Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc(OC(F)(F)F)cc3)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200 mg, 0.68 mmol, 1.00 equiv), 4-(trifluoromethoxy)phenylboronic acid (280 mg, 1.36 mmol, 1.99 equiv), Pd(PPh3)4 (157 mg, 0.14 mmol, 0.20 equiv), K3PO4 (577 mg, 2.73 mmol, 4.01 equiv), 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:40). This resulted in 120 mg (42%) of methyl 3-(isopropyl(methyl)amino)-2-(4-(trifluoromethoxy)phenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].CN(C)C(=O)C.C(#N)C.[Cl:36][CH2:37][C:38](Cl)=[O:39]>O>[OH:25][CH:22]([CH2:23][OH:24])[CH2:21][NH:20][C:18](=[O:19])[C:4]1[C:3]([I:26])=[C:2]([NH:1][C:38](=[O:39])[CH2:37][Cl:36])[C:15]([I:16])=[C:6]([C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8])[C:5]=1[I:17]
Reactant: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: O=C(Cl)CCl
Solvent: CC#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(CCl)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I

Procedure:
The general procedure for the process of the invention involves reacting 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with N,N-dimethylacetamide and chloroacetyl chloride. The resulting product is hydrolyzed with a base (such as sodium hydroxide). A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. Alternately, 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is reacted with N,N-dimethylacetamide, acetonitrile, and chloroacetyl chloride. The resulting product is hydrolyzed with a base. A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. This product is combined with an aqueous base and deionized water. 2-Chloroethanol is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. Alternately, N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide plus metal halide and deionized water are combined. Ethylene oxide is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. This product is suspended in water with acetate ions and hydrochloric acid added. This suspended solution can take place at or above atmospheric pressure. Generally about 1 to about 2 atmospheres above atmospheric pressure is used. After adding aqueous sodium hydroxide to, maintain the pH, the reaction yields N,N′-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisopthalamide. Finally, salts and low molecular weight impurities are removed.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:15][NH:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:7][CH:6]=1)=[O:4]>O=P(Cl)(Cl)Cl>[C:18]1([C:17]2[N:7]3[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:14]4[C:9]([C:8]3=[CH:15][N:16]=2)=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cnc(CNC(=O)c2ccccc2)c2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cn2c(-c3ccccc3)ncc2c2ccccc12
Temperature: 105 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
A mixture of the product from part 7 (1.97 g) in 10 ml of POCl3 is stirred at 105° C. for two hours, then cooled and concentrated under vacuum. The residue is treated with EtOAc and washed with saturated aqueous NaHCO3 solution and water. The organic solution is dried over Na2SO4, filtered and then concentrated to afford a solid. Recrystallization from 2-propanol yields the title compound as a yellow solid (0.7 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](OC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[SiH](C)O[SiH](C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[SiH](C)O[SiH](C)C
Agent: [F-]
Solvent: C1CCOC1
Product: OCCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
A 30-mL eggplant flask equipped with a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with nitrogen atmosphere. To the flask, methyl 3-phenylpropionate (167 mg, 1.0 mmol) and 1,1,3,3-tetramethyldisiloxane (336 mg, 2.5 mmol) were added through a syringe, and iron complex A (15 mg, 0.03 mol) was added as catalyst. The solution was stirred at room temperature for 3 hours. At 0° C., THF (1 mL) and tetrabutylammonium fluoride in THF (1 M, 1 mL) were then added to the solution, which was stirred at 0° C. for 1 hour. THF was distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (5/1) as developing solvent, obtaining 3-phenylpropan-1-ol (131 mg, 0.96 mmol, 96%). The results are shown as Entry 1 in Table 8. The resulting alcohol was identified for geometry by 1H and 13C-NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[C:6]2[N:14]1[CH:18]=[CH:17][CH:16]=[N:15]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]cc(-n3cccn3)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)ncc(-n3cccn3)c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
6-methoxy-4-(1H-pyrazol-1-yl) isoquinolin-1(2H)-one (0.25 g, 1.036 mmol) was taken in phosphorous oxychloride (5 mL) and stirred for 1 h at 100° C. The volatiles were evaporated and the crude was poured into ice. The pH was adjusted to 9.0, extracted with ethyl acetate and washed with brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The crude product was purified by silica gel chromatrography using 10% Ethyl acetate in Pet-ether to get 1-chloro-6-methoxy-4-(1H-pyrazol-1-yl)isoquinoline (0.019 g, 0.062 mmol, 6.00% yield) as solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77-8.84 (m, 2H) 8.74-8.84 (m, 1H) 8.52-8.58 (m, 2H) 8.52-8.57 (m, 1H) 8.28-8.34 (m, 1H) 8.27-8.34 (m, 2H) 7.90-7.96 (m, 1H) 7.77-7.83 (m, 1H) 7.46-7.52 (m, 1H) 7.32-7.38 (m, 1H) 6.58-6.66 (m, 1H) 3.96 (s, 3H). MS: MS m/z 260.10 (M++1).
Reaction SMILES: [CH:1]1([N:7]([CH3:15])[C@@H:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:34][CH2:35][CH2:36][NH2:37])=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[CH2:34][CH2:35][CH2:36][NH:37][C:9](=[O:11])[C@@H:8]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH3:15])[CH:12]([CH3:14])[CH3:13])=[CH:29][CH:28]=1
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)[C@@H](C(=O)O)N(C)C1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 358 mg (1.68 mmol) (S)-2-(cyclohexyl-methyl-amino)-3-methylbutyric acid, 0.88 mL (5 mmol) N,N-diisopropylethylamine, and 636 mg (1.68 mmol) O-Benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluorophosphate in 4 mL dry DMF was stirred at 3° for 60 minutes, at which time 500 mg (1.68 mmol) 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride was added, and the reaction stirred an additional 10 minutes at 3°, then warmed to 25° C. for 50 minutes at which time it was diluted with 20 mL diethyl ether, and washed with 20 mL saturated aqueous sodiumbicarbonate solution and twice with 20 mL brine, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue thus obtained was further purified by silica gel chromatography using 40% ethyl acetate in hexanes as eluant, followed by conversion to the hydrochloride salt by treatment with excess diethyl ether which had been saturated with hydrogen chloride gas to give 577 mg (68%) mp 82-86° C. APCI-MS m/z 457.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12](=[O:15])[CH2:13]Br)=[CH:4][C:3]=1[Cl:16].[C:17]1([CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]([CH2:13][N:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[OH:15])=[CH:4][C:3]=1[Cl:16]
Reactant: Nc1c(Cl)cc(C(=O)CBr)cc1C(F)(F)F
Reactant: c1ccc(CCOCCCCCNCc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(O)CN(CCCCCOCCc2ccccc2)Cc2ccccc2)cc1C(F)(F)F
Reaction time: 8 h
Yield: 53.8 %

Procedure:
1-[4-Amino-3-chloro-5-(trifluoromethyl)phenyl]-2-bromoethanone (0.55 g), N-[5-(2-phenylethoxy)pentyl]benzenemethanamine (0.52 g) and N,N-diisopropylethylamine (0.25 g) were stirred in tetrahydrofuran (15 ml) at room temperature under nitrogen for 40 h. The mixture was filtered and the filtrate evaporated in vacuo. The residue was dissolved in methanol (20 ml) and sodium borohydride (0.18 g) was added portionwise to the stirred solution at 0° under nitrogen. The mixture was left to stand at room temperature under nitrogen overnight, 2N hydrochloric acid (10 ml) added and the solvent evaporated in vacuo. The residue was partitioned between 8% sodium bicarbonate (100 ml) and ethyl acetate (100 ml), the organic phase separated, dried and evaporated in vacuo to give an oil. Purification by FCC on triethylamine deactivated silica (Merck 9385) eluting with cyclohexane-ethyl acetate (9:1) gave the title compound as a colourless oil (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4](I)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:15][C:16]1(C)C(C)(C)OB(C=C)O1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:15]=[CH2:16])[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C=Cc1c(C)c(Cl)cc(C(C)=O)c1OC
Temperature: 80 °C
Yield: 83.5 %

Procedure:
A mixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (1.0 g, 3.2 mmol, from Example 1, Step 2), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.66 mL, 3.9 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.26 g, 0.32 mmol) and potassium carbonate (1.3 g, 9.4 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was degassed with N2 and heated at 80° C. overnight. After cooled to room temperature, the reaction mixture was diluted with water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated and purified on a silica gel column (eluting with 0 to 10% EtOAc in hexanes) to give the desired product (0.60 g, 82%). LCMS calculated for C12H14ClO2 (M+H)+: m/z=225.1; Found:225.1
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[NH:29]C=O)=[O:21])[CH2:16][CH2:15]2)[C:10](=[O:32])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)C>[NH2:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:20]([CH:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:11]2[C:10](=[O:32])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[CH2:15][CH2:16]1)=[O:21]
Reactant: O=CNc1cc(F)ccc1C(=O)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(F)ccc1C(=O)C1CCN(CCn2c(=O)[nH]c3ccccc3c2=O)CC1

Procedure:
A mixture of 2.3 parts of N-[2-[1-[2-(1,4-dihydro-2,4-dioxo-3(2H)-quinazolinyl)ethyl]-4-piperidinylcarbonyl]-5-fluorophenyl]formamide, 33 parts of concentrated sulfuric acid and 144 parts of ethanol is stirred and refluxed for 1 hour. The reaction mixture is poured onto crushed ice and alkalized with a dilute sodium hydroxide solution. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone, yielding 0.4 parts of 3-[2-[4-(2-amino-4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)-quinazolinedione; mp. 269.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[C:21]([Mg]Br)([CH3:23])=[CH2:22]>>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:22]=[C:21]([CH3:23])[NH:18][C:5]2=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[N:7]=1
Reactant: C=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1ccc(Cl)nc1N1CCc2ccccc2C1
Product: Cc1cc2cc(Cl)nc(N3CCc4ccccc4C3)c2[nH]1

Procedure:
In accordance with the same procedures as in Step 3 of Example 642, except for using 2-(6-chloro-3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline prepared in Preparation 7 and isopropenylmagnesium bromide, the titled compound was obtained as yellow oil. (Yield: 35%) The product was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:30])[C@H:26]([CH2:28][OH:29])[NH2:27])C.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:22][O:24][C:25](=[O:30])[CH:26]([NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH2:28][OH:29]
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C(CO)NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.556 g (10 mmol) of L-serine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH2:39]([NH2:42])[C:40]#[CH:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:42][CH2:39][C:40]#[CH:41])=[O:18])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Reactant: C#CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C#CCNC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1

Procedure:
Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 35 mg, 0.080 mmol) in in CH2Cl2 (3 ml) was added EDC (25 mg, 0.15 mmol) and DMAP (15 mg, 0.09 mmol), followed by propargyl amine (7 mg, 0.09 mmol). The crude material was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as an oil.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:41]=[CH:40][C:38]([NH:39]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N3CCN(C)CC3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(4-methyl-piperazin-1-yl)-aniline
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=[C:6]2[C:5]=1[NH2:15])(=[O:3])[CH3:2].[S:16]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17]1.[OH-].[Na+]>C(O)C>[NH2:15][C:5]1[C:6]2[N:7]([C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=2)[CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH:2]=[CH:21][C:18]1[CH:19]=[CH:20][S:16][CH:17]=1
Reactant: O=Cc1ccsc1
Reactant: CC(=O)c1ccn2c(C)c(C)nc2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2c(N)c(C(=O)C=Cc3ccsc3)ccn2c1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5 g of 7-acetyl-8-amino-2,3-dimethylimidazo[1,2-a]pyridine, 2.9 g of thiophene-3-carboxaldehyde, 1.6 g of sodium hydroxide and 100 ml of ethanol is stirred at room temperature for 3 days. It is then concentrated in vacuo to half the volume, poured onto 100 ml of saturated aqueous ammonium chloride solution and extracted three times with 100 ml of methylene chloride each time. The combined organic phases are washed with a little water, the solvent is stripped off in vacuo and the residue is stirred in ethyl ether. After filtering off and drying in vacuo, 4.6 g of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[F:17]>C(O)(=O)C>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([F:17])=[C:10]([C:9]2[NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:15]=1
Reactant: Nc1ccccc1NC(=O)c1cc(Br)ccc1F
Solvent: CC(=O)O
Product: Fc1ccc(Br)cc1-c1nc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A suspension of N-(2-amino-phenyl)-5-bromo-2-fluoro-benzamide (5.64 g, 18.3 mmol) in acetic acid (20 mL) was heated at 60° C. After 30 min, the suspension became a solution and it was left overnight. The solvent was removed under reduced pressure and residue was triturated with DCM (10 mL) and filtered off. The precipitate was washed with DCM (3×10 mL) and dried to afford 4.76 g of the title compound (89%).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[CH:13]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH:13]1([CH2:19][N:20]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CC1CCCCC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.230 g, 1 mmol), C-cyclohexyl-methylamine (0.190 g, 1 mmol), and K2CO3 (0.230 g, 1.67 mmol) in toluene (6 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-cyclohexylmethyl-2,3-dihydro-isoindol-1-one (0.085 g, 37%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.18 (m, 5H), 1.72 (m, 6H), 3.46 (d, 2H), 4.38 (s, 2H) 7.42-7.53 (m, 3H), 7.85 (d, 1H). GC-MS: m/z 229 (M)+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].O.[CH3:8][C:9]1[CH:32]=[CH:31][CH:30]=[CH:29][C:10]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1B1OC(C)(C)C(C)(C)O1.Br[C:34]1[N:39]=[C:38]([CH2:40][NH:41][C:42]2[C:47]([CH:48]([CH3:50])[CH3:49])=[CH:46][CH:45]=[CH:44][C:43]=2[CH:51]([CH3:53])[CH3:52])[CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH:51]([C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([CH:48]([CH3:50])[CH3:49])[C:42]=1[NH:41][CH2:40][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([C:14]2[C:13]([CH2:12][NH:11][C:10]3[CH:29]=[CH:30][CH:31]=[CH:32][C:9]=3[CH3:8])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:19])[N:39]=1)([CH3:53])[CH3:52]
Reactant: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1
Reactant: Cc1ccccc1NCc1cccc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1ccccc1NCc1cccc(C)c1-c1cccc(CNc2c(C(C)C)cccc2C(C)C)n1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of 5.50 g (19 mmol) of Na2CO3×10H2O, 100 ml of water and 30 ml of methanol was purged with argon for 30 min. The obtained solution was added to a mixture of 2.60 g (7.7 mmol) of 2-methyl-N-[3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]aniline, 2.68 g (7.7 mmol) of N-[(6-bromopyridin-2-yl)methyl]-2,6-diisopropylaniline, and 0.44 g (0.39 mmol) of Pd(PPh3)4 in 120 ml of toluene. This mixture was stirred for 12 h at 70° C., then cooled to room temperature. The organic layer was separated, the aqueous layer was extracted with 3×50 ml of ethyl acetate. The combined organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um; eluent: hexane-triethylamine=20:1, vol.). Yield 2.10 g (57%) of white crystalline solid. Anal. calc. for C33H39N3: C, 82.97; H, 8.23; N, 8.80. Found: C, 83.19; H, 8.45; N, 8.62. 1H NMR (CDCl3): δ 7.71 (m, 1H), 7.37 (m, 1H), 7.28-7.32 (m, 2H), 7.22-7.26 (m, 2H), 7.00-7.13 (m, 5H), 6.61 (m, 1H), 6.47 (m, 1H), 4.25 (s, 2H), 4.10 (s, 2H), 3.98 (br.s, 1H), 3.82 (br.s, 1H), 3.31 (s, J=6.9 Hz, 2H), 2.14 (s, 3H), 2.09 (s, 3H), 1.21 (d, J=6.9 Hz, 12H).