in DMF (70 mL) was added potassium carbonate (14.5 g, 105 mmol) and potassium iodide (581 mg, 3.5 mmol). The solution was heated at 80° C. for 15 h and subsequently poured into DCM (100 mL). The mixture was extracted with H2O (×4), 1N HCl (×2) and brine, dried over MgSO4 and concentrated in vacuo. The resulting foam was purified by trituration with Et2O to yield the title compound (11.9 g):
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:42]=[C:43]1[CH2:48][CH2:47][CH:46]([C:49]([O-])=[O:50])[CH2:45][CH2:44]1>ClCCl>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:49]([CH:46]2[CH2:47][CH2:48][C:43](=[O:42])[CH2:44][CH2:45]2)=[O:50])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: O=C1CCC(C(=O)[O-])CC1
Reactant: NCc1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(C(=O)NCc2nccnc2Cl)CC1
Reaction time: 16 h
Yield: 104.7 %

Procedure:
To a stirred suspension of 2-aminomethyl-3-chloropyrazine hydrochloride (3.89 mmol, 0.70 g) in dichloromethane (25 mL) at room temperature was subsequently added triethylamine (7.78 mmol, 1.08 mL), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (4.67 mmol, 1.77 g) and finally 4-oxocyclohexanecarboxylate (3.89 mmol, 553 mg). After stirring for 16 hours, the suspension filtered over decalite. The decalite was washed with dichloromethane. The filtrate was washed with water, dried (sodium sulfate) and concentrated in vacuo. The resulting crude product was purified by column chromatography on silica gel (ethyl acetate). The product was dissolved in dichloromethane, washed with water and concentrated in vacuo to afford 1.09 g of the title compound.
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:17][C:18]([F:25])([F:24])[CH2:19][CH2:20][C:21](Cl)=[O:22].Cl>C(OCC)C.C(O)C>[CH2:15]([O:14][C:6](=[O:13])[CH:7]([C:21](=[O:22])[CH2:20][CH2:19][C:18]([F:25])([F:24])[F:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:16]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(Cl)CCC(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)CCC(F)(F)F)C(=O)OCC
Temperature: 55 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
0.1 ml of carbon tetrachloride was added to a mixture of 20.35 g of magnesium(turnings) and 148 ml of ethanol and then heated at 55° C. A mixed solution of 197 ml of ethanol, 700 ml of diethyl ether and 168 g of diethyl malonate was added to the reaction mixture over 1 hour. Two hours later the reaction solution was cooled to -5° C. and 112 g of 4,4,4-trifluorobutyryl chloride was added to the solution under an atmosphere of nitrogen, then the resultant reaction mixture was left at an ambient temperature for 1 hour. Then the mixture was allowed to react further 12 hours. After completion of the reaction, the reaction solution was poured into a 5% hydrochloric acid solution and extracted three times with diethyl ether. The ether layers were combined and washed twice with brine and dried over anhydrous magnesium sulfate. The filtered ether solution was evaporated under reduced pressure. The obtained residue was distilled under reduced pressure to yield 179 g of the desired 4,4,4-trifluoro-butyrylmalonic acid diethyl ester in a yield of 90%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:28]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=2)[C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][C:11]([C:35]1[CH:36]=[CH:37][C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:33][CH:34]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1c(C=O)c2cc(Br)ccc2n1-c1ccc(OC(C)C)cc1
Product: CCOC(=O)c1c(C=O)c2cc(-c3ccc(C(C)(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (a) Example 67 from 5-bromo-3-formyl-1-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (4.07 g, 9.46 mmol; see step (b) above) and 4-tert-butylphenylboronic acid (2.53 g, 14.19 mmol). Yield 4.16 g (91%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:36])([C:32]([F:35])([F:34])[F:33])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[Cl:1][C:2]1[C:11]([O:12][S:24]([C:23]([F:28])([F:29])[C:22]([F:30])([F:31])[C:21]([F:20])([F:36])[C:32]([F:35])([F:34])[F:33])(=[O:26])=[O:25])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(Cl)c(O)c1Cl
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.2 %

Procedure:
9.5 g (43.0 mmol) of methyl 2,4-dichloro-3-hydroxybenzoate in 240 ml of acetonitrile were admixed with 8.6 g (62.2 mmol) of potassium carbonate and then with 9.5 ml (52.8 mmol) of nonafluoro-n-butanesulfonyl chloride. The reaction mixture was stirred at room temperature (RT) for 16 h. For workup, the contents were poured onto ice-water and the mixture was extracted with ethyl acetate. The organic phase was dried and the filtrate was freed of the solvent on a rotary evaporator. The residue was purified by chromatography, which gave 3.5 g of clean product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)[CH:7]=1
Reactant: Cc1cncc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)c1
Yield: 46922 %

Procedure:
A mixture of 3-methyl-5-[4-hydroxy-1-[4-(methylsulfonyl) phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine from step 4 (3.8 g, 0.0095 mmol) and p-toluenesulfonic acid monohydrate (0.91 g, 0.0048 mmol) in 150 mL of toluene was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was partitioned between water and methylene chloride. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo and the crude product was purified by chromatography on silica gel (ethyl acetate/acetone, 98:2) to give 3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine as a yellow solid (1.7 g, 47%): mp (DSC) 196°-198° C; Anal. Calc'd. for C17H14F3N3O2S: C, 53.54, H, 3.70, N, 11.02, 8.41. Found: C, 53.50, H, 3.65, 10.82, S, 8.55.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5](I)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1)CCC.[F-].[Cs+]>C(#N)C.[Cu](I)I.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:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:25]2[CH:30]=[CH:29][N:28]=[N:27][CH:26]=2)=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1
Reactant: Oc1cc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: Oc1cc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1-c1ccnnc1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
2-Chloro-5-iodo-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 51, 230 mg, 0.57 mmol) was dissolved in acetonitrile (3 mL), 4-(tributylstannyl)pyridazine (273 mg, 0.75 mmol), caesium fluoride (173 mg, 1.14 mmol), copper iodide (22 mg, 0.114 mmol) and tetrakis(triphenylphosphine)palladium (0) (70 mg, 0.06 mmol) were added. The reaction was stirred at 45° C. for 1.5 hours and then after cooling to room temperature was partitioned between ethyl acetate (100 mL) and water (50 mL) containing 0.880 ammonia (1 mL). The mixture was stirred for 20 minutes. The ethyl acetate phase was separated and washed with an aqueous solution of potassium fluoride (1.5 g in 20 mL), 1M hydrochloric acid (20 mL) and aqueous ammonia (1 mL 0.880 in 50 mL water). The ethyl acetate was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica eluting with a gradient of dichloromethane:methanol 100:0 to 95:5 to give the title compound (144 mg, 0.40 mmol, 71%) as a white solid.
Reaction SMILES: CC(S([NH:7][C@@H:8]([C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][CH:15]=1)[CH3:9])=O)(C)C.Cl>CO>[F:19][C:16]([F:17])([F:18])[C:13]1[N:12]=[CH:11][C:10]([C@H:8]([NH2:7])[CH3:9])=[CH:15][N:14]=1
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1cnc(C(F)(F)F)nc1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of 2-methyl-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}propane-2-sulfinamide (7.23 g, 24.5 mmol) in methanol (100 mL) was added HCl (4.0 M in dioxane; 18.5 mL, 74.0 mmol). The mixture was stirred at ambient temperature. After 1 h, the mixture was concentrated to give the title compound (4.6 g).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([N:11]([CH3:26])[C:12](=[O:25])[N:13]([CH3:24])[C:14]2=[O:23])=[CH:9]1)C.O.[OH-].[Li+]>C1COCC1>[CH3:26][N:11]1[C:10]2=[CH:9][N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3])[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]2[C:14](=[O:23])[N:13]([CH3:24])[C:12]1=[O:25]
Reactant: CCOC(=O)CCCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCCC(=O)O)cc2n(C)c1=O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
4-(1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-butyric acid ethyl ester (step 1)(1.01 g, 2.73 mmol) was dissolved in THF (10 ml) and water (10 ml) and lithium hydroxide (0.655 g, 27.3 mmol) were added. The mixture was stirred at 60° C. for 5 hours. Further lithium hydroxide (0.655 g, 27.3 mmol) was added and the mixture stirred at 60° C. for a further 24 hours. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was acidified using 1M HCl(aq) and extracted with chloroform (5×). The combined organic phases were passed through a hydrophobic frit and evaporated under reduced pressure. The title product was obtained as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.[OH-].[Na+]>C1COCC1>[C:29]([NH:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[C:20](=[O:32])[N:19]([CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1)[CH2:4][C:3]([OH:33])=[O:2])[CH2:27]2)(=[O:31])[CH3:30]
Reactant: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To the THF solution of 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (2.5 g, 5.4 mmol) was added dropwise 10N NaOH (1 ml, 10 mmol) and was stirred at room temperature overnight. The resulted suspension was filtered and the solid was dissolved in water (20 ml). The aqueous solution was acidified to pH=4 to obtain a milky suspension. The suspension was extracted with EtOAc (50 ml×3). The organic layer was washed with water (50 ml×2), brine (30 ml), dried over Na2SO4 and concentrated to give white solid (2.3 g, 96% yield): mp 105-107° C.; 1HNMR (CDCl3): δ 1.42 (J=7.5 Hz, 3H, OCH2CH3), 2.22 (s, 3H), 3.11 (dd, J=5, 12 Hz, 1H, CH2), 3.25 (dd, J=10, 15 Hz, 1H, CH2), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.12 (d, J=17.5 Hz, 1H, CH2N), 4.38 (d, J=17.5 Hz, 1H, CH2N), 5.81 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 6.96 (m, 3H, Ar), 7.13 (d, J=7.5 Hz, 1H, Ar), 7.45 (m, 1H, Ar), 8.43 (d, J=7.5 Hz, 1H, Ar), 10.25 (s, 1H, NHCO). 13CNMR (CDCl3): δ 14.6, 24.8, 36.7, 46.8, 51.7, 64.9, 111.8, 111.3, 115.9, 117.1, 117.3, 118.0, 118.9, 120.1, 122.8, 133.5, 136.7, 137.8, 140.1, 141.2, 150.9, 169.47, 169.49, 173.5; Anal. Calcd. for C22H22F2N2O6+0.22H2O: C, 58.41; H, 5.00; N, 6.19. Found: C, 58.06; H, 4.92; N, 5.90.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cnc(-c2ccc([N+](=O)[O-])cc2)s1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1cnc(-c2ccc(N)cc2)s1
Yield: 74.4 %

Procedure:
The same operation as in Example (90d) was performed using ethyl 2-(4-nitrophenyl)-1,3-thiazole-5-carboxylate obtained in Example (91a) (0.18 g, 0.65 mmol), 10% Pd/C (wet, 0.1 g), ammonium formate (0.2 g, 3.24 mmol) and methanol (5 mL), to obtain 0.12 g of the crude title compound as a yellow solid (75%).
Reaction SMILES: [Cl:1][C:2]1[C:10](I)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:10]([CH:12]2[CH2:14][CH2:13]2)=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: OB(O)C1CC1
Reactant: Clc1nn2ccccc2c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Clc1nn2ccccc2c1C1CC1
Temperature: 100 °C

Procedure:
A mixture of the title compound from Example 1 Step A (0.250 g, 0.898 mmol), palladium acetate (0.020 g, 0.090 mmol), cyclopropyl boronic acid (0.154 g, 1.80 mmol), cesium carbonate (0.878 g, 2.69 mol), and triphenylphosphine (0.047 g, 0.180 mmol) in tetrahydrofuran (8.98 mL) was heated in a sealed tube at 100° C. for 18 hours. The reaction mixture was then cooled to room temperature, filtered and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography on silica gel (0-15% ethyl acetate in hexanes) provided the title compound: LCMS m/z 192.93 [M+H]+, 194.89 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.29 (d, J=7.0 Hz, 1 H), 7.49 (d, J=12.8 Hz, 1 H), 7.21 (dd, J=7.5, 7.5 Hz, 1 H), 6.70 (dd, J=6.3, 6.3 Hz, 1 H), 1.79-1.74 (m, 1 H), 0.98-0.95 (m, 2 H), 0.75-0.73 (m, 2 H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:13])=[C:10]([CH3:12])[S:11][C:5]=2[N:4]=[C:3]1[S-:14].[K+].NC1SC(C)=C(C)C=1C(OCC)=O.Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:35][CH2:34]1.C(O)C>C(Cl)(Cl)Cl>[NH2:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([CH3:13])=[C:10]([CH3:12])[S:11][C:5]=2[N:4]=[C:3]1[S:14][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=2)[CH2:35][CH2:34]1
Reactant: Cc1sc2nc([S-])n(N)c(=O)c2c1C
Reactant: ClCCCN1CCN(c2ccc3ccccc3n2)CC1
Agent: CCOC(=O)c1c(N)sc(C)c1C
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: Cc1sc2nc(SCCCN3CCN(c4ccc5ccccc5n4)CC3)n(N)c(=O)c2c1C
Yield: 49.7 %

Procedure:
A mixture of 80 mg of potassium 3-amino-5,6-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-thiolate, which was prepared from ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate; 104 mg of 2-[4-(3-chloropropyl)piperazin-1-yl]quinoline as prepared in the Step 1-1-B; and 5 ml of ethanol, was heated under reflux for 4.5 hours. After cooling off the reaction mixture, chloroform was added, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=100: 1) to provide 72 mg (50%) of 3-amino-5,6-dimethyl-2-[3-(4-quinolin-2-ylpiperazin-1-yl)-propylthio]-3H-thieno[2,3-d]pyrimidin-4-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C)C=O>[CH3:15][O:14][N:12]([CH3:13])[C:10](=[O:11])[CH:9]=[CH:8][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([S:17][CH3:16])=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CON(C)C(=O)C=Cc1cccc(Br)c1
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: CN(C)C=O
Product: CON(C)C(=O)C=Cc1cccc(-c2ccc(SC)cc2)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 104.6 %

Procedure:
3-(3-Bromo-phenyl)-N-methoxy-N-methylacrylamide (14.5 g, 53.7 mmol) prepared in Step 1, 4-(methylthio)phenylboronic acid (18.0 g, 107.4 mmol), Pd(PPh3)4 (3.1 g, 2.7 mmol) and sodium carbonate (17.1 g, 161.1 mmol) were added to a mixed solvent of N,N-dimethylformamide (100.0 mL) and distilled water (10.0 mL). The reaction mixture was stirred at 80° C. for 20 hours, quenched with a saturated solution of ammonium chloride, and then extracted with diethyl ether three times. The combined extract was washed with 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=1/3) to give 17.6 g of the titled compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1B(O)O>>[Br:8][C:6]1[CH:5]=[C:4]([OH:9])[CH:3]=[C:2]([C:17]2[CH:16]=[C:15]([F:18])[CH:14]=[CH:13][C:12]=2[O:11][CH3:10])[CH:7]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1cc(O)cc(Br)c1

Procedure:
Example 54 was synthesized in 4 steps from 3-,5-dibromophenol. 2-Methoxy-5-fluorophenyl boronic acid was reacted as described above, step 1. In this manner was isolated 5-bromo-5′-fluoro-2′-methoxy-biphenyl-3-ol, which was then reacted with 3-fluorophenyl boronic reacted as described above, Step 2. In this manner, 3,5″-difluoro-2″-methoxy-[1,1′;3′,1″]terphenyl-5′-ol was obtained.