Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)=[O:2].[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:12]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[O:2])[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: c1cn[nH]c1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cccc(-n2cccn2)c1
Reaction time: 24 h

Procedure:
A mixture of 3-formylphenylboronic acid (2.00 g, 13.34 mmol), pyrazole (0.46 g, 6.67 mmol), copper(II) acetate (1.82 g, 10.01 mmol), pyridine (1.10 mL, 13.34 mmol), and powdered 4A molecular sieves (2.5 g) in dichloromethane (20 mL) was stirred under an air atmosphere for 24 h. The mixture was then filtered through Celite, the filtered solids were washed with MeOH, and the combined filtrate was concentrated. Purification by chromatography (SiO2, 3:1 hexane/ethyl acetate) yielded the title compound. MS 173 (M+H)+.
Reaction SMILES: C([Mg]Br)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[CH:10]2.[C:17]([CH2:21][CH2:22][C:23](Cl)=[O:24])([O:19][CH3:20])=[O:18].[NH4+].[Cl-]>CCOCC.[Cl-].[Zn+2].[Cl-].ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:16])=[C:10]2[C:23](=[O:24])[CH2:22][CH2:21][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CCC(=O)Cl
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCC(=O)c1c(C)[nH]c2ccc(OC)cc12
Reaction time: 0.33 h

Procedure:
To a solution of ethylmagnesium bromide in ether (3.0M; 7.1 mL; aldrich) was added a solution of 5-methoxy-2-methylindole (3.29 g) in ether (18 mL) at r.t. After 20 min, addition of a solution of zinc chloride in ether (1M; 20.4 mL; aldrich) resulted in the formation of a thick yellow solid. The suspension was stirred mechanically for 30 min before the rapid addition of a solution of 3-carbomethoxypropionyl chloride (2.6 mL) in ether (10 mL). The resulting mixture was vigorously stirred at r.t. for 3 h before the addition of saturated aqueous NH4Cl and dichloromethane. The two phases were separated and the organic phase was washed successively with saturated aqueous NaHCO3 and brine, dried (MgSO4) and evaporated. Trituration of the residue in ether afforded the title compound as a pink solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])([O-:12])=[O:11].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.CC([O-])(C)C.[Na+]>COCCOC.CCOC(C)=O>[CH3:9][NH:8][C:4]1[CH:3]=[C:2]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N+:10]([O-:12])=[O:11])[N:7]=[CH:6][N:5]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CNc1cc(Cl)ncn1
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CNc1cc(Nc2ccccc2[N+](=O)[O-])ncn1
Temperature: 90 °C
Yield: 35 %

Procedure:
A mixture of (6-chloro-pyrimidin-4-yl)-methyl-amine (1 g, 7 mmol), 2-nitro-phenylamine (965 mg, 7 mmol), Brettphos (279 g, 0.35 mmol) and tBuONa (2 g, 21 mmol) in DME (50 mL) was heated to 90° C. for 1 hour under nitrogen atmosphere. The reaction was concentrated, and the residue was purified by flash chromatography on silica eluting with DCM:EtOAc=10:1-4:1 to obtain the title compound (600 mg, yield: 35%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 2.94 (d, 3H), 4.99 (bs, 1H), 5.82 (s, 1H), 7.04 (t, 1H), 7.60 (t, 1H), 8.21 (d, 1H), 8.33 (s, 1H), 8.75 (d, 1H), 9.91 (s, 1H); MS (ESI): 246 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]([CH2:37][CH2:38][OH:39])[CH2:20][N:21]([CH3:36])[C:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[C:26]([C:34]#[N:35])[CH:25]=2)=[O:23])[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C@H:19]([CH2:37][CH:38]=[O:39])[CH2:20][N:21]([CH3:36])[C:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[C:26]([C:34]#[N:35])[CH:25]=2)=[O:23])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CN(C[C@@H](CCO)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1cc(C#N)cc2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A solution of oxalyl chloride (15.9 g, 125.4 mmol) dissolved in DCM (350 mL) was cooled to −78° C. DMSO (19.6 g, 251 mmol) was added dropwise over 10 minutes while maintaining the temperature of the reaction mixture below −70° C. The mixture was stirred for 30 min at −78° C. A solution of N-[(S)-2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-3-cyano-1-naphthamide (26.8 g, 62.7 mmol) was dissolved in DCM (350 mL) and added dropwise over 30 min while maintaining the temperature of the mixture below −70° C. The mixture was allowed to stir for one h at −78° C., then warmed to −50° C. and stirred for another 30 minutes. The mixture was cooled to −78° C. and a solution of triethylamine (25.4 g, 251 mmol) dissolved in DCM (70 mL) was added dropwise over 10 min. The mixture was then allowed to warm gradually to ambient temperature and stir for 20 hours. The mixture was then washed with 0.5N hydrochloric acid (2×250 mL), water (250 mL), and saturated sodium bicarbonate (250 mL). The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel; 0-20% Et2O in DCM) to provide the desired product as a light yellow foam (26.0 g, 97%). MS: 425 (M+H). 1H-NMR (DMSO-d6) δ2.63 (bs, 3H, NCH3); 2.99-3.93 (m, 5H, CH); 6.91-7.15 (m, 1H, aromatic); 7.33-7.81 (m, 6H, aromatic); 8.62 (s, 1H, aromatic); 9.45 and 9.73 (singlets, 1H total, CHO).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].[CH:13](OC)(OC)[O:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[N:4]=[CH:13][O:14][CH3:15]
Reactant: Cc1cc([N+](=O)[O-])cc(N)c1C
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC=Nc1cc([N+](=O)[O-])cc(C)c1C

Procedure:
66.4 g of 2,3-dimethyl-5-nitroaniline, 0.4 l of trimethyl orthoformate and 1.6 g of para-toluenesulphonic acid are mixed and heated to reflux for 3 hours.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7]Br)=[CH:3][CH:2]=1.[C:9]([OH:18])(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:12].O>CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[OH:12][C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[C:9]([O:18][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[O:17]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=C(OCc1ccccc1)c1ccccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
BnBr (1.75 mL, 14.631 mmol) was added to a solution of salicylic acid (2.0 g, 14.625 mmol) in TBAF (17.5 mL, 1 M solution in THF) and the reaction mixture was stirred at r.t. overnight (16 h). The organic layer was poured into H2O (100 mL) and extracted with EtOAc (70 mL). It was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (2% EtOAc/hexanes) to furnish 2.53 g of benzyl 2-hydroxybenzoate (colourless oil, yield: 76%).
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]4)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.B1([C:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH:40]=2)OC(C)(C)C(C)(C)O1.C(=O)(O)[O-].[Na+].CCOC(C)=O>O1CCOCC1.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.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:8][C:5]1[C:4]2[C:9]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:15]4)=[CH:10][S:11][C:3]=2[C:2]([C:39]2[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH:40]=2)=[CH:7][N:6]=1
Reactant: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c3c(-c4ccc5c(c4)CCN5C(=O)Cc4ccccc4)csc23)CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A mixture of 7-iodo-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (298 mg, 0.583 mmol), 3,6-dihydro-2H-pyridine-1-N-Boc-4-boronic acid pinacol ester (238 mg, 0.770 mmol), and PdCl2(dppf)-CH2Cl2 adduct (24 mg, 0.029 mmol) in 1,4-Dioxane (6 mL) and saturated aqueous sodium bicarbonate (2 mL, 2.000 mmol) was degassed with Nitrogen for 10 minutes in a microwave vial. The vial was then capped and the mixture was stirred at 120° C. in the microwave reactor for 30 min. LCMS showed complete conversion to the product. The mixture was cooled, poured into water (50 mL), and extracted with ethyl acetate (2×50 mL). The extracts were washed with brine (1×75 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (Analogix, 40 g SiO2, 25%-100% EtOAc in hexanes gradient over 45 minutes, then EtOAc for 5 minutes) to give 1,1-dimethylethyl 4-{4-amino-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-7-yl}-3,6-dihydro-1(2H)-pyridinecarboxylate (280 mg, 0.494 mmol, 85% yield) as a beige solid. LC/MS (ES) m/z=567 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[C:21]1([CH:27]2[CH2:29][O:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(CC)CC>C(Cl)Cl>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH2:29][CH:27]([OH:28])[C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Reactant: c1ccc(C2CO2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCN(CC(O)c1ccccc1)CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 14.2 %

Procedure:
A mixture of 34.6 mg (0.128 mmol) 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 23 mg (0.192 mmol) 2-phenyl-oxirane and 38 mg (0.384 mmol) NEt3 in 2 mL DCM were stirred at 50° C. for 2 h and concentrated. The residue was taken up in methanol and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 7.1 mg (14%) of the title compound. MS m/e: 391.4 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:37]
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A165) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([F:17])[CH:6]=1.[C:18](=[O:20])=[O:19]>C1COCC1>[F:17][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19]
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: O=C=O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)c(F)c1
Temperature: -10 °C
Yield: 740.3 %

Procedure:
A suspension of magnesium (0.968 g, 3.98 mmol) and a few crystals of iodine in anhyd THF (200 mL) were treated with dropwise addition of 10 mL of a solution of 4-bromo-2-fluorobiphenyl (10.0 g, 3.98 mmol) in THF (100 mL). The mixture was heated to gentle reflux and a reaction ensued. At that time, the remaining solution of 4-bromo-2-fluorobiphenyl was added dropwise to the flask over a 3-minute period. The contents were then stirred at reflux under argon until no magnesium consumption was observed. The reaction mixture was subsequently cooled to −10° C. and treated with dry ice (˜70 g). The reaction mixture was quenched with 20% aqueous hydrochloric acid (50 mL), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×20 mL), and the combined organic layer was washed with brine (30 mL), dried over anhyd sodium sulfate and concentrated to about ⅓ of its original volume. The contents were treated with hexane (200 mL), and the precipitate was filtered and dried under high vacuum to afford 3-fluoro-4-phenylbenzoic acid (6.37 g, 74%) as a white, crystalline solid. 1H-NMR (DMSO-d6): δ7.48 (m, 3H); 7.59 (m, 2H); 7.66 (dd, J=8.1, 8.1 Hz, 1H); 7.76 (dd, J=1.5, 11.6 Hz, 1H); 7.85 (dd, J=1.5, 8.1 Hz, 1H); 13.30 (br s, 1H). Anal. Calcd for C13H9FO2: C, 72.22; H, 4.20; F, 8.79. Found: C, 71.95; H, 4.11; F, 9.07.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(C(Cl)=O)=O.[CH2:20]([CH2:22][NH2:23])O.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C(Cl)Cl.C1COCC1.CCOC(C)=O.CC#N.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[O:13][CH2:20][CH2:22][N:23]=3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: O=C(O)C1(c2ccc(I)cc2)CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Ic1ccc(C2(C3=NCCO3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Part A. To a slurry of 1-(4-iodo-phenyl)-cyclopropane-carboxylic acid (0.693 g, 2.41 mmol) in CH2Cl2 (3.0 mL) at 0° C. was added (COCl)2 (0.40 mL, 4.6 mmol) dropwise. The reaction was warmed to rt and stirred under N2 for 1 h. The reaction was monitored by LC/MS. Upon completion the reaction was concentrated on the rotary evaporator and diluted with CH2Cl2 (3 mL). Ethanolamine (0.30 mL, 4.54 mmol) was added drop-wise and the reaction stirred for 1.5 h. The reaction was then quenched with H2O and extracted with EtOAc (2×). The organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The crude 1-(4-iodo-phenyl)-cyclopropanecarboxylic acid (2-hydroxy-ethyl)-amide was taken directly to the next reaction without further purification. LC/MS (ESI+) 332.2 (M+H)+, tR=2.16 min (10–90% CH3CN/H2O in a 4-min run). It was dissolved in THF (10.0 mL) and methoxycarbonylsulfamoyl triethylammonium hydroxide inner salt (0.61 g, 2.56 mmol) was added. The reaction was heated to 70° C. for 2 h and then cooled. The reaction mixture was diluted with EtOAc and washed with H2O (2×), brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica, EtOAc:Hexanes 3:1) to 2-[1-(4-iodo-phenyl)-cyclopropyl]-4,5-dihydro-oxazole (0.41 g, yield: 55%). LC/MS (ESI+) 314.0 (M+H), tR=1.62 min (10–90% CH3CN/H2O in a 4-min run). 1H NMR (CDCl3) δ 7.65 (d, J=8 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 4.32 (t, J=9.5 Hz, 2H), 3.87 (t, J=9.1, 9.6, 2H), 1.67 (m, 2H), 1.23 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([C:23](O)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([N:14]1[CH2:13][CH2:12][C@H:11]2[C@H:16]([N:9]([C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=3)[CH2:10]2)[CH2:15]1)=[O:24]
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(C)nc(N2C[C@H]3CCN(C(=O)c4ccccc4-c4ccccc4)C[C@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1S,6R)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and biphenyl-2-carboxylic acid for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C25H26N4O, 398.5; m/z found 399.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.56-7.25 (m, 7H), 7.24-6.72 (m, 2H), 6.44-6.17 (m, 1H), 4.57-3.20 (m, 6H), 3.01-2.40 (m, 2.5H), 2.37-2.00 (m, 6H), 1.38-1.31 (m, 1.5H).
Reaction SMILES: Cl.[CH3:2][C@@H:3]([NH2:11])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C1C=CC=CN=1)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:11][C@H:3]([CH3:2])[CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1
Reactant: C[C@@H](N)CN1CCOCC1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](CN1CCOCC1)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 93 %

Procedure:
Reflux a mixture of (R)-1-methyl-2-morpholin-4-yl-ethylaminehydrochloride (0.04 mol, 8.7 g), 5-bromo-2-fluoronitrobenzene (0.048 mol, 10.5 g), triethylamine (0.20 mol, 20.2 g) and dimethylaminopyridine (0.0004 mol, 0.048 g) in ethyl acetate (220 mL) for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 10% ethyl acetate in hexanes as eluent to obtain the title compound (12.8 g, 95%) as an orange solid. 1H NMR (400 MHz, CDCl3) δ 1.29 (d, 3H), 2.47-2.51 (m, 5H), 2.53-2.58 (m, 1H), 3.64-3.69 (m, 4H), 3.72-3.78 (m, 1H), 6.78 (d, 1H), 7.46 (dd, 1H), 8.30 (d, 1H), 8.33 (d, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[C@:6]23[O:10][C@:9](O)([CH2:11][C:12](=[CH2:13])[C@@H:5]2[CH2:4][CH2:3]1)[C@H:8]([CH:15]([CH3:17])[CH3:16])[CH2:7]3.[Mn]([O-])(=O)(=O)=[O:19].[K+]>C(O)(=O)C>[CH3:16][C:15]1[C:8]2[C:7]([CH:6]=[C:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:12]([CH3:13])[CH2:11][C:9]=2[O:10][CH:17]=1)=[O:19]
Reactant: C=C1C[C@@]2(O)O[C@@]3(C[C@H]2C(C)C)[C@@H](C)CC[C@@H]13
Reactant: O=[Mn](=O)(=O)[O-]
Agent: C/C1=C/C(=O)c2c(C)coc2C/C(C)=C\CC1
Agent: [K+]
Solvent: CC(=O)O
Product: CC1=CC(=O)c2c(C)coc2CC(C)=CCC1

Procedure:
2.45 g (0.01 mol, 96%) of curcumol was dissolved in 40 mL of acetic acid, and to it was added an aqueous solution dissolved with 4 g potassium permanganate. The mixture was heated under reflux for several hours followed by removal of the organic solvent under vacuum. The mixture was extracted with 100 mL of 50% ethyl acetate and water. The ethyl acetate was washed with water several times and dried over anhydrous sodium sulfate. The solvent wad removed under vacuum to afford a dark solid. After separated by silica gel column, 1.45 g of white curzerenone derivative was obtained, yield: 61%, HPLC: 98%, Melting point: 138-140° C., i.e. Compound No. 31 of formula (III) wherein Z is O.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]1[CH:20]=O)=[O:6])[CH:2]=[CH2:3].C(O)C.[C:25]1([NH2:35])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]1[CH2:20][NH:35][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1C=O
Reactant: Nc1cccc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.1 %

Procedure:
A mixture of (2S,4S)-2-formyl4-BOCsulfanyl-pyrrolidine-1-carboxylic acid allyl ester (compound(1)) ( 711 mg), ethanol(25 ml), 1-naphthylamine(333 mg) and 3A molecular sieves(4.5 g.) was stirred under an argon atmosphere at ambient temperature for 6 hours. Acetic acid (0.4 ml) was added followed by sodium cyanoborohydride(l 70 mg). The mixture was then stirred for a further 20 hours when the sieves were removed by filtration. The filtrate was concentrated under reduced pressure and the residue applied to a silica column and eluted with ethyl acetate/hexane(20:80) to give (2S,4S)-1-allyloxycarbonyl-2[(naphthalen-1-ylamino )-methyl]-4-BOCsulfanylpyrrolidine (compound(31)) as a clear oil (560 mg).
Reaction SMILES: [N+:1]([O-:27])([O:3][CH2:4][C:5]1[N:9](C(=O)C)[C:8](=[O:13])[N:7]([C:14](=[O:16])[CH3:15])[C:6]=1[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:2].N1CCCCC1.O>C(OCC)C.C(OCC)(=O)C>[N+:1]([O-:27])([O:3][CH2:4][C:5]1[NH:9][C:8](=[O:13])[N:7]([C:14](=[O:16])[CH3:15])[C:6]=1[C:17](=[O:26])[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)=[O:2]
Reactant: COc1ccc(C(=O)c2c(CO[N+](=O)[O-])n(C(C)=O)c(=O)n2C(C)=O)cc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)c2c(CO[N+](=O)[O-])[nH]c(=O)n2C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold solution (10° C.) of 1.9 g of [1,3-diacetyl-4-(4-methoxybenzoyl)-1,3-dihydro-2-oxo-2H-imidazol-5-yl]-methyl nitrate in 30 ml of ethyl ether and 20 ml of ethyl acetate there is added a solution of 470 mg of piperidine in 10 ml of ethyl ether and the solution is stirred at 25° C. for 30 minutes. Water (30 ml) is added and the precipitate which forms is separated and recrystallized twice from ethyl acetate to give [1-acetyl-1,3-dihydro-5-(4-methoxybenzoyl)-2-oxo-2H-imidazol-4-yl]methyl nitrate melting at about 165°-166° C. with decomposition.
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O.O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CC1(O)Cc2ccccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=Cc2ccccc2C1
Temperature: 0 °C
Yield: 81.2 %

Procedure:
2-Methyl-2-indanol (66.2 g) was dissolved in toluene (500 ml) in a 1 liter flask equipped with a Dean-Stark trap. To this solution p-toluene sulfonic acid (2 g) and a small amount of hydroquinone were added, and the mixture was refluxed for 2.5 hours. After 8 ml of H2O was generated, the reaction mixture was cooled to 0° C. and H2O (1 liter), also cooled to 03C., was added. The organic phase was separated and washed three times with water (500 ml). The toluene was evaporated and the residue (with trace of hydroquinone added) was distilled at reduced pressure to give 2-methylindene (47.2 g, 48%) as clear slightly green liquid.