Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[C:12]1([C:18]#[C:19][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9](=[O:11])[CH3:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)Cc1ccccc1Br
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)Cc1ccccc1C#Cc1ccccc1
Yield: 80.8 %

Procedure:
A solution of 28.3 g (112 mmole) of 2-bromophenyl-2-propanone, 14.7 ml (134 mmole) of phenylacetylene, 1.8 g (2.24 mmole) of bis(triphenylphosphine) palladium (II) chloride and 0.85 g (4.48 mmole) of copper (I) iodide in 250 ml of triethylamine under nitrogen was heated under reflux for 31/2hours. An additional 3.6 ml of phenylacetylene, 0.36 g of palladium complex and 0.1 g copper (I) iodide were added. The mixture was heated under reflux for 31/2 hours. An addtional 5.0 ml of phenylacetylene, 0.36 g of palladium complex and 0.17 g of copper (I) iodide were added. The mixture was heated under reflux for 2 hours. An additional 5.0 ml of phenylacetylene was added. The mixture was heated under reflux for 31/2 hours. The solvent was evaporated in vacuo and the residue taken up in ether. The ether was washed with water and brine, dried (K2CO3) and the solvent evaporated in vacuo. The residue was flash chromatographed on silica gel with ethyl acetate:hexane, 9:1, as eluant. The solvent was evaporated from the major compound bearing fraction to afford 21.2 g (81% yeild) of 2-[(phenyl)ethynyl]phenyl-2-propanone as an oil.
Reaction SMILES: [C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O.N1C(=O)C2NC=NC=2NC1=O.[N+:31]([C:34]1[CH:35]=[N:36][C:37]2[C:42]([C:43]=1O)=[CH:41][CH:40]=[CH:39][CH:38]=2)([O-:33])=[O:32].P(Cl)(Cl)([Cl:47])=O>>[N+:31]([C:34]1[CH:35]=[N:36][C:37]2[C:42]([C:43]=1[Cl:47])=[CH:41][CH:40]=[CH:39][CH:38]=2)([O-:33])=[O:32]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Product: O=[N+]([O-])c1cnc2ccccc2c1Cl

Procedure:
Compound 6 was prepared as described elsewhere [Van Galen, P. J. M. et. al. 1H-imidazo[4,5-c]quinolin-4-amines: Novel Non-Xanthine Adenosine Antagonists. J. Med. Chem. 1991, 34, 1202-1206]. In brief, 3-Nitro-4-hydroxyquinoline 5 (5.7 g, 30 mmol) was added to phosphorus oxychloride (70.0 g, 41.2 ml, 450 mmol) with stirring. The mixture was refluxed for 30 minutes. After cooling the solvent was poured over crushed ice while stirring. After 1 hour the solid that was formed was filtered off, washed with cold water and dissolved in ethyl acetate. The solution was extracted with ice-cold NaOH (1 M) till pH=8-9 and dried over MgSO4. The solvent was evaporated and the residue was dried. Yield: 5.05 g (81%). Mp.: 118°-119° C. 1H NMR (DMSO-d6): δ 7.94-8.11 (m, 2H, Ar); 8.25 (d, 1H, J=8.0 Hz, Ar); 8.47 (d, 1H, J=9.5 Hz, Ar); 9.42 (s, 1H, Ar).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:16](#[N:19])[CH:17]=[CH2:18]>CN(C)C=O>[C:16]([CH2:17][CH2:18][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)#[N:19]
Reactant: C=CC#N
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCCn1cnc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
4-Nitroimidazole (6.87 g, 60 mmol), triethylamine (18.2 g, 180 mmol) and acrylonitrile (9.55 g, 180 mmol) were dissolved in N,N-dimethylformamide (100 ml), and the solution was stirred at 100° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and chloroform was added to the concentrate. Solids deposited were collected by filtration and dried to obtain 9.2 g of the title compound.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=C)=[CH:10][N:9]=1>O.COCCOC.[Os](=O)(=O)(=O)=O>[CH3:7][C:8]1[N:9]=[CH:10][C:11]([CH:14]=[O:2])=[CH:12][CH:13]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
80 g (0.37 mole) of sodium periodate in 200 ml of water are added dropwise with vigorous stirring to 23 g (0.19 mole) of 2-methyl-5-vinyl pyridine in 800 ml of ethylene glycol dimethyl ether. 1.0 g (0.04 mole) of osmium tetroxide is then added while cooling with a mixture of ice and common salt, after which the mixture is stirred for 8 hours at room temperature in a nitrogen atmosphere. The oil remaining after removal of the solvent by evaporation in vacuo is taken up in a little water and extracted three times with ethyl acetate. Drying of the organic phase over sodium sulfate and concentration by evaporation in vacuo leave 20 g (87%) of a light brown oil which is immediately further processed.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]([O:15][C:16](=[O:25])[CH:17]([CH:22]([CH3:24])[CH3:23])[CH2:18][C:19]([OH:21])=O)[CH3:14].[C:26]1([CH:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:13]([O:15][C:16](=[O:25])[CH:17]([CH2:18][C:19](=[O:21])[NH:38][CH:35]1[CH2:34][CH2:33][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:37][CH2:36]1)[CH:22]([CH3:24])[CH3:23])[CH3:14]
Reactant: CCOC(=O)C(CC(=O)O)C(C)C
Reactant: NC1CCC(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(CC(=O)NC1CCC(c2ccccc2)CC1)C(C)C
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.80 g) was added to a solution of 4-dimethylaminopyridine (0.04g) and Intermediate 10 (0.54 g) in dichloromethane (30 ml) and the solution was stirred for 30 min, then a solution of Intermediate 14 (0.50 g) in dichloromethane (5 ml) was added and the mixture was stirred overnight. The solvent was removed in vacuo and the resulting slurry dissolved in ethyl acetate (100 ml), washed with water (10 ml), aqueous sodium bicarbonate (10 ml) and brine (10 ml), dried over magnesium sulphate (1 g) and the solvent removed in vacuo. The resulting oil was purified by flash chromatography (silica, eluent 30% ethyl acetate/hexane) to yield the title compound as a yellow solid (0.26 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:17](=O)[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(O)(O)(=O)=O.[CH3:25][O:26][C:27](=[NH:29])[NH2:28].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[NH:29][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:28]=1
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A reaction mixture containing 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, ethyl ester (2.62 g, 10.0 mmole), 2-methylpseudourea sulfate (1.72 g, 10.0 mmole), and sodium bicarbonate (2.52 g, 30.0 mmole) in dimethylformamide (10 ml) was heated at 65°-70° C. for 16 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and filtered. The filtrate was washed with water and brine, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a yellow oil which was purified by flash chromatography (5% ethyl acetate in dichloromethane). The resulting foam was crystallized from isopropyl ether/hexanes to provide 2.41 g of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester as a colorless crystalline product; melting point 103.5°-105° C. TLC (silica gel; ethyl acetate: hexanes 50:50) Rf =0.31
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].ClCCl.CCN=C=N[CH2:16][CH2:17][CH2:18][N:19](C)C.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[C:30]1[C:34]([C:35]([OH:37])=O)=[C:33]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[O:32][N:31]=1>CN(C1C=CN=CC=1)C.CC(C)=O.ClCCl>[C:3]1([C:1]([NH:19][CH2:18][C@@H:17]2[CH2:16][CH2:23][CH2:24][C@H:30]([NH:31][C:35]([C:34]3[C:30]([C:24]4[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=4[Cl:22])=[N:31][O:32][C:33]=3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:37])[CH2:34]2)=[O:2])[CH:41]=[CH:40][CH:39]=[CH:38][CH:33]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCCCc1onc(-c2c(F)cccc2Cl)c1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCCCc1onc(-c2c(F)cccc2Cl)c1C(=O)N[C@H]1CCC[C@@H](CNC(=O)c2ccccc2)C1
Yield: 69 %

Procedure:
In a fashion similar to that described for preparation 108, a compound from preparation 105 (0.1 g, 0.3 mmol), TFA (2 mL), dichloromethane (1.5 mL), EDCI (0.086 g, 0.45 mmol), DMAP (0.007 g, 0.06 mmol), 3-(2-chloro-6-fluoro-phenyl)-5-hexyl-isoxazole-4-carboxylic acid (0.117 g, 0.36 mmol), and dichloromethane (1.5 mL) gave the title compound (0.112 g, 69%) after column chromatography (silica gel, acetone/dichloromethane gradient). Mass Spectrum (FIA) (m/z) 540.5 [M+1].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[NH:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)[C:19]([NH2:21])=[NH:20].[C:31]([O-:34])([OH:33])=[O:32].[Na+]>N1C=CC=CC=1>[C:31](=[O:32])([OH:34])[OH:33].[NH:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([O:17][C:14]2[CH:13]=[CH:12][C:11]([S:10][CH2:9][CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:16][CH:15]=2)=[O:27])=[CH:24][CH:23]=1)[C:19]([NH2:21])=[NH:20]
Reactant: Oc1ccc(SCCOC2CCCCO2)cc1
Reactant: O=C([O-])O
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Solvent: c1ccncc1
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc(SCCOC3CCCCO3)cc2)cc1
Product: O=C(O)O
Temperature: 25 °C

Procedure:
96.08 g of 4-hydroxyphenyl 2-(tetrahydropyran-2-yloxy)ethyl sulfide synthesized by the above process (2) was dissolved in 800 ml of pyridine. 4-Guanidinobenzoyl chloride was added to the solution under cooling with ice and the mixture was stirred at room temperature for 24 h or longer. A saturated aqueous sodium hydrocarbonate solution was added thereto under cooling with ice and the precipitate thus obtained was recovered by filtration, washed with water, then acetone and finally ethyl acetate and dried to obtain 104 g of 4-(2-tetrahydropyran-2-yloxyethylthio)phenyl 4-guanidinobenzoate carbonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:26][CH3:27])[CH2:22][CH2:23][C:24]#[N:25])[C:11](=[O:28])[C@@H:10]([CH2:29][C:30]([OH:32])=[O:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CCC#N)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](CCC#N)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
To a solution of 57 mg (0.11 mmol) of tert-butyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan-3-yl)-2-oxopiperidin-3-yl)acetate (Example 30, Step B) in DCM (359 μL) was added trifluoroacetic acid (415 μL, 5.38 mmol) at 0° C. After being stirred at 25 C for 2 h, solvents were removed under reduced pressure and the residual TFA was removed by azeotroping with toluene under reduced pressure three times. Separation of the crude product by reversed phase HPLC (45 to 70% AcCN/H2O in 30 min, 3 time runs, tR=18.52 min) provided the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[N:6]=1.[NH2:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([C:29]2[C:34]3[O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:33]=3[CH:32]=[CH:31][CH:30]=2)=[O:28])[CH:22]=[CH:23][C:24]=1[CH3:25]>C(Cl)Cl>[CH3:25][C:24]1[CH:23]=[CH:22][C:21]([NH:26][C:27]([C:29]2[C:34]3[O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:33]=3[CH:32]=[CH:31][CH:30]=2)=[O:28])=[CH:20][C:19]=1[NH:18][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:17][CH:16]=1
Reactant: Cc1nc(COc2ccc(C(=O)O)cc2)cs1
Reactant: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1N
Solvent: ClCCl
Product: Cc1nc(COc2ccc(C(=O)Nc3cc(NC(=O)c4cccc5c4oc4ccccc45)ccc3C)cc2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.6 %

Procedure:
4-(2-Methylthiazol-4-ylmethoxy)benzoic acid (0.095 g) was added to a stirred mixture of N-(3-amino-4-methylphenyl)dibenzofuran-4-carboxamide (0.12 g), diisopropyethyllamine (0.2 ml), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.134 g) and methylene chloride (22 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was purified by column chromatography on an ion exchange column (isolute SCX column) using initially a 1:1 mixture of ethyl acetate and methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. The product so obtained was triturated under ethyl acetate. There was thus obtained the title compound (0.051 g); NMR Spectrum: (DMSOd6) 2.25 (s, 3H), 2.65 (s, 3H), 5.2 (s, 2H), 7.15 (d, 2H), 7.25 (d, 1H),7.4-7.65 (m, 5H), 7.8-7.9 (m, 3H), 7.98 (d, 2H), 8.2 (d, 1H), 8.35 (d, 1H), 9.8 (d, 1H), 10.4 (s, 1H); Mass Spectrum: M+H+ 548.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([OH:9])[CH:3]=1.[CH3:10][CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1.CN(C)C=O>ClCCl.CO>[CH3:1][C:2]1[N:7]=[C:6]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]2[CH3:10])[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: CC1NCCc2ccccc21
Reactant: Cc1cc(O)nc(Cl)n1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(N2CCc3ccccc3C2C)n1
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A mixture solution of 6-methyl-2-chloro-4-hydroxypyrimidine(6 g, 37.5 mmol) prepared in the above Step 1, 1-methyl-1,2,3,4-tetrahydroisoquinoline(11.6 g, 78.8 mmol) and N,N-dimethylformamide(30 ml) was stirred at 120 for 2 hours and cooled to give a solid. The resulting solid was dissolved in a mixture solution of dichloromethane and methanol and the undissolved materials were filtered off. The filtrate residue was washed many times with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 7.1 g of titled compound. (Yield: 74.1%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)CCC>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>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: OCc1cc2cc(Br)ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: OCc1cc2cc(-c3cnccn3)ccc2o1
Temperature: 95 °C

Procedure:
To a solution of (5-bromo-benzofuran-2-yl)-methanol (1 g, 4.4 mmol) and 2-tributylstannylpyrazine (1.6 g, 3.7 mmol) in 15 mL toluene at room temperature under argon, was added tetrakis(triphenylphosphine)palladium (0) (130 mg), and the mixture was heated at 95° C. overnight. The precipitate was allowed to cooled, extracted with ethyl acetate, washed with brine and dried over MgSO4. Filtration afforded 2.1 g of crude product that was further purified by chromatography to afford (5-pyrazin-2-yl-benzofuran-2-yl)-methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[Si:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.O>C1(C)C=CC=CC=1.CCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:10]([O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: N#Cc1ccnc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cc(C#N)ccn2)cc1
Temperature: 50 °C

Procedure:
A solution composed of 2-bromo-4-pyridinecarbonitrile (5.00 g, 36.1 mmol), 4-[(tert-butyldimethylsilyl)oxy]aniline (8.06 g, 36.1 mmol), sodium tert-butylate (4.50 g, 46.9 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.458 g, 1.08 mmol) in toluene (50 mL) is purged with nitrogen. Tris(dibenzylideneacetone)-dipalladium(0) (0.99 g, 1.08 mmol) is then added to the reaction mixture, and then the batch is heated at 50° C. for 1.5 hours. The mixture is then allowed to cool to ambient temperature. Water is added and the reaction mixture is extracted with ethyl acetate (3×20 mL). The combined organic phases are washed with brine, and then concentrated under reduced pressure. The crude product is absorbed onto silica gel and purified by chromatography over silica gel using ethyl acetate and heptane as eluants. The product obtained is dissolved in the warm state in heptane and precipitates, with stirring, at ambient temperature, and then at 0° C. After filtration, the expected compound is obtained in the form of a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[CH:22]=[CH:21][C:9]2[N:10]([CH2:17][CH2:18][CH2:19][OH:20])[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[N:12][C:8]=2[CH:7]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][C:9]2[N:10]([CH2:17][CH2:18][CH2:19][OH:20])[C:11]([CH2:13][CH:14]([CH3:16])[CH3:15])=[N:12][C:8]=2[CH:7]=1
Reactant: COC(=O)C=Cc1ccc2c(c1)nc(CC(C)C)n2CCCO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc2c(c1)nc(CC(C)C)n2CCCO

Procedure:
3-[1-(3-hydroxy-propyl)-2-isobutyl-1H-benzimidazol-5-yl]-acrylic acid methyl ester (prepared according to the Example 1, step 1-3) (126.6 mg, 0.4 mmol) and 10% Pd/C (40 mg) in 10 mL of MeOH was hydrogenated using a hydrogen balloon overnight. After filtration through short-column silica gel, the filtrate was evaporated under reduced pressure to give 3-[1-(3-hydroxy-propyl)-2-isobutyl-1H-benzimidazol-5-yl]-propionic acid methyl ester (127 mg) in quantitative yield: MS m/z (M+H)+: 319; 1H NMR (400 MHz, MeOD) δ 0.95 (6H, d, J=6.4 Hz), 1.92 (2H, m), 2.19 (1H, m), 2.60 (2H, t, J=8.0 Hz), 2.74 (2H, d, J=7.2 Hz), 2.96 (2H, t, J=7.6 Hz), 3.50 (2H, t, J=4.1 Hz), 3.54 (3H, s), 4.25 (2H, t, J=7.2 Hz), 7.05 (1H, d, J=8.0 Hz), 7.30-7.40 (2H, m); 13C NMR (100 MHz, MeOD) δ 20.9 (2C), 27.3, 30.1, 31.5, 34.6, 35.3, 39.5, 50.1, 57.4, 109.1, 116.4, 122.1, 132.6, 134.2, 141.3, 154.2, 173.2.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=[O:4])=[O:3].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:41]1[NH:46][CH2:45][CH2:44][N:43]2[CH2:47][CH2:48][CH2:49][C@H:42]12>ClCCl.CO>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH:21]([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=2)[N:22]2[CH2:23][CH2:24][N:25]([C:8]([C:7]3[CH:6]=[C:5]([S:2]([N:46]4[CH2:45][CH2:44][N:43]5[CH2:47][CH2:48][CH2:49][C@@H:42]5[CH2:41]4)(=[O:4])=[O:3])[CH:13]=[CH:12][CH:11]=3)=[O:9])[CH2:26][CH2:27]2)=[CH:29][CH:30]=1
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cccc(S(=O)(=O)N2CCN3CCC[C@@H]3C2)c1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-(chlorosulfonyl)benzoyl chloride (0.359 g, 1.5 mmol) in anhydrous dichloromethane (40 mL) was added 1-(bis(4-fluorophenyl)methyl)piperazine (0.433 g, 1.5 mmol) in dichloromethane (4 mL) slowly over 10 minutes at room temperature. Then sodium carbonate (0.64 g, 6 mmol) was added. The mixture was stirred at room temperature overnight. Then (R)-octahydropyrrolo[1,2-a]pyrazine (0.208 g, 1.65 mmol) was added. The mixture was stirred at reflux for 20 minutes, and then at room temperature for 3 days. Methanol (5 mL) was added, the mixture was stirred for 20 minutes, then filtered, and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=20:1) to give the titled compound: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.09 (m, 1H), 1.55 (m, 2H), 1.72 (m, 1H), 1.90 (m, 4H), 2.10 (m, 1H), 2.20-2.50 (m, 6H), 2.90 (m, 2H), 3.58-3.78 (m, 4H), 4.42 (s, 1H), 7.12 (m, 4H), 7.42 (m, 4H), 7.71 (m, 3H), 7.80 (m, 1H); MS (ESI) m/z 581 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][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].[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])#[N:23].C(N(CC)CC)C>C1COCC1>[C:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][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])=[O:28])#[N:23]
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 5 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and m-cyanobenzoyl chloride (0.4 g, 2.5 mmol) in THF (30 mL) was cooled to 5° C. Triethylamine (0.5 g, 4.8 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (40 mL). The mixture was filtered, and the solid was slurried with warmed ethanol (20 mL) to give 3-cyano-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide (0.8 g, 92%) as a white solid: mp 282-284° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.34-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.41-4.62 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.8 and 13 Hz, 1H, CH), 7.48-7.74 (m, 4H, Ar), 8.01 (d, J=7.7 Ha, 1H, Ar), 8.17 (d, J=7.9 Hz, 1H, Ar), 8.31 (s, 1H, Ar), 9.28 (t, J=5.0 Hz, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.69, 31.17, 46.26, 51.60, 111.50, 118.26, 121.79, 128.35, 129.80, 130.82, 130.89, 131.65, 132.08, 134.14, 134.79, 135.00, 140.25, 164.54, 168.02, 170.98, 172.81; Anal. calcd. for C22H18N4O4: C, 65.67; H, 4.51; N, 13.92. Found: C, 65.38; H, 4.42; N, 13.77.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([OH:9])=[N:6][C:7]=1[CH3:8].CC1C=CC(S(O[CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])(=O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([O:9][CH2:22][CH2:23][C:24]([CH3:26])([OH:27])[CH3:25])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Br)c(C)nc1O
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Product: Cc1cc(Br)c(C)nc1OCCC(C)(C)O
Yield: 75.8 %

Procedure:
According to the method of (Example 36) <Step 1>, from 5-bromo-3,6-dimethylpyridin-2-ol (0.74 g) and 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (1.0 g), the subject compound (0.80 g) was obtained as a white solid.