Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]([CH3:21])[CH:4]=1)#[N:2]>C(O)C.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]([CH3:21])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)C=Cc1cccn1-c1ccc(C#N)cc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cccn1-c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)acrylate (6C) (8.0 g, 28.6 mmol) in ethanol was added 10% Pd/C (0.8 g). The mixture was stirred under 1 atm of H2 for 30 min at room temperature and filtered. The resultant filtrate was concentrated to dryness affording the crude product of ethyl 3-(1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (7.5 g), which was used for the next step without further purification: LC-MS m/z 283.0 [M+H]+, purity 68%.
Reaction SMILES: [C:1](=O)([O-])O.[Na+].Cl.[CH3:7][O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@H:14](CN)[CH2:13][CH2:12]1)=[O:10].C1C2C(COC(N=C=S)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[CH3:7][O:8][C:9]([C:11]1([CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:10]
Reactant: O=C([O-])O
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Agent: Cl
Agent: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: COC(=O)C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
Sodium hydrogen carbonate (1.68 g, 20.0 mmol) was added to a solution of trans-4-aminomethyl cyclohexanecarboxylic acid methyl ester hydrochloride (2.07 g, 10.0 mmol) obtained in Step 1, 9-fluorenylmethoxycarbonyl isothiocyanate (2.81 g, 10.0 mmol) in chloroform (40 ml) while ice-cooled. The reaction solution was stirred at room temperature for 16 hours, piperidine (5 ml, 50 mmol) was added, and the mixture was stirred at room temperature for further 6 hours. Trans-4-thiouredide methylcyclohexane carboxylic acid methyl ester (1.55 g, 67%) was obtained by concentrating the reaction solution in vacuo and purifying the obtained solid by silica gel column chromatography (ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19])=[N:7][N:6]=[CH:5]2.[F:20][C:21]1[CH:22]=[C:23]([SH:27])[CH:24]=[CH:25][CH:26]=1>CCN(CC)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P[C-]1C=CC=C1)(C)C.[C-]1(PC(C)C)C=CC=C1.[Fe+2]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:9]3[C:4](=[CH:3][C:2]([S:27][C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=4)=[CH:11][CH:10]=3)[CH:5]=[N:6][N:7]=2)=[C:13]([CH3:19])[CH:14]=1
Reactant: Fc1cccc(S)c1
Reactant: Cc1cc(F)ccc1-c1nncc2cc(Cl)ccc12
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nncc2cc(Sc3cccc(F)c3)ccc12
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-1-(4-fluoro-2-methylphenyl)phthalazine (0.197 g, 0.72 mmol), palladium(II) acetate (0.011 g, 0.049 mmol), 1,1′-bis(isopropylphosphino)ferrocene (0.022 g, 0.053 mmol) and 3-fluorothiophenol (0.080 ml, 0.95 mmol) in 2 mL of Et3N was sealed in a glass tube purged with argon and heated at 100° C. in an oil bath for 17 h. The reaction mixture was cooled to RT and diluted with MeOH. The solution was evaporated onto silica gel and purified by flash chromatography (ISCO 80 g column, eluting with 15-45% EtOAc in hexanes) to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: M+1=365.1
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[C:16]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35]Cl)[N:34]=2)=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][CH:32]=[C:33]([CH2:35][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:34]=2)=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: O=C(c1ccccc1)c1ccc(-c2nc(CCl)co2)cc1
Product: O=C(c1ccccc1)c1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(4-benzoylphenyl)-4-chloromethyloxazole to give 2-(4-benzoylphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 78%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 112-113° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:18])=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[CH3:18][C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2
Reactant: COc1ccc(-n2c(C)cc3ccccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2ccccc2n1-c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(4-Methoxyphenyl)-2-methyl-1H-indole (175 mg, 0.73 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0° C. Boron tribromide (2.19 mL, 1 M solution in dichloromethane, 2.19 mmol) was added dropwise, and the reaction was stirred for 2 hours. The reaction was quenched by addition of saturated sodium bicarbonate solution, then extracted with dichloromethane followed by ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. The reaction was assumed to be quantitative. LC-MS (C15H13NO calc'd 223) m/z 224 (M+H).
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][CH2:3]1.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([O-:8])=[O:7]>>[CH:2]1([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N+:6]([O-:8])=[O:7])[CH2:5][CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrC1CCC1
Product: O=[N+]([O-])c1ccccc1OC1CCC1

Procedure:
In a similar manner as in Example 1, bromocyclobutane was reacted with o-nitrophenol to yield 2-cyclobutoxynitrobenzene; which was reduced to the corresponding aniline; reacted with N-methylolpyrrolidone to form the corresponding N-methylenepyrrolidonyl derivative; which was acylated with chloroacetyl chloride to form the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([CH2:18][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4]2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (6.11 g, 28.1 mmol), 4-(bromomethyl)biphenyl (9.04 g, 36.6 mmol, 1.3 equiv), potassium iodide (467 mg, 2.81 mmol, 0.1 equiv) and potassium carbonate (9.72 g, 70.3 mmol, 2.5 equiv) were combined in N,N-dimethylformamide (10 mL) and stirred at ambient temperature for 18 hours. The mixture was poured into water (100 mL) and ethyl acetate (100 mL) and aged for 2 hours. The mixture was filtered, the filtrate discarded and the solid was dissolved in dichloromethane (100 mL), dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CO.C1C[O:30]CC1>O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:15]([NH:17][OH:18])=[O:16])(=[O:30])=[O:13])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)C(C(=O)NO)C2CCCCC2)cc1
Reactant: C1CCOC1
Solvent: CO
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)C(C(=O)NO)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-{[4-(2-butynyl oxy)phenyl]sulfinyl}-2-cyclohexyl-N-hydroxyacetamide (180 mg, 0.52 mmol) in MeOH/THF at room, wxone (5.0 g, excess) was added in water (20 ml). Reaction mixture was stirred at room temperature for 6 hrs and filtered. Methanol-THF layer was concentrated and extracted with chloroform. The organic layer was washed well with water, dried, filtered and concentrated. The product was purified by silica gel column chromatography by eluting it with 4:1 ethyl acetate; hexane and 2-{[4-(2-butynyl oxy)phenyl]sulfonyl}-2-cyclohexyl-N-hydroxyacetamide was isolated as a white solid. mp: 191° C.; Yield: 45 mg (24%); MS: 366.3 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ 0.95-1.12 (band, 5H), 1.58 (m, 5H), 1.85 (t, J=2.22 Hz, 3H), 2.05 (m, 1H), 3.63 (d, J=9.1 Hz, 1H), 4.87 (d, J=2.34 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 7.76 (d, J=9 Hz, 2H), 9.01 (s, 1H), 10.7 (s, 1H).
Reaction SMILES: [OH-].[K+].N(N(C)[C:6](N)=O)=O.[N+](=C)=[N-].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][C:15]=1[NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:30][CH:29]=1)=[O:27]>O.C(OCC)C.C(Cl)Cl>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][C:15]=1[NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH3:6])=[O:37])=[CH:30][CH:29]=1)=[O:27]
Reactant: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CCC(=O)O)cc1
Reactant: CN(N=O)C(N)=O
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 0 °C
Yield: 94.1 %

Procedure:
A mixture of 50% potassium hydroxide in H2O (30 mL) and diethyl ether (100 mL), stirred at 0° C., was treated portion wise with solid N-nitroso-N-methyl urea (3.0 g, 29.1 mmol). The reaction mixture was stirred for 30 min then transferred into a separatory funnel, the aqueous layer was discarded and the yellow ethereal phase (diazomethane solution) was cooled to −78° C. in an Erlenmeyer flask. A suspension of the acid 230 (20 mg, 0.055 mmol) in DCM (2 mL) was treated with the diazomethane solution in diethyl ether (3 mL) and the yellow solution was stirred at room temperature for 3 h, concentrated and the residue was purified by flash chromatography (eluent: 2% isopropanol in DCM) to provide title compound 231 (19.7 mg, 94% yield).
Reaction SMILES: C(O)(=O)/C=[CH:3]/[C:4](O)=[O:5].[N:9]1([CH2:14][CH2:15][CH2:16][NH:17][C:18]2[C:26]3[CH:27]=[CH:28][CH:29]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[N:19]=2)[CH:13]=[N:12][CH:11]=[N:10]1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[N:19]1[C:20]2[C:25]3[C:24](=[CH:29][CH:28]=[CH:27][C:26]=3[C:18]=1[N:17]([CH2:16][CH2:15][CH2:14][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:4](=[O:5])[CH3:3])[CH:23]=[CH:22][CH:21]=2
Reactant: O=C(O)/C=C/C(=O)O
Reactant: c1cc2c3c(cccc3c1)C(NCCCn1cncn1)=N2
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(CCCn1cncn1)C1=Nc2cccc3cccc1c23
Temperature: -10 °C

Procedure:
Three and three-tenths grams of the free base of Example 69 and 10 ml of acetic anhydride were added to 5 ml of pyridine, and the mixture then refluxed for 15 minutes. The volatiles were removed in vacuo and the residue partitioned between 100 ml of dichloromethane and 100 ml of saturated NaHCO3 solution. The dichloromethane layer was dried over MgSO4. The dichloromethane solution was heated to boiling and hexane added until turbidity resulted (about 300 ml). The mixture was then cooled at -10° C. The precipitate of the title compound was collected, washed with hexane, and dried; yield, 1.9 grams; mp 128° C.-129° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:5]2[O:4][C:3]([CH2:2][N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:2][C:3]4[O:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=1
Reactant: C1CNCCNC1
Reactant: COc1cc2nc(CCl)oc2c(OC)c1OC
Product: COc1cc2nc(CN3CCCN(Cc4nc5cc(OC)c(OC)c(OC)c5o4)CC3)oc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxybenzoxazole (152 mg) and homopiperazine (28 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH2:7].N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>CN(C)C(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ncccn1
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: O=C(Nc1ncccn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of pyrimidine-2-amine (2.00 g, 21.0 mmol) and pyridine (5.10 ml, 63.0 mmol) in N,N-dimethylacetamide (50 ml) was added 2,2,2-trichloroethyl chloroformate (4.34 ml, 31.5 mmol) with ice-cooling, and the mixture was stirred for 40 minutes with ice-cooling. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate and the desired product (2.57 g, 45.2%) as a solid was collected by filtration.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[Br:14][CH2:15][C:16](Br)=[O:17]>ClCCl>[Br:14][CH2:15][C:16]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[C:7]([F:6])[CH:8]=1)=[O:17]
Reactant: Nc1cccc(F)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1cccc(F)c1
Reaction time: 8 h

Procedure:
To a suspension of sodium bicarbonate (1 g) and 3-fluoroaniline (0.46 g) in dichloromethane (100 mL) was added 2-bromoacetyl bromide (0.36 mL) by dropwise addition. After stirring overnight the reaction mixture was washed with water, dried with magnesium sulfate and evaporated to yield the sub-titled compound (1.07 g).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1C=CC=CC=1.ClC1[N:36]=[C:35]([Cl:37])[CH:34]=[CH:33][N:32]=1.IC1C=CC=CC=1>>[Cl:37][C:35]1[N:36]=[C:24]([N:4]2[CH:5]=[CH:6][C:7]([CH2:9][N:10]3[C:14]([CH2:15][C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[CH:13][N:12]=[CH:11]3)=[CH:8][C:3]2=[O:2])[N:32]=[CH:33][CH:34]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3nccc(Cl)n3)c(=O)c2)cc1

Procedure:
4-{3-[1-(6-Chloro-pyrimidin-2-yl)-2-oxo-1,2-dihydro-pyridin-4-ylmethyl]-3H-imidazol-4ylmethyl}-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2,4-dichloropyrimidine for the iodobenzene in Step 3.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:21][N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)=[C:10]([CH:20]=1)[CH2:11][NH:12][C:13](=[O:19])[C@@H:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.[OH:27][C:28]1([C:41](O)=[O:42])[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[OH:27][C:28]1([C:41]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:14]2[C:13]([NH:12][CH2:11][C:10]2[CH:20]=[C:6]([Cl:5])[CH:7]=[CH:8][C:9]=2[CH2:21][N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)=[O:19])=[O:42])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=2[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2
Reactant: O=C(NCc1cc(Cl)ccc1CN1CC(O)C1)[C@@H]1CCCN1
Reactant: O=C(O)C1(O)c2ccccc2-c2ccccc21
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(NCc1cc(Cl)ccc1CN1CC(O)C1)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
EDC (49.5, 0.26 mmol) was added to a stirred mixture of N-{5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzyl}-L-prolinamide (55.8 mg, 0.17 mmol), 9-hydroxy-9-H-fluoren-9-ylcarboxylic acid (40.9 mg, 0.18 mmol) and HOAT (11.7 mg, 0.086 mmol) in DMF (1.25 mL). After 16 h the mixture was concentrated and the residue was partitioned between EtOAc and 10% NaHCO3. The organic layer was washed with water and brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica (ammonia saturated CHCl3/MeOH, 98:2) to give the title compound as a glass: HRMS (FAB) calcd C30H31ClN3O4 (M+1) 554.1817, found 554.1855.
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][C@@:4]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:24]=[N:23][C:22]([C:25]4([C:28]([OH:30])=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:39][NH:40][CH3:41]>>[CH3:39][N:40]([CH3:41])[C:28]([C:25]1([C:22]2[N:23]=[N:24][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:37])[CH3:38])([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:14][CH:15]=3)=[CH:20][CH:21]=2)[CH2:27][CH2:26]1)=[O:30]
Reactant: CNC
Reactant: C[C@@H](c1ccc(-c2ccc(C3(C(=O)O)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(C3(C(=O)N(C)C)CC3)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 21 %

Procedure:
The title compound was prepared from 1-[6-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridazin-3-yl]-cyclopropanecarboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: 21% of theory; LC (method 1): tR=1.79 min; Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:17]3[O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:25][C:26]1[N:31]=[C:30]([NH:1][C:2]2[CH:3]=[C:4]([NH:9][C:10]([C:12]3[C:17]4[O:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:16]=4[CH:15]=[CH:14][CH:13]=3)=[O:11])[CH:5]=[CH:6][C:7]=2[CH3:8])[CH:29]=[CH:28][N:27]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(Cl)n1
Temperature: 120 °C
Yield: 40.8 %

Procedure:
A mixture of N-(3-amino-4-methylphenyl)dibenzofuran-4-carboxamide (1.5 g), 2,4-dichloropyrimidine (1.4 g), N,N-di-isopropylethylamine (2.9 ml) and n-butanol (70 ml) was stirred and heated to 120° C. for 76 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of isohexane and ethyl acetate as eluent. The material so obtained was triturated under ethyl acetate. There was thus obtained the title compound (0.83 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 6.53 (d, 1H), 7.31 (d, 1H), 7.43-7.65 (m, 4H), 7.79 (m, 2H), 7.84 (d, 1H), 8.1 (d, 1H), 8.21 (d, 1H), 8.34 (d, 1H), 9.62 (s, 1H), 10.42 (s, 1H); Mass Spectrum: M+H+ 429 and 431.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=[C:18]3[N:17]=[C:16]2[CH3:28])=[C:12]([Cl:31])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O>[C:1]([N:9]([C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=[C:18]3[N:17]=[C:16]2[CH3:28])=[C:12]([Cl:31])[CH:11]=1)[CH3:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)c4ccccc4)cc3Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)c4ccccc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
To a solution of methyl 3-(4-(N-benzoylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in N,N-dimethylformamide (3 ml) was added 60% sodium hydride (in mineral oil, 30.4 mg) at room temperature. After 15 min, methyl iodide (108 mg) was added and the mixture was stirred at room temperature for 2 hr. Ice water was poured thereinto and the mixture was extracted with ethyl acetate. The organic layer was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the objective compound (305 mg) as a pale-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([NH:1][C:38](=[O:40])[CH3:39])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:12])=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(N)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(-c2c(NC(C)=O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a stirred solution of N-{2-amino-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Description 85) (40 mg, 0.087 mmol) in DCM (3 mL) was added triethylamine (0.036 mL, 0.261 mmol) and acetyl chloride (7.42 ul, 0.104 mmol) and the mixture stirred at RT for ca. 1 h. NaHCO3 solution (25 mL) was then added and the mixture extracted with DCM (20 mL×3) and the combined organics dried and concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-50% ethyl acetate in DCM and was then further purified by MDAP (acidic conditions), to give the title compound (5.8 mg). LCMS (A) m/z: 502 [M+1]+, Rt 1.05 min (acidic).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:5][C:6](=O)[CH:7]=1)=[O:4].[C:9]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[C:9](/[CH:19]=[C:6]1\[CH:7]=[C:2]([CH3:1])[C:3]([O:5]\1)=[O:4])(=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: O=C(C=Cc1ccccc1)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC1=C/C(=C\C(=O)C=Cc2ccccc2)OC1=O
Yield: 72.5 %

Procedure:
A solution of 2-methylmaleic anhydride (3) (1.8 g, 16.1 mmol) in benzene (10 mL) is added to a refluxed solution of 4 (5.5 g, 13.5 mmol) in benzene (50 mL) under nitrogen. After refluxing for 6 hrs, TLC indicated complete consumption of 12. The reaction mixture is evaporated to dryness, and the residue is chromatographied on silica gel using hexanes-acetone (4:1) to yield E-4-cinnamoylmethylidene-2-methylbut-2-en-4-olide (5) (2.35 g, 73%) as yellow needles [from chloroform-methanol (1:1)]: mp 160–161 C°, UV (MeOH), ?max (log e) 208 (4.18), 238 (3.98), 334 (4.50) nm; IR (KBr) ?max, 1770, 1678, 1627, 1588, 1451, 1375, 1209, 1098, 1039, 990, 911, 877, 754, 698, 545; 1H NMR (400 MHz, CDCl3) d 8.10 (1H, s, H-3), 7.64 (1H, d, J=16.0 Hz, H-4′), 7.59 (2H, m, H-6′,10′), 7.42 (3H, m, H-7′,8′,9′), 6.88 (1H, d, J=16.0 Hz, H-3′), 6.48 (1H, s, H-1′), 2.11 (3H, s, Me-2); 13C NMR (100 MHz, CDCl3) d 188.3 (s, C-2′), 169.2 (s, C-1), 159.2 (s, C-4), 144.0 (d, C-4′), 137.0 (d, C-3), 136.4 (s, C-2), 134.3 (s, C-5′), 131.0 (d, C-8′), 129.1 (2C, d, C-6′,10′), 128.6 (2C, d, C-7′,9′), 127.5 (d, C-3′), 106.0 (d, C-1′), 11.2 (q, Me-2) (NMR assignments were based on 2D HMBC and NOESY experiments); HRESIMS m/z [M+H]+ 241.0841 (calcd for C15H13O3, 241.0859), [M+Na]+ 263.0659 (calcd for C15H12O3Na, 263.0678), [M+K]+ 279.0400 (calcd for C15H12O3K, 279.0418).