Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCC3CCOC3)c2n1
Yield: 64 %

Procedure:
A solution of N2-butyl-8-(methoxy)-9-[2-(tetrahydro-3-furanyl)ethyl]-9H-purine-2,6-diamine (181 mg) in methanol (1 mL) was treated with 4N HCl in 1,4-dioxane (0.5 mL) for 1.5 h. The reaction was evaporated and the residue treated with water then basified with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried to give the title compound (111 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([C:32]([NH:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])=[O:33])[CH2:19][CH2:18]2)[C:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2c(-c3cccnc3)csc2n1
Reactant: COc1ccccc1N=C=O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1NC(=O)N1CCN(c2nc(N)nc3scc(-c4cccnc4)c23)CC1
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of Example 10 (50 mg, 0.15 mmol) in dichloromethane (2 mL) and acetonitrile (1 mL) was added 2-methoxyphenyl isocyanate (21 μL, 0.16 mmol). The reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 0.5% to 3% methanol in dichloromethane), yielding the title compound (42 mg) as a white powder. MS (m/z) 462 [M+H]+.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24].[CH2:25](Cl)[CH:26]1[O:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH2:25][CH:26]3[CH2:27][CH2:28][CH2:29][O:30]3)[CH2:15]1)[CH:8]=[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:24]
Reactant: ClCC1CCCO1
Reactant: CCOC(=O)c1cn(CC2CCNC2)c2ccc(I)cc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC2CCN(CC3CCCO3)C2)c2ccc(I)cc2c1=O
Temperature: 70 °C
Reaction time: 36 h
Yield: 32 %

Procedure:
Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 126, 500 mg, 1.08 mmol) was suspended in dimethyl formamide (3 mL) then tetrahydrofurfuryl chloride (1 mL) and potassium carbonate powder (400 mg, 22.2 mmol) were added. The reaction was stirred at 70° C. for 36 h. Water (15 mL) was added and the suspension was extracted with ethyl acetate (3×10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was chromatographed on a 4 g Analogix column using 0-10% methanol in dichloromethane. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 181 mg (32% yield) of ethyl 6-iodo-4-oxo-1-((1-((tetrahydrofuran-2-yl)methyl)pyrrolidin-3-yl)methyl)-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[C:21]([CH2:30][CH:31]=O)=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=1)[C:25]#[N:26].C([BH3-])#N.[Na+]>CO>[F:19][C:20]1[C:21]([CH2:30][CH2:31][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:18]=[CH:17][C:12]4[C:13](=[O:16])[O:14][CH2:15][C:11]=4[CH:10]=3)[CH2:2][CH2:3]2)=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=1)[C:25]#[N:26]
Reactant: COc1cc(CC=O)c(F)cc1C#N
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)c(F)cc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (94 mg, 0.33 mmol) and 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile (58 mg, 0.30 mmol) in methanol (3.0 mL) at 0° C. was added sodium cyanoborohydride (29 mg, 0.47 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 5-fluoro-2-methoxy-4-(2-{4-[2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 424.3 [M+1]+. (0.068 μM)
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH:22]=C1CCP(C2C=CC=CC=2)C1(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18].C(O)(=O)C1C=CC=CC=1.C1C=CC=CC=1>CCCCCC>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=[CH:22][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C=C1CCP(c2ccccc2)C1(c1ccccc1)c1ccccc1
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CCOC(=O)C=CC=C(c1ccccc1)c1ccccc1
Reaction time: 3.5 h
Yield: 82.4 %

Procedure:
β-Phenylcinnamaldehyde (3.36 g), (carbethoxymethylene)triphenylphospholane (5.68 g), and benzoic acid (0.2 g) were added to anhydrous benzene (80 mL), and the mixture was refluxed under stirring for 3.5 hours. Subsequently, the resultant mixture was cooled to room temperature and condensed under reduced pressure. n-Hexane was added to the residue, and the insoluble matter was collected through filtration and washed several times with n-hexane. The filtrate and the resulting wash liquid were combined and condensed under reduced pressure. The product was purified through silica gel column chromatography (silica gel 40 g, eluent; n-hexane:ethyl acetate=50:1), to thereby yield 3.70 g of the product of interest (yield 82.4%).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:13]2[C:17]3[CH:18]=[CH:19][C:20]([N+:22]([O-])=O)=[CH:21][C:16]=3[N:15]=[CH:14]2)[CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1.C([O-])=O.[NH4+].O>C(O)C.[Pd]>[NH2:22][C:20]1[CH:19]=[CH:18][C:17]2[N:13]([CH:7]([C:4]3[CH:5]=[CH:6][C:1]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:2][CH:3]=3)[CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:14]=[N:15][C:16]=2[CH:21]=1
Reactant: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2cc(N)ccc21
Temperature: 25 °C

Procedure:
To a solution of methyl 3-(1,1′-biphenyl)-4-yl-3-(5-nitro-1H-benzimidazol-1-yl)propanoate (47 mg, 117 μmol) in ethanol (2 mL) was added palladium on carbon (9.0 mg, 10% active Pd), ammonium formate (37 mg, 587 μmol) and water (0.5 mL). The solution was heated at reflux for 4 hours, the cooled to room temperature, and filtered through Celite®. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method B, Mobile Phase I) RT=2.26 min, MH+ 372].
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1.[NH3:24]>>[NH2:24][C:3]1[N:4]=[N:5][C:6]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])=[N:9][C:7]=2[N:8]=1
Reactant: N
Reactant: CCCOc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2nc(N)nnc2c(=O)[nH]1

Procedure:
In a similar manner to that described in Example 87, 3-methylthio-8-oxo-6-(2-propoxyphenyl)-7,8-dihydropyrimido[4,5-e][1,2,4]triazine (1.42 g) was reacted with ethanolic ammonia (70 ml) for 20 hours to give the crude title compound, (0.80 g) which together with another sample (0.17 g), similarly prepared, was recrystallized from ethanol to afford the title compound, 0.54 g, m.p. 255-256° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:8]([C:36]2[CH:41]=[C:40]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH3:51])=[CH:45][CH:44]=3)[C:39]([Cl:52])=[CH:38][C:37]=2[O:53]CC=C)[O:7]1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.C(OCC)(=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:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:10]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:8]([C:36]2[CH:41]=[C:40]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH3:51])=[CH:45][CH:44]=3)[C:39]([Cl:52])=[CH:38][C:37]=2[OH:53])[O:7]1)(=[O:3])[CH3:2]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of ((2R,3R,4R,5S,6S)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl acetate (20, 2.51 g, 3.23 mmol) in tetrahydrofuran (40 mL) were added sodium borohydride (984 mg, 0.026 mol) and tetrakis(triphenylphosphine)palladium (373 mg, 0.323 mmol). The reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with ethyl acetate and quenched with saturated sodium hydrogen carbonate, extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Flash chromatography on a Biotage® apparatus (silica gel, 10 to 35% tetrahydrofuran in hexanes gradient) gave the title compound (45, 2.19 g, 2.97 mmol, 92%) as colorless oil.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCCC1>[C:7](#[N:8])[CH:9]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCCCCC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCC=CC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (165 mL, 0.165 mol) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (27 mL, 0.17 mol) in tetrahydrofuran (100 mL). The reaction was warmed to room temperature and then cooled to 0° C. again after stirring for 30 min. To the reaction mixture was added a solution of hexanal (18 mL, 0.15 mol) in tetrahydrofuran (150 mL). The reaction was stirred overnight, allowed to warm up to room temperature. The reaction was quenched with water and extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over MgSO4, concentrated, and purified on silica gel (eluting with 0 to 15% EtOAc in hexanes) to provide the desired product (˜17 g, 92%) as a mixture of cis and trans isomers. MS calculated for C8H14N(M+H)+: m/z=124.113. Found: 124.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.Cl[C:9]1[N:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:15]([C:12]1[CH:11]=[N:10][C:9]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)=[N:14][CH:13]=1)[CH2:16][CH3:17]
Reactant: OC1CCNCC1
Reactant: CCCc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(O)CC2)nc1
Temperature: 110 °C

Procedure:
A suspension of piperidin-4-ol (12 g, 119 mmol), 2-chloro-5-propylpyrimidine (20.44 g, 131 mmol) and potassium carbonate (49.2 g, 356 mmol) in DMF (100 mL) was heated at 110° C. for 12 h and cooled to rt. The mixture was diluted with EtOAc (250 ml) and washed with H2O (3×). After drying over Na2SO4, the organic layer was evaporated to give a yellow oil. The crude oil was purified on a flash chromatography (SiO2, 0 to 10% MeOH/CH2Cl2) to give a yellow solid. MS (ESI) 222 (M+H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2].I[C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[CH3:41])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=1)=[O:18]>>[CH:1]([NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:39]2[CH:38]=[C:16]([CH:15]=[CH:14][C:40]=2[CH3:41])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:22]([C:34]([F:37])([F:36])[F:35])[CH:21]=2)=[O:18])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1ccc(NC(C)C)nn1
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(NC(C)C)nn1

Procedure:
The title compound was synthesized from N-isopropyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 67-68° C.; 1H NMR (300 MHz, CDCl3) δ: 8.97 (1H, s), 8.06 (1H, s), 7.98-8.01 (1H, d, J=9.0 Hz), 7.97 (1H, s), 7.83-7.85 (1H, d, J=6.0 Hz), 7.58-7.60 (1H, d, J=6.0 Hz), 7.30-7.32 (2H, m), 6.61-6.64 (1H, d, J=9.0 Hz), 5.05 (1H, s), 4.02-4.05 (1H, m), 3.70 (2H, s), 2.79-2.99 (8H, brs), 2.66 (3H, s), 2.52 (3H, s), 1.29 (6H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C30H34F3N6O: 551.2741. found: 551.2734.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[N:30]=[C:29]([CH2:31][N:1]3[CH:2]([C:10]4[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=4[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]3=[O:8])[CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Reactant: O=Cc1cccc(-n2cccn2)n1
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2cccn2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with 6-(1H-pyrazol-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.49 min.; [M+H]+: 393.79 g/mol.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[C:20]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21]>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:35][C:32]2[CH:31]=[CH:30][C:29]([C:20]([CH3:22])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:21])=[CH:34][CH:33]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(C)(C)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 4-cumylphenol in a manner analogous to that described for Example 5, Step B. MS(ES) for C28H28O4[M+NH4]+: 446.2.
Reaction SMILES: [N:1]1[C:2](=[O:10])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:11](Br)[C:12]#[CH:13]>CN(C)C=O>[C:12]1([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]([CH2:8][C:7]#[CH:6])[C:2]2=[O:10])[CH:13]=[CH:9][CH:4]=[CH:5][CH:11]=1
Reactant: C#CCBr
Reactant: O=C1N=c2ccccc2=N1
Solvent: CN(C)C=O
Product: C#CCn1c(=O)n(-c2ccccc2)c2ccccc21
Reaction time: 0.25 h

Procedure:
1.76 g (15.7 mmol) was added to a solution of 3 g (14.2 mmol) of 1.3-dihydro-1-phenyl 2H. benzimidazol-2-one in 30 ml of dimethylformamide and the mixture was stirred under nitrogen for 15 minutes. propargyl bromide, 1.4 ml (15 mmol) was then added and stirring was continued for 30 minutes at room temperature and 15 minutes on the steam bath. The product was precipitated by dilution with saturated aqueous sodium bicarbonate solution and was filtered off, washed with water and sucked dry. It was dissolved in methylene chloride and the solution was passed over a plug of silica gel using methylene chloride. The filtrate was evaporated and the residue was crystallized from methylene chloride/ethyl acetate to give colorless crystals of 1.3-dihydro-1-phenyl-3-(2-propynyl)-2H-benzimidazol-2 one with m.p. 145°-147°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[CH3:44][O:45][C:46]1[CH:58]=[CH:57][C:49]2[C:50]([CH2:53][C:54](O)=[O:55])=[CH:51][O:52][C:48]=2[CH:47]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:54](=[O:55])[CH2:53][C:50]3[C:49]4[CH:57]=[CH:58][C:46]([O:45][CH3:44])=[CH:47][C:48]=4[O:52][CH:51]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc2c(CC(=O)O)coc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(CC(=O)NCc3cccc4c3C(=O)N(C3CCC(=O)NC3=O)C4=O)coc2c1
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 2-(6-methoxy-1-benzofuran-3-yl)-acetic acid were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). After stirring at room temperature overnight, the mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]2-(6-methoxy-benzofuran-3-yl)-acetamide (0.76 g, 73%) as a white solid: mp 143-145° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.41 min. (98%); 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.91 (m, 1H), 3.60 (s, 2H), 3.79 (s, 3H), 4.74 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.8 Hz, 1H), 6.85-6.89 (dd, J=2.2 and 8.6 Hz, 1H), 7.15 (d, J=2.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.64-7.81 (m, 4H), 8.69 (t, J=5.9 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.51, 30.90, 37.91, 48.83, 55.53, 95.93, 111.42, 114.55, 120.21, 120.91, 121.90, 127.12, 131.49, 133.29, 134.63, 139.06, 142.19, 155.57, 157.68, 166.90, 167.43, 169.78, 172.63, 172.73; Anal. Calcd. for C25H21N3O7: C, 63.16; H, 4.45; N, 8.84. Found: C, 62.90; H, 4.44; N, 8.74.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=O)[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[OH-].[NH4+]>>[CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH:6]=[C:5]([C:16]2[CH:17]=[CH:18][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CN1C(C)(C)CC(=O)CC1(C)C
Reactant: Oc1ccccc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: CN1C(C)(C)C=C(c2ccc(O)cc2)CC1(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 33.5 %

Procedure:
1,2,2,6,6-Pentamethyl-piperidin-4-one (8.64 g, 50.00 mmol) and phenol (4.98 g, 53.00 mmol) were melted together at 60° C. in a 100 mL round bottomed flask after which 13.5 mL of concentrated hydrochloric acid was added dropwise. The yellow solution was stirred at 70° C. for 24 hours. The mixture was poured into a beaker containing ice. Ammonium hydroxide was added carefully while stirring until the pH reached 7˜8. The mixture was extracted with EtOAc five times. The organic phases were combined, dried (Na2SO4) and concentrated. The residue was purified by chromatography on a silica gel column, eluting with 7N NH3 in methanol/dichloromethane to give 4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydropyridin-4-yl)-phenol (4.11 g, 34%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([OH:18])[C:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:16]=3[CH:17]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]([OH:18])[C:11]4[CH:12]=[CH:13][CH:14]=[N:15][C:16]=4[CH:17]=3)=[CH:4][CH:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Oc1nc(-c2ccc(Br)cc2)cc2ncccc12
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: CN(C)C=O
Product: COc1ccc(-c2ccc(-c3cc4ncccc4c(O)n3)cc2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a suspension of 7-(4-bromophenyl)-[1,6]-naphthyridin-5-ol (0.135 g, 0.45 mmol)) in DMF (4 mL), was added tetrakis(triphenylphosphine)palladium (0.025 g, 0.02 mmol). After 15 minutes, 4-methoxyphenylboronic acid (0.090 g, 0.60 mmol) and sodium carbonate (2 M aqueous solution, 0.5 mL, 1 mmol) was added. The mixture was heated to 100° C. for 12 hours and then cooled to room temperature. The white solid was collected by filtration and washed with water to afford the title compound (0.110 g).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[C@H:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[C@H:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1)(=[O:26])=[O:25]
Reactant: O=C1N[C@H](CO)C[C@H]1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1C[C@@H](Cc2ccccc2)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the crude product from Step 2, in 5 ml of methylene chloride cooled to 0° C. was added triethylamine (42 mg, 0.41 mmol) and methanesulfonyl chloride (47 mg, 0.41 mmol). The reaction was slowly allowed to warm to room temperature and was stirred for 18 hr after which time it was diluted with 30 ml of methylene chloride, washed with 30 ml of 10% citric acid solution, dried filtered and concentrated to afford the product as an oil.