Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][CH2:13][C:14]([OH:16])=O.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][CH2:13][C:14]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16]
Reactant: O=C(O)CCC1CCc2ccccc2C1=O
Reactant: C1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2CCC1CCC(=O)N1CCCCC1
Yield: 86.2 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-oxo-2-naphthalenepropanoic acid (6.3 g), piperidine (3.7 g) and BOP Reagent (15.4 g) in dichloromethane (150 ml) was added dropwise triethylamine (3.5 g) at 25° C., and the mixture was refluxed for three hours. The reaction mixture was washed successively with water and 10% hydrochloric acid, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate=10:1), and the fractions containing the desired compound were combined, and concentrated under reduced pressure to give the desired compound (7.1 g) as an oily product.
Reaction SMILES: [CH2:1]([C@H:8]1[C:12]([CH3:14])([CH3:13])[O:11][C:10](=[O:15])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].C(OCC)(=O)C>O1CCCC1>[CH3:23][C:22]([CH3:25])([CH3:24])[C:21]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([CH3:13])([CH3:14])[O:11][C:10]1=[O:15])=[O:26]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)OC(=O)N[C@H]1Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1C(=O)OC(C)(C)[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Reaction of the auxiliary (10) (0.085 g, 0.415 mmol) in solution in tetrahydrofuran (2 ml) at -78° C. with butyllithium (1.6M, 0.262 ml, 0.419 mmol) and pivaloyl chloride (0.056 ml, 0.456 mmol) for 30 minutes and then at room temperature for 2 hours with work-up and flash column chromatography using 30% ethyl acetate/40-60 petroleum ether furnished the title compound (19) as an oil (0.104 g, 87%); νmax (CDCl3) 1742 cm-1 ; δH (CDCl3 ; 300 MHz) 1.30 (3H, s, C(CH3)2), 1.34 (6H, s, C(CH3)3), 1.35 (3H, s, C(CH3)2), 2.86 (1H, dd, J=9.3 and 14.2, CH2Ph), 3.05 (1H, dd, J=4.1 and 14.2, CH2Ph), 4.53 (1H, dd, J=4.2 and 9.3, CHCH2), 7.18-7.28 (5H, m, ArCH); δC (125 MHz; CDCl3) 22.10 (CH3), 26.29 (CH3), 28.07 (CH3), 35.24 (CH2), 41.68 (C), 65.47 (CH), 81.80 (C), 126.94 (CH), 128.76 (CH), 129.38 (CH), 137.19 (C), 152.03 (CO), 179.49 (CO); m/z (CI+, NH3) 290 (M+ +1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.[CH:12]([Mg]Br)=[CH2:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]2[NH:9][CH:12]=[CH:13][C:3]=12
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Cc1ncc(Br)c2cc[nH]c12
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
5-Bromo-2-methyl-3-nitropyridine (217 mg, 1 mmol) was dissolved in THF (10 mL) and the solution was cooled to −50° C. under argon. Vinylmagnesium bromide (3 mL, 1M in THF) was added immediately in one portion, resulting in a bright orange solution. The orange solution was stirred at −40° C. for 30 min and the reaction was quenched by the addition of NH4Cl (10 mL of saturated. aqueous solution). The mixture was diluted with water and extracted with EtOAc (2×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. The crude material was purified by chromatography on silica (Si—PPC) using EtOAc in cyclohexane (20-80%) as eluent to give the product as a pale yellow crystalline solid (63 mg, 30%). 1H NMR (CDCl3) 8.23 (s, 1H), 7.41-7,45 (m, 1H), 6.62-6.65 (m, 1H), 2.73 (s, 3H)
Reaction SMILES: Cl[C:2]1[N:14]=[C:13]([O:15][CH2:16][CH:17]([F:19])[F:18])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][CH2:7]C(F)F)=[O:5].[CH3:20][O-:21].[Na+].O>C1COCC1>[F:18][CH:17]([F:19])[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:21][CH3:20])[N:14]=1
Reactant: C[O-]
Reactant: O=C(OCC(F)F)c1ccc(OCC(F)F)nc1Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC(F)F)nc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.4 %

Procedure:
To a stirred solution of 2,2-difluoroethyl 2-chloro-6-(2,2-difluoroethoxy)nicotinate (2.9 g, 9.8 mmol, Step-1) in THF (35 mL) is added sodium methoxide (1.58 g, 29.2 mmol) at 0° C. Then the mixture is stirred at rt for 15 hours. The mixture is poured into water and extracted with DCM (10 mL×3). The combined organic layer is washed with water, brine, and dried over sodium sulfate. The organic solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (4:1 to 1:4) to give 615 mg (26% yield) of the title compound as white solid.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][CH2:8][CH:9]([C:26](=[O:28])[NH2:27])[NH:10][C:11](=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClC(Cl)C>[C:26]([CH:9]([NH:10][C:11](=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:7][C:6]([OH:29])=[O:5])(=[O:28])[NH2:27]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(Nc2ncccn2)cc1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: NC(=O)C(CCC(=O)O)NC(=O)c1ccc(Nc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Carbamoyl-4-[4-(pyrimidin-2-ylamino)-benzoylamino]-butyric acid tert-butyl ester was dissolved in dichloroethane (10 mL), followed by the addition of TFA (5 mL). The mixture was stirred at room temperature for 4 hrs. TLC indicated the reaction was complete. Solvents were then removed by rotavap and the residue was washed with EtOAc. A solid was collected by filtration and dried in vacuum oven overnight. 4-Carbamoyl-4-[4-(pyrimidin-2-ylamino)-benzoylamino]-butyric acid was obtained in quantitative yield (285 mg). MS (ESI) m/z 344.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[Se:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:14]([O-])=O.[Na+]>S(=O)(=O)(O)O>[N:1]1[C:2]2[C:3]3[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=3[Se:5][C:6]=2[C:7](=[O:8])[NH:9][N:14]=1
Reactant: NC(=O)c1[se]c2ccccc2c1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]nnc2c1[se]c1ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
To an ice cold (0° C.) solution of 3-aminobenzo[b]selenophene-2-carboxamide (1.0 g, 4.16 mmol) in concentrated sulfuric acid (25 mL) was added a cold (0° C.) solution of sodium nitrite (0.316 g, 4.58 mmol) in concentrated sulfuric acid (10 mL) for 10 min (while adding, the temperature should keep between −5-0° C.). After addition, the mixture was stirred at 0° C. for 1 h and at rt for 2 h. The reaction mixture was cooled, poured into crushed ice slowly with stirring for 15 min and stirred at the same temperature for 15 min. The solution was extracted with ethyl acetate (3×200 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered, evaporated the solvent to give the product as a yellow color solid (200 mg, 19%), mp 176-178° C. 1H NMR (400 MHz, DMSO-d6): δ 15.48 (1H, s, —NH), 8.53-8.58 (1H, m, H-9), 8.41-8.46 (1H, m, H-6), 7.74-7.80 (2H, m, H-7,8).
Reaction SMILES: OS(O)(=O)=O.[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].[CH:14]([C:16]([CH3:18])=O)=[CH2:15]>O1CCOCC1>[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:8]=1[N:9]=[CH:15][CH:14]=[C:16]2[CH3:18]
Reactant: C=CC(C)=O
Reactant: Nc1ccccc1F
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1ccnc2c(F)cccc12
Yield: 41.4 %

Procedure:
Add H2SO4 (14.4 mL, 270 mmol) to a solution of 2-fluoroaniline (20.0 g, 180 mmol) in 1,4-dioxane (1 L) at room temperature. Heat the mixture to reflux and add methyl vinyl ketone (19.5 mL, 270 mmol) in 1,4-dioxane (50 mL) dropwise over 3 hours. Continue to heat for 1 hour after the addition, then remove the solvent under vacuum. Dissolve the residue in water (100 mL), neutralize with Na2CO3 and extract with CH2Cl2. Wash the combined organic extracts with water and brine, dry with anhydrous Na2SO4 and filter the mixture. Concentrate the filtrate; chromatograph the residue with silica gel (elute with 20% EtOAc in hexanes) to give the title compound 12 g (41%) as a yellowish solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.CC([N:12]([CH2:16][C@@H:17]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][N:34]=2)[CH:32]=1)=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C(=O)[O-])(C)C>C(Cl)Cl>[NH2:12][CH2:16][C@@H:17]([NH:25][C:26]([C:28]1[S:29][CH:30]=[C:31]([C:33]2[N:37]([CH3:38])[N:36]=[CH:35][N:34]=2)[CH:32]=1)=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cn1ncnc1-c1csc(C(=O)N[C@@H](Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncnc1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.6 %

Procedure:
TFA (1 ml) was added to a solution of 1,1-dimethylethyl[(2S)-2-({[4-(1-methyl-1H-1,2,4-triazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (100 mg, 0.226 mmol) in DCM (5 ml). The reaction was stirred at RT for 30 min. The solvent was removed and the residue was purified by reverse phase HPLC (10% org˜60% org) to give the title compound as a white solid (90 mg, 87%). LC-MS (ES) m/z 342.2 (M+H)+, 1H NMR (d4-MeOH, 400 MHz) δ 8.23 (s, 1H), 8.03 (m, 2H), 7.22-7.31 (m, 5H), 4.60 (m, 1H), 4.08 (s, 3H), 3.10-3.20 (m, 2H), 3.00 (m, 2H).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=1)=O.[N+]([O-])(O)=O.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([NH:27][C:28]([NH2:30])=[NH:29])[CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>CC(O)C>[F:19][C:20]([F:31])([F:32])[C:21]1[CH:22]=[C:23]([NH:27][C:28]2[N:30]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=3)[CH:4]=[CH:3][N:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Reactant: N=C(N)Nc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O=[N+]([O-])O
Product: FC(F)(F)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
150 mg (0.71 mmol) of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one are suspended in 1.5 ml of 2-propanol. 190 mg (0.712 mmol) of 3-trifluoromethylphenyl-guanidine nitrate and 31 mg (0.783 mmol) of sodium hydroxide are added and the reaction mixture is stirred for 18 h under RF. It is then cooled to RT and filtered, and the material retained on the filter is washed with 2-propanol and water and dried at 50° under HV to give N-(3-trifluoromethyl-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([N:18]([CH3:20])[CH3:19])=[C:16]([S:21]([C:23]([F:26])([F:25])[F:24])=[O:22])[C:15]([C:27](=[N:29][OH:30])[NH2:28])=[N:14]1.O.[C:32]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([N:18]([CH3:20])[CH3:19])=[C:16]([S:21]([C:23]([F:25])([F:26])[F:24])=[O:22])[C:15]([C:27]2[N:28]=[CH:32][O:30][N:29]=2)=[N:14]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)c1c(S(=O)C(F)(F)F)c(C(N)=NO)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: COC(OC)OC
Solvent: O
Product: CN(C)c1c(S(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 4375 %

Procedure:
1-(2,6-dichloro-4-trifluoromethylphenyl)-5-dimethylamino-4-trifluoromethylsulfinyl-3-pyrazolecarboxamide oxime 0.59 g (1.18 mmol) was dissolved in 5 ml of trimethyl orthoformate, and then 5 mg of p-toluenesulfonic acid monohydrate was added. After the mixture was was stirred at room temperature for 3 hrs, trimethyl orthoformate was distilled off in vacuo, and then added 40 ml of ethyl acetate. The ethyl acetate solution was washed twice with 15 ml of aqueous saturated sodium hydrogencarbonate solution, and then once with 15 ml of aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 583 mg (1.15 mmol) of the title compound as a colorless crystal. Yield 97%.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[N:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:24]1([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[C:10]([NH:12][CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=2)=[N:11][C:2]([C:34]2[CH:35]=[N:30][CH:31]=[N:32][CH:33]=2)=[N:3]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Reactant: COC(=O)c1ccc(CNc2nc(Cl)nc3cccc(-c4ccccc4)c23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNc2nc(-c3cncnc3)nc3cccc(-c4ccccc4)c23)cc1
Temperature: 110 °C
Reaction time: 12 h
Yield: 65.7 %

Procedure:
To a solution of methyl 4-((2-chloro-5-phenylquinazolin-4-ylamino)methyl)benzoate (550 mg, 1.36 mmol) in DMF (16 mL) and H2O (0.5 mL) under nitrogen were added pyrimidine-5-ylboronic acid pinacol ester (422 mg, 2.04 mmol) and potassium carbonate (377 mg, 2.72 mmol). The resulting mixture was degassed with nitrogen for 15 min and then (1,1′-bis(diphenylphosphino)ferrocene)-palladium (II) chloride dichloromethane complex (50 mg, 0.068 mmol) was added. Upon completion of addition, the reaction mixture was again degassed for 10 min. with nitrogen. The reaction mixture was then heated to 110° C. where it stirred for 12 h. After this time, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was quenched by the addition of water and then extracted with ethyl acetate. The organic layer was washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography using 0.5% MeOH in CH2Cl2 to afford methyl 4-((5-phenyl-2-(pyrimidin-5-yl)quinazolin-4-ylamino)methyl)benzoate (400 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.62 (s, 2H), 9.31 (s, 1H), 7.93-7.86 (m, 4H), 7.54-7.49 (m, 5H), 7.37 (d, J=6.8 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 5.94 (t, J=4.8 Hz, 1H), 4.71 (d, J=5.2 Hz, 1H), 3.85 (s, 3H). LCMS Method C: retention time 2.15 min, [M+1]=448.2. HPLC Method B: purity 98.5%, retention time 9.81 min.
Reaction SMILES: [I:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[I:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Ic1ncnc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(I)ncnc21

Procedure:
206 mg (0.84 mmol) of 4-iodo-7H-pyrrolo[2,3-d]pyrimidine was dissolved in 1 mL DMF. 37 mg (0.92 mmol) of 60% sodium hydride was added followed by 58 μL (0.92 mmol) of iodomethane. The reaction was quenched by adding 10 mL of water, the solid filtered off, washed with 10 mL of water, then 10 mL of hexanes and dried. Yield: 142 mg of a tan powder, 90% pure.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[I:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2>S(=O)(=O)(O)O>[I:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2
Reactant: O=C1Cc2c(I)cccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1Cc2c(ccc([N+](=O)[O-])c2I)N1
Reaction time: 1 h

Procedure:
A mixture of concentrated sulfuric acid (0.73 mL) and concentrated nitric acid (0.14 mL) was added slowly to a solution of 1,3-dihydro-4-iodo-2H-indol-2-one (0.5 g, 1.93 mmol) (see T. Fukuyama, supra, and Kende, supra) in concentrated sulfuric acid (6 mL) at −5° C. with stirring. The mixture was stirred for an additional 15 min at −5° C. then poured into ice. After standing for 1 h, solid was collected by filtration and washed with water, and dried in a vacuum oven to give 1,3-dihydro-4-iodo-5-nitro-2H-indol-2-one. (Yield 0.46 g, 78%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:37]3[CH2:38][CH2:39][CH:34]([OH:33])[CH2:35][CH2:36]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: OC1CCNCC1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 4-hydroxypiperidine. A yellow solid 98 was obtained (0.0299 g, 66%). 1H-NMR (CDCl3, 400 MHz) δ 1.76–1.84 (m, 2H), 2.02–2.10 (m, 2H), 3.69–3.76 (m, 2H), 3.83 (s, 3H), 4.01–4.07 (m, 2H), 4.12–4.17 (m, 1H), 6.95 (d, J=6.6 Hz, 1H), 6.99 (s, 1H), 7.01–7.07 (m, 3H), 7.46–7.52 (m, 3H), 7.85 (s, 1H), 8.23 (d, J=6.6 Hz, 1H). MS (APCI) m/z 461 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([C:15]3[CH:24]=[C:23]4[C:18]([CH2:19][CH2:20][NH:21][CH2:22]4)=[CH:17][CH:16]=3)[N:12]=[C:11]([NH2:25])[N:10]=2)[CH2:5][CH2:4]1.F[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1.CN1CCOCC1>CN1CCCC1=O>[NH2:25][C:11]1[N:12]=[C:13]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][N:21]([C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=4)[CH2:22]3)=[CH:17][CH:16]=2)[CH:14]=[C:9]([N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)[N:10]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(c3ccc(C#N)cc3)CC4)nc(N)n2)CC1
Temperature: 180 °C

Procedure:
A mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (17 mg, 0.039 mmol), 4-fluorobenzonitrile (7.1 mg, 0.058 mmol) and 4-methylmorpholine (13 μL, 0.12 mmol) in N-methylpyrrolidinone (0.4 mL) was heated at 180° C. overnight. After cooling, the mixture was filtered, diluted with methanol, and purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=426.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Reactant: COc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(COc2ccc(-c3ccccc3OC)cc2)c(C)o1
Yield: 21 %

Procedure:
A degassed mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylic acid methyl ester (119) (200 mg, 0.54 mmoles), 1-bromo-2-methoxy-benzene (80 μl, 0.65 mmoles), 2M aqueous cesium carbonate (11.0 ml) and), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (44 mg) in 1,4-dioxan (30 ml), under an argon atmosphere was heated at 95° C. for 18 hours. After cooling, the mixture was concentrated, the residue dissolved in ethyl acetate and washed with brine and dried. After evaporation of the solvent, the residue was purified by flash chromatography using cyclohexane/ethyl acetate 9:1 v/v as eluent to afford compound 125 (40 mg) as an oil. LC/MS System A; Rt=4.14 mins, m/z (ES+)=353 weak (M+H for C21H20O5).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]5[CH:25]=[CH:26][S:22][CH:23]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: OCc1ccsc1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccsc4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 3-thienylmethanol (121 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (80 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([O:14][CH3:15])[C:10](=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Mg]Br>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)([O:14][CH3:15])[C:10]([OH:23])([CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-4-methoxy-3-oxo-piperidine-1-carboxylic acid tert-butyl ester (470 mg, 1.38 mmol) in anhydrous tetrahydrofuran (10 mL) at 0° C. was added methylmagnesium bromide (1.4 M in diethyl ether, 2.96 mL, 4.15 mmol) and the resulting mixture was stirred at that temperature for 3 h. Excess organomagnesium was quenched by the addition of saturated aqueous ammonium chloride and the reaction was allowed to warm to rt. To the biphasic mixture was added water and ethyl acetate. The phases were separated and the organic phase washed with brine, dried over magnesium sulfate, filtered, dried and concentrated to afford a crude residue which was purified by silica gel chromatography (100% methylene chloride −97.5% methylene chloride/2.5% methanol gradient) to afford pure 4-(4-chloro-phenyl)-3-hydroxy-4-methoxy-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (269 mg, 58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 29; the configuration of the stereocenter is arbitrarily assigned) and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described for Intermediate 7. LC (method 4): tR=1.02 min; Mass spectrum (ESI+): m/z=478 [M+H]+.