Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][C@H:45]1[CH:50]2[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:47]12[CH2:52][CH2:51][CH:50]([CH2:49][CH2:48]1)[C@H:45]([NH:44][C:17]([C:15]1[CH:16]=[C:2]([OH:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:46]2
Reactant: O=C(O)c1cc(O)cc2oc(-c3ccccc3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc(O)cc2oc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
A mixture of 6-hydroxy-2-phenylbenzoxazole-4-carboxylic acid (104 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (87 mg, 0.44 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.20 mL, 1.4 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford (S)—N-(1-azabicyclo[2.2.2]oct-3-yl)-6-hydroxy-2-phenylbenzoxazole-4-carboxamide (29 mg, 30%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 10.22 (br s, 1H), 9.29 (d, J=7.4 Hz, 1H), 8.17-8.13 (m, 2H), 7.67-7.63 (m, 3H), 7.46 (d, J=2.3 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 4.09-4.06 (m, 1H), 3.30-3.27 (m, 1H), 2.90-2.86 (m, 2H), 2.77-2.72 (m, 2H), 2.62-2.59 (m, 1H), 1.99-1.94 (m, 2H), 1.69-1.63 (m, 3H); MS (ESI+) m/z 364 (M+H); HPLC>99% (AUC), tR=11.90 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=O.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(O)(C)C.O.CN1CCCC1=O>[CH:17]1([NH:22][C:11]([C:7]2[CH:8]=[CH:9][C:10]3[C:5](=[CH:4][CH:3]=[C:2]([C:14]([NH:45][CH:50]4[CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:16])[CH:1]=3)[CH:6]=2)=[O:13])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCC1
Reactant: c1ccncc1
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CC(C)O
Product: O=C(NC1CCCC1)c1ccc2cc(C(=O)NC3CCCC3)ccc2c1
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A 300 ml four-necked flask equipped with a stirrer, thermometer, condenser and gas inlet was charged with 6.48 g (0.03 mole) of 2,6-naphthalenedicarboxylic acid, 5.61 g (0.066 mole) of cyclopentylamine, 20.46 g (0.066 mol) of triphenyl phosphite, 25 g of pyridine and 100 g of N-methylpyrrolidone, and the reaction was carried out in a nitrogen gas atmosphere at 100° C. for 3 hours, with stirring. After cooling, the reaction mixture was poured in 700 ml of isopropyl alcohol/water (1:1) for reprecipitation and washing. The mixture was stirred for 2 hours and the precipitate was then recovered by filtration and dried under reduced pressure at 110° C. to provide 9.03 g (yield 86%) of N,N′-dicyclopentyl-2,6-naphthalenedicarboxamide. This compound was a white powder melting at 375.4° C. (decomp.). The elemental analysis and characteristic infrared absorptions are shown in Table 1.
Reaction SMILES: [F:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[C:14]=1[CH3:21].[F:22][C:23]([F:36])([F:35])[S:24]([O:27]S(C(F)(F)F)(=O)=O)(=[O:26])=[O:25]>C(OCC)C>[O-:27][S:24]([C:23]([F:36])([F:35])[F:22])(=[O:26])=[O:25].[F:1][CH2:2][S+:3]([C:18]1[CH:17]=[C:16]([CH3:19])[C:15]([CH3:20])=[C:14]([CH3:21])[C:13]=1[CH3:12])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(C)c(C)c1C
Reactant: Cc1ccc(S(=O)CF)cc1
Solvent: CCOCC
Product: Cc1ccc([S+](CF)c2cc(C)c(C)c(C)c2C)cc1
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
1-((Fluoromethyl)sulfinyl)-4-methylbenzene (3 g, 17.42 mmol) of example 5 was dissolved in dry diethyl ether (100 ml) under nitrogen atmosphere. 1,2,3,4-Tetramethylbenzene (2.60 mL, 1.0 eq) was added to the previous solution and then the mixture was cooled to a temperature below −10° C. Trifluoromethanesulfonic anhydride (2.93 mL, 1 eq) was added slowly maintaining the same temperature. The mixture was stirred at the same temperature, until the reaction was complete. A pink suspension was formed and after 3 hours, turned into a light grey suspension. The precipitate triflate salt was isolated by filtration, washed with diethyl ether at 0° C. and dried under vacuum at a temperature below 30° C. 5.68 g (79.44%) of the desired product was obtained as a white solid.
Reaction SMILES: [K].[NH:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.Cl[C:8]([O:10][CH3:11])=[O:9].CS(C)=O>C1CCCCC1>[C:8]([N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1)([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cl
Reactant: c1cc[nH]c1
Agent: [K]
Solvent: CS(C)=O
Solvent: C1CCCCC1
Product: COC(=O)n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Potassium (5.85 g, 0.15 mol) was added to a solution of 10 ml pyrrole (0.145 mol) in 80 ml hot cyclohexane in several portions. The mixture was refluxed for 1 hour. To this cold solution was added 15 g (0.16 mol) methyl chloroformate slowly. After addition, the mixture was stirred at room temperature for 30 minutes. During this period, 2.5 ml dimethyl sulfoxide was added for catalysis. After quenching with ice-water, the organic layer was separated and the aqueous layer extracted with ether. The combined organic layer was washed with 10% sodium bicarbonate, sat. sodium chloride and dried over magnesium sulfate. Removal of solvent yielded 17.4 g of a liquid. Bulb to bulb distillation gives 16.5 g N-carbomethoxy pyrrole 21 as a colorless liquid, yield 91%. The product requires storage at −20° C.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]=[C:4](SC)[CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]=[C:4]([NH:30][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSC1=Nc2ccccc2C(=O)N(C)C1c1ccccc1
Reactant: NCCc1ccccc1
Product: CN1C(=O)c2ccccc2N=C(NCCc2ccccc2)C1c1ccccc1
Temperature: 240 °C
Reaction time: 1 h

Procedure:
A mixture of 7.41 g (0.025 m) of 3,4-dihydro-4-methyl-2-methylthio-3-phenyl-5H-1,4-benzodiazepine-5-one and 12.11 g (0.100 m) of phenethylamine is heated in an oil bath for 6 hours. The temperature of the oil bath is slowly raised to 240° C and held there for 1 hour. After cooling to room temperature, the residual oil is crystallized from ether to give the crude product, 3,4-dihydro-4-methyl-2-phenethylamino-3-phenyl-5H-1,4-benzodiazepine-5-one. Recrystallization from ethyl acetate and ethyl acetate-ether gives a pure product, 3,4-dihydro-4-methyl-2-phenethylamino-3-phenyl-5H-1,4-benzodiazepine-5-one, a white solid, m.p. 173°-174.5° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[Na+].[NH2:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>>[NH2:29][C:30]1[CH:31]=[C:32]([NH:33][C:2]2([C:26]#[N:27])[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:4][CH2:3]2)[CH:34]=[CH:35][CH:36]=1
Reactant: Nc1cccc(N)c1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: [C-]#N
Agent: [Na+]
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C#N)(Nc4cccc(N)c4)CC3)c(F)c2)C(=O)O1
Yield: 46 %

Procedure:
By using procedure as described in Example 45 and by reacting (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide with sodium cyanide and 3-aminoaniline the compound was obtained in 46% yield.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)=[O:7]
Reactant: CC(=O)OCC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CO)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Yield: 80.7 %

Procedure:
3-(4-(3(S)-Acetoxyacetamidopyrrolidin-1-yl)-3-fluorophenyl)-5(S)-(3-isoxazolylaminomethyl)oxazolidin-2-one (105 mg, 0.23 mM) and potassium carbonate (300 mg, 2.2 mM) were stirred at ambient temperature under nitrogen in methanol (20 ml) for 20 minutes. The mixture was evaporated to dryness and triturated with water (10 ml) to gave the desired product (77 mg ). NMR (DMSO-d6) δ: 1.83 (hextet, 1H); 2.14 (hextet, 1H); 3.20 (m, 1H); 3.29 (m overlapped by H2O, ˜1H); 3.42 (t overlapping m, 3H); 3.49 (m, 1H); 3.75 (dd, 1H); 3.82 (s, 2H); 4.07 (t, 1H); 4.37 (m, 1H); 4.83 (m, 1H); 5.37 (br, 1H); 6.00 (d, 1H); 6.51 (t, 1H); 6.75 (t, 1H); 7.10 (dd, 1H); 7.41 (dd, 1H); 7.85 (d, 1H); 8.37 (d, 1H). MS (ESP): 420 (MH+) for C19H22FN5O5
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:13]=[N:12][C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:16]([O:20][C:21](=[O:32])[NH:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][OH:31])[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[C:16]([O:20][C:21](=[O:32])[NH:22][CH:23]1[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][C:4]2[CH:13]=[N:12][C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:27][CH2:28]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1cccc2ncc(Cl)nc12
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)nc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
Sodium hydride (98% purity, 148 mg, 6.10 mmol, 1.5 eq) is added at room temperature to a stirred solution of 2-chloro-8-methoxy-quinoxaline (800 mg, 4.07 mmol, 1.0 eq) in N,N-dimethylformamide (80 mL), followed by [1-(2-hydroxy-ethyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (1.17 g, 4.07 mmol, 1.0 eq). After 15 hours stirring at room temperature and 4 hours at 80° C., solvent is evaporated, and the residue is extracted with dichloromethane (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: cyclohexane:ethyl acetate:methanol, 1:3:0 to 0:9:1, v/v/v) to afford {1-[2-(8-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester as an orange solid (825 mg, 48% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][N:5]([C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN(CCN1CCOCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
A solution of N-tert-butoxycarbonyl glycine methyl ester (9.4 mL, 63.6 mmol) in DMF (250 mL) was cooled in an ice bath and treated with NaH (60% dispersion in mineral oil, 2.85 g, 71.2 mmol). After stirring at 0° C. under N2 for 30 min and then at room temperature for 30 min, the mixture was cooled in an ice bath and treated with a solution of 4-(2-chloroethyl)morpholine (10.5 g, 70 mmol) in DMF (50 mL). After stirring at 0° C. for 30 min, the mixture was stirred at room temperature overnight. The mixture was diluted with H2O (600 mL) and then extracted with EtOAc (5×300 mL). The combined organic layers were washed with H2O (4×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2) gave the title compound (0.79 g, 4%) as a colorless oil: MS (ESI) m/e 303 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)=[CH2:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([CH:19]=[CH2:20])=[CH:22][CH:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: C=Cc1ccc(CN)cc1
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 4-vinylbenzylamine hydrochloride and DBU in DME. ES-MS m/e (%): 318 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].S(=O)(=O)(O)[OH:24]>>[NH2:2][C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])=[O:24]
Reactant: COc1ccc(C(=O)Nc2ccc(C(C)(C)C#N)cc2)cc1
Reactant: O=S(=O)(O)O
Product: COc1ccc(C(=O)Nc2ccc(C(C)(C)C(N)=O)cc2)cc1

Procedure:
5 g. N-[4-(1-Cyano-1-methylethyl)-phenyl]-4-methoxybenzamide (Example 27) are stirred for 20 hours at ambient temperature in 100 ml. concentrated sulphuric acid, poured on to ice, the precipitate is filtered off with suction, dissolved in hot glacial acetic acid, water added thereto until the commencement of turbidity and then left to cool. There are obtained 2.2 g. (42% of theory) of the title compound in the form of colourless crystals; m.p. 234°-235° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[C:4]([CH3:9])=[N:3]1.[NH2:10][C:11]1[CH:16]=[N:15][C:14]([Br:17])=[CH:13][N:12]=1.[B-][N+](C)(C)C.C(O)(=O)C>C(OCC)(=O)C>[Br:17][C:14]1[N:15]=[CH:16][C:11]([NH:10][CH2:7][C:5]2[C:4]([CH3:9])=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:12][CH:13]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Cc1nn(C)cc1C=O
Agent: [B-][N+](C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nn(C)cc1CNc1cnc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (142 mg, 1.145 mmol), 2-amino-5-bromopyrazine (200 mg, 1.149 mmol), borane trimethylamine complex (126 mg, 1.73 mmol) and glacial acetic acid (137 mg, 2.29 mmol) in anhydrous methonol (3 ml) was stirred at room temperature overnight. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over MgSO4 and filtered. The filtrate was concentrated to give 300 mg of (5-bromo-pyrazin-2-yl)-(1,3-dimethyl-1H-pyrazol-4-ylmethyl)amine as crude product, which was used for next step reaction without further purification. Crude yield: 93%.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18][C:19]([C@@H:21]([NH:28][C:29]([C@H:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32][C:33](OCC)=[O:34])=[O:30])[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)=[O:20])[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:45][NH:46][CH3:47]>>[CH:1]1([CH2:7][C@H:8]([NH:18][C:19](=[O:20])[C@@H:21]([NH:28][C:29](=[O:30])[C@@H:31]([CH2:32][C:33](=[O:34])[N:46]([CH3:47])[CH3:45])[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)[C@@H:9]([OH:17])[CH2:10][C@@H:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=[CH2:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)OCC)Cc1ccccc1)C(C)C
Reactant: CNC
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)N(C)C)Cc1ccccc1)C(C)C
Yield: 20 %

Procedure:
80 mg (0.13 mmol) of ethyl (R)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-4-phenylbutyrate were taken up in 2 ml of a 5.6 molar alcoholic dimethylamine solution and heated to reflux for 3 hours. The solution was then evaporated and the residue was chromatographed on silica gel with a 20:1 mixture of methylene chloride and methanol to obtain 33 mg (20%) of (S)-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]-α-[(R)-α-[(dimethylcarbamoyl) methyl]hydrocinnamamido]imidazole-4-propionamide as an amorphous powder. MS: 608 (M+H)+.
Reaction SMILES: [NH2-].[Na+].[OH:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.S(OC)(O[CH3:23])(=O)=O.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:23][O:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: OCCOC1CCCCCCCCCCC1
Reactant: COS(=O)(=O)OC
Agent: [NH2-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: COCCOC1CCCCCCCCCCC1
Reaction time: 1 h

Procedure:
25 g of sodium amide was introduced into 150 ml of xylene and heated to boiling under agitation. Within one hour, 114 g (0.5 mol) of 2-hydroxyethyl-cyclododecyl-ether, dissolved in 750 ml of xylene, was allowed to drip into the boiling suspension. To complete the alcoholate formation, the mixture was heated under reflux for another two hours. Thereafter 44 g (0.35 mol) of dimethyl sulfate was added dropwise and the reaction mixture heated under reflux for another four hours. Then, the reaction mixture was poured into a mixture of ice and 35 g of sodium hydroxide. The organic phase was washed with water, dried over Na2SO4, and then fractionated.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CCCCCCC>[CH2:8]([O:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]1[NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[O:1]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(O)C(N)=O
Reactant: COc1cccc(OCc2ccccc2)c1C=O
Solvent: O
Solvent: CCCCCCC
Product: COc1cccc(OCc2ccccc2)c1C1NC(=O)C(C)(C)O1
Temperature: 240 °C
Yield: 60.7 %

Procedure:
A mixture of commercially available 2-hydroxyisobutyramide (638.5 mg, 3 eq), 2-benzyloxy-6-methoxy-benzaldehyde (500 mg) (Katritzky A. R. et al ARKIVOC 2001, 2, 3, 3-12) is heated at 240° C. for 5 min using microwave irradiation (Lecolier S. et al Chimica Therapeutica 1969, 4,6, 437-445). The crude oil is poured into water and extracted with DCM. The combined organic extracts are dried (MgSO4), filtered and concentrated to yield a crude oil. FC (EN n-heptane: 1/1 to 1/0) gives the title compound as a yellow solid (0.41 g, 61%); LC-MS: tR=0.65 min; [M+H]+=328.22.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[C:38]([CH3:43])[N:39]=[C:40]([CH3:42])[CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (240 mg, 59%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:20][CH2:21][CH3:22])=[C:14]([O:17][CH2:18][CH3:19])[CH:15]=3)[CH:10]=[C:9]([CH2:23][OH:24])[C:8]=2[CH2:25][OH:26])=[CH:3][CH:2]=1.[CH3:27][O:28][CH2:29][CH2:30][I:31].C(OCC)(=O)C>CN(C)C=O>[I-:31].[OH:26][CH2:25][C:8]1[C:9]([CH2:23][OH:24])=[CH:10][C:11]2[C:16](=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([O:20][CH2:21][CH3:22])[CH:12]=2)[C:7]=1[C:4]1[CH:5]=[CH:6][N+:1]([CH2:30][CH2:29][O:28][CH3:27])=[CH:2][CH:3]=1
Reactant: CCOc1cc2cc(CO)c(CO)c(-c3ccncc3)c2cc1OCC
Reactant: COCCI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc2cc(CO)c(CO)c(-c3cc[n+](CCOC)cc3)c2cc1OCC
Product: [I-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a suspension of 1-(4-pyridyl)-2,3-bis(hydroxy-methyl)-6,7-diethoxynaphthalene (7.0 g) in dry dimethylformamide (14 ml) is added 2-methoxyethyl iodide (7.35 g), and the mixture is stirred at 80° C. overnight. The mixture is allowed to cool, and thereto added ethyl acetate. The precipitated crystal is collected by filtration to give 4-[2,3-bis(hydroxymethyl)-6,7-diethoxy-1naphthyl]-N-(2-methoxyethyl)pyridinium iodide (8.50 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:23]=[CH:22][C:21]3[C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][CH2:27][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:18][CH:19]=4)[C:14](=O)[C:13]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:37])=[N-].CCOCC.[CH3:43][OH:44]>>[CH3:43][O:44][C:14]1[C:15]2[C:20]([C:21]3[CH:22]=[CH:23][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:12][C:13]=3[CH:37]=1)=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:16]=2
Reactant: CO
Reactant: O=C1c2cc(OCCCN3CCCCC3)ccc2-c2ccc(OCCCN3CCCCC3)cc21
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COc1cc2cc(OCCCN3CCCCC3)ccc2c2ccc(OCCCN3CCCCC3)cc12
Temperature: 25 °C

Procedure:
A solution of 4.7 g (0.01 mole) of 2,7-bis(3-piperidinopropoxy)fluoren-9-one in methanol is stirred and treated with approximately 0.085 mole of diazomethane by co-distillation with ether into the reaction mixture at a temperature of -15° to -31° C. The reaction mixture is allowed to warm slowly to room temperature overnight. The volatile materials are removed on the steam bath in vacuo and the residue triturated with pentane to induce crystallization. The resulting solid is dissolved in a mixture of pentane and ether, washed several times with a dilute solution of sodium hydroxide, washed with water, dried over anhydrous sodium sulfate, treated with charcoal, filtered and most of the volatile solvents removed from the filtrate. The residue is recrystallized from pentane and again from a methanol-water mixture to yield the desired 9-methoxy-2,7-bis(3-piperidinopropoxy) phenanthrene: m.p. 118.5°-9.5° C., λmaxMeOH 259, and E1cm1% 1430.