Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3([C:17]([F:20])([F:19])[F:18])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:35]>C(O)(C(F)(F)F)=O.CO.CCOCC>[ClH:35].[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]4([C:17]([F:18])([F:19])[F:20])[CH2:16][CH2:15]4)=[O:13])[C:4]=23)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4(C(F)(F)F)CC4)c23)C1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4(C(F)(F)F)CC4)c23)C1
Yield: 94 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(1-(trifluoromethyl)cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (65 mg, 0.12 mmol) in TFA (5 mL) was stirred at room temperature for 1.5 hours and concentrated in vacuo. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 12M column, 3-65% CH3CN/water gradient; 14 CV). The residue obtained was dissolved in minimal methanol, and 2N HCl in ether was added. The precipitate formed was filtered and dried under high vacuum to yield (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(trifluoromethyl)cyclopropanecarboxamide hydrochloride (58 mg, 94% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.97 (br s, 1H), 9.32 (s, 1H), 8.39 (s, 2H), 8.27 (s, 1H), 7.63 (s, 1H), 3.50-3.22 (m, 4H), 3.15-3.04 (m, 1H), 2.20-2.10 (m, 1H), 1.90-1.78 (m, 1H), 1.76-1.46 (m, 4H), 1.36-1.44 (m, 2H); LCMS (APCI+) m/z 429.2, 446.1, 448.0 (M+H)+, Retention time=2.07 minutes (Method 3).
Reaction SMILES: C(O)[C@H]1O[C@H]([O:8][C@:9]2(CO)[O:13][C@H:12](CO)[C@@H:11](O)[C@@H:10]2O)[C@H](O)[C@@H](O)[C@@H]1O.[CH3:24][C:25](OCC1CS[C@@H]2[C@H](NC(/C(/C3N=C(N)SC=3)=N\OC)=O)C(=O)N2C=1C([O-])=O)=O.[Na+].[CH2:55]1[C@H:60](N)[C@@H:59](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H:58](O)[C@@H:57](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H:56]1[NH2:87].C(NC1N=C2C(NC=N2)=CN=1)C1C=CC=CC=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[NH:87]1[C:56]2[C:57](=[CH:58][CH:59]=[CH:60][CH:55]=2)[CH:25]=[C:24]1[CH:10]([CH2:11][CH3:12])[C:9]([OH:8])=[O:13]
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: c1ccc(CNc2ncc3[nH]cnc3n2)cc1
Product: CCC(C(=O)O)c1cc2ccccc2[nH]1
Reaction time: 0.12 h

Procedure:
To produce transgenic oilseed rape plants binary vectors in Agrobacterium tumefaciens C58C1-pGV2260 or Escherichia coli were used (Deblaere et al, 1984, Nucl. Acids. Res. 13, 4777-4788). For transforming oilseed rape plants (var. Drakkar, NPZ Nordeutsche Pflanzenzucht, Hohenlieth. Germany) a 1:50 dilution of an overnight culture of a positively transformed agrobacteria colony in Murashige-Skoog medium (Murashige and Skoog 1962 Physiol. Plant. 15, 473) containing 3% of saccharose (3MS medium) was used. Petioles or hypocotyledons of freshly germinated sterile rape plants (approx. 1 cm2 each) were incubated in a Petri dish with a 1:50 agrobacteria dilution for 5-10 minutes. This was followed by 3-day concubation in darkness at 25_C on 3MS medium containing 0.8% of Bacto-Agar. After three days, culturing was continued with 16 hours of light/8 hours of darkness and in a weekly cycle on MS medium containing 500 mg/l of Claforan (sodium cefotaxime), 50 mg/l of kanamycin, 20 microM of benzylaminopurine (BAP) and 1.6 g/l of glucose. Growing shoots were transferred onto MS medium containing 2% of saccharose, 250 mg/l of Claforan and 0.8% of Bacto-Agar. If after three weeks no roots had formed 2-indolylbutyric acid was added to the medium as a growth hormone for rooting purposes.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([NH:24][C:7]1[C:2]([Br:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=[C:5]([NH2:11])[N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: NCc1ccccc1
Solvent: C1COCCO1
Product: Nc1nc(NCc2ccccc2)c(Br)c(-c2ccco2)n1
Temperature: 100 °C
Yield: 71.1 %

Procedure:
To a stirred suspension of 200 mg (0.66 mmol) 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine in 5 ml dioxane was added 0.16 ml (1.46 mmol) benzylamine and the mixture heated at 100° C. for 2 hour. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in ether/hexane afforded 162 mg (71%) N4-benzyl-5-bromo-6-furan-2-yl-pyrimidine-2,4-diamine as a white crystalline solid. EI-MS m/e (%): 346 (M{81Br}+, 50), 344 (M{79Br} +51), 265 (46), 106 (100), 91 (61).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[C:40]1([CH2:46][S:47](Cl)(=[O:49])=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:2])=[O:39])=[CH:9][CH:8]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:47]([CH2:46][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:49])=[O:48])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: O=C(O)c1ccc(NCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 72 %

Procedure:
The intermediate from step 12 was treated with α-toluenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 72% yield.
Reaction SMILES: [C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[CH:8]=2)[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:25]([O:27]C)Cl.O>C(Cl)Cl.[N+](C)([O-])=O>[C:1]1([C:7]2[NH:19][C:10]3=[C:11]4[C:16](=[CH:17][CH:18]=[C:9]3[C:8]=2[CH:25]=[O:27])[CH:15]=[N:14][CH:13]=[CH:12]4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc3ccc4cnccc4c3[nH]2)cc1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: C[N+](=O)[O-]
Product: O=Cc1c(-c2ccccc2)[nH]c2c1ccc1cnccc12
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 2-phenyl-1H-pyrrolo[2,3-f]isoquinoline XIXA (2.75 mmol) in DCM (13 mL) and nitromethane (13 mL), cooled to 0° C., aluminum chloride (8.25 mmol) and dichloromethylmethylether (5.5 mmol) were added dropwise. The mixture was kept at 4° C. overnight and poured dropwise into stirred ice-cooled water. The solid product was filtered and the layers were separated. The aqueous layer was extracted with DCM and AcOEt. The combined organic layers, washed with water, dried (Na2SO4) and concentrated, were joined to the previously described solid affording the title compound in 51% yield. ESI (+) MS: m/z 273 (MH+). 1H NMR: 7.66-7.71 (m, 3H), 7.91-7.96 (m, 2H), 8.19 (d, J=8.79, 1H), 8.71 (d, J=8.55, 1H), 8.79 (d, J=6.35, 1H), 8.93 (d, J=6.35, 1H), 9.77 (s, 1H), 10.12 (s, 1H), 13.80 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:19])=[C:12]3[S:18][CH:17]=[CH:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:29][CH3:30].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:19])[C:12]3[S:18][CH:17]=[CH:16][C:13]=3[N:14]([CH2:29][CH3:30])[CH:15]=2)=[O:9])=[CH:20][CH:21]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccsc2c1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sccc21
Temperature: 100 °C

Procedure:
N-(4-chlorobenzyl)-7-hydroxythieno[3,2-b]pyridine-6-carboxamide (Example 1, 885 mg)was dissolved in DMF (20 mL) and to the solution was added potassium carbonate (1.92 g) and iodoethane (1.1 mL). The mixture was heated to 100° C. for 16 h. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3×25 mL) followed by brine (25 mL), dried (MgSO4), and concentrated. The crude product was purified by column chromatography (EtOAc/heptane, 1/1; CH2Cl2/methanol, 100/1) and the resulting solid was recrystallized from ethanol to afford 590 mg of the title compound as a white solid.
Reaction SMILES: COC1C=C(C2C=C(N)NN=2)C=CC=1.C(N(C(C)C)CC)(C)C.Br[CH2:25][CH2:26][CH2:27][C:28]([NH:30][C:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=2)[NH:33][N:32]=1)=[O:29].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CC(N(C)C)=O.C(Cl)Cl>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([C:34]2[NH:33][N:32]=[C:31]([NH:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:35]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: C1COCCN1
Reactant: COc1cccc(-c2cc(NC(=O)CCCBr)n[nH]2)c1
Agent: COc1cccc(-c2cc(N)[nH]n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cccc(-c2cc(NC(=O)CCCN3CCOCC3)n[nH]2)c1
Temperature: 60 °C

Procedure:
A solution of 4-bromobutyryl chloride chloride (0.104 mL, 0.9 mmol) in dry DMA (1 mL) was cooled to −10° C. (ice/water bath) under N2; 5-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine (170 mg, 0.9 mmol) and diisopropylethylamine (0.315 mL, 1.8 mmol) in dry DMA (1 ml) were added. Upon complete conversion to the intermediate 4-bromo-N-[5-(3-methoxy-phenyl)-1H-pyrazol-3-yl]-butyramide (as monitored by LC-MS), morpholine (0.079 mL, 0.9 mmol) was added and the mixture was heated at 60° C. for 16 hours. The residue was dissolved in DCM (2 mL) and washed with sat. Na2CO3 solution, The organic phase was concentrated under reduced pressure and the crude product was purified by SiO2 column (gradient from Acetonitrile 100% to MeCN/MeOH, NH3 90/10). The fractions containing the title compound were collected to afford 17 mg (5.5% of yield).
Reaction SMILES: [CH:1]([C:4](=[N:6][OH:7])[NH2:5])([CH3:3])[CH3:2].[O-]CC.[Na+].[CH3:12][N:13]1[CH2:18][C:17]([C:19]([O:21]C)=O)=[CH:16][CH2:15][CH2:14]1.Br.[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)C>[C:24]([O-:29])(=[O:28])[C:25]([O-:27])=[O:26].[CH3:12][NH+:13]1[CH2:14][CH2:15][CH:16]=[C:17]([C:19]2[O:7][N:6]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[CH2:18]1.[CH3:12][NH+:13]1[CH2:14][CH2:15][CH:16]=[C:17]([C:19]2[O:21][N:6]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[CH2:18]1
Reactant: CC(C)C(N)=NO
Reactant: O=C(O)C(=O)O
Reactant: COC(=O)C1=CCCN(C)C1
Agent: Br
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1noc(C2=CCC[NH+](C)C2)n1
Product: O=C([O-])C(=O)[O-]
Temperature: 80 °C
Yield: 37 %

Procedure:
816 mg(8.0 mmol) of isopropylcarboxamide oxime was added to a solution of sodium ethoxide (7.8 mmol) in 20 ml of distilled ethanol and 5 g molecular sieves. The mixture was stirred at room temperature for 10 min whereafter 1.0 g(4.23 mmol) of arecoline, HBr was added. The mixture was heated at 80° C. for 12 hours, filtered, and evaporated in vacuo. 10 ml of water was added to the residue and the mixture was extracted with ether (3×50 ml). The combined extracts were dried with MgSO4 and evaporated in vacuo. The residue was dissolved in 5 ml of 99.9% ethanol and a solution of 380 mg(4.23 mmol) of oxalic acid in 10 ml of 99.9% ethanol was added. Crystallization from ether gave the title compound in 37% yield. M.P. 133°-134° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]([O:19][CH3:20])=[O:18])[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:9]=1[O:10]C)([CH3:3])[CH3:2].B(Br)(Br)Br.C(OCC)C.CCCCCC>ClCCl>[CH3:20][O:19][C:17](/[CH:16]=[CH:15]/[C:6]1[CH:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1)=[O:18]
Reactant: COC(=O)C=Cc1cc(C(C)C)c(OC)c(C(C)C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)/C=C/c1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 72.5 %

Procedure:
Methyl 3-(3,5-diisopropyl-4-methoxyphenyl)acrylate (610 mg) and boron tribromide (10 mL) were combined in dichloromethane (10 mL) and the mixture was allowed to stir at 0° C. for 5 hours. The reaction was quenched with water and extracted with dichloromethane. The organics were washed (brine), dried (sodium sulfate), filtered, and condensed. Chromatography, with ethyl ether:hexane (gradient 10:90 to 20:80) as the eluent, provided material that was recrystallized from hexane to give the title compound as a white solid (420 mg); 1H-NMR (CDCl3) δ=1.28 (d, 12H, CH(CH3)2), 3.16 (m, 2H, CH(CH3)2), 3.80(S, 3H, OCH3), 5.10 (S, 1H, OH), 6.32 (d, 2H, CH═CH), 7.24 (S, 2H, Ar—H), 7.66 (d, 2H, CH═CH).
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH:10]=O.[Cl-].[NH4+].C(OCC)C>CN(C)C=O.BrCBr.[Zn]>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH:10]=[CH2:1]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: BrCBr
Solvent: CCOCC
Product: C=Cc1cc(OC)cc(OC)c1
Reaction time: 0.25 h
Yield: 373.9 %

Procedure:
Zinc powder (purity; 85%, 14.75 g) is suspended in N,N-dimethylformamide (50 ml) under argon atmosphere, and thereto is added dropwise with stirring acetyl chloride (1.06 g) at 50° C. over a period of 10 minutes, and then the mixture is stirred for 15 minutes. To the mixture is added dropwise a solution of 3,5-dimethoxybenzaldehyde (10 g) in dibromomethane (15.69 g) over a period of 20 minutes, and the mixture is stirred for 30 minutes. The reaction solution is cooled with ice, and thereto is added dropwise a saturated aqueous ammonium chloride solution (40 ml), and further thereto is added diethyl ether. The insoluble materials are removed by filtration, and the filtrate is extracted with diethyl ether. The extract is washed successively with 10% hydrochloric acid, water, 10% aqueous sodium hydroxide solution, and a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure to give 3,5-dimethoxystyrene (8.29 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:19]=[C:18]([F:20])[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][C:3]=1[O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(F)cc2F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Oc2cc([N+](=O)[O-])c(F)cc2F)cc1
Temperature: 0 °C
Yield: 63 %

Procedure:
In 16.ml of concentrated sulfuric acid, 3.29 g (11.8 mmol) of ethyl 4-(2,4-difluorophenoxy)benzoate was dissolved at the temperature not higher than 5° C. To the resulting mixture, 520 pl of fuming nitric acid was added at -5° C. or lower under stirring, followed by stirring for 30 minutes at the same temperature. The reaction mixture was poured into ice water and the insoluble matter so precipitated was collected by filtration. The resulting compound was dissolved in chloroform. The resulting solution was washed successively with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (developing solvent: hexane:ethyl acetate=8:1) to give 2.42 g (63%) of ethyl 4-(2,4-difluoro-5-nitrophenoxy)benzoate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=O)[C:14]=2[C:22]([OH:24])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:26][CH:27]1[CH2:33][CH2:32][C:31](=[O:34])[NH:30][C:28]1=[O:29]>N1C=CC=CC=1>[O:29]=[C:28]1[CH:27]([N:26]2[C:22](=[O:24])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][C:13]=3[NH:12][C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[C:16]2=[O:18])[CH2:33][CH2:32][C:31](=[O:34])[NH:30]1
Reactant: NC1CCC(=O)NC1=O
Reactant: CCOc1cc(Nc2cccc(C(=O)O)c2C(=O)O)ccc1OC
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1cc(Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)ccc1OC
Yield: 67 %

Procedure:
A mixture of 3-(3-ethoxy-4-methoxyphenylamino)phthalic acid (0.85 g, 2.6 mmol) and rac-α-aminoglutarimide hydrochloride (0.43 g, 2.6 mmol) in pyridine (10 mL) was heated to reflux for 16 hours. The mixture was cooled and evaporated under vacuum. The residue was dissolved in ethyl acetate (150 mL), washed with dilute aqueous HCl (2×100 mL) and water (2×100 mL), and evaporated. The residue was chromatographed in 95:5 methylene chloride-methanol, eluting 0.72 g of the product, in 67% yield: mp 162-164° C.; 1H NMR (CDCl3) δ 1.46 (t, J=7.0 Hz, 3H), 2.11-2.18 (m, 1H), 2.72-2.94 (m, 3H), 3.89 (s, 3H), 4.06 (q, J=7.0 Hz, 3H), 4.96 (dd, J=12.0 Hz, J=5.0 Hz, 1H), 6.76-6.89 (m, 3H), 7.14-7.19 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 7.86 (s, 1H), 8.43 (s, 1H); 13C NMR (CDCl3) δ 14.7, 22.8, 31.4, 49.0, 56.2, 64.5, 109.9, 110.8, 112.1, 113.1, 116.4, 118.5, 131.7, 132.4, 135.9, 145.2, 147.4, 149.1, 167.5, 168.4, 169.4, 171.1; Anal. calcd for C22H21N3O6: C, 62.41; H, 5.00; N, 9.92. Found: C, 62.16; H, 4.89; N, 9.72.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1.Cl.[CH:23](O)([CH3:25])[CH3:24]>>[CH:23]([O:12][C:11](=[O:13])[CH:10]([O:9][C:8]1[CH:15]=[CH:16][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=2[Cl:1])=[CH:6][CH:7]=1)[CH3:14])([CH3:25])[CH3:24]
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)O
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Reaction time: 8 h

Procedure:
55 g of 4-(2',4'-dichlorophenoxy)-α-phenoxy-propionic acid were suspended in 500 ml of isopropanol. While stirring, hydrogen chloride was fed in, whereupon the temperature rose to about 50° C. While the feed of hydrogen chloride was continued, the suspension was refluxed for 5 hours and the reaction mixture was then allowed to stand overnight. After the excess alcohol had been distilled off, the solution was poured on water and then extracted with methylene chloride. The methylene chloride extract was washed with dilute bicarbonte solution and then twice with water and dried over sodium sulfate. After filtration the solution was concentrated and then distilled under greatly reduced pressure. 34 g of 4-(2',4'-dichlorophenoxy)-α-phenoxy-propionic acid isopropyl ester were obtained, boiling point 182°-185° C. under a pressure of 0.04 mm mercury.
Reaction SMILES: C(=O)([O-])O[C:3]1[CH:8]=[CH:7][C:6]([N+]([O-])=O)=[CH:5][CH:4]=1.Cl.C[Si](C)(C)C[CH2:18][O:19][C:20]([N:22]1CCC(C2C=CC=C(CN)C=2)CC1)=[O:21].CN([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)C.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:20](=[O:21])([O:19][CH2:18][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH:45]2[CH2:46][CH2:41][NH:42][CH2:43][CH2:44]2)[CH:8]=1)[NH2:22]
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(c2cccc(CN)c2)CC1
Reactant: CN(C)c1ccccn1
Reactant: O=C([O-])Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)OCc1cccc(C2CCNCC2)c1
Reaction time: 0.25 h

Procedure:
p-Nitrophenyl carbonate Wang resin (11.00 g, 15 mmol) and anhydrous dimethylformamide (100 ml) were placed in a peptide synthesis vessel and the resin was allowed to swell for 15 minutes. This was then treated with 4-(3-aminomethyl-phenyl)-piperidine-1-carboxylic acid 2-trimethylsilanyl-ethyl ester hydrochloride (7.50 g, 21 mmol) in 50 ml dimethylformamide, dimethylaminopyridine (0.72, 6 mmol) and diisopropylethyl-amine. The peptide vessel was shaken at room temperature for 24 hours, then washed thoroughly with dimethylformamide (×5), methanol (×2), dimethylformamide (×2), methanol (×2), dichloromethane (×3), methanol (×2), dichloromethane (×2), methanol (×3), and dried. The resin was then treated with tetrahydrofuran to swell the resin and then allowed to drain. Then anhydrous tetrahydrofuran (100 ml) and tetrabutylammonium fluoride (75 ml, 1M in tetrahydrofuran) were added and the resin shaken for 18 hours. The resin was drained and washed with tetrahydrofuran (×5), methanol (×3), dichloromethane (×3), methanol (×3), dichloromethane (×3), methanol (×3) and dried to give (3-piperidin-4-yl-benzyl) carbamate Wang resin (12.30 g).
Reaction SMILES: Br[C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22].[NH4+:23].[OH-]>O1CCOCC1>[NH2:23][C:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]=1[CH:4]=[CH:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C:10]2=[O:22]
Reactant: [NH4+]
Reactant: C[C@]12CCC(=O)C(Br)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@]12CCC(=O)C(N)=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 75 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 4-bromoandrosta-4,6-diene-3,17-dione (545 mg, 1.5 mmole), dioxane (15 ml) and 30% NH4OH aqueous solution (30 ml) is stirred at 75° C. in a pressure vessel during 8 hours. After cooling to room temperature, the reaction mixture is worked up as described in the Example I. There are obtained 126 mg (0.42 mmole, 28% yield) of the title compound as a yellowish solid.
Reaction SMILES: [OH-:1].[Na+].Br[C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][C:6](Br)([CH2:7]3)[CH2:5]1)[CH2:11]2.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br-].[Br-].[Br-].[Al+3]>>[OH:21][C:15]1[CH:20]=[CH:19][C:18]([C:4]23[CH2:13][CH:8]4[CH2:9][CH:10]([CH2:12][C:6]([C:4]5[CH:13]=[CH:8][C:7]([OH:1])=[CH:6][CH:5]=5)([CH2:7]4)[CH2:5]2)[CH2:11]3)=[CH:17][CH:16]=1
Reactant: Oc1ccccc1
Reactant: BrC12CC3CC(C1)CC(Br)(C3)C2
Reactant: [OH-]
Agent: [Al+3]
Agent: [Br-]
Agent: [Na+]
Product: Oc1ccc(C23CC4CC(C2)CC(c2ccc(O)cc2)(C4)C3)cc1
Temperature: 60 °C

Procedure:
A 500 ml five-necked flask equipped with a thermometer, a stirrer, a reflux condenser, an inlet for nitrogen gas and a discharge pipe connected to a trap containing a 30% by weight aqueous solution of sodium hydroxide was cooled in an ice bath. Into the flask, 6.47 g (0.022 moles) of 1,3-dibromoadamantane, 200 ml of phenol and 2.6 g (0.01 mole) of aluminum tribromide were placed. The resultant mixture was stirred at 0° C. for 6 hours and, then, the reaction was allowed to proceed under heating at 60° C. for 4 hours. The reaction product was poured into 2,000 liters of acidic ice water. After the ice melted, an organic layer was taken out, washed with pure water and a saturated aqueous solution of sodium chloride and poured into methanol to separate the product. The obtained product was dried under a reduced pressure, and 3.5 g of a product was obtained.