Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Cl.[CH:14]([N:17]([CH:21]([CH3:23])[CH3:22])[CH2:18][CH2:19]Cl)([CH3:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][CH2:18][N:17]([CH:21]([CH3:23])[CH3:22])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Product: CC(C)N(CCN1C(=O)C(=O)c2cc(Br)ccc21)C(C)C
Yield: 82.9 %

Procedure:
By using 5-bromoisatin and 2-diisopropylaminoethyl chloride hydrochloride, a method analogous to that described in Reference Example 7 was carried out to obtain 5-bromo-1-(2-diisopropylaminoethyl)isatin having a melting point of 91°-93° C. (yield: 82.9%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].[Cs+].Cl[C:17]1[CH:25]=[C:24]2[C:20]([C:21]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:22][N:23]2[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19][CH:18]=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:2][C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:22][N:23]3[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(C(C)(C)C)cc3)ccc12
Temperature: 102 °C
Yield: 89.3 %

Procedure:
840 mg of 4-tert-butylphenylboronic acid, 1.24 g of caesium fluoride, 13.5 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)-ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 25, in 30 cm3 of dioxane. The mixture is heated at about 102° C. for 21 hours and the temperature is then allowed to return to room temperature and the reaction medium is diluted with 75 cm3 of ethyl acetate, filtered through a sinter funnel packed with Celite and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The work-up and the purification are performed by analogy with Example 41. 1.13 g of N-[6-[4-(1,1-dimethylethyl)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are thus obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[C:8]([O:16]CC2C=CC=CC=2)=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[C:8]([OH:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: [H][H]
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(Cc2cccc(C(=O)O)c2O)c(OC)c(OC)c1OC
Yield: 98.3 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoic acid (0.52 g, 1.15 mmol) was dissolved in ethanol (10 ml) and after adding thereto an ethanol suspension (3 ml) of 5% Pd—C (0.15 g), the solution was stirred at room temperature for 16 hours in a hydrogen stream. The reaction solution was filtered, the filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.41 g, 1.13 mmol, 98%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]2[N:10]([CH3:13])[CH:11]=[N:12][C:4]=2[CH:3]=1.ClC1N=C(SC)C2N=CN(C)C=2C=1.[C:27]([N:31]1[CH:35]=[C:34](C2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C.O.COCCOC>[C:27]([N:31]1[CH:35]=[C:34]([C:2]2[N:7]=[C:6]([S:8][CH3:9])[C:5]3[N:10]([CH3:13])[CH:11]=[N:12][C:4]=3[CH:3]=2)[CH:33]=[N:32]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CSc1nc(Cl)cc2ncn(C)c12
Reactant: CC(C)(C)n1cc(C2OC(C)(C)C(C)(C)O2)cn1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: CSc1nc(Cl)cc2c1ncn2C
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CSc1nc(-c2cnn(C(C)(C)C)c2)cc2ncn(C)c12
Reaction time: 1 h

Procedure:
To a mixture of 6-chloro-3-methyl-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.02 and 6-chloro-1-methyl-4-(methylthio)-1H-imidazo[4,5-c]pyridine 2.03 (prepared as previously described, ˜1:2 mixture of regioisomers, 1.25 g, 5.85 mmol),1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole (2.20 g, 8.78 mmol), and Cs2CO3 (5.72 g, 17.6 mmol) was added DME (20 mL) and water (10 mL) and the solution was degassed for 10 min. [1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (397 mg, 0.585 mmol) was added and the reaction was heated to 100 deg C. for 1 hour. Upon cooling, the aqueous layer was removed, EtOAc and water were added, and the layers separated. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (EtOAc 0-->5% MeOH gradient) to afford 6-(1-tert-butyl-1H-pyrazol-4-yl)-3-methyl-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.39 and 6-(1-tert-butyl-1H-pyrazol-4-yl)-3-methyl-4-(methylthio)-3H-imidazo[4,5-c]pyridine 2.40, which were isolated as a mixture and carried directly into the next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:20]([O:22]C)=[O:21])[C:18](=[O:19])[N:8]2[C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][CH2:11][C@@H:7]2[CH2:6]1.O[Li].O>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:20]([OH:22])=[O:21])[C:18](=[O:19])[N:8]2[C@@H:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:10][CH2:11][C@@H:7]2[CH2:6]1
Reactant: COC(=O)C1(CCCCl)C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(CCCCl)C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Temperature: 0 °C

Procedure:
The (3R,7aS)-methyl 6-(3-chloropropyl)-5-oxo-3-phenyl-hexahydropyrrolo[1,2-c]oxazole-6-carboxylate (36.90 g) was dissolved in 300 mL of THF and the mixture cooled to 0° C. A solution of LiOH.H2O (22.97 g, 0.548 mol, 5.0 equiv) in water (273 mL, 2.0 M) was cooled to 5° C. and added to the THF solution. The mixture was stirred at 10° C. and the progress of the hydrolysis monitored by LC/MS. After 3 h the methyl ester was completely consumed. EtOAc (100 mL) was added and concentrated HCL added till the pH<2. The mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with 100 mL EtOAc, the combined organic layers washed with brine, dried over Na2SO4, filtered and evaporated. The (3R,7aS)-6-(3-chloropropyl)-5-oxo-3-phenyl-hexahydropyrrolo[1,2-c]oxazole-6-carboxylic acid was isolated as a tan solid (32.65 g, 92% yield) after removal of residual solvent in vacuo.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[C:21]([F:23])[C:20]([CH2:24][CH:25]([C:30](=O)[CH2:31][CH2:32][CH2:33][CH3:34])[C:26](OC)=[O:27])=[C:19]([F:36])[CH:18]=1)#[N:10].O>CO>[CH2:31]([C:30]1[N:4]=[C:2]([CH3:3])[NH:5][C:26](=[O:27])[C:25]=1[CH2:24][C:20]1[C:21]([F:23])=[CH:22][C:17]([C:12]2[C:11]([C:9]#[N:10])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:18][C:19]=1[F:36])[CH2:32][CH2:33][CH3:34]
Reactant: CC(=N)N
Reactant: CCCCC(=O)C(Cc1c(F)cc(-c2ccccc2C#N)cc1F)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCc1nc(C)[nH]c(=O)c1Cc1c(F)cc(-c2ccccc2C#N)cc1F
Yield: 63.1 %

Procedure:
To a suspension of acetamidine hydrochloride (3.9 g) in methanol (30 mL) were added sodium methoxide (28% methanol solution, 12 mL) and then methyl 2-[(2′-cyano-3,5-difluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (7.93 g), and the mixture was stirred for 15 hr. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was triturated with diisopropyl ether to give the title compound (5.11 g, 63%) as pale-yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][OH:24]>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=[C:9]([O:19][CH2:21][CH2:22][CH2:23][OH:24])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCBr
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: OCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1

Procedure:
The procedure in Example 4 is followed but using 4,6-diphenyl-2-pyridone (15 g), freshly distilled 3-bromo-1-propanol (16.5 cc), silver carbonate (8.4 g) and toluene (600 cc). The reaction mixture is refluxed for 144 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 7-3). (white solid; m.p.=94° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].C(N(C(C)C)CC)(C)C.[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[Br:13][C:10]1[CH:11]=[CH:12][C:2]([NH:1][C:29]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:30])=[C:3]([C:4](=[O:5])[N:6]([CH3:7])[CH3:8])[CH:9]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(Br)ccc1NC(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 38.6 %

Procedure:
2-Amino-5-bromo-N,N-dimethyl-benzamide (2.00 g, 8.22 mmol), di-iso-propyl ethyl amine (6.5 ml, 37.32 mmol), 4-morpholinecarbonyl chloride (4.3 ml, 37.46 mmol), and chloroform (20 ml) were combined and stirred for 18 hours at 50° C. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (50% to 100% ethyl acetate in hexanes) to give 1.13 g (39%) of morpholine-4-carboxylic acid (4-bromo-2-dimethylcarbamoyl-phenyl)-amide. 1H-NMR (250 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.56-7.45 (m, 2H), 7.42 (t, J=9.3 Hz, 4H), 3.35-3.28 (m, 4H), 2.96-2.86 (m, 6H); MS: m/z 356.0+358.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.O.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH:35]=[C:34]([NH2:36])[CH:33]=[N:32]2)[CH2:27][CH2:26]1>CO>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:36][C:34]2[CH:33]=[N:32][N:31]([CH:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[CH:35]=2)=[N:3][CH:4]=1
Reactant: CN1CCC(n2cc(N)cn2)CC1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Solvent: CO
Solvent: O
Product: CN1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 70 °C
Yield: 17 %

Procedure:
A solution of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.060 g, 0.21 mmol) in MeOH (1.0 mL) and water (0.1 mL) containing 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.039 g, 0.21 mmol) was heated at 70° C. for 48 hours. The mixture was adsorbed onto silica gel and purified by silica column chromatography (Combiflash Rf, 4 g SiO2 Cartridge, 0-50% MeOH in DCM). Further purification by HPLC (eluting with 30-100% gradient in acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid, flow rate 4.0 mL/min) gave the title compound 18 as a light yellow solid (0.015 g, 17%). LCMS-C: rt 4.31 min; m/z 480 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1OCCN1CCOCC1

Procedure:
A solution of 10% Pd/C (0.25 g) was added to a solution of 4-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-morpholine Compound 42a3 (1.4 g, 5.0 mmol) in EtOAc (50 mL). The solution was exposed to 40 PSI of hydrogen gas for a period of 1 hr. The catalyst was removed by filtration through Celite 545 and the solvent was removed to give 3-methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine Compound 42a (1.1 g). MS 253 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[C:7](=[O:15])[NH:6][C:5]=2[N:4]([CH3:16])[N:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CN(C=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:17][CH:12]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7](=[O:15])[NH:6][C:5]3[N:4]([CH3:16])[N:3]=[C:2]([CH3:1])[C:14]=3[C:13]1=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C)c2[nH]c(=O)c3c(c12)CCCC3
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1nn(C)c2[nH]c(=O)c3c(c12)C(Br)CCC3
Yield: 86.5 %

Procedure:
A solution of EXAMPLE 1 (966 mg, 4.45 mmol) in a mixture of chloroform (30 mL) and N,N′-dimethylformamide (2 mL) was treated with N-bromosuccinimide (791 mg, 4.45 mmol) and catalytic 2,2′-azobis(2-methylpropionitrile) (5 mg) at 65° C. for 18 hours. The mixture was cooled, concentrated and the residue partitioned between ethyl acetate and brine. The organic phase was washed with water, concentrated and purified by flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes to provide 1.14 g (87%) of the title compound. MS (DCI/NH3) m/z 297 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[N+:40]([O-:42])=[O:41].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([OH:31])=[C:33]([N+:40]([O-:42])=[O:41])[CH:34]=2)[CH2:21][CH2:20]1)=[O:16])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c([N+](=O)[O-])c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.35 mmol), 4-hydroxy-3-nitrobenzaldehyde (1.22 mmol), methanol (3.8 mL), and acetic acid (0.175 mL) was added NaBH3CN (1.58 mmol) in methanol (3.2 mL). The reaction mixture was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Variant™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated. The resulting material was dissolved into ethyl acetate/methanol=5/1, loaded onto Varian™ Si column, eluted off using ethyl acetate/methanol 5/1 (10 mL), and concentrated to give 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-hydroxy-3-nitrobenzyl)piperidine (175 mg, 87%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[NH:14]1[CH:18]=[CH:17][N:16]=[C:15]1[C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: N#Cc1ccc(Cl)c2cccnc12
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2ncc[nH]2)c2cccnc12
Yield: 60 %

Procedure:
5-Chloro-8-quinolinecarbonitrile, 0.50 g, and imidazole, 1.80 g, were dissolved into 30 ml of pyridine. To the solution 0.36 g of anhydrous potassium carbonate was added and the mixture was heated under reflux for 8 hours. After separating indissolved substance by filtration, the solvent was evaporated and the residue was refined by column chromatography on silica gel using chloroform as an eluent. The crystals obtained were recrystallized from ethanol to yield 0.35 g (yield: 60%) of 5-imidazolyl-8-quinolinecarbonitrile (Compound No. 20).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>CC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[C:6]([NH:8][C:9]1[C:10]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:12]([O:15][CH2:38][C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CC(C)c1ccc(C(=O)Nc2cc(O)ccc2NC(=O)c2cccc(C#N)c2)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1ccc(C(=O)Nc2cc(OCC(=O)OCc3ccccc3)ccc2NC(=O)c2cccc(C#N)c2)cc1
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-N2-(4-isopropylbenzoyl)-4-hydroxy-1,2-benzenediamine (502 mg, 1.26 mmol), acetone (15 mL), and potassium carbonate (216 mg, 1.56 mmol) was added by benzyl 2-bromoacetate (0.4 mL, 2.52 mmol). After stirring overnight, the reaction was concentrated and the residue was chromatographed (100% CH2Cl2 to 10% EtOAc/CH2Cl2) to give the title compound as a solid (532 mg, 77%), IR(CHCl3): 2965, 1759, 1654, 1610, 1514, 1175 cm−1; NMR(300 MHz, CDCl3): δ1.28 (s, 3H), 1.30 (s, 3H), 3.00 (m, 1H), 4.50 (s, 2H), 5.22 (s, 2H), 6.71 (d, 1H, J=9.3), 6.93 (s, 1H), 7.31 (m, 7H), 7.54 (d, 1H, J=21), 7.60 (t, 1H, J=7.8), 7.78 (d, 1H, J=8.7), 7.89 (d, 2H, J=8.1), 8.19 (d, 1H, J=8.1), 8.30 (s, 1H), 8.74 (br s, 1H), 9.48 (br s, 1H); MS(FD): 547.
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=O)[CH:28]2[CH:23]([CH2:24][CH:25]=[CH:26][CH2:27]2)[C:22](=[O:29])[O:21]1>>[CH2:1]([N:19]1[C:20](=[O:21])[CH:28]2[CH:23]([CH2:24][CH:25]=[CH:26][CH2:27]2)[C:22]1=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCN
Reactant: O=C1OC(=O)C2CC=CCC12
Product: CCCCCCCCCCCCCCCCCCN1C(=O)C2CC=CCC2C1=O
Temperature: 110 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Octadecylamine (5.31 g) was added to 4,7,3a,7a-tetrahydroisobenzofuran-1,3-dione (3.00 g). After being stirred for 2 hours at 110° C., the reaction mixture was purified by silica gel column chromatography (silica gel 80 g, chloroform), thereby yielding the entitled compound (7.85 g) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([C@@H:11]2[C@@H:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[NH:12]2)=[O:10])=[CH:5][CH:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([CH:11]2[CH:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[O:10])=[CH:19][CH:20]=1
Reactant: OB(O)c1ccccn1
Reactant: C=CC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccc(OC)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC1C(=O)N(c2ccccn2)C1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.8 %

Procedure:
A mixture of β-lactam 59 (60 mg, 0.22 mmol), Pyridin-2-boronic acid (81 mg, 0.66 mmol), copper acetate (120 mg, 0.66 mmol), triethylamine (0.153 mL, 1.1 mmol) and activated 4A molecular sieves (270 mg) in dichloromethane (5 mL) was stirred at room temperature for 2 days. The reaction mixture was filtered through celite and the filtrate was concentrated. Preparative TLC (20% EtOAc/Hexanes) of the residue gave the desired product 80 (19.2 mg, 24.8%) 1HNMR (300 MHz, CDCl3): 2.60 (m, 2H), 3.49 (m, 1H), 3.81 (s, 3H), 4.41 (d, J=2.61 Hz, 1H), 5.11-5.21 (m, 4H), 5.82 (m, 1H), 6.85 (d, J=8.7 Hz, 2H), 7.01 (m, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.66-7.72 (m, 2H); 8.19 (d, J=4.7 Hz, 1H) Anal. C20H20N2O4, Mol. Wt.: 352.38. Found: ESI-MS: 352.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Br:18]Br>C(O)(=O)C>[Br:18][C:10]1[C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=[C:4]2[C:9]=1[O:8][CH2:7][CH2:6][CH:5]2[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: BrBr
Reactant: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Solvent: CC(=O)O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(O)c2Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
To a stirred solution of ethyl 6-chloro-7-hydroxychroman-4-carboxylate (5.14 g, 20.0 mmol) in glacial acetic acid (50 mL) at ambient temperature was added bromine (1.2 mL, 24 mmol), in six equal portions, waiting 30-60 seconds between each addition for the bromine color to be discharged. Following completion of addition, the solution was concentrated and the residue concentrated from toluene, then partitioned between ethyl acetate (200 mL) and 5% sodium bisulfite (100 mL). The organic was layer dried over sodium sulfate, then stirred with activated charcoal (2 g) at ambient temperature for 20 minutes. The charcoal was removed by filtration through a glass microfibre filter and the filtrate was concentrated to afford ethyl 8-bromo-6-chloro-7-hydroxychroman-4-carboxylate as a light brown oil (6.05 g, 90% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:16])[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].[Cl:18][C:19]1[C:20]([C:36]#[N:37])=[C:21]([CH:33]=[CH:34][CH:35]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[Cl:18][C:19]1[C:20]([C:36]#[N:37])=[C:21]([CH:33]=[CH:34][CH:35]=1)[O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:16][C:8]2[CH:9]=[CH:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:17])[CH3:1])[CH:7]=2)(=[O:30])=[O:31])=[CH:27][CH:28]=1
Reactant: CN(C)CCOc1cc(N)ccc1C(F)(F)F
Reactant: N#Cc1c(Cl)cccc1Oc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: CN(C)CCOc1cc(NS(=O)(=O)c2ccc(Oc3cccc(Cl)c3C#N)cc2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 3-(2-dimethylamino-ethoxy)-4-trifluoromethyl-phenylamine (0.10 g, 0.4 mmol) in CHCl3 (2.5 mL) was added 4-(3-chloro-2-cyano-phenoxy) benzenesulfonyl chloride (0.13 g, 0.4 mmol) at rt. After stirring at rt for 72 h, the solvent was evaporated and the residue was purified by vacuum filtration through silica gel eluting successively with 4% MeOH in CH2Cl2 and 10% MeOH in CH2Cl2 followed by a mixture of CH2Cl2, MeOH and conc. NH4OH (90:10:1). The solvent was removed from the desired fractions and the residue was recrystallized from a mixture of MeOH and EtOAc to afford the title compound as a white solid; yield 0.01 g (5%): LCMS 540 (M++H).