Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(C)C.[O:21]1[C:25]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[CH:30][CH:29]=2)=O)=[CH:24][N:23]=[CH:22]1>C1COCC1>[O:21]1[C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)=[CH:32][CH:33]=2)=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:24][N:23]=[CH:22]1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1cnco1
Reactant: CCOC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(c1ccc(OC2CCCCO2)cc1)c1cnco1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (31.5 mmol, 1 M in THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at −78° C. After 20 minutes at −78° C., a solution of 75.2 (21 mmol) in THF (60 mL) was added dropwise and the reaction was maintained at −78° C. for 1.5 hours. The reaction was quenched saturated NH4Cl (aq) and warmed to room temperature. The mixture was extracted with EtOAc (500 mL), the organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated with silica gel under reduced pressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane) to afford compound 75.3 (4.83 g, 14 mmol). MS ESI (pos.) m/e 344.2 (M+H).
Reaction SMILES: C1(=O)[N: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][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C(O)CCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: NCCCCCCCCCCCCCCCCC(=O)O
Temperature: 20 °C
Yield: 42 %

Procedure:
A solution of 3.4 g of 17-phthalimidoheptadecanoic acid in 60 cm3 of methanol is stirred for 1 hour, at a temperature in the region of 80° C., in the presence of 1.67 g of hydrazine hydrate. The solution is cooled to around 20° C. and the solid is separated by filtration and dried in air. The residue (1.92 g) is taken up in 180 cm3 of distilled water. The solid is separated by filtration, washed with a total of 45 cm3 of distilled water and dried under reduced pressure (13.5 Pa) at a temperature in the region of 40° C. 980 mg of 17-aminoheptadecanoic acid are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5]=[CH:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=2)[N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])[N:25]=1)=[O:15]
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)nc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)nc2)C1
Temperature: 125 °C
Reaction time: 3 h
Yield: 71.6 %

Procedure:
4-(6-bromo-pyridin-3-yl)-2-oxo-3-butenoic acid methyl ester (615.0 mg, 2.3 mmol) prepared in Step 1 and 2-chlorophenylhydrazine hydrochloride (450.0 mg, 2.5 mmol) were added to acetic acid (10.0 mL). The reaction mixture was stirred at 125° C. for 3 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The reaction mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 650.0 mg of the titled compound as a pale yellow liquid.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.[CH3:50][O:51]CC(O)=O.CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:10]1[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:12][CH:13]=[CH:14][C:9]=1[CH:5]([NH:4][C:1](=[O:3])[CH2:2][O:51][CH3:50])[C:6]([OH:8])=[O:7]
Reactant: COCC(=O)O
Reactant: CC(=O)NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCC(=O)NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reaction time: 16 h
Yield: 74 %

Procedure:
To a stirred solution of Example 13 Part A compound (222 mg, 0.45 mmol) under argon at room temperature in CH2Cl2 (1.5 mL) was added triethylamine (85 μL, 0.6 mmol), HOAt (69 mg, 0.5 mmol) and methoxyacetic acid (46 mg, 0.5 mmol) was added EDAC (96 mg, 0.5 mmol). After 16 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 153 mg (74% yield). LC/MS gave the correct molecular ion [(M+H)+=518] for the desired compound.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][OH:20].N1C=CC=CC=1>C(O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[N:19][OH:20])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C=NO)cc1
Yield: 90 %

Procedure:
To a solution of 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile (which may be prepared as described in Preparation of Intermediate 16; 15.21 g, 61.5 mmol) in toluene (100 mL) at 0° C. under argon was added dropwise di-isobutylaluminum hydride (1.0 M in toluene, 15 mL, 15 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, after which it was cooled to 0° C. and charged with 100 mL of saturated aqueous Rochelle salt solution. The mixture was allowed to stir for 14 hours after which the mixture was extracted three times with EtOAc. The combined organic phases were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure gave 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzaldehyde which was used without further purification. To a solution of the aldehyde in ethanol was added hydroxylamine hydrochloride (4.66 g, 67 mmol) and pyridine (5.4 mL, 67 mmol). The reaction mixture was stirred until no starting material was observed by TLC and then all volatiles were removed under reduced pressure. The resulting product was suspended in water and the aqueous phase was extracted three times with diethyl ether. The combined organic phases were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure gave 4-(tert-butyl-dimethyl-silanyloxymethyl)-benzaldehyde oxime (14.60 g, 90%) as a white solid. LRMS (ESI+): m/z [M+H]+ 266.1; 1H NMR (300 MHz, CDCl3) δ ppm 11.12 (s, 1H), 8.05 (s, 1H), 7.50 (d, 2H), 7.24 (d, 1H), 4.64 (s, 2H), 0.82 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15](Br)[CH:16]=1.[OH-].[Na+]>CN(C=O)C.O>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:16]=1
Reactant: Oc1ccccc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cncc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
Sodium hydride (1.35 g of 80% in mineral oil, 45.0 mmol) was added to a stirred solution of phenol (4.26 g, 45.3 mmol) in DMF (30 mL) at 0° C., under nitrogen. The mixture was stirred at room temperature for 3 h, treated with 3,5-dibromopyridine (4.0 g, 16.9 mmol) and heated at 100° C. for 48 h. The reaction mixture was cooled to room temperature, poured into a mixture of water (100 mL) and 5M sodium hydroxide (10 mL), and extracted with ether (3×60 mL). The combined ether extracts were dried (Na2SO4), filtered, and rotary evaporated to a pale yellow semi-solid (4.9 g). This was chromatographed on a silica gel (200 g) column with hexane/ethyl acetate/chloroform (8:1:1, v/v) as eluant to give 2.86 g (68% yield) of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30]3[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:36][C:35]2[C:30]([NH:29][CH2:28][CH:25]3[CH2:26][CH2:27][N:22]([C:19]4[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: Nc1cccnc1NCC1CCN(c2ccncc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1NCC1CCN(c2ccncc2)CC1)c1ccc(Cl)s1
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
A solution of 5-chlorothiophene-2-carboxylic acid (120 mg, 0.72 mmol) in methylene chloride and DMF (0.005 mL) was treated with oxalyl chloride (0.105 mL, 1.20 mmol). After 0.25 h, the mixture was concentrated and the residue was dissolved in chloroform. This solution was added dropwise to a solution of N2-[1-(4-pyridyl)piperidin-4-ylmethyl]-2,3-pyridinediamine (170 mg, 0.6 mmol) in pyridine and chloroform. The reaction mixture was then purified using a procedure similar to that described in Example 2, Part D, yielding 160 mg (58%) of the title compound as a hydrochloride salt.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[Cl:10][C:11]1[C:21]([Cl:22])=[CH:20][C:14]2[O:15][C:16]([F:19])([F:18])[O:17][C:13]=2[CH:12]=1>>[Cl:22][C:21]1[C:11]([Cl:10])=[CH:12][C:13]2[O:17][C:16]([F:19])([F:18])[O:15][C:14]=2[C:20]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: FC1(F)Oc2cc(Cl)c(Cl)cc2O1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)c(Cl)cc2c1OC(F)(F)O2
Temperature: 25 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
A precooled mixture of 140 ml of 100% strength nitric acid and 200 ml of 100% strength sulphuric acid is added dropwise at 5° to 10° C. (internal temperature) with good stirring to 219 g (0.96 mol) of 5,6-dichloro-2,2-difluorobenzo[1.3]dioxole. The reaction mixture is then subsequently stirred at room temperature for 6 h. It is added to ice-water and extracted with ether, and the extract is dried and concentrated. 233 g (89% of theory) of 5,6-dichloro-4-nitro-2,2-difluoro-benzo(1.3)dioxole having a melting point of 29°-30° C. are obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14]C1C=CC([N+]([O-])=O)=CC=1)=O)[CH:6]=[N:5]2.[CH2:24]([NH:26][CH2:27][CH2:28][NH:29]C(=O)C1C=CN=C(F)C=1)[CH3:25]>>[CH2:24]([NH:26][CH2:27][CH2:28][NH:29][C:12]([C:7]1[CH:6]=[N:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=1)=[O:14])[CH3:25]
Reactant: CCNCCNC(=O)c1ccnc(F)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cnc2cc(I)ccc2n1
Product: CCNCCNC(=O)c1cnc2cc(I)ccc2n1
Yield: 92 %

Procedure:
This compound was prepared, starting from compound 24 (0.35 g, 0.83 mmol), according to the procedure developed for compound 36. Reaction time at room temperature: 28 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 98/2, v/v) to give compound 54 (0.27 g, 0.76 mmol) as a beige solid. Yield 92%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.28; 1H NMR (200 MHz, CDCl3) δ 1.18 (t, 3H, J=7.1 Hz), 1.57 (se, 1H), 2.76 (q, 2H, J=7.1 Hz), 2.97 (t, 2H, J=6.1 Hz), 3.68 (q, 2H, J=6.0 Hz), 7.83 (d, 1H, J=8.8 Hz), 8.08 (dd, 1H, J=1.9, 8.8 Hz), 8.34 (m, 1H), 8.60 (d, 1H, J=1.9 Hz), 9.65 (s, 1H).
Reaction SMILES: [C:1]([NH:11][CH:12]([C:17](=[O:20])[CH2:18][CH3:19])[C:13]([O:15]C)=[O:14])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:18]([C:17]1[O:20][C:1]([CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][C:12]=1[C:13]([OH:15])=[O:14])[CH3:19]
Reactant: CCC(=O)C(NC(=O)C=Cc1ccccc1)C(=O)OC
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1oc(C=Cc2ccccc2)nc1C(=O)O
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl 2-cinnamoylamino-3-oxovalerate (8.25 g), phosphorus oxychloride (5.6 ml) and toluene (80 ml) was refluxed with stirring for 40 minutes. The solvent was then distilled off and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the oily residue was dissolved in ethanol (30 ml). To the solution was added 2N sodium hydroxide (30 ml) and the mixture was heated on a water bath at 90° C. for 5 minutes. After cooling, the reaction mixture was adjusted to pH 2 with 2N hydrochloric acid and diluted with water. The resulting crystalline precipitate was collected by filtration to give 5-ethyl-2-styryl-4oxazolecarboxylic acid; yield 7.12 g (97.7%). Recrystallization from ethanol gave colorless prisms melting at 143°-144° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18](Br)=[CH:17][N:16]=2)=[CH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(=[NH:37])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].Cl.ON.C([O-])(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6](=[O:23])[N:7]([CH:9]1[CH2:14][CH2:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([NH2:37])=[CH:17][N:16]=2)=[CH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)cnc1C1=CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(N)cnc1C1=CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]-N-methylcarbamic acid-tert-butyl ester (1.25 g) in toluene (17 ml) were added palladium acetate (18 mg), benzophenone imine (0.6 ml), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (51 mg) and sodium tert-butoxide (473 mg) at room temperature, and stirred at 120° C. for 0.5 hours. Then, after the mixture was cooled to room temperature, hydroxyamine monohydrochloride (683 mg) and sodium acetate (1.6 g) were added thereto, and stirred at the same temperature for 4 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and extracted with 10% methanol/chloroform solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was purified with basic silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (987 mg) as a pale yellow solid.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:12]=[C:11]([S:13][CH3:14])[N:10]=[CH:9][N:8]=1.[Sn:15](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[CH3:14][S:13][C:11]1[CH:12]=[C:7]([Sn:15]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH3:19])[N:8]=[CH:9][N:10]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CSc1cc(I)ncn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(SC)ncn1
Reaction time: 0.17 h

Procedure:
A solution of iPrMgCl (2M in THF solution, 5 mL, 10 mmol) is added slowly to a solution of 4-iodo-6-methylsulfanyl-pyrimidine 35 (2.53 g, 10 mol) in THF (50 mL) at −78° C. After 10 minutes, Bu3SnCl (2.75 mL, 10 mmol) is added. After reaction overnight, the reaction mixture is concentrated. The crude product is purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 0% to 10% to afford 4-methylsulfanyl-6-tributylstannanyl-pyrimidine (36).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24](O)[CH2:25][C:26]2[N:27]([C:31]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=[CH:29][N:30]=2)=[CH:20][CH:19]=1.[C:51]1(=[O:61])[NH:55][C:54](=[O:56])[C:53]2=[CH:57][CH:58]=[CH:59][CH:60]=[C:52]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([N:55]2[C:51](=[O:61])[C:52]3[C:53](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:54]2=[O:56])[CH2:25][C:26]2[N:27]([C:31]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=[CH:29][N:30]=2)=[CH:22][CH:23]=1
Reactant: OC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
Di-tert-butyl azodicarboxylate (0.808 g, 3.51 mmol) was added portionwise to 1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethanol (Intermediate 86) (1.36 g, 2.92 mmol), phthalimide (0.473 g, 3.22 mmol) and triphenylphosphine (0.921 g, 3.51 mmol) in THF (25 mL) at room temperature over a period of 15 minutes. The resulting solution was stirred at room temperature for 60 minutes then concentrated by evaporation and purified by flash silica chromatography, elution gradient 20 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 2-(1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethyl)isoindoline-1,3-dione (1.78 g, 102%) as a colourless foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)(=[O:12])=[O:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.I[CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:54]=[CH:53][C:41]2[N:42]([CH3:52])[C:43](=[O:51])[C:44]([CH3:50])([CH3:49])[C:45](=[O:48])[N:46]([CH3:47])[C:40]=2[CH:39]=1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([CH2:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:54]=[CH:53][C:41]2[N:42]([CH3:52])[C:43](=[O:51])[C:44]([CH3:49])([CH3:50])[C:45](=[O:48])[N:46]([CH3:47])[C:40]=2[CH:39]=1)(=[O:11])=[O:12])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1cccnc1
Reactant: CN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCc3cccnc3)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
2-Nitro-N-(2-pyridin-3-ylethyl)benzenesulfonamide (1.8 g, 5.8 mmol) and potassium carbonate (1.0 g, 7.2 mmol) were added to a DMF solution (30 ml) of 7-(3-iodopropoxy)-1,3,3,5-tetramethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (2.0 g, 4.8 mmol) and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:2→ethyl acetate→ethyl acetate:methanol=20:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 2.29 g (yield: 80%) of 2-nitro-N-(2-pyridin-3-ylethyl)-N-[3-(1,3,3,5-tetramethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]benzenesulfonamide as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[C:19]([CH3:20])=[C:18]([CH2:21]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH:26][CH:27]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[C:19]([CH3:20])=[C:18]([CH2:21][N:29]4[CH2:30][CH2:31][CH2:32][C@@H:28]4[C@@H:27]([OH:26])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c1c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Reactant: OC(c1ccccc1)C1CCCN1
Product: Cc1c(CN2CCC[C@@H]2[C@@H](O)c2ccccc2)sc2c1c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C

Procedure:
Analogous to the procedures described in Example 2, N-(4-chlorobenzyl)-2-(chloromethyl)-3,7-dimethyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 30) is treated with 2-(hydroxy(phenyl)methyl)pyrrolidine (Preparations 2) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Br[C:23]1[CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=[N:27][CH:28]=1>COCCOC.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>[Cl:1][C:2]1[C:12]([C:23]2[CH:28]=[N:27][CH:26]=[C:25]([CH2:29][OH:30])[CH:24]=2)=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: Cn1c(=O)oc2cc(Cl)c(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: OCc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Cn1c(=O)oc2cc(Cl)c(-c3cncc(CO)c3)cc21
Temperature: 100 °C
Yield: 44.3 %

Procedure:
A mixture of 6-Chloro-3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (60 mg, 0.194 mmol), (5-Bromo-pyridin-3-yl)-methanol (36.4 mg, 0.194 mmol), polymer bound Pd(PPh3)4 (44.1 mg, 4.85 μmol) in DME (5 mL) was heated to 100° C. for 4 hr. After filtration through a pad of Na2SO4, the solution was concentrated, and the residue was purified by column (MeOH—CH2Cl2, v/v, 1%-2.5%-4.0%) and yielded colorless solid (25 mg). 1H NMR (400.3 MHz, CDCl3): δ 3.35 (s, 3H), 4.77 (s, 2H), 6.85 (s, 1H), 7.31 (s, 1H), 7.74 (s, 1H), 8.53 (s, 1H), 8.57 (s, 1H). HRMS (ESI): calculated for C14H11ClN2O3: 290.04582. Found: 290.04666.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[C:24]([O:26][CH2:27][CH3:28])=[O:25])=O)C1C=CC=CC=1>CCO.[Pd]>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reaction time: 3 h
Yield: 70.2 %

Procedure:
To a solution of ethyl 1-benzyloxycarbonyl-4-(tert-butoxycarbonyl)-2-piperazinecarboxylate (2.49 g) (Tet. Lett. 30(39), 5193-5196) in EtOH was added Pd/C (0.25 g). The solution was degassed with nitrogen and hydrogen gas was bubbled into the mixture. The reaction mixture was stirred for 3 hours under hydrogen atmosphere. The mixture was filtered through Celite and concentrated to give 1.15 g of ethyl 4-(tert-butoxycarbonyl)-2-piperazinecarboxylate. (2) To a solution of the compound obtained above in THF (10 mL) was added 3,5-dichlorophenyl isocyanate (1.00 g). After stirring overnight, the solution was concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/4, Chromatotron) afforded ethyl 1-[N-(3,5-dichlorophenyl)carbamoyl]-4-tert-butoxycarbonyl-2-piperazinecarboxylate (1.36 g). MS (m/z) 446 (MH+). (3) The compound obtained above was treated in a manner similar to Example 1 (4) to yield 4-(tert-butoxycarbonyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.72 g). MS (m/z) 422 (M++Na) mp 60.2° C.