Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[O:37][CH:38]=[CH:39][CH:40]=1)CCC.O>O1CCCC1.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>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:36]1[O:37][CH:38]=[CH:39][CH:40]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3ccco3)cc12
Yield: 74.7 %

Procedure:
A solution of tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.48 g, 1 mmol), tri-n-butyl(2-furyl)tin (0.31 ml, 1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in tetrahydrofuran (20 ml) was refluxed at 80° C. for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-6-(2-furyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.35 g, 76.1%) as crystals.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:28])[CH3:27]>C1(C)C=CC=CC=1.C(O)C.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>[C:26]([C:29]1[CH:34]=[C:33]([C:2]2[C:3](=[O:19])[C:4]([CH3:18])([CH3:17])[O:5][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
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: Cc1ccccc1
Solvent: CCO
Product: CC(=O)c1cccc(C2=C(c3ccc(S(C)(=O)=O)cc3)OC(C)(C)C2=O)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
To a stirred solution of 4-bromo-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone (170 mg) in 30 ml toluene and 10 ml ethanol, were added 25 mg of tetrakis(triphenylphosphine)palladium(0), 10 ml of saturated aqueous sodium carbonate, and 130 mg of 3-acetylbenzeneboronic acid. The reaction solution was stirred at 90° C. for 12 hours. Then the solvent was removed under reduced pressure. The resulting residue was extracted with water and dichloromethane. The organic layer was concentrated in vacuo and the resulting residue was separated by column chromatography (hexane/ethylacetate=2:1) to afford 100 mg of 4-(3-acetylphenyl)-2,2-dimethyl-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. mp: 189-190° C. NMR: δ1.60 (s, 6H), 2.59 (s, 3H), 3.07 (s, 3H), 7.48 (m, 2H), 7.82 (d, J=8.7 Hz, 2H), 7.90 (m, 2H), 7.94 (d, J=8.4 Hz, 2H). IR (cm−1): 1690, 1620, 1589, 1149, 958, 770.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[CH:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C([N:15]([CH2:18][CH3:19])CC)C.O>ClCCl>[CH:6]1([NH:12][S:1]([NH:15][CH:18]2[CH2:19][CH2:8][CH2:7][CH2:6][CH2:11]2)(=[O:3])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(CC)CC
Reactant: NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
Under a nitrogen atmosphere, a solution of 98.5% sulfuryl chloride (10.0 mL, 121 mmol) in 40 mL of dichloromethane is added dropwise at 0° C. to a solution of cyclohexylamine (30.0 g, 303 mmol) and triethylamine (84 mL, 606 mmol) in 150 mL of dichloromethane. The reaction mixture is stirred 4 hours at 0° C., neutralized with water, and diluted in dichloromethane (300 mL). The organic components are successively washed with diluted hydrochloric aqueous solution, NaHCO3 aqueous solution and brine, dried (Na2SO4), and concentrated under reduced pressure. The residue is suspended in ether, filtered through Büchner, and the precipitate is washed two times with 100 ml of ether to yield white crystals of N,N′-bis(cyclohexyl)sulfamide (14.0 g, 45%).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][CH2:6][NH:5][C@@H:4]1[C:8]([OH:10])=O)[CH3:2].Cl.[CH:12]([O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][S:21][CH3:22])[NH2:18])([CH3:14])[CH3:13].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH:12]([O:15][C:16](=[O:23])[C@H:17]([CH2:19][CH2:20][S:21][CH3:22])[NH:18][C:8](=[O:10])[C@@H:4]1[C@@H:3]([CH2:1][CH3:2])[CH2:7][CH2:6][NH:5]1)([CH3:14])[CH3:13]
Reactant: CC[C@H]1CCN[C@@H]1C(=O)O
Reactant: CSCC[C@H](N)C(=O)OC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC[C@H]1CCN[C@@H]1C(=O)N[C@@H](CCSC)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]3(S)-ethyl-proline (2.4 g, 0.008 mol), methionine isopropyl ester hydrochloride (2.21 g, 0.0097 mol), HOBT (1.49 g, 0.0097 mol) and EDC (1.86 g, 0.0097 mol) were dissolved in DMF (15 mL) at room temperature and treated with N-methylmorpholine (3 mL, 0.024 mol). The reaction mixture was stirred overnight at room temperature, then concentrated and partitioned between EtOAc and H2O. The organic layer was washed with aq satd NaHCO3 solution, brine, and dried (MgSO4). The crude product was chromatographed on a flash silica gel column eluting with hexane: EtOAc, 7:3 to give N-(t butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]3(S)-ethyl-prolyl-methionine isopropyl ester.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:16])[CH2:14][OH:15])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(C=C(C)CO)cc1
Reactant: [H][H]
Agent: [Pd]
Product: CCC(C)(C)c1ccc(CC(C)CO)cc1

Procedure:
70 g of 3-(p-tert.amyl-phenyl)-2-methyl-allyl alcohol are dissolved in 700 ml of alcohol, treated with 7 g of 5% palladium/carbon and hydrogenated until the hydrogen uptake has been completed. The catalyst is subsequently filtered and the alcohol is evaporated. By distillation there is obtained pure 3-(p-tert.amyl-phenyl)-2-methyl-propanol of boiling point 124°-129° C./0.04 Torr.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:30][C:31]2[CH:35]=[CH:34][S:33][CH:32]=2)[CH:9]2[CH2:14][CH2:13][N:12]([C@H:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:22]([CH3:28])=[N:23][CH:24]=[N:25][C:26]=3[CH3:27])=[O:20])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:41][O:40][C:38](=[O:39])[CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C@H:15]([CH3:29])[CH2:16][CH2:17][NH:18][C:19]([C:21]3[C:26]([CH3:27])=[N:25][CH:24]=[N:23][C:22]=3[CH3:28])=[O:20])[CH2:13][CH2:14]2)[CH2:30][C:31]2[CH:35]=[CH:34][S:33][CH:32]=2)=[CH:6][CH:7]=1
Reactant: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(O)cc2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Temperature: 80 °C
Yield: 43.4 %

Procedure:
A mixture of COMPOUND 296 (290 mg, 0.59 mmol), methyl bromoacetate (141 mg, 0.92 mmol) and K2CO3 (123 mg, 0.89 mmol) in DMF (5.8 mL) was heated at 80° C. overnight to afford {4-[(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-acetic acid methyl ester as a brown oil (145 mg, 42%) following work-up and purification.
Reaction SMILES: [O:1]1C[O:4][CH2:3][C:2]21CCC1C(O1)C2.CNC[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH2:21]>>[O:1]1[C:18]2([CH2:17][CH2:16][CH:15]([OH:21])[CH2:20][CH2:19]2)[O:4][CH2:3][CH2:2]1
Reactant: C1OCC2(CCC3OC3C2)O1
Reactant: O
Reactant: CNCc1ccccc1
Product: OC1CCC2(CC1)OCCO2

Procedure:
Spiro[7-oxabicyclo[4.1.0]heptane-3,2'-[1,4]dioxolane] was reacted with methyl(phenylmethyl)amine in the presence of water at 90° C. to give a 92% yield of trans-7-[methyl(phenylmethyl)amino[-1,4-dioxaspiro[4.5]decan-8-ol, bp 158°-161° C. (0.005 mm Hg). This amino alcohol was reacted with methanesulfonylchloride in the presence of triethylamine in methylene chloride solution at 0° C., and the resulting sulfonate ester was reacted with pyrrolidine in the presence of water at 90° C. to give a mixture of diamines, which were debenzylated by hydrogenation using a palladium on carbon catalyst to give a mixture (approximately 1:1 by nmr) of the subtitled diamines. The yield is 74% from the starting amino alcohol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:10][N:11]([CH2:17][C:18]([O-:20])=O)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:33]1C=CN=C1)=O.[OH-].[NH4+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[N:10][N:11]([CH2:17][C:18]([NH2:33])=[O:20])[C:12]=2[C:13]([F:14])([F:16])[F:15])=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1ccc(-c2nn(CC(=O)[O-])c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nn(CC(N)=O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
To a solution of [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (Example 10) (0.24 g, 0.54 mmol) in THF (6 mL) was added 0.10 g of 1,1'-carbonyldiimidazole at 25° C. under nitrogen. After gas evolution had ceased (approx. 30 minutes), 6 mL conc. ammonium hydroxide was added and the mixture stirred at 25° C. for 18 hours. The reaction mixture was diluted with water, extracted with two portions ethyl acetate and the organic layer washed successively with dilute aqueous HCl and brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from chloroform/acetone gave [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide as a white crystalline solid (0.15 g, 34%). Elemental analysis for C19H15N3F4SO3Calc'd: C, 51.70, H, 3.42, N, 9.52. Found: C, 51.46, H, 3.35, N, 9.39.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:10](=O)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:10]1[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([CH3:14])[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(=O)[nH]1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-6-methyl-1H-pyrimidin-2-one (11.0 g, 50.0 mmol) and phosphoryl chloride (20 mL) according to step 3 of the general procedure I. Obtained as an off-white solid (6.8 g, 57%). MS (ISP) 239.0 [(M+H)+]; mp 116-117° C.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4].[NH2:25][CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][NH:25][C:3]([C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[C:14]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:15][O:16][CH:17]=3)=[CH:7][N:6]=2)=[O:4])[CH2:29][CH2:28]1
Reactant: NCC1CC1
Reactant: COC(=O)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Product: O=C(NCC1CC1)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Yield: 52 %

Procedure:
As described for example 13 g, 5-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (75 mg, 0.23 mmol) was converted, using aminomethylcyclopropane instead of 2,2,2-trifluoroethylamine, to the title compound (44 mg, 52%) which was obtained as a light yellow solid. MS: m/e=427.0 [M+OAc]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>C1COCC1.C1(C)C=CC=CC=1>[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:33])[N:2]([CH3:1])[C:3]2[N:8]=[C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH2:21]4)=[CH:14][CH:15]=3)[N:6]=[CH:5][N:4]=2)=[CH:27][C:26]=1[C:34]([F:35])([F:36])[F:37]
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCN1CCN(c2ccc(Nc3ncnc(NC)n3)cc2)CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN1CCN(c2ccc(Nc3ncnc(N(C)C(=O)Nc4ccc(F)c(C(F)(F)F)c4)n3)cc2)CC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of N-methyl-N′-[4-(4-ethyl-piperazin-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine (24 mg, 0.077 mmol) in 1.5 ml THF and 2.5 ml toluene, 4-fluoro-3-trifluoromethyl-phenyl-isocyanate (25 μl, 0.17 mmol) is added and the mixture is stirred for 5 h at 100° C. Workup analogously as described in Example 171 gives the title compound: ESI-MS: 519 [MH]+; tR=4.3 min (purity: 100%, gradient J); TLC: Rf=0.43 (DCM/MeOH 9).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[CH3:7]S(C)=O.[C:11]1([S:17]([CH2:20][CH:21]([O:23]C2CC2)O)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([S:17]([CH:20]([O:5][CH:1]2[CH2:2][CH2:7]2)[CH:21]=[O:23])(=[O:18])=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(C)=O
Reactant: O=S(=O)(CC(O)OC1CC1)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=CC(OC1CC1)S(=O)(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Oxalyl chloride (444 mg, 3.5 mmol) was added to a stirred solution of DMSO (312 mg, 4 mmmol) in dichloromethane (30 ml) with cooling from a dry ice/acetone bath, followed after 10 min by a solution of 2-(1-benzenesulfonyl)cyclopropyloxyethanol (625 mg, 2.8 mmol) in dichloromethane (5 ml). The resulting thick suspension was stirred a further 15 min prior to adding triethylamine (505 mg, 5 mmol), removing the cooling bath and stirring a further 1 h. The solution was then washed sequentially with water (15 ml), 10% aqueous citric acid (15 ml), saturated aqueous sodium hydrogen carbonate (15 ml), and brine (15 ml), before being dried (MgSO4), and evaporated to leave the product as a gum (585 mg), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2I)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.C(OCC)(=O)C>CN(C=O)C.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>[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([C:13]=1[NH:12][C:4]1[C:5]([CH3:11])=[C:6]2[C:10](=[C:2]([Cl:1])[CH:3]=1)[NH:9][CH:8]=[CH:7]2)[C:19]#[N:20]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Cc1c(Nc2c(I)cncc2C#N)cc(Cl)c2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3ccccc3o2)cc(Cl)c2[nH]ccc12
Temperature: 60 °C
Yield: 15 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile (122 mg, 0.3 mmol) in DMF (4 mL) was added 2-benzofuranboronic acid (162 mg, 0.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) under nitrogen atmosphere and the reaction mixture was heated at 60° C. overnight. After the solution was cooled to room temperature, ethyl acetate was added, and the organic phase was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane) to give 5-(1-benzofuran-2-yl)-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile (18 mg, 15%). HPLC retention time: 13.4 min.(g); MS: 399.3 (M+H); and HRMS: 399.1009.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)=[CH2:23]>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=[CH:22][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C=Cc1ccccn1
Reactant: Ic1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1
Product: C(=Cc1ccccn1)c1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1

Procedure:
The title compound was prepared according to the method in Example 6 using (1H-Indol-5-yl)-(6-iodo-quinazolin-4-yl)-amine (200 mg, 0.52 mmol) and 2-vinylpyridine (65 mg, 67 uL, 0.62 mmol).
Reaction SMILES: C(OC(=O)C)(=O)C.O[CH:9]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]2OCCO2)=[CH:24][CH:23]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([O:18]COC)[CH3:17])=[CH:12][CH:11]=1.[H][H].[N:35]1C=CC=C[CH:36]=1>[Pd].C(O)C.O>[CH3:36][NH:35][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:23][CH:24]=1
Reactant: c1ccncc1
Reactant: COCOC(C)c1ccc(C(O)c2ccc(C3OCCO3)cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Solvent: O
Product: CNCc1ccc(Cc2ccc(C(C)O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 ml of acetic anhydride was dropwise added to a comprising 22.8 g of the 2-[4-[α-hydroxy-4-(1-methoxymethyloxyethyl)benzyl]phenyl]-1,3-dioxolane prepared in the step (a) and 30 ml of pyridine, and the obtained mixture was stirred at room temperature for 3 hours. After the completion of the reaction, 10 ml of water was added to the reaction mixture and the obtained mixture was further stirred for 30 minutes and poured onto ice-water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt successively, dried and distilled to remove the solvent, giving a colorless oil. 2 ml of pyridine, 100 ml of ethanol and 3 g of palladium/carbon were added to the oil and the obtained mixture was stirred in a hydrogen atmosphere at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was filtered and the filtrate was subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography [hexane/ethyl acetate (85:15)] to give 21 g of the title compound.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:20][NH:21][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(CN)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CNC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3,4-di-methoxybenzylamine (0.151 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added. and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((3,4-di-methoxyphenyl)methyl)amino-piperidine carboxylate. Yield: 162 mg. To a solution of tert-butyl 4-((3,4-di-methoxyphenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((3,4-di-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((3,4-Di-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 54 mg; 13C-NMR (CD3OD, rotamers): δ 25.9, 27.3, 40.0, 40.1, 43.5, 43.8, 44.1, 51.4, 53.5, 54.6, 55.4, 110.2, 111.0, 111.9, 112.2, 114.0, 114.2, 118.6, 119.4, 127.1, 127.4, 129.9, 130.0, 130.5, 132.1, 148.2, 148.7, 149.2, 149.7, 158.98, 159.05, 173.3, 173.6.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:34])[N:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:12]=[C:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=1)#[N:2].[C:35]([O:38][C:39]1[CH:40]=[CH:41][C:42](Cl)=[N:43][CH:44]=1)(=[O:37])[CH3:36].C1(C)C(C)=CC=CC=1>C(OCC)(=O)C.CCCCCC>[C:35]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:13]2[CH:14]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[C:10](=[O:34])[N:11]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:12]=2)=[N:43][CH:44]=1)(=[O:37])[CH3:36]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(-c2ccccc2C#N)c(=O)n(-c2ccccc2)c1
Reactant: CC(=O)Oc1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: CC(=O)Oc1ccc(-c2cc(-c3ccccc3C#N)c(=O)n(-c3ccccc3)c2)nc1
Temperature: 120 °C
Reaction time: 8.5 h
Yield: 38.4 %

Procedure:
3.42 g of 3-(2-cyanophenyl)-1-phenyl-5-(tri-n-butyl stannyl)-1,2-dihydropyridin-2-one, 1.57 g of 5-acetoxy-2-chloropyridine and 352 mg of tetrakistriphenylphosphine palladium were added to 40 ml of xylene, and the mixture was stirred at 120° C. in a nitrogen atmosphere for 8.5 hours. The reaction mixture was refined by silica gel chromatography (ethyl acetate/hexane-based solvent), to obtain 953 mg of the subject compound.