Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[Na+].Br[C:8]1[CH:9]=[C:10]([C:14]2[N:23]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]([CH2:32][CH3:33])[CH3:31])=[CH:26][CH:25]=3)[C:22](=[O:34])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:11]=[N:12][CH:13]=1.[NH:35]([CH2:38][CH3:39])[CH2:36][CH3:37]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH:30]([C:27]1[CH:28]=[CH:29][C:24]([N:23]2[C:22](=[O:34])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]2[C:10]2[CH:11]=[N:12][CH:13]=[C:8]([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH:9]=2)=[CH:25][CH:26]=1)([CH2:32][CH3:33])[CH3:31]
Reactant: CCC(C)c1ccc(-n2c(-c3cncc(Br)c3)nc3ccccc3c2=O)cc1
Reactant: CCNCC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCC(C)c1ccc(-n2c(-c3cncc(N(CC)CC)c3)nc3ccccc3c2=O)cc1
Yield: 5.9 %

Procedure:
Pd(OAc)2 (0.026 g, 0.12 mmol), DPPF (0.055 g, 0.10 mmol) and NaOtBu (0.049 g, 0.52 mmol) were added to a mixture of 2-(5-bromopyridin-3-yl)-3-(4-sec-butylphenyl)quinazolin-4(3H)-one (0.175 g, 0.40 mmol) and Et2NH (0.06 mL, 0.60 mmol) in toluene (2 mL). The mixture was microwaved at 90° C. and 300 W (max. power) with cooling for 3 hours, before being concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% to 60% EtOAc in heptane, plus further purification by flash chromatography on silica gel, eluting with 30% to 90% EtOAc in heptane, afforded the title compound as a white solid (0.010 g, 5%). 1H-NMR (300 MHz, DMSO-d6): δ8.20 (d, J=6.9 Hz, 1H), 7.84-7.98 (m, 3H), 7.77 (d, J=7.9 Hz, 1H), 7.55-7.68 (m, 1H), 7.26 (d, J=7.8 Hz, 2H), 7.08-7.20 (m, 2H), 6.80 (s, 1H), 3.06-3.23 (m, 4H), 2.51-2.65 (m, 1H), 1.35-1.60 (m, 2H), 1.08-1.20 (m, 3H), 0.81-1.00 (m, 6H), 0.62 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 427 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][CH:27]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:28][CH:27]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 85.6 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (98.6 mg, 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][S-:20].[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(CC)CC>C([O-])(O)=O.[Na+].[Cl-].[Na+].O.C(Cl)Cl.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].CO.O1CCOCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([S:20][CH3:19])=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(C2(NC(=O)OC(C)(C)C)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
In a Biotage microwave vial was placed [1-(5-iodo-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (500 mg, 1.39 mmol), sodium thiomethoxide (292 mg, 4.17 mmol) and Xantphos (80 mg, 0.14 mmol). The vial was flushed with Ar. 1,4-Dioxane (7.5 ml) and Et3N (0.48 mL, 2.78 mmol) were added. Ar was bubbled through the reaction solution for 15 minutes. Pd2(dba)3 (65 mg, 0.07 mmol) was added and the reaction was thermally heated to 100° C. After 8 h, the reaction was transferred to a separatory funnel, diluted with saturated NaHCO3 and brine, and extracted with EtOAc (2×50 mL). The combined organic layers were dried, filtered and evaporated to give a black oil. Flash chromatography (10 g silica, 0-10% MeOH in DCM) yielded 300 mg of [1-(5-methylsulfanyl-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester as a dark oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][C:28]1=[O:37])[C:25]#[CH:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][C:28]3=[O:37])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Reactant: C#CCN1C(=O)CCc2ccccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CCc4ccccc43)cc1C(c1ccccc1F)=NC2
Reaction time: 0.17 h

Procedure:
A mixture of 0.84 g (2 mmol) of 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine, 0.48 g (2.6 mmol) of 3,4-dihydro-1-(2-propynyl)-2(1H)quinolinone, 80 mg of triphenylphosphine, 20 mg of cuprous iodide, 1.5 ml of triethylamine and 50 ml of dimethylformamide was deqassed with argon for 10 minutes. Palladium acetate, 25 mg, was then added and stirring was continued for 18 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic layer was separated. dried and evaporated and the residue was chromatographed over 50 g of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. Crystallization of the combined clean fractions from ethyl acetate gave colorless crystals of 1-{3-[6-(2-fluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][ 1,4]benzodiazepin 8-yl]-2-propynyl}3,4 dihydro-2(1H)-quinolinone with m.p. 236°-239°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C=CC=CC(=O)O)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(CCCCC(=O)O)c1

Procedure:
A solution of the product from step (i) (36.8 g) in ethanol (300 ml) was hydrogenated over 10% palladium on carbon (1 g) at 1 atmosphere pressure for 3 days. The catalyst was removed by filtration and the mother liquor was evaporated under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:3]([F:13])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Na+].[Na+].[H][H]>C(#N)C>[F:13][C:3]1[CH:2]=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:10])[F:11]
Reactant: Fc1ccc(C(F)(F)F)c(F)c1Cl
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc(C(F)(F)F)c(F)c1
Yield: 66.6 %

Procedure:
100 g of 3-chloro-2,4-difluorobenzotrifluoride in 500 ml of acetonitrile and 60 g of pulverulent sodium carbonate were initially introduced into a hydrogenation apparatus equipped with a diffuser stone and a stirrer. 10 g of catalyst (5% by weight of metallic palladium on activated charcoal) were then added, and hydrogen was passed in at 80° C. for 10 hours. Subsequently, the batch was cooled and filtered, and the filtrate was distilled via a column packed with perforated rings made of stainless steel. 56 g of 2,4-difluorobenzotrifluoride having a boiling point of 105° to 106° C. at 1,030 mbar were obtained. The refractive index nD20 was 1.3968.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11]2)=[C:4]([F:17])[CH:3]=1.[OH-].[Na+].Cl[CH:21]([F:23])[F:22]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1CCCCC1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[C:14](=[O:15])[N:13]([CH:21]([F:23])[F:22])[C:12]([CH3:16])=[N:11]2)=[C:4]([F:17])[CH:3]=1
Reactant: COc1cc(-n2nc(C)[nH]c2=O)c(F)cc1Cl
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCCCC1
Product: COc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
A stirred mixture of 10.0 g (0.039 mole) of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 10.0 g (0.031 mole) of tetrabutylammonium bromide and 10.0 grams (0.25 mole) of sodium hydroxide in 250 mL of cyclohexane was warmed to 60° C. Chlorodifluoromethane (10.0 g, 0.12 mole) was bubbled into the reaction mixture. After complete addition the reaction mixture was warmed to reflux where it stirred for one hour. The hot solution was decanted from a pot residue and cooled to ambient temperature. Methylene chloride was added to the cooled mixture to dissolve a solid precipitate. The mixture was washed with 10% hydrochloric acid then with an aqueous 10% sodium hydroxide solution. The organic layer was dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 5.0 g of 1-(4-chloro-2-fluoro-5-methoxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one; mp 86°-88° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:41])[C:5]2[N:6]=[CH:7][N:8]([C:39]=2[N:40]=1)[C@@H:9]1[O:38][C@H:28]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:19]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@H:10]1[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[CH3:42][C:43]1[CH:44]=[C:45]([CH2:49][CH2:50][OH:51])[CH:46]=[CH:47][CH:48]=1>>[CH3:42][C:43]1[CH:44]=[C:45]([CH2:49][CH2:50][O:51][C:2]2[N:3]=[C:4]([NH2:41])[C:5]3[N:6]=[CH:7][N:8]([C:39]=3[N:40]=2)[C@@H:9]2[O:38][C@H:28]([CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@@H:19]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@H:10]2[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:46]=[CH:47][CH:48]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Cc1cccc(CCO)c1
Product: Cc1cccc(CCOc2nc(N)c3ncn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c3n2)c1
Temperature: 50 °C

Procedure:
To a dry 250-mL, 3-neck roundbottom flask was added 2-chloro-2′,3′,5′-tri-O-(TERT-butyldimethylsilyl)adenosine (5 g, 7.8 mmol, Example 1) and 2-(3-methylphenyl)ethanol (15 mL). The mixture was flushed with nitrogen for 5–10 minutes, then heated to 50° C. To this mixture was added sodium hydride (1.56 g, 39 mmol, as a 60% dispersion in mineral oil) at such a rate as to avoid excessive gas evolution. The reaction was maintained at 50° C. until the predominant component was the product by HPLC (partially deprotected products were also seen). The reaction was then cooled to room temperature, carefully quenched with water (40 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (120 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford a brown oil. This material was purified by passing through a plug of silica gel, eluting with CH2Cl2, 5% methanol in CH2Cl2, and 10% methanol in CH2Cl2. Those fractions containing products were combined and evaporated to dryness, to afford a mixture of starting material and monosilyl-protected and disilyl-protected alkylated products in a ratio of 2:5:12. This mixture was used without further purification in the next step.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH3:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[Cl:11]>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]([N:9]1[C:10]([Cl:11])=[C:6]([CH3:5])[N:7]=[CH:8]1)=[O:4]
Reactant: Cc1nc[nH]c1Cl
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)n1cnc(C)c1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
104 g of methyl isocyanate were added dropwise to 233 g of 4-methyl-5-chloroimidazole in 1 liter of chloroform in a stirred flask provided with a thermometer and a reflux condenser. During the addition, the temperature increased to 40° C. Refluxing was carried out for 2 hours, the reaction solution was evaporated down under reduced pressure, the hot residue was dissolved in 400 ml of toluene, the solution was filtered with carbon and cooled, and the precipitated crystals were filtered off under suction, washed with toluene and dried to give 237 g (68.3%) of 1-N-methylcarbamyl-4-methyl-5-chloroimidazole of melting point 94.1°-94.4° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:23]3[CH:24]=[N:19][CH:20]=[N:21][CH:22]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: OB(O)c1cncnc1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(-c2noc(-c3cncc(-c4cncnc4)c3)n2)nc1
Yield: 7.6 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (42 mg, 0.1385 mmole), 5-pyrimidylboronic acid (26.6 mg,0.208 mmole) and Pd(PPh3)4 (23.99 mg, 0.021 mmole) in a solution of 2M sodium carbonate (1.5 mL) and ethylene glycol dimethyl ether (1.5 mL) was heated overnight at 105° C. Standard workup afforded 3.2 mg (8%) of 3-(2-pyridyl)-5-[5-(5-pyrimidyl)-pyrid-3-yl ]-1,2,4-oxadiazole (3.2 mg, 7.6%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](OC(=O)CCl)=O>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:24]([CH2:23][Cl:22])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2cccc(Br)c2C1=O
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(Br)c2C1=O
Yield: 82.6 %

Procedure:
16.9 g (48.3 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime were stirred with 9.5 g (55.5 mmol) of chloroacetic anhydride in 100 ml of N,N-dimethylformamide at room temperature for 1 hour and at 105° for 3 hours. After evaporating the solvent the residue was dissolved in methylene chloride and the solution was washed with saturated sodium bicarbonate solution. By drying the organic phase over magnesium sulfate, evaporation of the solvent and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 9/1 there were obtained 16.3 g (84%) of 7-bromo-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5, 6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 242°-244°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:17]2[CH:21]=[CH:20][N:19]([CH2:22][CH2:23]OS(C)(=O)=O)[N:18]=2)[S:5][C:6]=1[C:7](=[O:16])[NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:7]([C:6]2[S:5][C:4]([C:17]3[CH:21]=[CH:20][N:19]([CH2:22][CH2:23][NH:36][C:33]4[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=4)[N:18]=3)=[N:3][C:2]=2[CH3:1])=[O:16])[CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nc(-c2ccn(CCOS(C)(=O)=O)n2)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-c2ccn(CCNc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from methanesulfonic acid 2-(3-{4-methyl-5-[(pyridin-3-ylmethyl)-carbamoyl]-thiazol-2-yl}-pyrazol-1-yl)-ethyl ester and 4-fluoro-phenylamine as describe in Example 77 and isolated as a white solid (0.032 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.72 (d, J=8 Hz, 1H), 7.39 (d, J=2 Hz, 1H), 7.28-7.34 (m, 1H), 6.89 (t, J=8 Hz, 2H), 6.83 (d, J=2 Hz, 1H), 6.51-6.56 (m, 2H), 6.09 (bs, 1H), 4.65 (d, J=8 Hz, 2H), 4.47 (t, J=6 Hz, 2), 3.58-3.63 (m, 2H), 2.76 (s, 3H); MS (M+H)+=436.9; Rt=1.20 min; HRMS (M+H)+=437.12.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C@H:15]([NH:18][C:19]([N:21]2[C:27](=[O:28])[C@H:26]([CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[O:37][CH3:38])[CH2:25][NH:24][C:23](=[N:39][O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:22]2)=[O:20])[CH2:16][CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].Cl>C(O)(=O)C>[ClH:36].[NH2:1][C:2]1[CH:14]=[C:13]([C@H:15]([NH:18][C:19]([N:21]2[C:27](=[O:28])[C@H:26]([CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[O:37][CH3:38])[CH2:25][NH:24][C:23](=[N:39][O:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:22]2)=[O:20])[CH2:16][CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c(N)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC[C@@H](NC(=O)N1CC(=NOc2ccccc2)NC[C@@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 161.7 %

Procedure:
To the compound 77a (523 mg) obtained at Step (1), 1M hydrochloric acid in acetic acid solution (18 ml) was added, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated, then the residue was diluted with ethyl acetate. To this solution, a 1M hydrochloric acid in acetic acid solution was added and the mixture was stirred. Further, diethyl ether was added, and the precipitated solid was collected by filtration to obtain the title compound (410 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:58]=[CH:57][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:14][C@H:13]2[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][CH:49]=3)=[O:45])[CH2:40][CH2:39]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].SCCO>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[SH:17][C@@H:15]1[CH2:16][N:12]([C:10]([O:9][CH2:8][C:7]2[CH:57]=[CH:58][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])[C@H:13]([CH2:37][N:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([N+:54]([O-:56])=[O:55])=[CH:52][CH:53]=3)=[O:45])[CH2:42][CH2:43]2)[CH2:14]1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: OCCS
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCN(C[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
To a solution of (2S,4S)-1- (4-nitrobenzyloxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-yl]methyl-4-(triphenylmethylthio)pyrrolidine (2.76 g) in trifluoroacetic acid (15 ml) was added 2-mercaptoethanol (0.31 ml) under ice-cooling and the mixture was stirred at ambient temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in toluene (20 ml) and the solution was evaporated in vacuo to give a syrup. The syrup was dissolved in ethyl acetate (60 ml) and washed successively with saturated aqueous sodium hydrogen carbonate (30 ml) and saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-yl]methylpyrrolidine (0.93 g).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[C:10](Br)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29]B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[C:10]([CH3:29])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CB(O)O
Reactant: Cc1cc(C)c(-c2cccc3c2c(=O)c(Br)cn3Cc2ccccc2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(-c2cccc3c2c(=O)c(C)cn3Cc2ccccc2)c(C)c1
Temperature: 95 °C
Reaction time: 22 h
Yield: 59.5 %

Procedure:
1-Benzyl-3-bromo-5-mesitylquinolin-4(1H)-one (0.277 g, 0.64 mmol), methyl boronic acid (0.384 g, 6.4 mmol), potassium carbonate (0.443 g, 3.2 mmol), and Pd(PPh3)4 (0.37 g, 0.32 mmol) were diluted in dioxane (4 mL). Water (0.11 mL, 6.4 mmol) was added and the reaction stirred at 95° C. for 22 hr. The solution was then cooled and filtered through GF/F paper and concentrated. Flash chromatography (40% ethyl acetate/hexanes) gave the title compound as a white solid (0.14 g, 60%).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].CC([O-])(C)C.[K+].C(C1[C:16](F)=[C:17]([F:33])[C:18]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21])(=O)C>C1COCC1>[F:33][C:17]1[C:16]2[O:5][N:4]=[C:2]([CH3:3])[C:1]=2[CH:24]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[C:18]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1F
Reactant: CC(C)=NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(C)noc2c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of acetone oxime (3.17 g, 43.3 mmol) in THF (40 ml) was added t-BuOK (43.3 ml, 1 M in THF, 43.3 mmol). After stirring at room temperature for 30 min, the mixture was cooled to −78° C. To the mixture was added a solution of methyl 5-acetyl-3,4-difluoro-2-(2-fluorophenylamino)benzoate (4.0 g, 12.4 mmol) in THF (70 ml) dropwise. After stirring at −78° C. for 15 min, the reaction was warmed to 0° C. and stirred at the temperature for 4 h. The reaction was quenched with saturated aqueous NH4Cl solution (200 ml) and extracted with EtOAc (2×200 ml). The organic solution was washed with brine (100 ml), dried over MgSO4 and concentrated. To the resulting oil was added a mixture of 5% HCl solution (100 ml) and MeOH (100 ml). The resulting suspension was heated at reflux for 1.5 h. The reaction was cooled to room temperature, concentrated to half volume, and diluted with EtOAc (200 ml). The organic solution was washed with brine (100 ml), dried over Na2SO4 and concentrated. Silica gel chromatography (EtOAc:Hexanes=25:75) yielded 2.84 g (72%) of methyl 7-fluoro-6-(2-fluorophenylamino)-3-methylbenzo[d]isoxazole-5-carboxylate as a white solid.