Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH:13]=2)O1.Cl[C:29]1[CH:34]=[N:33][N:32]2[C:35]([C:38]3[CH:39]=[C:40]([NH:44][C:45]([NH:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[O:46])[CH:41]=[CH:42][CH:43]=3)=[CH:36][N:37]=[C:31]2[CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[F:52][C:49]([F:50])([F:51])[CH2:48][NH:47][C:45]([NH:44][C:40]1[CH:39]=[C:38]([C:35]2[N:32]3[N:33]=[CH:34][C:29]([C:9]4[CH:10]=[N:11][N:12]([CH:14]5[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]5)[CH:13]=4)=[CH:30][C:31]3=[N:37][CH:36]=2)[CH:43]=[CH:42][CH:41]=1)=[O:46]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)cnn23)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
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: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A mixture of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.830 g, 2.20 mmol, Combi-Block, Cat. No. FM-2957), N-[3-(7-chloroimidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (0.739 g, 2.00 mmol), tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.100 mmol) and sodium carbonate (0.636 g, 6.00 mmol) in dioxane (15 mL) and water (5 mL) was degassed and recharged with nitrogen three times, and heated and stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (gradient: 0-50%) to afford the desired product (0.965 g, 82.5%). LCMS (M+H)+: m/z=585.2.
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1.[Cl:37][C:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40][N:39]=1.C(#N)C.C([O-])(=O)C.[K+]>O.ClCCl>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[C:6]3[C:7]([O:11][CH:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:8][CH:9]=[CH:10][C:5]=3[N:4]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:3]=2)[CH:41]=[CH:40][N:39]=1
Reactant: Ic1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccnc(OC3CCOCC3)c12
Reactant: OB(O)c1ccnc(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: Clc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)ccn1
Temperature: 100 °C
Yield: 66.5 %

Procedure:
To a microwave vial was charged 3-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.00 g, 1.70 mmol), 2-chloropyridin-4-ylboronic acid (0.281 g, 1.79 mmol) and bis(diphenylphosphino)ferrocenepalladium chloride (139 mg, 0.170 mmol). Acetonitrile (11 mL, 210 mmol) and 1.0 M of potassium acetate in water (4.1 mL) were then added and the reaction mixture was degassed with nitrogen for 10 minutes and then heated to 100° C. under microwave irradiation for 30 minutes. Upon reaction completion, the reaction mixture was diluted with dichloromethane, filtered through Celite® and concentrated in vacuo. The crude residue was purified by column chromatography eluting with 0-100% EtOAc in heptane to give the title compound (0.648 g, 66%). LC-MS (Method H): m/z=573.4 [M+H]+; 1.56 min. 1H-NMR (400 MHz, CDCl3): δ 8.37 (d, J=5.2, 1H), 8.13 (s, 1H), 7.80 (d, J=5.2, 1H), 7.54 (d, J=6.2, 1H), 7.35-7.27 (m, 9H), 7.22-7.14 (m, 6H), 5.90 (d, J=6.2, 1H), 5.55-5.46 (m, 1H), 4.01-3.92 (m, 2H), 3.69-3.60 (m, 2H), 2.23-2.13 (m, 2H), 1.99-1.87 (m, 2H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH:27]([F:29])[F:28])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[CH3:32][C:33]([CH3:35])=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:14][C:11]1[C:12]([CH3:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH:33]([CH3:35])[CH3:32])[CH2:6]2)[C:8]([O:30][CH3:31])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH:27]([F:28])[F:29])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (27 mg, 0.054 mmol), acetone (4.4 μL, 0.060 mmol), and triethylamine (23.5 μL, 0.169 mmol) in methylene chloride (0.4 mL) was added sodium triacetoxyborohydride resin (47 mg, 0.11 mmol). The resulting mixture was stirred for 2 h at room temperature. The mixture was filtered and concentrated and dried in vacuo to give 22 mg of the crude the product which will be used without purification. LCMS calculated for C22H28ClF2N6O (M+H)+: m/z=465.2; Found: 465.1.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([CH3:9])[C:6]([OH:8])=[O:7].[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CC(=Cc1ccc(F)cc1F)C(=O)O
Agent: O=[Pt]
Solvent: CO
Product: CC(Cc1ccc(F)cc1F)C(=O)O
Reaction time: 0.5 h

Procedure:
In 800 ml of methanol, 60 g (0.3 mol) of 2,4-difluoro-α-methylcinnamic acid with 1.5 g of platinum oxide catalyst is shaken under an initial pressure of 42 lbs of hydrogen until one equivalent of hydrogen is absorbed. The reaction time is 30 minutes. The catalyst is removed by filtration and washed with methanol. The methanol, when evaporated off, leaves near colorless 2,4-difluoro-α-methyldihydrocinnamic acid as an oil which is used in the next step without further purification.
Reaction SMILES: C([C:5]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:7]2[C:8]([NH:10][C:11](=[O:12])[C:6]=12)=[O:9])CCC.Cl[Si](Cl)(C)[Si:19]([CH3:22])(C)[CH3:20]>CC1C=CC=CC=1C.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>[CH2:15]([N:10]1[C:11](=[O:12])[C:6]2=[C:5]([SiH:19]([CH3:22])[CH3:20])[C:15]([Cl:16])=[CH:14][CH:13]=[C:7]2[C:8]1=[O:9])[CH2:5][CH2:6][CH3:7]
Reactant: C[Si](C)(C)[Si](C)(Cl)Cl
Reactant: CCCCc1c(Cl)ccc2c1C(=O)NC2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCCCN1C(=O)c2ccc(Cl)c([SiH](C)C)c2C1=O
Yield: 24 %

Procedure:
A reaction mixture containing 5 gm (0.021 moles) of n-butyl-4-chlorophthalimide and 3.95 gm (0.021 moles) of 1.2 dichlorotetramethyldisilane dissolved in 10 ml of o-xylene was heated to 150° C. in the presence of 5 mole % tetrakis(triphenylphosphine)palladium. After 24 hours reaction time, GC and GC/MS analysis showed a 24% yield of N-butyl-4-chlorodimethylsilyl-phthalimide. The product is readily isolatable by vacuum distillation.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35].ClCl.N1C(=O)CC(=O)NC1=O>C(Cl)Cl.CO>[C:1]([S:4][CH2:5][CH:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]([NH:9][CH2:10][C:11]([NH:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)O
Reactant: CN(C)CCN
Agent: CCOC(=O)Cl
Agent: ClCl
Agent: O=C1CC(=O)NC(=O)N1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)NCCN(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A 2.61 g (0.01 mole) sample of (±)-N-[2-(acetylmercaptomethyl)-4-methyl-1-oxopentyl]glycine is slurried in 50 ml of CH2Cl2. Triethylamine (1.08 g, 0.01 mole) is added to give a solution which is cooled to -10° C. and treated with 1.08 g (0.01 mole) of ethyl chloroformate. After 1/2 hour, a solution of N,N-dimethylethylenediamine (0.88 g, 0.01 mole) in 10 ml of CH2 Cl2 is added, and stirring from -5° C. to +25° C. continued for 2 hours. The mixture is evaporated and triturated with ethyl acetate. The triethylamine hydrochloride is filtered and the filtrates evaporated to an oil, 3.6 g. A 2.95 g sample of oil is dissolved with 1 equivalent of barbituric acid in methanol, filtered and evaporated to a foam. Addition of acetonitrile gives a white solid which is washed (briefly) with absolute ethanol and then acetonitrile. Recrystallization from 100 ml of acetonitrile gives a white powder, 1.3 g of (±)-N2 -[2-[(acetylthio)methyl]-4-methyl-1-oxopentyl]-N-[2-(dimethylamino)ethyl]glycinamide, barbituric acid (1:1) salt (34%), m.p. 151°-154°, which analyzes correctly for a salt with 1.0 mole of barbituric acid and 0.5 mole of water.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].O1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[BH4-].[Na+].[CH2:13]([O-])[CH3:14]>C(O)C>[O:8]1[CH:9]=[CH:10][C:6]([CH:1]2[NH:4][CH2:14][CH2:13][NH:3][CH2:2]2)=[CH:7]1
Reactant: C1COCCO1
Reactant: NCCN
Reactant: CC[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1cc(C2CNCCN2)co1
Temperature: 25 °C

Procedure:
To a solution of 6.25 ml of n-butyl lithium in ether at -78° C., under argon, was added 1.46 g of 3-bromofuran. The reaction was stirred at -78° C. for 30 minutes and then a solution of 1.13 g of N-acetyl-N,-O-dimethylhydroxyamine in ether was added. The mixture was stirred for an additional hour at -78° C., then raised to room temperature and quenched with dilute acid. The mixture was extracted several times with ether. The extracts were combined, dried and evaporated, giving 8.88 g of solid. A solution of this solid in 200 ml of dioxane was added to a mixture of 9.99 g of selenium dioxide, 1.62 ml of water and 200 ml of dioxane, which had been heated at 55° C. until a solution formed. This mixture was refluxed for 4 hours, then cooled and filtered through hydrous magnesium silicate. The filtrate was concentrated and purified by silica gel chromatography, eluting with hexane:ethyl acetate (4:1), giving 5.1 g of solid. To a solution of 4.544 g of this solid in 100 ml of ethanol at.0° C., under argon, was added dropwise a solution of 1.8 g of ethylene diamine in 20 ml of ethanol, followed by 10 ml of dioxane. This mixture was stirred at room temperature for 3-hours, then cooled to 0° C. and 2.42 g of sodium borohydride was added. This mixture was stirred at 0° C. for 2 hours, then quenched with water and evaporated. The residue was recrystallized from dichloromethane, giving 3.35 g of 3-(3-furanyl)piperazine.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[CH:26][CH:27]=1)=[S:11]
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=S)NC(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(NC(N)=S)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To a stirred near solution of tert-butyl N-(4-{[(benzoylamino)carbothioyl]amino}benzyl)-carbamate (10.4 g, 27.0 mmol) in MeOH (150 ml) was added a solution of K2CO3 (8.5 g, 61.5 mmol) in 15 ml water. The solution was stirred at room temperature for 24 hours and filtered to remove a white precipitate. The filtrate was evaporated in vacuo to yield 100% (7.6 g) of the desired product as an off-white solid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:24]=[C:23]2[O:25][CH2:26][CH2:27][O:28][C:22]2=[CH:21][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)=O.[Cl:29][CH2:30][C:31](=O)[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)(=O)C>[Cl:29][CH2:30][C:31]1[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:8]2[C:7](=[CH:24][C:23]3[O:25][CH2:26][CH2:27][O:28][C:22]=3[CH:21]=2)[N:6]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1ccc(C(=O)c2cc3c(cc2N)OCCO3)cc1OC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCl)nc2cc3c(cc2c1-c1ccc(OC)c(OC)c1)OCCO3
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
Conc. sulfuric acid (0.3 ml) was added to a mixture of 2-amino-4,5-ethylenedioxy-3',4'-dimethoxybenzophenone (6.5 g), ethyl 4-chloroacetoacetate (3.7 g) and acetic acid (60 ml), and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water and made alkaline with 2N sodium hydroxide, and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethyl acetate (7:3, v/v) gave ethyl 2-chloromethyl-6,7-ethylenedioxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (5.5 g, 60%). This compound was recrystallized from acetone. Colorless prisms, mp. 197°-198° C.
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.Cl[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1.C(=O)([O-])[O-:44].[K+].[K+].O>CS(C)=O>[CH2:17]([O:16][C:15]1[CH:10]=[CH:11][C:12]([O:44][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccc2ccccc2n1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(COc2ccc(Oc3ccc4ccccc4n3)cc2)cc1
Yield: 126.6 %

Procedure:
In 50 ml of dimethylsulfoxide, 12 g of hydroquinone monobenzyl ether, 8.2 g of 2-chloroquinoline and 8.3 g of potassium carbonate were dissolved and the mixture was heated at 150° to 160° C. for 4 hours to react them. After cooling, the reaction mixture was poured into water and the product was extracted with ether for several times and the ether layer was washed with an aqueous solution of sodium hydroxide and then with water and the ether layer was dehydrated over sodium sulfate. The solvent was distilled off. The resulting crude crystal was washed with diisopropyl ether to obtain 12 g (yield 75%) of 2-(4-benzyloxyphenoxy)quinoline. All of the intermediate was dissolved in 200 ml of a mixed solvent of tetrahydrofuran and ethanol (5:1) and 1.5 g of palladium-carbon type catalyst was added and 880 ml of hydrogen gas was fed into the mixture to carry out the hydrogenation at the atmospheric pressure. After the hydrogenation, the catalyst was separated by a suction filtration and the solvent was distilled off and the residue was washed with chloroform-n-hexane type solvent to obtain 6.3 g (yield 74%) of white crystal of 2-(4-hydroxyphenoxy)quinoline (m.p. 177° C.).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:19]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)[C@@H]1CCC(=O)N1C(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A solution of 21.9 g (0.1 mol) of benzyl (L)-pyroglutamate (prepared according to Example II(1)) in 150 ml of benzene is added over an hour to a suspension of 4.8 g (0.1 mol) of sodium hydride in 15 ml of dry benzene. The mixture is stirred for one hour at ordinary temperature and 14.1 g (0.1 mol) of benzoyl chloride diluted in benzene are then introduced. The reaction mixture is stirred for 4 hours at 55° C. and then for 18 hours at ordinary temperature. After the mixture has been washed with water, the solvent evaporated off and the residue taken up with ether, white crystals of melting point=101°/2° C. are obtained; yield=70%; Rf=0.68 (A).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][C:13]=1[OH:21].N>>[F:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][C:13]=1[OH:21]
Reactant: O=C(O)c1ccc(F)c(O)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Oc1cc(-c2nc(-c3cccnc3)no2)ccc1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-fluoro-3-hydroxybenzoic acid (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.45 (dd, J=11.1, 8.7 Hz, 1 H), 7.62-7.71 (m, 2 H), 7.78 (dd, J=8.3, 2.0 Hz, 1 H), 8.43 (dt, J=7.9, 1.8 Hz, 1 H), 8.82 (dd, J=5.0, 1.8 Hz, 1 H), 9.24 (d, J=2.0 Hz, 1 H) ppm; MS (DCI/NH3) m/z 258 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[Cl:38])=[O:28])([CH3:25])([CH3:24])[CH3:23].O>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[Cl:38])[C:18]([CH:11]1[C:10](=[O:21])[C@@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)cc1Cl
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Triethylamine (21.3 mL, 153 mmol) was added in two portions to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 10.9 g, 51 mmol) in dichloromethane (100 mL), giving a thick suspension. Dichloromethane (30 mL) was added, followed by N′-(2-chloro-4-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 33; 9.8 g, 37.6 mmol). The reaction mixture was placed in an oil-bath at 50° C., heated at this temperature for 6 hours and then allowed to cool to room temperature and stir for 1 h. The reaction mixture was poured into water (200 mL) and two layers were separated. The organic layer was washed with water (2×200 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated, and then dried under high vacuum for 90 min to give N′-(2-chloro-4-fluoro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (14.9 g, 90%) as a pale foam.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]3[NH:15][C:16]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[C:23](=[N:31]O)[C:22]=5[CH:21]=[CH:20][CH:19]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:35]([OH:38])(=O)[CH3:36].[CH2:39](O)C>O.[Zn]>[CH:35]([O:38][CH:34]([CH3:33])[CH3:11])([CH3:36])[CH3:39].[N:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:34]=[CH:33][C:14]3[NH:15][C:16]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[CH:23]([NH2:31])[C:22]=5[CH:21]=[CH:20][CH:19]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: CCO
Reactant: O=C(NCCN1CCCC1)c1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4=NO)nc2c1
Agent: [Zn]
Solvent: O
Product: CC(C)OC(C)C
Product: NC1c2ccccc2-c2c(-c3nc4cc(C(=O)NCCN5CCCC5)ccc4[nH]3)cccc21

Procedure:
The procedure used in Example 216 is followed. In a 20 ml round-bottomed flask under an argon atmosphere, dissolve 303 mg of 4-{5-[2-(pyrrolidin-1-yl)ethylaminocarbonyl]-1H-benzimidazol-2-yl}-9H -fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 1.5 ml of ethanol and 1.5 ml of water and 1.5 ml of acetic acid, at room temperature. Add 175 mg of zinc in three stages, and, between each addition, stir for approximately one hour to two hours. Add Celite and filter. The filtrate is concentrated under reduced pressure. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (9/1 by volume) and then formation of a paste with diisopropyl ether, in this way we obtain 257 mg of 4-{5-[2-(pyrrolidin-1-yl)ethylaminocarbonyl]-1H-benzimidazol-2-yl}-9H-fluorene-9(R,S)-amine, in the form of a beige solid, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1.N1C=CC=CC=1.CS([Cl:21])(=O)=O.O>CN(C)C=O>[Cl:21][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC1C=CCC1
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCC1C=CCC1
Temperature: 70 °C

Procedure:
3-(4-Hydroxybut-1-yl)cyclopentene {2-cyclopentene-1-butanol}(51 g, 0.37 moles) is diluted in dimethylformamide (100 ml) and added to pyridine (38 g, 0.40 moles). The solution is stirred and methane sulfonyl chloride (46 g, 0.40 moles) is added dropwise in the course of 10 minutes. The reaction is then heated in a 70° C. water bath for 30 minutes. Then the mixture is cooled and water (1 liter) is added over 20 minutes. The reaction is partitioned between hexane (500 ml) and the organic phase separated. The aqueous layer is extracted with hexane (2×500 ml) and the extracts combined with the organic layer. The solvent volume is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The solid is filtered off and the remaining solvent removed leaving a clear yellow oil. The crude product is fractionally distilled under reduced presure leaving a clear, colorless oil (43 g, 0.27 moles), BP 40° C./0.2 mm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:8])[CH2:3][CH2:2]1.[C:29](Cl)(=[O:31])[CH3:30].C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl>[C:29]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])=[O:8])[CH2:3][CH2:2]1)(=[O:31])[CH3:30]
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2ccccc2c1NC(=O)C1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-[(Piperidin-4-yl)carbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (140 mg) obtained in Example 228 is suspended in dichloromethane (10 ml), and thereto are added acetyl chloride (30 μl) and triethylamine (74 μl) under ice-cooling, and the mixture is stirred at room temperature for 6 hours. The reaction solution is diluted with chloroform, washed successively with water, 5% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is dissolved in ethyl acetate, and treated with activated carbon. The resulting residue is recrystallized from ethyl acetate to give the title compound (38 mg).