Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1.[Br:20]Br>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Br:20])[O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:8][N:7]=1
Reactant: BrBr
Reactant: Oc1cccc(Oc2ncc(C(F)(F)F)cc2Cl)c1
Solvent: ClC(Cl)Cl
Product: Oc1cc(Oc2ncc(C(F)(F)F)cc2Cl)ccc1Br
Yield: 42.9 %

Procedure:
In 150 ml of chloroform, 5.5 g of 2-(3-hydroxyphenoxy)-3-chloro-5-trifluoromethyl pyridine was dissolved and then, 3.5 g of bromine was added dropwise to the solution at a temperature of 10° to 15° C. After the reaction, the reaction product was washed with water, with a sodium bicarbonate aqueous solution, with a saturated sodium thiosulfate solution and then, with water and dried over anhydrous sodium sulfate. Chloroform was distilled off under a reduced pressure and the resulting crystals were washed with hexane and dried to obtain 3.0 g of 2-(3-hydroxy-4-bromophenoxy)-3-chloro-5-trifluoromethyl pyridine having a melting point of 124° to 127° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)[CH3:26]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(O)CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (Enantiomer A) and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]acetic acid ethyl ester.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]([C:19]([F:22])([F:21])[F:20])=[CH:13][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.S([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:13]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[NH:11][C:12]=1[C:19]([F:22])([F:20])[F:21]
Reactant: COC(=O)c1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Br
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
Bromine (2.3 mL, 43.7 mmol) is added to a solution of methyl 2-(p-chlorophenyl)-5-(trifluoromethyl)pyrrole-3-carboxylate (8.44 g, 29.2 mmol) and sodium acetate (3.6 g, 43.7 mmol) in acetic acid. The reaction mixture is stirred for 30 minutes, diluted with a 0.4 wt/wt% sodium sulfite solution and extracted with diethyl ether. The organic extracts are combined, washed with saturated sodium hydrogen carbonate solution, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain an oil which solidifies to give the title product as a solid (9.2 g) which is identified by 1H and 13C NMR spectral analyses.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:14])[C:6]1=[O:15])(=[O:3])[CH3:2].[H-].[Na+].[CH3:18][S:19][CH2:20]Cl.O>CN(P(N(C)C)(N(C)C)=O)C>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14][CH2:18][S:19][CH3:20])[C:6]1=[O:15])(=[O:3])[CH3:2]
Reactant: CSCCl
Reactant: CC(=O)NC1Cc2c(O)cccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CSCOc1cccc2c1CC(NC(C)=O)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-acetylamino-4-hydroxy-1-indanone 10.25 g (0.05 m) in 50 ml of dry HMPA under N2 is added 2.6 g (0.055 m) of a 50% oil dispersion of sodium hydride in portions. After stirring at room temperature for 1/2 hr, 5.3 g (0.055 m) of chloromethyl methyl sulfide is added, and the mixture is stirred overnight. Water is added and the mixture is extracted with ethyl acetate which is back-washed with water. After drying (Na2SO4) and concentration, the desired product is obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37]([NH:39][NH2:40])=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[N:26][CH:27]=1)#[N:21]>C(O)CCC>[Si:1]([O:8][CH2:9][C@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]2[C:37]([C:34]3([C:31]4[CH:32]=[CH:33][C:28]([C:25]5[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=5)=[CH:29][CH:30]=4)[CH2:36][CH2:35]3)=[N:39][N:40]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Reactant: N#Cc1ccc(-c2ccc(C3(C(=O)NN)CC3)cc2)nc1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OC[C@@]1(C)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Temperature: 140 °C
Reaction time: 5 h
Yield: 53.8 %

Procedure:
The compound (418 mg, 1.31 mmol) obtained in Example 4-1) and the compound (364 mg, 1.31 mmol) obtained in Example 60-3) were dissolved in 1-butanol (5 mL), and the mixture was stirred at 140° C. for 5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=0% to 20%) to obtain the title compound (375 mg, 54%) in a white solid form.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)=[N:24][O:25][C:26]=2[CH2:27][OH:28])=[N:16][CH:15]=1>O1CCOCC1>[F:36][C:31]1[CH:30]=[C:29]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH2:27][OH:28])[O:25][N:24]=2)[CH:34]=[CH:33][C:32]=1[F:35]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Trimethylaluminium solution (2M in toluene, 0.8 mL, 1.60 mmol) was added to a solution of 2,2,2,-trifluoroethylamine (108 mg, 1.06 mmol) in dioxane (5 mL). The mixture was stirred for 1 h at 50° C. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=2:3 to 3:2) to afford the title compound (70 mg, 59%) as a white solid. MS: m/e=444.2 [M+H]+.
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]#[N:17])[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([OH:31])=[O:30]>CC(C)=O>[N:1]1([NH:7][C:8](=[O:18])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:28][C:29]([OH:31])=[O:30])=[C:11]([C:16]#[N:17])[CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1cc(C(=O)NN2CCOCC2)ccc1O
Reactant: O=C(O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cc(C(=O)NN2CCOCC2)ccc1OCC(=O)O
Yield: 78.9 %

Procedure:
3-Cyano-4-hydroxybenzoic acid (4-morpholinyl)amide (232 mg, 1.0 mmol), sodium iodide (150 mg, 1.0 mmol), potassium carbonate (415 mg, 3.0 mmol) and chloroacetic acid (189 mg, 2.0 mmol) are suspended in acetone (12 mL) and refluxed for 5 hours. The reaction solution is evaporated to remove the solvent under reduced pressure, partitioned by adding water and ethyl acetate, and adjusted to pH=2-3 with hydrochloric acid. The aqueous layer is separated and re-extracted with ethyl acetate (×2). The solutions are combined and washed with saturated brine. The organic layer is dried over magnesium sulfate, and evaporated to remove the solvent under reduced pressure. The precipitated crude crystals are suspended in methanol-diethyl ether, and filtered to give 3-cyano-4-carboxymethoxybenzoic acid (4-morpholinyl)amide (241 mg, 83%). Mp: 205-206° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl>CN(C)C=O.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:11][O:12][CH3:13])=[CH:6][N:7]=1
Reactant: COCCl
Reactant: Oc1ccc(F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(F)nc1
Reaction time: 1 h
Yield: 109.5 %

Procedure:
Add 6-fluoro-pyridin-3-ol (3.5 g, 30.95 mmol) to a suspension of sodium hydride (1.49 g, 37.14 mmol) in dimethylformamide (20 mL). Stir the mixture for 1 hour. Add chloromethyl methyl ether (2 g, 25.0 mmol). Stir the mixture at room temperature overnight. Dilute the mixture with ethyl acetate and water. Wash the organic layer with water and saturated aqueous sodium chloride. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo to brown oil. Purify by column chromatography (10% ethyl acetate in hexane) to afford the title compound (4.30 g, 88.4%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.48 (s, 3H), 5.15 (s, 2H), 6.85 (dd, J=3.6 Hz, J=8.8 Hz, 1H), 7.47 (m, 1H), 7.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].[CH:12]([NH:15][CH:16](C)C)(C)C.C(Cl)(=O)C(C)(C)C.CNC>ClCCl>[CH3:12][N:15]([CH3:16])[C:8]([C:7]1[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=1[Cl:1])=[O:9]
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Cl)nnc1Cl
Reaction time: 0.42 h
Yield: 61.9 %

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid (500 mg, 2.59 mmol) was dissolved in dichloromethane (2 mL), treated with di-iso-propylamine (454 μL, 2.59 mmol) and cooled in an ice water bath. Pivaloyl chloride (318 μL, 2.59 mmol) was added and the mixture was stirred for 25 minutes. 2 M dimethylamine (2.59 mL, 5.18 mmol) was added and the reaction was stirred 15 h. The mixture was washed with saturated ammonium chloride (1×), saturated sodium bicarbonate (1×), and dried over sodium sulfate to afford 3,6-dichloro-pyridazine-4-carboxylic acid dimethylamide (353 mg, 62.2%). MS: m/z 220 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][OH:43])=[CH:37][CH:36]=1>COCCOC.CCO>[OH:43][CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:23])=[CH:13][CH:14]=2)=[CH:36][CH:37]=1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: OCCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(CCO)cc2)cc1
Temperature: 92.5 °C
Reaction time: 1.5 h

Procedure:
Mix propane-2-sulfonic acid{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide (0.10 g), 0.1 equiv of tetrakis triphenylphosphine palladium (0), 2 equiv of 2M sodium carbonate aqueous solution in DME (2 mL) and EtOH(1 mL) and warm to 90-95° C. After warming two min, add 2-(4-bromo-phenyl)-ethanol (1.3 equiv) and stir at that temperature for 1.5 h. Evaporate solvents over Celite® and purify by silica gel Strata® cartridges eluting with hexanes-EtOAc gradient to give 0.041 g of the title compound. MS (ES+) (m/z): 402 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]3)=[O:11])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl[C:23]1[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([C:4]2[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]3[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:23]4[N:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=4)[CH2:14][CH2:13]3)=[O:11])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: NCC1CCN(C(=O)OCc2ccc(C3CC3)cc2)CC1
Reactant: Fc1cnc(Cl)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc(C2CC2)cc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of (4-cyclopropyl-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (0.10 g, 0.35 mmol), 2-chloro-5-fluoro-pyrimidine (EXAMPLE 71, Step 1, 0.046 g, 0.35 mmol) and triethylamine (0.097 mL, 0.69 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-cyclopropyl-benzyl ester. M.S.(M+1):385.31
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])=[CH:4][N:3]=1.[CH2:27]([CH2:29][NH2:30])[OH:28]>O1CCOCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:30][CH2:29][CH2:27][OH:28])=[N:3][CH:4]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: NCCO
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cl)nc1
Solvent: C1COCCO1
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(NCCO)nc1
Reaction time: 8 h
Yield: 58.7 %

Procedure:
Compound 32 (391 mg, 1.00 mmol) was dissolved in 1,4-dioxane (4 mL), and ethanolamine (0.300 mL, 5.00 mmol) was added thereto, followed by stirring overnight under heating and reflux. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium chloride and chloroform were added to the resulting residue, and the precipitated solid was collected by filtration to afford the entitled Compound 33 (244 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[NH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][C:21]=2[S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: ClSc1ccc(Cl)cc1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)cc2)[nH]1
Solvent: ClCCl
Product: FC(F)(F)c1cc(Sc2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
A solution of p-chlorophenylsulfenyl chloride (0.80 g, 4.48 mmol) in methylene chloride is added dropwise over 20 minutes to a stirred solution of 2-(p-chlorophenyl)-5-trifluoromethylpyrrole (1.0 g, 4.07 mmol) in methylene chloride. The reaction mixture is stirred at room temperature for 90 minutes, diluted with methylene chloride, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 1:10 ethyl acetate/hexanes solution gives the title product as an off-white solid (0.96 g, mp 39°-54° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:18]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C(=O)c1ccccc1
Reaction time: 16 h
Yield: 85.3 %

Procedure:
Ethyl 5-nitroindole-2-carboxylate (3.1) (1.5 g, 6.41 mmol) in CH2Cl2 (30 ml) was treated with benzoyl chloride (1.19 ml, 10.26 mmol), Et3N (891 μl, 6.41 mmol) and DMAP (783 mg, 6.41 mmol). The mixture was stirred for 16 h. 10% NaHCO3 (10 ml) and CH2Cl2 (10 ml) were added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with H2O (10 ml), 5% HCl (10 ml) and H2O (10 ml). The solution was dried (MgSO4) and concentrated. The 10 residue was crystalised from EtOAc/Hex 1:9 to afford 1.85 g (87%) of 3.2 as a yellow powder: 1H NMR (250 MHz, CDCl3) δ ppm 8.66 (d, 1H), 8.25 (d, 1H), 7.80 (d,1H), 7.6-7.72 (m, 3H), 7.48 (m, 3H), 4.00 (q, 2H), 1.10 (t, 3H). FABMS (NBA/NaI) m/z 339 (M+H+ expected 339)
Reaction SMILES: F[C:2]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([C:2]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:3]=2[C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)=[O:5])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)cc1
Reactant: C1COCCN1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure described for example 1 from 1-{4-[4-(2-Fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone and morpholine (85%, yellow solid, MS (m/e): 439.3 (M+H, 100%)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[N:29]1([C:35]2[N:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:14][C:12]([N:8]1[C:6]2[N:7]=[C:2]([C:38]3[CH:39]=[N:40][C:35]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[CH:36][CH:37]=3)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]=2[C:10]([CH3:11])=[N:9]1)([CH3:13])[CH3:15]
Reactant: OB(O)c1ccc(N2CCOCC2)nc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCOCC4)nc3)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1
Reaction time: 0.67 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.174 mmol), [6-(4-morpholinyl)-3-pyridinyl]boronic acid (47.1 mg, 0.226 mmol), DME (3 mL), water (1.00 mL), sodium carbonate (0.261 mL, 0.523 mmol) and PdCl2(dppf)-CH2Cl2 adduct (11.38 mg, 0.014 mmol) wherein the reaction time was 40 min. The crude product was purified by column chromatography (eluent: gradient of 0 to 15% (9:1 MeOH/NH4OH)/DCM). The final product was collected as a solid, 61 mg (65%). LCMS E-S (M+H)=530.0 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (s, 9 H), 2.12 (s, 3 H), 2.24 (s, 3 H), 2.38 (s, 3 H), 3.52-3.64 (m, 4 H), 3.68-3.80 (m, 4 H), 4.38 (d, J=5.05 Hz, 2 H), 5.88 (s, 1 H), 6.99 (d, J=9.09 Hz, 1 H), 7.61 (s, 1 H), 8.34 (dd, J=8.84, 2.53 Hz, 1 H), 8.68 (t, J=5.05 Hz, 1 H), 8.97 (d, J=2.27 Hz, 1 H), 11.53 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a light brown solid (37 mg, 53%). 1H NMR (CDCl3): 9.63 (dd, J=0.9, 1.8 Hz, 1H), 8.73-8.68 (m, 2H), 7.43-7.39 (m, 1H), 6.93 (s, 1H), 6.88 (d, J=8.1 Hz, 2H), 6.83 (dd, J=1.8, 8.1 Hz, 1H), 6.77 (s, 1H), 6.06 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]1[C:11](=[O:12])[C:10]([C:13]([NH:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])=[C:9]([OH:24])[C:8]2[CH2:25][N:26]([C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH2:27][C:7]1=2.C([O-])([O-])=O.[Na+].[Na+].[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CC(N(C)C)=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>[C:2]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]2[C:11](=[O:12])[C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])=[C:9]([OH:24])[C:8]3[CH2:25][N:26]([C:28](=[O:33])[CH2:29][CH2:30][CH:31]=[CH2:32])[CH2:27][C:7]2=3)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: C=CCCC(=O)N1Cc2c(O)c(C(=O)NCC(=O)OC(C)(C)C)c(=O)n(Cc3cccc(Br)c3)c2C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCCC(=O)N1Cc2c(O)c(C(=O)NCC(=O)O)c(=O)n(Cc3cccc(-c4ccccc4)c3)c2C1
Temperature: 115 °C

Procedure:
tert-Butyl N-{[1-(3-bromobenzyl)-4-hydroxy-2-oxo-6-pent-4-enoyl-2,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyridin-3-yl]carbonyl}glycinate (50 mg, 0.09 mmol, prepared in similar fashion to Intermediate 5 (compound 5-1) was dissolved in DMA (2 mL) in a 10 mL reaction tube of a CEM Corporation Discover 300 Watt microwave reactor. Aqueaous Na2CO3 (2 M, 0.8 mL, 1.6 mmol), phenylboronic acid (20 mg, 0.16 mmol) and bis(triphenylphosphine)palladium(II) chloride (7 mg, 0.009 mmol) were added and the tube was purged with nitrogen, capped and inserted into the microwave reactor and heated at 115° C., for 15 min. The reaction was diluted with EtOAc, washed with 2 M HCl, dried (Na2SO4), filtered and concentrated. The residue was purified on a C-18 reverse phase chromatography column eluted with 0-100% MeCN in water. The desired fractions were concentrated, diluted with EtOAc and washed with 2 M HCl. The organic portion was isolated, dried (Na2SO4), filtered and concentrated affording the title compound, E43-1. HPLC/MS: 501.9 (M+1); Rt=3.22 min.