Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:11]3[C:12]([CH3:20])=[CH:13][N:14]([CH:17]([CH3:19])[CH3:18])[C:15]=3[CH:16]=2)=[CH:4][CH:3]=1.[CH3:34][C@H:35]1[NH:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]1.CC(C)([O-])C.[Na+]>[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O1CCOCC1>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:40]3[CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36][C@H:35]3[CH3:34])=[N:7][CH:6]=2)[CH:16]=[C:15]2[C:11]=1[C:12]([CH3:20])=[CH:13][N:14]2[CH:17]([CH3:19])[CH3:18])=[O:22]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(Cl)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)C[C@H]4C)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Yield: 15.8 %

Procedure:
Added 6-(6-chloropyridin-3-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (131 mg, 0.283 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (70.8 mg, 0.354 mmol), sodium tert-butoxide (59.8 mg, 0.623 mmol) and 1,4-Dioxane (2 mL) to a microwave vial and degassed for 10 minutes. Added Pd XPhos (10.45 mg, 0.014 mmol) and heated to 100° C. for 16 hours. Concentrated, added DCM and water. Filtered, separated phases. Extracted aqueous phase twice more with DCM. Combined DCM extracts and washed with water, brine, dried (MgSO4), filtered and rotovapped off DCM. The residue was purified via Biotage (0% to 5% MeOH:DCM; 10 g-HP-silica gel column). Obtained 28 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J=6.32 Hz, 3H), 1.44-1.57 (m, 15H), 2.06 (s, 3H), 2.28 (s, 3H), 2.39 (s, 3H), 2.87-3.36 (m, 3H), 3.57 (s, 1H), 3.86-4.30 (m, 3H), 4.50 (d, J=9.35 Hz, 1H), 4.58-4.79 (m, 3H), 5.87 (s, 1H), 6.64 (d, J=8.59 Hz, 1H), 7.01 (s, 1H), 7.45 (s, 1H), 7.76 (d, J=8.08 Hz, 1H), 8.46 (d, J=2.27 Hz, 1H), 12.42 (br. s., 1H). LCMS: [M+H]+ 627.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: OCC=Cc1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
3-(3-Chlorophenyl)acrylic acid (5.0 g) was dissolved in methanol (30 ml), concentrated sulfuric acid (0.5 ml) was added, and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was concentrated, and the residue was washed with water. The obtained pale-yellow powder was dissolved in methylene chloride (130 ml), 1M diisobutylaluminum hydride/toluene solution (52 ml) was added dropwise at −78° C., and the mixture was stirred as it was at −78° C. for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was stirred at room temperature. Aluminum salt was collected by filtration through celite, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the object product (3.29 g) as a yellow oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[F:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:28]2[CH2:29][CH2:30][CH:25]([F:24])[CH2:26][CH2:27]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: FC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(F)CC1
Temperature: 65 °C
Yield: 34.9 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 4-fluoropiperidine hydrochloride (0.057 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and evaporated to dryness. The residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (36.4 mg, 35%). LCMS calculated for C16H17ClFN2O (M+H)+: m/z=307.1; Found: 307.0.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][CH2:37][CH2:38]O)=[CH:31][CH:30]=1>C(Cl)Cl.[Al]>[Br:1][CH2:38][CH2:37][O:36][CH2:35][C:32]1[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCOCc1ccc(F)cc1
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(COCCBr)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution of 2-{[(4-fluorophenyl)methyl]oxy}ethanol (122 mg, 0.717 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vial was capped, wrapped in aluminum foil, and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (80 mg, 48%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]5[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]5)=[CH:32][N:31]=4)[C:26](=[O:42])[N:25]([CH3:43])[N:24]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH:36]5[CH2:41][CH2:40][N:39]([S:56]([CH3:55])(=[O:58])=[O:57])[CH2:38][CH2:37]5)=[CH:32][N:31]=4)[C:26](=[O:42])[N:25]([CH3:43])[N:24]=3)[C:18]=1[CH2:44][OH:45])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C3CCN(S(C)(=O)=O)CC3)cn2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
In a 10 mL round-bottomed flask, 6-tert-butyl-8-fluoro-2-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(5-(piperidin-4-yl)pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)phthalazin-1(2H)-one (35.03 mg, 57.5 μmol, Eq: 1.00) was combined with DCM (3 ml) and cooled to 0° C. DIPEA (8.91 mg, 12.0 μl, 68.9 μmol, Eq: 1.2) was added, followed by addition of methanesulfonyl chloride (6.58 mg, 4.48 μl, 57.5 μmol, Eq: 1). The reaction mixture was stirred at 0° C. to room temperature for 1 hr. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 5% of MeOH in 50% EtOAc/Hexane) to afford white solid (16 mg, 45%). (M+H)+=688.4 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.56 (s, 1H), 8.48 (br. s., 1H), 8.29 (br. s., 1H), 8.20 (br. s., 1H), 7.42-7.70 (m, 6H), 7.04 (d, J=8.2 Hz, 1H), 4.42 (br. s., 2H), 4.11 (q, J=7.0 Hz, 2H), 3.95 (d, J=11.3 Hz, 2H), 2.82 (s, 3H), 2.74-2.81 (m, 2H), 2.62 (t, J=11.5 Hz, 1H), 2.04 (s, 3H), 1.77-1.99 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([N+:15]([O-])=O)[C:11]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:20][CH:19]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:36])[CH3:37])=[CH:30][CH:29]=2)[C:8]2[C:13]([CH:14]=1)=[C:12]([NH2:15])[C:11]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:23]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c([N+](=O)[O-])c(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(N)c(-c3ccc(OC(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Reaction time: 10 h
Yield: 85.9 %

Procedure:
A stirred mixture of 1,5-bis(4-isopropoxyphenyl)-4-nitroindole-2-carboxylic acid ethyl ester (335 mg, 0.67 mmol; see Example 4(b)) and Pd/C (10%, 120 mg) in EtOAc was hydrogenated at ambient pressure and temperature for 10 h and filtered through Celite®. The filter cake was washed with EtOAc and the combined filtrates were concentrated and purified by chromatography to yield the sub-title compound (272 mg, 86%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[I:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH3:28]>>[I:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[C:27]=1[CH3:28]
Reactant: Cc1[nH]cnc1I
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: Cc1c(I)ncn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (0.33 g, 1.0 mmol) and commercially available 4-iodo-5-methyl-imidazole (0.25 g, 1.2 mmol) according to the general procedure IVa. Obtained as an off-white solid (0.43 g, 85%). MS (ISP) 498.8 [(M+H)+]; mp 202° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]([CH2:20][C:21]([O:23]CC)=[O:22])[C:7]1[CH:12]=[C:11]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[CH3:19])C.[OH-].[Na+]>CO.O1CCCC1>[CH3:19][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)=[CH:12][C:7]=1[N:6]([CH2:5][C:4]([OH:26])=[O:3])[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2noc(C)n2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C)c(N(CC(=O)O)CC(=O)O)c2)no1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
The compound (10.32 g, 28.56 mmol) obtained in step A was dissolved in a methanol (100 ml)-tetrahydrofuran (40 ml) mixed solvent. 1N sodium hydroxide (110 ml) was added with stirring at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (150 ml) was added, and the precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound (8.64 g, yield 99%) as a colorless solid.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>C([Mg]Cl)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:19][C:20]1[N:25]=[C:24]([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1cc(I)nc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Clc1ccnc(Cl)n1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)n2)c1

Procedure:
The title compound was prepared from 2-iodo-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example A.58) (2.55 g, 7.0 mmol), i-PrMgCl/ZnCl2 and commercially available 2,4-dichloropyrimidine (1.08 g, 7.21 mmol) according to the general procedure IVc protocol b. Obtained as a light brown solid (0.896 g, 37%). MS (ISP) 350.3 [(M+H)+] and 352 [(M+2+H)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1)C(OC)=O.[Cl-].[Li+].O>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1
Reactant: COC(=O)C(C(=O)OC)c1cc(Cl)cc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1cc(Cl)cc(OCc2ccccc2)c1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(3-benzyloxy-5-chloro-phenyl)-malonic acid dimethyl ester (21 g, 60.2 mmol) and lithium chloride (3.06 g, 72.2 mmol) in DMSO:H2O (10:1; 200 mL) was stirred at 150° C. for 5 hours. After cooling to room temperature, H2O (500 mL) was added, and the mixture was extracted with EtOAc:hexanes (1:10; 1.5 L total) to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[N:7]([C:10]2[S:11][C:12]([C:16]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:6]=[N:5]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>O1CCCC1.C(OCC)(=O)C>[CH3:33][S:34]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[N:7]([C:10]2[S:11][C:12]([C:16](=[O:17])[NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[C:13]([CH3:15])[N:14]=2)[CH:6]=[N:5]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-n2cnn(CCO)c2=O)sc1C(=O)NCc1cccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1nc(-n2cnn(CCOS(C)(=O)=O)c2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To the solution of 2-(1-(2-hydroxyethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide (0.20 g, 0.56 mmol) and triethylamine (0.15 mL, 1.11 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise methanesulfonyl chloride (0.08 g, 0.67 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 3 hours, diluted with ethyl acetate (15 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford the title compound as a yellow solid in 70% yield (0.17 g): 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.55-8.51 (m, 1H), 8.31 (s, 1H), 7.72-7.66 (m, 1H), 7.31-7.25 (m, 1H), 6.26 (t, J=5.8 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 4.54 (t, J=5.1 Hz, 2H), 4.19 (t, J=5.1 Hz, 2H), 3.02 (s, 3H), 2.65 (s, 3H); MS (ES+) m/z 439.2 (M+1).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][N:5]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>O1CCCC1.C(#N)C>[C:16]([O:15][C:13](=[O:14])[CH2:12][N:5]([CH2:4][CH2:3][CH2:2][Br:40])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])([CH3:19])([CH3:18])[CH3:17]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)CN(CCCO)C(=O)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(CCCBr)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of tert-butyl [(3-hydroxypropyl)-trifluoroacetylamino]acetate (35 mmol) were solubilized in 150 ml of tetrahydrofuran. 12.4 g of triphenylphosphine (47.3 mmol) were added and the reaction mixture was thermostated at 15-20° C. 15.1 g of carbon tetrabromide (45.6 mmol), dissolved in 60 ml of acetonitrile, were added dropwise using a dropping funnel and the whole was stirred at room temperature for 4 hours.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[C:4]([NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[N:3]=1.[CH3:30][C:31]1([CH3:53])[CH2:36][CH:35]([NH:37][CH2:38][CH2:39][NH:40][CH:41]2[CH2:46][C:45]([CH3:48])([CH3:47])[NH:44][C:43]([CH3:50])([CH3:49])[CH2:42]2)[CH2:34][C:33]([CH3:52])([CH3:51])[NH:32]1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:47][C:45]1([CH3:48])[CH2:46][CH:41]([N:40]([C:2]2[N:3]=[C:4]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[N:5]=[C:6]([NH:8][CH:9]3[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH2:14]3)[N:7]=2)[CH2:39][CH2:38][N:37]([CH:35]2[CH2:36][C:31]([CH3:53])([CH3:30])[NH:32][C:33]([CH3:52])([CH3:51])[CH2:34]2)[C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:5]=[C:4]([NH:19][CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[N:3]=2)[CH2:42][C:43]([CH3:50])([CH3:49])[NH:44]1
Reactant: CC1(C)CC(NCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CC1(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: CC1(C)CC(Nc2nc(NC3CC(C)(C)NC(C)(C)C3)nc(N(CCN(c3nc(NC4CC(C)(C)NC(C)(C)C4)nc(NC4CC(C)(C)NC(C)(C)C4)n3)C3CC(C)(C)NC(C)(C)C3)C3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1

Procedure:
21.15 g (0.05 moles) of 2-chloro-4,6-bis(2,2,6,6-tetramethyl-4-piperidylamino)-1,3,5-triazine (prepared according to example 2A), 8.45 g (0.025 moles) of 1,2-bis-(2,2,6,6-tetramethyl-4-piperidylamino)ethane, 2 g 0.05 of sodium hydroxide and 150 ml of xylene were boiled for 16 hours under stirring. After removing the reaction solvent, the residue was washed with water, dried at 100° C./l mm and crystallized from benzene.
Reaction SMILES: [CH2:1]([N:4]([C:42]1[C:47]([C:48]([O:50]CC)=[O:49])=[CH:46][C:45]([C:53]([F:56])([F:55])[F:54])=[CH:44][N:43]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO>[CH2:1]([N:4]([C:42]1[C:47]([C:48]([OH:50])=[O:49])=[CH:46][C:45]([C:53]([F:54])([F:55])[F:56])=[CH:44][N:43]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1ncc(C(F)(F)F)cc1C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1ncc(C(F)(F)F)cc1C(=O)O

Procedure:
Ethyl 5-iodopyridin-2-one-3-carboxylate, prepared by the method of Taylor, J. Org. Chem. 54, 36 (1989), is treated with tert-butyldimethylsilyl chloride (TBSCl) in methylene chloride containing triethylamine to give the O-silylated pyridine. Treatment of ethyl 2-tert-butyldimethylsilyloxy-5-iodopyridine-3-carboxylate with bis(trifluoromethyl)cadmium in the presence of copper (I) bromide in dimethylformamide gives the ethyl 2-tert-butyldimethylsilyloxy-5-trifluoromethylpyridine-3-carboxylate compound. Treatment of the silyloxy compound with aqueous hydrochloric acid in tetrahydrofuran removes the silyl protecting group. Treatment of ethyl 2-hydroxy-5-trifluoromethylpyridine-3-carboxylate with phosphorus oxychloride affords the 2-chloro compound. Treatment of ethyl 2-chloro-5-trifluoromethylpyridine-3-carboxylate with N-triphenylmethyl-5-[2-(4'-propylaminomethyl-biphenyl)]tetrazole, prepared as described in Example 72B, in tetrahydrofuran containing triethylamine affords the tertiary amine. Treatment of ethyl 2-{N-propyl-N-[(2'-[N-triphenylmethyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}-5-trifluoromethyl-pyridine-3-carboxylate with p-toluenesulfonic acid monohydrate in methanol to detritylate followed by sodium hydroxide in methanol hydrolysis gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29]([CH:36]=O)=[N:28]1>CO.N1CCCCC1>[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:28]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ncccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ncccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0362 g, 0.100 mmol) in methanol (3 mL) was added with 1H-pyrazolo[3,4-b]pyridine-3-carboxaldehyde (0.0147 g, 0.100 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-pyrazolo[3,4-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0352 g, 72%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[C:22]([CH3:24])[C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:25][NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[C:22]([CH3:24])[C:18]([C:19]([N:26]([CH3:25])[CH:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CNC1CCN(C)CC1
Reactant: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)O
Product: Cc1cc(-n2ncc(-c3ccc(C#N)cc3)c2O)ncc1C(=O)N(C)C1CCN(C)CC1

Procedure:
The title compound was prepared in a manner similar to Example 412 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)-4-methylnicotinic acid and N,1-dimethylpiperidin-4-amine. ESI-MS m/z (M+H)+ calc'd for C24H26N6O2, 431.21; found 431.5.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C1(N=C=NC2CCCCC2)CCCCC1.[N:24]1[CH:29]=[CH:28][CH:27]=[N:26][C:25]=1[S:30][CH2:31][C:32](O)=[O:33]>CN(C=O)C>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:32](=[O:33])[CH2:31][S:30][C:25]1[N:26]=[CH:27][CH:28]=[CH:29][N:24]=1
Reactant: O=C(O)CSc1ncccn1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CSc1ncccn1)ON1C(=O)CCC1=O
Reaction time: 16 h

Procedure:
12.31 g (107 mMol) N-hydroxysuccinimide and 22.70 g (110 mMol) dicyclohexylcarbodiimide were added at −35° C. to a solution of 18.27 g (107 mMol) (Pyrimidin-2-ylsulfanyl)-acetic acid (a) dissolved in 200 ml DMF. The reaction mixture was stirred for 16 h under argon. The residue was filtered and the filtrate was evaporated in vacuo to dryness. The remaining product was dissolved under reflux in 400 ml ethyl acetate, the hot solution was filtered and the mixture was subjected to a chromatographic purification (Florisil) using ethyl acetate. The compound was then recrystallised from ethyl acetate.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 4-methylbenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 316.1 (M+1). 1H NMR (500 MHz, CDCl3): δ partial 8.60 (s, 1H); 8.41 (br s, 1H); 8.09 (br s, 1H); 7.86 (m, 1H); 7.20 (d, J=8.0 Hz, 1H); 6.83 (d, J=5.3 Hz, 1H); 5.80 (br s, 1H); 4.71 (d, J=5.8 Hz, 2H); 2.37 (s, 3H).