Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][C:14]=2Cl)(=[O:3])[CH3:2].C(N(CC)CC)C>[Pd].C(OCC)(=O)C>[C:1]([O:4][CH2:5][CH:6]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][CH:14]=2)(=[O:3])[CH3:2].[CH3:2][C:1]([O:4][CH2:5][CH:6]([CH2:20][O:21][C:22]([CH3:23])=[O:24])[CH2:7][CH2:8][N:9]1[C:10]2[N:11]=[C:12]([NH2:19])[N:13]=[CH:14][C:15]=2[N:16]=[CH:17]1)=[O:3]
Reactant: CC(=O)OCC(CCn1cnc2c(Cl)nc(N)nc21)COC(C)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-amino-6-chloropurine (15.4 g, 43 mmole), 5% palladium on carbon (6.16 g), triethylamine (6.6 ml, 47 mmole) and ethyl acetate (77 ml) was stirred at 50° C. under a hydrogen atmosphere at 1 bar pressure in an autoclave for 3 to 5 hours. After completion of the reaction the mixture was removed from the autoclave which was washed out with ethyl acetate (30 ml) keeping the washings at 50° C. The main reaction mixture was filtered through a celite bed followed by the washings and finally with ethyl acetate (30 ml). Water (46 ml) was added to the combined ethyl acetate filtrate plus washings. The ethyl acetate was evaporated to dryness to leave a crude white solid. This was recrystallised from n-butanol (62 ml), stirring the cooled solution at 0 to 5° C. for 3 h before filtration. The product was filtered off and washed with the mother liquors. The solid was reslurried in n-heptane (50 ml) stirred for 30 minutes and filtered. The product was dried at 40° C. for 16 h under vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][C:34]3([C:38]([O:40]CC)=[O:39])[CH2:37][CH2:36][CH2:35]3)[C:30]3[C:25](=[CH:26][C:27]([CH3:43])=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([NH:20][C:21]([C:23]2[CH:32]=[C:31]([O:33][C:34]3([C:38]([OH:40])=[O:39])[CH2:37][CH2:36][CH2:35]3)[C:30]3[C:25](=[CH:26][C:27]([CH3:43])=[CH:28][CH:29]=3)[N:24]=2)=[O:22])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)c3ccc(C)cc3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(OC3(C(=O)O)CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 3 h

Procedure:
A solution of 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-(ethoxycarbonyl)cyclobut-1-oxy)quinoline (220 mg, 0.29 mmol) in 50% trifluoroacetic acid-methylene chloride (6 mL) was stirred at ambient temperature for 1 hour. The solvent was evaporated in vacuo and the residue was dissolved in methanol (5 ml). LiOH (5 mL, 0.025 M) was added and the reaction stirred for 3 hours. The solvent was evaporated and the residue was purified by preparative HPLC to afford 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(1-carboxycyclobut-1-oxy)quinoline, as a white solid (190 mg, 95%, trifluoroacetic acid salt); NMR (DMSO-d6) 1.15 (t, 3), 1.82 (m, 1), 2.00 (m, 3), 2.30 (m, 2), 2.51 (s, 3), 2.56 (m, 2), 2.68 (m, 2), 3.40 (m, 6), 3.62 (m, 2), 4.00 (q, 2), 4.98 (m, 1), 6.98 (s, 1), 7.52 (dd, 1), 7.88 (s, 1), 8.14 (d, 1), 8.85 (d, 1) ppm.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[S:8](=[O:17])(=[O:16])[C:7]2[S:18][C:19]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:20][C:6]1=2)(=O)[CH3:2].B.CSC.CSC>O1CCCC1>[CH2:14]([O:13][CH2:12][CH2:11][CH:9]1[S:8](=[O:16])(=[O:17])[C:7]2[S:18][C:19]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:20][C:6]=2[CH:5]([NH:4][CH2:1][CH3:2])[CH2:10]1)[CH3:15]
Reactant: CCOCCC1CC(NC(C)=O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCNC1CC(CCOCC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21

Procedure:
To a stirred solution of 4-acetamido-5,6-dihydro-6-(2-ethoxyethyl)-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (6.8 g, 0.017 mol) in tetrahydrofuran (20 ml) heated under nitrogen to reflux was added borane-methyl sulfide (17 ml, 0.170 mol) dropwise over 1/2 hr. The reaction was heated at reflux for 2 hr. while allowing the methyl sulfide to distill off. Then the mixture was concentrated in vacuo to a yellow gum. Then 6N HCl (30 ml) was added followed by water (30 ml) and the mixture was heated on the steam bath for 1/4 hour. The solution was basified with excess sodium bicarbonate and was extracted with ethyl acetate (300 ml). The aqueous solution was again extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried, filtered and concentrated in vacuo to obtain a white foam (5.3 g) mixture of cis and trans isomers. Chromatography on silica gel gave 2.28 g of the a-isomer and 0.17 g of the β -isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH2:9])[CH:8]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=O)=[CH:26][CH:25]=1.N1C=CC=CC=1>C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)=[C:7]([NH:9][CH2:31][CH2:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH:8]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(CCNc2cc(OC)ccc2C2CCc3cc(OC)ccc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.9 %

Procedure:
A mixture of 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (700 mg), 4-methoxyphenylacetyl chloride (680 mg) and pyridine (10 ml) was stirred for 2 hours at room temperature. The reaction mixture was diluted with a saturated aqueous solution of sodium bicarbonate, the crystal that was precipitated was filtered, rinsed with water, then dried at 50° C. overnight. The total amount of the resulting N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2-(4-methoxyphenyl)acetamide (crude product) was used according to an analogous synthetic method to Example 337 described below to provide the title compound (690 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[N+:24]([O-])([OH:26])=[O:25]>>[N+:24]([C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][C:2]=1[CH3:1])([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
50.5 g (0.40 mol) of 6-methyluracil (Merck) are introduced in portions over the course of one hour with stirring at 0 to +5° C. into a solution of 200 ml of 100% nitric acid (fuming) and 50 g of phosphorus pentoxide. When the exothermic reaction is complete, the mixture is stirred at +5° C. for a further 5 hours. The reaction mixture is subsequently poured into 1 kg of ice-water. The resultant precipitate is filtered, washed with water and then dried to constant weight, giving 37 g (54%) of 5-nitro-6-methyluracil, pale-yellow powder, m.p. 281° C. with decomposition.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([Cl:30])[CH:24]=[CH:23]2.C1COCC1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([Cl:30])[CH:24]=[CH:23]3)[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: Clc1ccc2cc(CBr)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1Cc1ccc2nc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 3-oxopiperazine-1-carboxylic acid benzyl ester (4.65 g, 19.8 mmol) and 6-bromomethyl-2-chloroquinoline (5.40 g, 21.0 mmol) in 80 mL of a 3:1 mixture of THF:DMF at 0° C. is added sodium hydride (0.81 g, 20.2 mmol, 60% mineral oil dispersion). The resulting mixture is stirred for 1 hour at 0° C. then at room temperature for 18 hours. The reaction mixture is quenched with saturated NH4Cl solution, then diluted with EtOAc. The organic layer is washed sequentially with 1N HCl, water, saturated NaHCO3 and saturated NaCl, then dried over MgSO4, filtered and concentrated. The crude product is triturated in Et2O/hexanes/EtOAc and filtered to afford the title compound (6.96 g, 17.0 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ8.08 (d, 1H), 8.00 (d, 1H), 7.69 (s, 1H), 7,63 (dd, 1H), 7.41 (d, 1H), 7.35 (s, 5H), 5.15 (s, 2H), 4.78 (s, 2H), 4.28 (s, 2H), 3.70 (m, 2H), 3.32 (bs, 2H).
Reaction SMILES: BrBr.Cl[CH2:4][CH2:5][CH2:6][C:7](=[O:9])[CH3:8].[CH2:10]([SH:13])[CH2:11][CH3:12].[OH-].[K+]>C(Cl)Cl.CO>[C:7]([C:6]1([S:13][CH2:10][CH2:11][CH3:12])[CH2:4][CH2:5]1)(=[O:9])[CH3:8]
Reactant: CC(=O)CCCCl
Reactant: CCCS
Agent: BrBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCSC1(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32 %

Procedure:
A solution of 134 g (0.83 mol) of bromine in 130 ml of methylene chloride is added dropwise at 10° C. with stirring to a solution of 100 g (0.83 mol) of 5-chloropentan-2-one in 400 ml of methylene chloride. The reaction mixture is stirred for a further hour at room temperature, then washed using water and dilute aqueous sodium carbonate solution and dried over sodium sulphate. The mixture is concentrated by stripping off the solvent under reduced pressure, and the residue is taken up in 200 ml of methanol and 63 g (0.83 mol) of n-propylmercaptan are added at 5° C. with stirring. A mixture of 93 g of potassium hydroxide powder in b 500 ml of methanol is then added dropwise. The reaction mixture is initially stirred for 2 hours at room temperature and then for 4 hours at 40° C. The mixture is then concentrated by stripping off the solvent under reduced pressure and the remaining residue is taken up in methylene chloride. The organic solution is washed successively using water, dilute aqueous sodium hydroxide solution and again using water, then concentrated under reduced pressure and then subjected to a vacuum distillation. In this manner, 42 g (32% of theory) of 1-acetyl-1-propylmercaptocyclopropane of boiling point 107° C./20 mbar are obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([C:51]1[CH:52]=[C:53]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)[CH:54]=[CH:55][C:56]=1[F:57])#[N:50]>CN(C=O)C>[C:49]([C:51]1[CH:52]=[C:53]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=2)[CH:54]=[CH:55][C:56]=1[F:57])#[N:50]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: N#Cc1cc(-c2cccc(N)c2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)ccc1F
Temperature: 25 °C
Yield: 42.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′-cyano-4′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.011 g of product in 46% yield: LCMS (ESI) m/z 401 (MH+).
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[NH:12][NH2:13]>CO.C(O)(=O)C>[C:16]([O:15][C:11]([NH:12][N:13]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C1CCc2ccccc21
Reactant: CC(C)(C)OC(=O)NN
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NN=C1CCc2ccccc21

Procedure:
A solution of indan-1-one (5.0 g) and tert-butyl carbazate (5.0 g) in methanol (20 ml) containing glacial acetic acid (1 drop) was boiled and stirred under reflux for 1.5 hours. The mixture was cooled and evaporated under reduced pressure. The residue was recrystallized from ethanol to give indan-1-one tert-butyloxycarbonyl-hydrazone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:15])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)O[CH:8]=1.CC(O)=O.[NH2:20][C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1>O>[C:23]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=[C:21]([N:20]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:15])[CH:5]=[C:6]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:22]=1
Reactant: Nc1cccc(-c2ccccc2)c1
Reactant: COc1coc(-c2ccccc2)cc1=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cn(-c2cccc(-c3ccccc3)c2)c(-c2ccccc2)cc1=O
Temperature: 130 °C
Yield: 44 %

Procedure:
To a solution of 5-methoxy-2-phenyl-4H-pyran-4-one (35 mg, 0.17 mmol) in a 1:1 mixture of AcOH:water (0.6 mL) was added 3-aminobiphenyl (59 mg, 0.35 mmol). The reaction vessel was sealed and heated at 130° C. for 3 h before being cooled to room temperature and purified by reversed phase HPLC (2 cm×5 cm CI 8, acetonitrile-water gradient, 0.05% TFA added) to provide (44%) 1-(biphenyl-3-yl)-5-methoxy-2-phenylpyridin-4(1H)-one. LC/MS (M+H)+ 354.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:37][C:38]1([C:44]2[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=2)[CH:43]2[CH:39]1[CH2:40][NH:41][CH2:42]2.C(N(CC)CC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([N:41]2[CH2:42][CH:43]3[CH:39]([C:38]3([C:44]3[CH:45]=[C:46]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:47]=[CH:48][CH:49]=3)[CH3:37])[CH2:40]2)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Reactant: O=C(O)CCc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccc(Cl)c(Cl)c3)CC21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
To a solution of 3(3,4-dichlorophenyl)propanoic acid (35 mg, 0.16 mmol) in N,N-dimethylfonnarnide (4 ml) was added 1-hydroxybenzotriazole monohydrate (26 mg, 0.17 mmol) and 1-(3dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol). After stirring at room temperature for 5 min the mixture was treated with the hydrochloride salt of N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl)methanesulfonamide (Peparation 53, 52 mg, 0.17 mmol) and triethylarnine (33 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 72 h before concentrating in vacuo. Water (10 ml) was added and the reaction mixture was extracted with ethyl acetate (2×15 ml). The combined organic extracts were washed with water (10 ml) and saturated brine (10 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a light brown oil. The residue was purified by chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 amnionia (300:8:1) to afford the title compound as a white foam (38 mg, 51%).
Reaction SMILES: [C:1]1([C:7]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:12][CH2:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][C:19](=O)[CH2:20][CH2:21][C:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[OH-].[K+]>C(O)COCCOCCO.O>[C:1]1([C:7]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(CCC(=O)CCCCC(=O)CCC(CC(=O)O)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: O=C(O)CC(CCCCCCCCCCC(CC(=O)O)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 58 %

Procedure:
0.27 g of 3,3,14,14-tetraphenyl-6,11-diketohexadecane-1,16-dioic acid prepared as described in Example 23 and 0.23 ml of 85% hydrazine hydrate were added to a solution of 0.4 g KOH in 10 ml of triethyleneglycol. The mixture was heated at 120° C. for 24 h, then heated to 195° C. with the evaporation of water followed by reflux for 7 h. The mixture was cooled, diluted with water, extracted with ether, acidified and extracted into ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness to yield the title compound. 58% yield.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6](B(O)O)[C:5]=2[CH:4]=[CH:3][N:2]=1.[CH2:14]([O:16][C:17](=[O:35])[CH2:18][N:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[N:28][C:27]([NH2:30])=[C:26]3[O:31][C:32](Cl)=[CH:33][C:25]=23)[CH:21]=[N:20]1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:30][C:27]1[N:28]=[CH:29][C:24]([C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:35])[CH:23]=2)=[C:25]2[CH:33]=[C:32]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)[O:31][C:26]=12
Reactant: CCOC(=O)Cn1cc(-c2cnc(N)c3oc(Cl)cc23)cn1
Reactant: OB(O)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cn1cc(-c2cnc(N)c3oc(-c4cccc5cnccc45)cc23)cn1
Temperature: 100 °C
Yield: 20.9 %

Procedure:
A solution of isoquinoline-5-boronic acid (53.9 mg, 0.312 mmol) and ethyl[4-(7-amino-2-chlorofuro[2,3-c]pyridin-4-yl)-1H-pyrazol-1-yl]acetate (50.0 mg, 0.156 mol) in 1,4-dioxane (0.85 mL) and H2O (0.3 mL) was charged with potassium carbonate (32 mg, 0.23 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium dichloride (1 mg, 0.002 mmol) under an atmosphere of nitrogen. The mixture was heated in a microwave reactor at 100° C. for 40 min. Purification of the residue by flash chromatography (0 to 5% 7 N NH3/MeOH:EtOAc) afforded 27 mg (41%) of the title compound. 1H NMR (400 MHz, CD3OD) δ 9.36 (s, 1H), 8.57-8.63 (m, 1H), 8.52 (d, J=6.06 Hz, 1H), 8.37 (d, J=7.33 Hz, 1H), 8.27 (d, J=8.08 Hz, 1H), 8.18 (s, 1H), 7.98 (d, J=7.58 Hz, 2H), 7.85 (t, J=7.83 Hz, 1H), 7.55-7.62 (m, 1H), 7.53 (s, 1H), 4.28 (q, J=7.16 Hz, 2 H), 1.95 (s, 2H), 1.32 (t, 3H); MS (ESI): 415.16 [M+H]+; HPLC tR=0.94 min (TOF: polar—3 min).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:4]([CH3:16])=[N:3]1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][N:2]1[C:6]([O:7][C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:4]([CH3:16])=[N:3]1
Reactant: Cc1cccc(Oc2c(C)nn(C)c2O)c1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(Oc2c(C)nn(C)c2Oc2ccnc(Cl)n2)c1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
In 10 ml of acetonitrile were dissolved 0.220 g (1.00 mmol) of 1,3-dimethyl-4-(3-methylphenoxy)-5-hydroxypyrazole, 0.220 g (1.50 mmol) of 2,4-dichloropyrimidine and 0.210 g (1.50 mmol) of potassium carbonate. Thus obtained solution was stirred for 3 hours with refluxing. After completing the reaction, the reaction solution was poured into water, extracted with ethyl acetate and dried. The organic layer was concentrated. The residue was purified by means of silica gel column chromatography (developing solution: ethyl acetate-hexane (1:1 v/v)) to give 0.29 g of 1,3-dimethyl-4-(3-methylphenoxy)-5-(2-chloropyrimidine-4-yloxy)pyrazole.
Reaction SMILES: [CH:1]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[CH:2]2[C:3](=[O:13])[CH:4]=[CH:5][C:6]1=[O:12].C([O-])(O)=[O:15].[Na+].OO.O>CC(C)=O>[O:15]1[CH:4]2[CH:5]1[C:6](=[O:12])[CH:7]1[CH:2]([C:3]2=[O:13])[CH:1]2[CH2:11][CH:8]1[CH:9]=[CH:10]2
Reactant: O=C([O-])O
Reactant: O=C1C=CC(=O)C2C3C=CC(C3)C12
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1C2OC2C(=O)C2C3C=CC(C3)C12
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.35 %

Procedure:
A solution of tricyclo[6.2.1.02,7]undeca-4,9-diene-3,6-dione (14) (26.13 g, 150 mmol) in acetone (100 ml) was cooled to 0° C. on an ice-bath. To the solution was added saturated aqueous NaHCO3 (33 ml). To the mixture was added dropwise 34.5% aqueous hydrogen peroxide (142 ml) while keeping at 0° C. After the addition, the reaction mixture was stirred at 0° C. for 1 hr and then water (100 ml) was added. From the mixture solution, the product was extracted with diethyl ether (total 700 ml). The extract was washed with saturated aqueous NaCl and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to afford as the residue 4,5-epoxy-tricyclo[6.2.1.02,7]undec-9-ene-3,6-dione (15) (28.06 g, 148 mmol, 98.35% yield) in light yellowish white crystals.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[Mg].II.[O:15]=[C:16]([CH3:22])[CH2:17][CH2:18][CH2:19][C:20]#[N:21].Cl>O1CCCC1.O>[OH:15][C:16]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1)([CH3:22])[CH2:17][CH2:18][CH2:19][C:20]#[N:21]
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CC(=O)CCCC#N
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(CCCC#N)c1cccc(C(F)(F)F)c1
Temperature: 35 °C
Yield: 49 %

Procedure:
A mixture of 7.0 mL (0.05 mole) of 3-trifluoromethylphenyl bromide, 1.2 grams (0.05 mole) of magnesium and a crystal of iodine in about 70 mL of tetrahydrofuran was warmed to 35° C. to initiate the formation of the Grignard reagent. Upon formation of the Grignard reagent, the reaction mixture was cooled to ambient temperature and, with stirring, a solution of 5.8 mL (0.05 mole) of 5-oxohexanenitrile in 10 mL of tetrahydrofuran was added dropwise. The reaction mixture temperature increased to about 35° C., at which time the rate of addition was slowed to keep the reaction mixture temperature at about 35°-40° C. The complete addition required about 15 minutes. Upon completion of the addition, the reaction mixture was allowed to warm to ambient temperature, where it was stirred for 2 hours. After this time, the reaction mixture was poured into 200 mL of water and was acidified with aqueous 2N hydrochloric acid. The mixture was then extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 6.3 grams of 5-hydroxy-5-(3-trifluoromethylphenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure.