Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:20])[N:9]=2)[C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2[nH]ncc12
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cl)c2nn(C)cc12
Reaction time: 5 h
Yield: 71.3 %

Procedure:
To a solution of methyl 7-chloro-1H-indazole-4-carboxylate (5.40 g, 25.6 mmol) in ethyl acetate (150 mL) was added trimethyloxonium tetrafluoroborate (5.69 g, 38.5 mmol) at room temperature, and the mixture was stirred for 5 hr. The is reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (4.10 g, yield 71%).
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])#[N:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]([CH:36](OC)[O:37][CH3:38])[C:32]([O:34][CH3:35])=[O:33])[CH:19]=1.[F-].[K+]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2/[C:31](=[CH:36]\[O:37][CH3:38])/[C:32]([O:34][CH3:35])=[O:33])[CH:19]=1)#[N:3]
Reactant: COC(=O)C(c1ccccc1Oc1cc(Cl)ncn1)C(OC)OC
Reactant: N#Cc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 90 °C
Reaction time: 23 h

Procedure:
Methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3,3-dimethoxypropanoate in methylcyclohexane/chloromethoxypyrimidine (200.9 g, 59.91% strength) was vacuum distilled to leave the propanoate melt. A solution of the potassium salt of 2-cyanophenol was then prepared by mixing 2-cyanophenol (53.2 g) and potassium carbonate (81.2 g) in water (275 g). This solution was added to the methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3,3-dimethoxypropanoate melt, which had previously been cooled to 90° C. Potassium fluoride (15.9 g) and tetrabutylammonium bromide (21.5 g) was then added to the reaction solution. The resulting mixture was stirred at 105° C. for 23 hours. Any distillates were allowed to come off under atmospheric conditions. (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate was produced (77.9 area %).
Reaction SMILES: Br[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:13].[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:21][CH2:22]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(N3CCN(c4ccccc4)CC3)ccc12
Yield: 15.2 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (100 mg, 0.385 mmol), 1-phenylpiperazine (0.064 mL, 0.424 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), rac-BINAP (36 mg, 0.058 mmol) and NaOtBu (46 mg, 0.479 mmol) in DMA (3 mL) was heated in a microwave at 90° C. for 10 minutes. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(4-phenyl-piperazin-1-yl)-2H-phthalazin-1-one (20 mg) as an orange solid, 1H (400 MHz, d6-DMSO) δ: 3.32 (m, 4H), 3.61 (m, 4H), 6.81 (t, 1H), 7.00 (d, 2H), 7.15 (d, 1H), 7.24 (t, 2H), 7.62 (dd, 1H), 8.07 (d, 1H), 12.57 (s, 1H) ppm; m/z (M+1) 341.01.
Reaction SMILES: [Br:1]Br.[CH:3]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:12]=2)=[CH:9][N:8]=[C:7]1[CH3:28])([CH3:5])[CH3:4]>C(O)(=O)C>[Br:1][C:16]1[C:11]([C:10]2[N:6]([CH:3]([CH3:5])[CH3:4])[C:7]([CH3:28])=[N:8][CH:9]=2)=[N:12][C:13]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[N:14][CH:15]=1
Reactant: BrBr
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(S(C)(=O)=O)cc3)n2)n1C(C)C
Solvent: CC(=O)O
Product: Cc1ncc(-c2nc(Nc3ccc(S(C)(=O)=O)cc3)ncc2Br)n1C(C)C
Temperature: 60 °C
Yield: 111 %

Procedure:
Bromine (50 μl, 0.94 mmol) was added to a solution of 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-mesylanilino)pyrimidine (Example 69; 350 mg, 0.94 mmol) in glacial acetic acid (3.5 ml). The mixture was heated at 60° C. for 140 minutes and the volatiles were then removed by evaporation. The residue was azeotroped with water to give a gum, which was then triturated with EtOAc to give a solid (470 mg). This crude product was purified by chromatography on silica gel eluting with DCM/MeOH (98:2 increasing in polarity to 95:5). The purified product was triturated with EtOAc to give the title compound (125 mg, 30%) as a solid. NMR: 1.39 (d, 6H), 2.48 (s, 3H), 3.12 (s, 3H), 4.68 (sept, 1H), 7.20 (s, 1H), 7.81 (d, 2H), 7.92 (d, 2H), 8.79 (s, 1H), 10.28 (br s, 1H); m/z 450.
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH2:26]O)[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.S(Cl)([Cl:35])=O>>[Cl:35][CH2:26][C:24]1[NH:23][C:17]2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=[C:15]([C:6]3[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:2]=3[F:1])[C:16]=2[CH:25]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(CO)[nH]c2c1=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(CCl)[nH]c2c1=O

Procedure:
A mixture of Example 276 (0.50 g, 1.09 mmol) and thionyl chloride (5.0 mL, 69 mmol) was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the residue was dried under vacuo for 1 hour to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[NH:16][CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH3:22]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[N:16]([CH2:21][CH3:22])[CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sc3cc[nH]c3c2CC1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2sc3ccn(CC)c3c2CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a stirred solution of the product of Example 1, step (g) (0.068 g, 0.26 mmol) in DMF (4 ml) at 0° C. under argon was added NaH (60% dispersion by wt., 0.015 g, 0.39 mmol) followed by ethyl bromide (0.029 ml, 0.39 mmol). The reaction mixture was stirred at 0° C. for 2 hrs and then quenched by slow addition of saturated aqueous citric acid (40 ml). The aqueous mixture was extracted with DCM (3×). The combined DCM extracts were washed with water (2×), brine, dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 50% EtOAc in hexanes) gave the sub-titled compound as a tan solid (0.060 g). 1H NMR (CDCl3) δ 6.75 (d, J=3.0 Hz, 1 H), 6.24 (d, J=3.0 Hz, 1H), 4.40-4.08 (m, 4H), 3.96-3.62 (m, 4 H), 3.34-2.92 (m, 4 H), 1.42 (t, J=6.9 Hz, 3 H), 1.28 (t, J=6.9 Hz, 3H); MS: ESI (positive): 293 (M+H).
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:22]([OH:24])=O)[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][N:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:22]([NH:34][C@@H:32]([C:29]3[CH:28]=[N:27][C:26]([CH3:25])=[N:31][CH:30]=3)[CH3:33])=[O:24])[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[CH:14]=2)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(=O)(=O)C3CCCC3)c2)cc1
Reactant: Cc1ncc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(S(=O)(=O)C3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(cyclopentylsulfonyl)-4′-methylbiphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (40 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (140 μL, 0.80 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford the final product as a light color solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[O:6]=[C:7]=[N:8][CH:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:11]([CH3:21])([CH2:12][N:13]=[C:14]=[O:15])[CH2:10]1>O1CCCC1>[OH:1][CH2:2][CH2:3][N:4]([C:14]([NH:13][CH2:12][C:11]1([CH3:21])[CH2:10][CH:9]([NH:8][C:7]([N:4]([CH2:3][CH2:2][OH:1])[NH2:5])=[O:6])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16]1)=[O:15])[NH2:5]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: NNCCO
Solvent: C1CCOC1
Product: CC1(C)CC(NC(=O)N(N)CCO)CC(C)(CNC(=O)N(N)CCO)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a rapidly stirred mixture of 2-hydroxyethylhydrazine 16.74 g (0.22 moles) in 250 ml tetrahydrofuran was added dropwise isophorone diisocyanate ◯2 in 0.10 moles (22.23 g) in 180 ml tetrahydrofuran. After addition was complete, the solution was clear and colorless. The solution was stirred for an additional three hours at room temperature. The solvent was removed by rotary evaporation to yield a colorless syrup. Characterization by IR and NMR showed it to be predominantly the postulated structure. The sample was utilized without further purification in screening for antioxidant effectiveness.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl/[C:12](=[N:18]\[OH:19])/[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:10][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[O:19][N:18]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=1
Reactant: CCOC(=O)/C(Cl)=N/O
Reactant: C#CC(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(C(O)c2ccccc2)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
1-phenylprop-2-yn-1-ol (0.802 mL, 6.60 mmol) was added to a mixture of (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (0.50 g; 3.30 mmol) and sodium hydrogen carbonate (0.554 g; 6.60 mmol) in ethyl acetate (15 mL) and water (0.2 mL) and stirred at room temperature for 24 hours. The resulting mixture was filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 40% ethyl acetate in heptane) to yield 0.571 g (70%) of ethyl 5-(hydroxy(phenyl)methyl)isoxazole-3-carboxylate as a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:23])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12](Cl)=[CH:11][CH:10]=2)=[O:5])C.Cl.[O:25]1[CH2:30]COCC1>O>[CH3:14][C:9]1[CH:10]=[C:4]([C:6]2[C:7](=[O:23])[NH:8][C:9]3[C:14]([C:15]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][C:12]([CH:30]=[O:25])=[CH:11][CH:10]=3)[O:5][N:8]=1
Reactant: C1COCCO1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2[nH]c1=O
Agent: Cl
Solvent: O
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(C=O)ccc3[nH]c2=O)on1
Yield: 78 %

Procedure:
A mixture of 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (200 mg, 0.61 mmol), 10% HCl (1 mL) and dioxane (3 mL) was heated to reflux for 48 h. After cooling, water was added and the resulting precipitate was collected by filtration, washed with water and dried to afford 6-chloro-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid (a) (143 mg, 78%). MS: 300.5 (M+H).
Reaction SMILES: Cl[C:2]1[CH:13]=[C:12](F)[C:11](N2C(=O)C=C(C(F)(F)F)N=C2OC)=[CH:10][C:3]=1[C:4]([O:6]C(C)C)=[O:5].S(=O)(=O)(O)O>C(Cl)Cl>[C:4]([OH:6])(=[O:5])[C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:2]=1
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C(O)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 5 g of isopropyl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoate in 20 ml of methylene chloride is treated with 25 ml of concentrated sulphuric acid while stirring and cooling at 20°-25° C. The reaction mixture is stirred at room temperature for 20 minutes and poured onto 100 g of ice. The organic phase is separated, the aqueous phase is extracted twice with 15 ml of ethyl acetate each time and the combined organic phases are washed to neutrality with water. The solution is subsequently dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous residue is recrystallized from diethyl ether/n-hexane. There is obtained 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl[-benzoic acid, m.p. 205°-210° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].C1([C@@H](N)C)C=CC=CC=1.[CH:20]([C:22]([F:25])([F:24])[F:23])=[O:21].Cl>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[F:23][C:22]([F:25])([F:24])[C@H:20]([OH:21])[CH2:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: O=CC(F)(F)F
Agent: C[C@H](N)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(C[C@@H](O)C(F)(F)F)c1ccc(Cl)cc1
Temperature: 25.5 °C
Reaction time: 1.33 h
Yield: 98.9 %

Procedure:
At first, 5.5 g (40 mmol) of zinc chloride were added to a toluene solution (4 liters) containing 649 g (4.2 mol) of 4-chloroacetophenone (1b) as a ketone and 484 g (4.0 mol) of (S)-1-phenylethylamine ((S)-2a) as an optically active primary amine, followed by heating under reflux for 20 hr and by removing water (formed as a by-product) with a Dean-Stark tube during the reaction, in order to conduct the reaction. Then, 564 g (4.0 mol) of fluoral.ethylhemiacetal (4a) were dropped to the reaction liquid by spending 80 minutes at a temperature of not higher than 5° C., followed by stirring at 25-26° C. for 24 hr, thereby conducting the reaction. Then, 4-liter of 1N HCl were added to the reaction liquid, followed by stirring at room temperature for 1 hr, then washing with 2-liter of water, then concentration, and then vacuum drying, thereby obtaining 999 g of (R)-4,4,4-trifluoro-3-hydroxy-1-(4-chlorophenyl)-1-butanone ((R)-5ba, purity: 72%). Its optical purity was found to be 54% ee by the chiral HPLC as that of Example 1-30
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.O.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>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Oc1ccc(Br)nc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
A mixture of 6-bromo-3-pyridinol (1.28 g, 7.35 mmol), [4-(methylsulfonyl)phenyl]boronic acid (1.47 g, 7.35 mmol), and 2M Na2CO3 (5 mL) in DMF (15 mL) was treated with PdCl2(PPh3)2 (0.52 g, 0.74 mmol) and the mixture was heated at 50° C. overnight. The reaction was treated with additional catalyst (PdCl2(PPh3)2, 0.26 g, 0.37 mmol) and was heated at 50° C. overnight, then was heated at 90° C. overnight. The reaction was allowed to cool to room temperature and was diluted with EtOAc and water and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and concentrated. The resulting residue was treated with MeOH and cooled in an ice bath. The resulting precipitate was collected, washed with cold MeOH and air-dried and the filtrates were combined and set aside. The resulting tan solid was dissolved in 10% MeOH/CH2Cl2 and loaded onto a 220 g silica column, which was eluted with 1 to 5% MeOH/CH2Cl2 over 30 min, followed by 5% MeOH/CH2Cl2 for 30 min to provide 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (0.36 g, 20%) as a tan solid. The mother liquors from the MeOH trituration step were concentrated and purified by chromatography 1 to 5% MeOH/CH2Cl2 over 20 min to provide additional product (0.24 g, 33% overall yield) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=3)[CH:19]=[CH:18]2)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccc(Cl)cc3)c2c1

Procedure:
The titled compound (17 mg) as a light brown solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 4-chlorobenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[CH:34]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:39]([CH:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:40])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(C1CCCC1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 33.8 %

Procedure:
(5-Chloro-benzo[1,3]dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (100 mg, 0.29 mmol) and DIEA (0.15 mL, 0.88 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Cyclopentanecarbonyl chloride (0.04 mL, 0.35 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 70 (43 mg, 33% yield) as a white fluffy solid. LC-MS (M+H=439, obsd.=439).
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:5].[OH-].[Li+].Cl>CO>[CH3:12][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:5])[C:3]([OH:13])=[O:2]
Reactant: COC(=O)C(C)(C)c1ccccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccccn1
Reaction time: 12 h

Procedure:
A solution of 0.275 g of 2-methyl-2-pyridin-2-yl-propionic acid methyl ester [CAS 476429-22-8] in 10 ml of methanol at room temperature is admixed with 3.65 ml of 1M aqueous lithium hydroxide solution. After stirring for 12 hours, the reaction mixture is adjusted to pH 6-7 with 1M HCl and concentrated by evaporation. The residue is dissolved in 60 ml of 5:1 ethyl acetate/methanol, dried over sodium sulphate and concentrated by evaporation to provide the crude title compound as a yellow solid which is used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([I:10])[CH:5]=[CH:4][N:3]=1.CC(=CC)C.P([O-])([O-])([O-])=[O:17].[Na+].[Na+].[Na+].Cl([O-])=O.[Na+].Cl>C(O)(C)(C)C.O.ClCCl>[F:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]([I:10])[C:7]=1[C:8]([OH:17])=[O:9]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=Cc1c(I)ccnc1F
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c(I)ccnc1F
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 100 %

Procedure:
To a stirred solution of 2-fluoro-4-iodopyridine-3-carboxaldehyde (10.0 g, 39.8 mmol) in tert-butanol (350 mL) and water (100 mL) at room temperature were added 2-methyl-2-butene (42.1 ml, 398 mmol), sodium phosphate, monobasic, monohydrate (60.5 g, 438 mmol) and sodium chlorite (18.0 g, 199 mmol). The reaction mixture was stirred at room temperature for 75 min. The reaction mixture was diluted with dichloromethane and a 6M aqueous solution of hydrochloric acid was added until pH ˜2. The water layer was extracted with dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. Purification by MPLC (CH2Cl2/MeOH+1% AcOH: 100/0 to 80/20) afforded 2-fluoro-4-iodonicotinic acid (10.63 g, 39.8 mmol, 100% yield). MS (ESI pos. ion) m/z: 268 (MH+). Calc'd exact mass for C6H3FINO2: 267.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[C:24]([S:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:25]=[N:26]3)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[OH-:36].[Ca+2].[OH-:38]>ClCCl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:28]=[C:27]3[C:22]([CH:23]=[C:24]([S:29]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])(=[O:38])=[O:36])[CH:25]=[N:26]3)=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)CCSc1cnc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: COC(=O)CCS(=O)(=O)c1cnc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
3-Chloroperoxybenzoic acid (77%; 8.05 g, 36 mmol) was added portionwise to a solution of methyl 3-{[7-(4-fluorophenyl)quinolin-3-yl]thio}propanoate (5.57 g, 16 mmol) in dichloromethane (150 mL). The resulting mixture was stirred at room temperature under nitrogen for 1 hour. Calcium hydroxide (5.1 g, 69 mmol) was added portionwise and the resulting slurry stirred for 30 minutes. The mixture was filtered and the filter cake washed thoroughly with dichloromethane. The filtrate was evaporated and the residue purified by flash chromatography, eluting with 10-15% ethyl acetate/isohexane, to give methyl 3-{[7-(4-fluorophenyl)quinolin-3-yl]sulfonyl}propanoate as a white solid (5.09 g, 84%). 1H NMR (500 MHz, CDCl3) δ 9.30 (1H, d, J 2.2 Hz), 8.77 (1H, d, J 2.0 Hz), 8.39 (1H, s), 8.06 (1H, d, J 8.5 Hz), 7.95 (1H, dd, J 1.7, 8.5 Hz), 7.77-7.73 (2H, m), 7.25-7.21 (2H, m), 3.61 (3H, s), 3.59 (2H, t, J 7.5 Hz), 2.86 (2H, t, J 7.5 Hz); m/z (ES+) 374 [MH+].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH2:23]([O:22][C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCOC(=O)Nc1ccc2[nH]cc(C3=CCN(CC)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.068 mMol) ethyl chloroformate, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 315(M+1)