Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2C3C([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[CH:25]=2)=CC=CC=3)[CH:3]=1.C([Li])CCC.[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C.Cl.[CH3:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>ClCCl.C1COCC1>[CH:23]1[C:24]2[CH:25]=[C:12]([C:4]3[CH:5]=[C:6]([B:31]([OH:36])[OH:32])[C:7]4[C:2](=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:3]=3)[C:46]3[C:47](=[CH:48][CH:49]=[CH:50][CH:45]=3)[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: CCCCCC
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1cc(-c2cc3ccccc3c3ccccc23)cc2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: OB(O)c1cc(-c2cc3ccccc3c3ccccc23)cc2ccccc12
Temperature: -70 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
In argon atmosphere, a liquid mixture of 16.00 (41.74 mmol) of 4-bromo-2-(9-phenanthrenyl)naphthalene and 160 ml of dry THF was cooled to −70° C., and 32.2 ml (38.4 mmol) of a 1.56 M hexane solution of n-butyllithium was added dropwise under stirring. Further, the reaction mixture was stirred at −70° C. for 3 h. After adding 18.06 g (96.04 mmol) of triisopropyl borate while maintaining the temperature at −60° C. or lower, the mixture was stirred for one hour. The reaction mixture was heated, stirred at room temperature for 3 h, and left standing overnight. The reaction mixture was added with 50 ml of a concentrated hydrochloric acid while maintaining the temperature at 20° C. or lower by cooling on an ice bath and then stirred at room temperature for one hour. The reaction mixture was added with dichloromethane and allowed to separate into liquid phases. The organic phase was washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by distillation. After recrystallizing from toluene, 5.40 g (yield: 37%) of 2-(9-phenanthrenyl)naphthalene-4-boronic acid was obtained.
Reaction SMILES: [CH2:1]([C:4]1([N:17]([CH2:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:24]=2[CH:25]=[CH:26][N:27]3[S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:18](=[O:21])C=C)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[O:21]=[C:18]1[CH:3]=[CH:2][CH2:1][C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]2)[N:17]1[CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][N:27]2[S:32]([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: C=CCC1(N(Cc2cccc3c2ccn3S(=O)(=O)c2ccc(C)cc2)C(=O)C=C)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(CN4C(=O)C=CCC45CCN(C(=O)OC(C)(C)C)CC5)cccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of tert-butyl 4-allyl-4-(N-((1-tosyl-1H-indol-4-yl)methyl)acrylamido)piperidine-1-carboxylate (0.075 g, 0.13 mmol) in DCM (5.0 mL) was added Grubbs 2nd generation catalyst (0.006 g, 0.006 mmol) under argon and the reaction mixture was stirred at rt overnight. The dark brown solution was concentrated under reduced pressure and the crude product was purified by column chromatography (eluent: 25% ethyl acetate in hexane) to yield the title compound as a solid (0.060 g, 84%). LCMS RtA=0.523, [M+H]+=549.8
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.CN(C)[CH2:19][CH2:20]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[N:11]1([C:8]2[CH:7]=[C:3]([C:4]([O:6][CH2:19][CH3:20])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=2)[CH:15]=[CH:14][CH:13]=[CH:12]1
Reactant: O=C(O)c1cc(-n2cccc2)ccc1O
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-n2cccc2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
2-Hydroxy-5-(pyrrol-1-yl)benzoic acid (406 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-(pyrrol-1-yl)salicylate (170 mg, yield 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH2:7][C:8](=[O:22])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10](=O)[CH2:11][C:5]=2[CH:4]=1.[Cl-].[NH4+].O.ClCCl>C1COCC1>[CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH2:7][C:8](=[O:22])[N:9]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CN2C(=O)Cc3cc(OC)c(OC)cc3CC2=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN2C=Cc3cc(OC)c(OC)cc3CC2=O)cc1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1 g of LiBH(Et)3 (1.12 mmol, 1.33 eq, 1M solution in THF) is added to a solution of 7,8-dimethoxy-3-(4-methoxybenzyl)-1H-3-benzazepine-2,4(3H,5H)-dione (300 mg, 0.84 mmol) in THF (4.5 mL) at −78° C. The reaction mixture is held at that temperature for 1 hour 30 minutes with stirring and then hydrolysed with saturated aqueous ammonium chloride solution (4 mL). After a slow return to ambient temperature, 2 mL of water and 5 mL of dichloromethane are introduced, the aqueous phase is extracted with 10 mL of dichloromethane, and the organic phase is dried. The crude product obtained is purified by flash chromatography on a silica column (dichloromethane/methanol 98/2) to obtain the title product.
Reaction SMILES: Cl[CH2:2][C:3]([OH:5])=[O:4].[Br-:6].[Na+].S(=O)(=O)(O)O.[N+:13]([CH:16]([CH:19]([Br:21])[CH3:20])[CH2:17]O)([O-:15])=[O:14]>C1(C)C=CC=CC=1.O>[Br:6][CH2:2][C:3]([O:5][CH2:17][CH:16]([N+:13]([O-:15])=[O:14])[CH:19]([Br:21])[CH3:20])=[O:4]
Reactant: O=C(O)CCl
Reactant: [Br-]
Reactant: CC(Br)C(CO)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Br)C(COC(=O)CBr)[N+](=O)[O-]
Yield: 91.3 %

Procedure:
94.5g (1 mol) of chloroacetic acid, 132.6g (1.3 mol) of sodium bromide, 127.4g (1.3 mol) of c.-sulfuric acid, 100 ml of water, 198g (1 mol) of 2-nitro-3-bromo-n-butanol and 200g of toluene were used and treated in a similar way as described in Example 10. 291.2g of 2-nitro-3-bromo-n-butyl bromoacetate were obtained (91.3% yield of theory). Bp 130° C/ 0.3 mmHg, nD20 = 1.5060, D420 = 1.7876. 175g (98.9%) of potassium hydrogen sulfate was isolated.
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]1[CH2:23][CH2:22][N:7]2[CH2:8][C@@H:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[C:15]([C@@H:6]2[CH2:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[N+:24]([O-])([OH:26])=[O:25].C(Cl)(Cl)[Cl:29].[OH-].[Na+]>FC(F)(F)C(O)=O>[ClH:29].[ClH:1].[CH3:3][N:4]1[CH2:23][CH2:22][N:7]2[CH2:8][C@@H:9]([C:16]3[CH:17]=[CH:18][C:19]([N+:24]([O-:26])=[O:25])=[CH:20][CH:21]=3)[C:10]3[C:15]([C@@H:6]2[CH2:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: ClC(Cl)Cl
Reactant: O=[N+]([O-])O
Reactant: CN1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN2C[C@@H](c3ccc([N+](=O)[O-])cc3)c3ccccc3[C@@H]2C1
Reaction time: 2 h

Procedure:
To a stirred solution of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride (10.0 g, 0.0285 m) in trifluoroacetic acid (100 ml) maintained at 0° under nitrogen was added dropwise over a period of 30 minutes 90% nitric acid (25 ml). The mixture was stirred for 2 hours, then poured onto ice (1000 ml). Chloroform (200 ml) was added and the mixture basified to pH 11 with 50% NaOH. The layers were separated and the aqueous phase extracted with chloroform (2×200 ml). The combined chloroform extracts were washed with water (500 ml), dried over MgSO4, and evaporated to a yellow oil, 9.8 g. This was dissolved in methanol (200 ml), filtered, and the filtrate acidified with HCl gas. A white solid crystallized upon standing which was collected by filtration. This solid was recrystallized twice from methanol (200 ml) and water (10 ml) and vacuum dried at 95° for 24 hours to give 4.04 g of cis-1,3,4,6,7,11b-hexahydro-2-methyl-7-(4-nitrophenyl)-2H-pyrazino[2,1-a]isoquinoline dihydrochloride, m.p. 251°-252°.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:17]([CH2:35][C:36]1([C@H:39]2[CH2:43][C:42](=[O:44])[N:41]([C@H:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH3:46])[CH2:40]2)[CH2:38][CH2:37]1)[Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[CH2:5]([O:4][C:2]([CH:43]1[C:42](=[O:44])[N:41]([C@H:45]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH3:46])[CH2:40][C@H:39]1[C:36]1([CH2:35][O:17][Si:18]([C:31]([CH3:32])([CH3:34])[CH3:33])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:37][CH2:38]1)=[O:3])[CH3:6]
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](C2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)CC1=O
Reactant: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1C(=O)N([C@@H](C)c2ccccc2)C[C@H]1C1(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
Ethyl chloroformate (0.059 mL, 0.617 mmol) and a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 0.57 mL, 0.570 mmol) were sequentially added dropwise to a solution of (3R)-3-[1-(tert-butyldiphenylsiloxymethyl)cyclopropan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidine (258 mg, 0.518 mmol) in tetrahydrofuran (2 mL) at 0° C. over two minutes. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes, and a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 0.57 mL, 0.570 mmol) was further added. The mixture was stirred at room temperature for 2.5 hours and then ice-cooled. The reaction was quenched with a 10% citric acid solution (20 mL). The resulting mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (20 mL) and brine (20 mL) and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. Then, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4→1:2) to give 227 mg (77%) of the title compound as a colorless transparent gummy solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]=[CH:4][CH:3]=1.[C:7]([OH:11])(=[O:10])C=C.[CH2:12](C(C)=O)[CH3:13]>>[CH3:1][C:2]12[CH2:6][CH:5]([CH:12]=[CH:13]1)[CH2:4][CH:3]2[C:7]([OH:11])=[O:10]
Reactant: CCC(C)=O
Reactant: C=CC(=O)O
Reactant: CC1=CC=CC1
Product: CC12C=CC(CC1C(=O)O)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methylcyclopentadiene (8.01 g: 100 mmol) was dissolved in methyl ethyl ketone (10 mL), to which acrylic acid (7.93 g: 110 mmol) was added dropwise at 0° C. over 1 hour. The thus-obtained mixture was stirred at room temperature for 3 hours. Light components, such as the solvent and unreacted acrylic acid, were then distilled off under reduced pressure from the reaction mixture, whereby methyl-5-norbornene-2-carboxylic acid (14.9 g: 98 mmol) was obtained.
Reaction SMILES: [C]=O.C=C=[O:5].N([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=O.C(OCCCCCC)(=O)[CH2:16][C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:18]>>[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:18])[C:16]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:5]
Reactant: CCCCCCON=O
Reactant: CCCCCCOC(=O)CC(=O)OCCCCCC
Reactant: C=C=O
Agent: [C]=O
Product: CCCCCCOC(=O)C(=O)OCCCCCC

Procedure:
Using the same reaction tube and catalyst as in Example 1, a gaseous mixture consisting of carbon monoxide, ketene, n-hexyl nitrite and nitrogen (55:0.8:6.7:37.5, volume ratio) was introduced into the reaction tube at a rate of 39.6 l./hr. and the reaction was conducted at a temperature of 120° C. under ordinary pressure. After reaction, the reaction product was analyzed by gas chromatography. As the result, it was found that di-n-hexyl malonate was produced at a rate of 24 g/l·(catalyst)·hr. and di-n-hexyl oxalate was produced as a by-product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+].[N+:21]([C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)[CH2:27][OH:28])([O-:23])=[O:22]>CN(C=O)C>[N+:21]([C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)[CH2:27][O:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Reactant: OCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(COCCCCCCCCCCCCO)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
5.9 g (18.9 mmol) of 12-bromododecanol, 1.06 g (10 mmol) of sodium carbonate, 4.92 g of (25 mmol) of 3,5-dinitrobenzyl alcohol were dissolved in 50 mL of DMF and heated with stirring at 100° C. for 12 hours (under a nitrogen atmosphere). The reaction solution was poured into ice water to precipitate a solid, and the solid was recrystallized with methanol. Thus, 5.73 g (15 mmol) of 12-(3,5-dinitrobenzyloxy)-dodecanol was prepared. (The yield was 79%.)
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[CH:42][CH:41]=4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:41]=[CH:42][C:43]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)=[CH:44][CH:45]=4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: OCCO
Product: COC1=C(C)C(c2ccc(-c3ccccc3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 60 ml), 1-(1H-Benzo[d]imidazol-6-yl)-3-hydroxy-4-methyl-5-(biphen-4-yl)-1H-pyrrol-2(5H)-one (1 g, 2.63 mmol, 1 eq) and MeOH (20 ml); yield 0.070 g (17.7%); MS m/z: 396.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.39 (s, 1H), 8.14 (s, 1H), 7.76-7.72 (m, 1H), 7.59-7.28 (m, 11H), 5.88 (s, 1H), 3.96 (s, 3H), 1.75 (s, 3H); HPLC (METHOD [A]): rt 14.00 min (98.38%)
Reaction SMILES: [CH3:1][C@@H:2]1[C:31]([CH3:33])([CH3:32])[O:30][C@@:4]2([O:8][C@H:7]3[CH2:9][C@H:10]4[C@@H:15]5[CH2:16][CH2:17][C@H:18]6[CH2:23][C@H:22]([OH:24])[CH2:21][CH2:20][C@:19]6([CH3:25])[C@H:14]5[C@@H:13]([OH:26])[CH2:12][C@:11]4([CH3:27])[C@H:6]3[C@:5]2([OH:29])[CH3:28])[CH2:3]1.[CH3:34][C@@H:35]1[C:64]([CH3:66])([CH3:65])[O:63][C@:37]2([O:41][C@H:40]3[CH2:42][C@H:43]4[C@@H:48]5[CH2:49][CH2:50][C@H:51]6[CH2:56][C@H:55]([OH:57])[CH2:54][CH2:53][C@:52]6([CH3:58])[C@H:47]5[C@@H:46]([OH:59])[CH2:45][C@:44]4([CH3:60])[C@H:39]3[C@:38]2([OH:62])[CH3:61])[CH2:36]1>>[CH3:1][C@@H:2]1[C:31]([CH3:32])([CH3:33])[O:30][C@@:4]2([O:8][C@H:7]3[CH2:9][C@H:10]4[C@@H:15]5[CH2:16][CH2:17][C@H:18]6[CH2:23][C@H:22]([OH:24])[CH2:21][CH2:20][C@:19]6([CH3:25])[C@H:14]5[C:13](=[O:26])[CH2:12][C@:11]4([CH3:27])[C@H:6]3[C@:5]2([OH:29])[CH3:28])[CH2:3]1.[CH3:34][C@@H:35]1[C:64]([CH3:65])([CH3:66])[O:63][C@@:37]2([O:41][C@H:40]3[CH2:42][C@H:43]4[C@@H:48]5[CH2:49][CH2:50][C@H:51]6[CH2:56][C:55](=[O:57])[CH2:54][CH2:53][C@:52]6([CH3:58])[C@H:47]5[C:46](=[O:59])[CH2:45][C@:44]4([CH3:60])[C@H:39]3[C@:38]2([OH:62])[CH3:61])[CH2:36]1
Reactant: C[C@H]1C[C@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@H](O)CC[C@]6(C)[C@H]5[C@@H](O)C[C@]4(C)[C@H]3[C@@]2(C)O)OC1(C)C
Reactant: C[C@H]1C[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@H](O)CC[C@]6(C)[C@H]5[C@@H](O)C[C@]4(C)[C@H]3[C@@]2(C)O)OC1(C)C
Product: C[C@H]1C[C@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6CC(=O)CC[C@]6(C)[C@H]5C(=O)C[C@]4(C)[C@H]3[C@@]2(C)O)OC1(C)C
Product: C[C@H]1C[C@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@H](O)CC[C@]6(C)[C@H]5C(=O)C[C@]4(C)[C@H]3[C@@]2(C)O)OC1(C)C
Yield: 45 %
Yield: 40 %

Procedure:
Oxidation of epihippuristanol (10) to give epihippuristanol 11-one (13) and epihippuristanol 3,11-dione (14). Epihippuristanol (10, 31.4 mg) was oxidized in the same fashion as described above for hippuristanol (1). The crude product was separated by TLC (CHCl3/EtOAc, 1:1, v/v) to give 12.6 mg of epihippuristanol 11-one (13, 40%) and 14.0 mg of epihippuristanol 3,11-dione (14, 45%). Epihippuristanol 3,11-dione (14). white crystals, mp 226-229° C.; 1H NMR (CDCl3) δ 4.48 (brq, J=7.0 Hz, 1H), 2.82 (ddd, J=13, 6.5, 2 Hz, 1H), 2.57 (d, J=12 Hz, 1H), 2.45 (dt, J=6.5, 14 Hz, 1H), 1.30 (s, 3H), 1.28 (s, 3H), 1.22 (s, 3H), 1.08 (s, 3H), 0.98 (s, 3H), 0.94 (d, J=7 Hz, 3H); 13C NMR (CDCl3) δ 211.4, 209.9, 118.6, 84.5, 81.9, 79.0, 64.1, 63.2, 58.2, 55.8, 47.0, 45.9, 44.3, 41.0, 39.6, 38.0, 37.1, 35.8 (2C), 35.3, 32.3, 31.5, 29.0, 28.2, 26.0, 23.0, 17.6, 14.0, 11.1; IR (KBr) 3450, 1700 cm−1; EIMS m/z 458 (M+, 6), 443 (16), 400 (7), 330 (32), 315 (100%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C1(C)C=CC=CC=1>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:1]([C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)([CH3:3])[CH3:2])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: C=C(C)c1ccc(O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 134.0 grams (1.0 mole) of p-isopropenylphenol and 186.0 grams (2.0 moles) of aniline was stirred and heated to 150° C. To the mixture was added 5.0 grams of a solution obtained by adding 1.28 grams of 10% hydrochloric acid to 93 grams of aniline and stirring the mixture well. The reaction was carried out for 3.0 hours (10,800 s) at the 150° C. reaction temperature. The reaction product was cooled to 120° C. then 350 milliliters of toluene was added. The product was then cooled to 25° C. and the solid precipitated product was recovered by filtration. The crude product was slurried into 350 milliliters of methanol and heated to a reflux then maintained for 15 minutes (900 s). After cooling, the product was recovered by filtration and dried under vacuum to yield 4-(1-(4-aminophenyl)-1-methylethyl)phenol as a white powder. B. Synthesis of a Phenolic Functional Maleimide
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:8][N:9]=1)[C:5]#[N:6].Cl[CH:20](OCC)[CH2:21]Cl>CCOC(C)=O>[Cl:18][C:3]1[C:2]2[N:9]([CH:20]=[CH:21][N:1]=2)[CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:4]=1[C:5]#[N:6]
Reactant: CCOC(Cl)CCl
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cnc(N)c1Cl
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1Cl
Temperature: 150 °C
Yield: 59.4 %

Procedure:
In a sealed tube, a mixture of 2-amino-3-chloro-5-(2,4-dichloro-phenyl)-isonicotinonitrile (285 mg, 0.96 mmol) and 1,2-dichloro-1-ethoxy-ethane (0.64 mL, 5.25 mmol) was heated at 150° C. for 17 min under microwave irradiation. The reaction mixture was cooled to RT, poured into AcOEt (75 mL) and washed with a 2.0 M Na2CO3 solution in water (2×25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5→3:7) to yield the title compound (185 mg, 0.57 mmol, 60%) as a brownish solid. MS: 322 [M+1]+; HPLC: AtRet=2.17; TLC: RF 0.13 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=2)=[N:11][CH:12]=1.C(N(C(C)C)C(C)C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:21][CH:22]=2)=[N:11][CH:12]=1
Reactant: OCc1ccc(CCC#Cc2ccc(Br)cn2)cc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Brc1ccc(C#CCCc2ccc(CN3CCOCC3)cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
36 μL (0.46 mmol) methanesulphonic acid chloride are added to a solution, cooled to 0° C., of 120 mg (0.38 mmol) {4-[4-(5-bromo-pyridin-2-yl)-but-3-ynyl]-phenyl}-methanol (Example 2.20a) in 5 mL DCM. A solution of 78 μL (0.46 mmol) ethyldiisopropylamine in 1 mL DCM is slowly added dropwise, the mixture is stirred for a further 30 min at 0° C., then 80 μL (0.92 mmol) of morpholine are added, the mixture is allowed to come up to RT and kept at RT for 2 h. The mixture is evaporated down i.vac., the residue is combined with 20 mL EtOAc and 10 mL water, acidified with 1 M HCl and the phases are separated. The aqueous phase is combined with 2 M Na2CO3 solution, extracted with 20 mL EtOAc and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH2:13])[CH2:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][C:23](=[O:25])[CH3:24])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CC(N)CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(NC(C)=O)CC2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 7-methoxy-1,2,3,4-tetrahydronapthalen-2-ylamine (2.54 g; 14.3 mmol) in CH2Cl2 (20 mL) was added DIEA (3.4 mL) and the reaction mixture was cooled to 0° C. Acetyl chloride (1.22 mL; 17.1 mmol) was added dropwise at 0° C. and the reaction was allowed to warm to room temperature, then stirred for 18 h. The reaction mixture was diluted with CH2Cl2, washed with H2O, dried over Na2SO4, filtered and the solvent removed under reduced pressure to yield a crude solid. Purification by flash chromatography (SiO2) eluting with hexanes-EtOAc yielded N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:34])[C:8]2=[O:35])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[C:38]([N:31]1[CH2:30][CH2:29][N:28]([C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:16]3[CH:15]=[C:14]([Cl:34])[C:13]([CH2:12][CH:9]4[CH2:10][CH2:11][N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:8]4=[O:35])=[C:18]([Cl:19])[CH:17]=3)=[CH:25][CH:24]=2)=[O:27])[CH2:33][CH2:32]1)(=[O:40])[CH3:39]
Reactant: O=C(c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1)N1CCNCC1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)c2ccc(-c3cc(Cl)c(CC4CCN(C5CCCCC5)C4=O)c(Cl)c3)cc2)CC1
Yield: 73.9 %

Procedure:
Dissolve racemic 1-cyclohexyl-3-[3,5-dichloro-4′-(piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-pyrrolidin-2-one (0.082 g, 0.158 mmol) in dichloromethane (5 mL), add 1.0 N sodium hydroxide solution (0.5 mL) and acetyl chloride (0.020 mL, 0.281 mmol). Stir the mixture, sealed, overnight at room temperature. Dilute reaction with dichloromethane (20 mL) and wash with 1.0 N sodium hydroxide (10 mL) then brine (5 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with a gradient (100%) dichloromethane to 5% ammonia methanol/95% dichloromethane to obtain 0.065 g (74%) of product as a white foam: MS (m/z): 556 (M+).