Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][CH2:9][CH:10]([Se:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]C)=O)=[CH:5][CH:4]=1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[C:26]=1[CH3:34].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:24][C:25]1[C:26]([CH3:34])=[C:27]([N:31]2[C:11](=[O:13])[CH:10]([Se:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:9][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=3)[C:32]2=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1c(Br)cccc1N=C=O
Reactant: COC(=O)C(CNCc1ccc(OC)cc1)[Se]c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CC([Se]c3ccccc3)C(=O)N(c3cccc(Br)c3C)C2=O)cc1
Temperature: 65 °C
Yield: 100 %

Procedure:
A mixture of methyl 3-((4-methoxybenzyl)amino)-2-(phenylselanyl)propanoate (3.68 g, 9.73 mmol), 1-bromo-3-isocyanato-2-methylbenzene (2.27 g, 10.7 mmol), and K2CO3 (0.672 g, 4.86 mmol) in DMF (49 mL) was heated at 65° C. for 5 h. The cooled mixture was partitioned between water and EtOAc. And the organic phase was washed with brine, dried and concentrated to provide 3-(3-bromo-2-methylphenyl)-1-(4-methoxybenzyl)-5-(phenylselanyl)dihydropyrimidine-2,4(1H,3H)-dione as a light brown solid (5.43 g), used without further purification. Mass spectrum m/z 557, 559, 561 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](I)[CH3:32]>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:31][CH3:32])[CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=C1c2ccccc2C(=O)N1CCCNCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CCCN1C(=O)c2ccccc2C1=O)CCc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a mixture of N-[3-[2-(4-chlorophenyl)ethylamino]propyl]phthalimide (2.28 g, 6.65 mmol) and potassium carbonate (1.8 g, 13 mmol) in CH3CN (50 ml) was added ethyl iodide (1.6 ml, 20 mmol). The mixture was stirred at 70° C. for 16 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 2% methanol/chloroform) to afford N-[3-[[2-(4-chlorophenyl)ethyl](ethyl)amino]propyl]phthalimide (1.41 g, 57%): MS(ES+) m/e 371 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.84 (m, 2H), 7.71 (m, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 3.71 (t, J=7.3 Hz, 2H), 2.66 (m, 4H), 2.57 (m, 4H), 1.83 (m, 2H), 1.00 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:8]=[C:7]([Cl:22])[C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.Cl.[CH3:28][O:29][C:30](=[O:51])[C@@H:31]([NH2:50])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:49])[C:41]2[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:48])=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.O>[CH3:28][O:29][C:30](=[O:51])[C@@H:31]([NH:50][C:4](=[O:5])[C:3]1[C:7]([Cl:22])=[CH:8][C:9]([O:11][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:19]([CH3:20])[CH3:21])[CH:13]([CH3:14])[CH3:15])=[CH:10][C:2]=1[Cl:1])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:49])[C:41]2[C:42]([Cl:48])=[CH:43][CH:44]=[CH:45][C:46]=2[Cl:47])=[CH:35][CH:34]=1
Reactant: CC(C)[Si](Oc1cc(Cl)c(C(=O)O)c(Cl)c1)(C(C)C)C(C)C
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1c(Cl)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
To a solution of 2,6-dichloro-4-triisopropylsilanyloxy-benzoic acid (3.63 g, 10 mmol) in toluene (50 mL) was added an excess of thionyl chloride (11.89 g, 7.2 mL, 100 mmol) at room temperature. The resulting colorless solution was heated to reflux for 5 h and then it was cooled to room temperature and the solvent and excess thionyl chloride was removed under vacuum. The resulting residue was azeotrophed one time with toluene. Then, the above 2,6-dichloro-4-triisopropylsilanyloxy-benzoic acid chloride was dissolved in dichloromethane (50 mL) and the solid (S)-2-amino-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid methyl ester hydrochloride salt (4.1 g, 10 mmol) and DIPEA (3.87 g, 5.26 mL, 30 mmol) were added at room temperature. The resulting solution was stirred for 15 h at room temperature and water was added (˜200 mL) to the reaction mixture. Then, the organic compound was extracted into dichloromethane (2×150 mL). The combined organic layer was washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the crude residue which was purified using an ISCO (120 g) column chromatography to obtain 6.48 g (95%) of (S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-(2,6-dichloro-4-triisopropylsilanyloxy-benzoylamino)propionic acid methyl ester as a white solid. ES(+)-HRMS m/e calcd. for C33H38Cl4N2O5Si (M+H)+ 711.1377, obsd. 711.1377.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]2[O:13][C:14](=[O:16])[CH3:15])=[C:4](Cl)[N:3]=1.[Cl:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[C:33]([F:38])[CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([O:18][C@H:17]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([Cl:1])=[N:3][C:4]=3[NH:35][C:34]2[CH:36]=[CH:37][C:31]([Cl:30])=[CH:32][C:33]=2[F:38])[O:23][C@@H:22]1[CH2:24][O:25][C:26](=[O:28])[CH3:27])(=[O:21])[CH3:20]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Nc1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2,6-dichloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine 2(1.09) in toluene (25 ml) was added palladium acetate (50 mg), 4-chloro-2-fluoroaniline (0.5 ml) and bis[2-(diphenylphosphino)phenyl] ether 3(120 mg) and the reaction stirred at 20° C. for 15 min. Caesium carbonate (872 mg) was added and the mixture heated at 90° C. for 16 hours. The reaction mixture was cooled to 20° C. and partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was washed with brine (100 ml), dried with magnesium sulphate and the solvent removed in vacuo. Purification by flash chromatography on silica gel, eluting with ethyl acetate:cyclohexane (1:1) gave the title compound (400 mg).
Reaction SMILES: [H-].[Na+].[N+:3]([CH2:6][CH3:7])([O-:5])=[O:4].[O:8]=[C:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1>O1CCCC1>[OH:8][C:9]1([CH:6]([N+:3]([O-:5])=[O:4])[CH3:7])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1
Reactant: CC[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC([N+](=O)[O-])C1(O)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a suspension of sodium hydride (72 mg, 1.75 mmol, 60% wt) in tetrahydrofuran (1 mL) cooled to 0° C. was added nitroethane (125 μL, 1.75 mmol). The suspension was allowed to warm to room temperature and was stirred for 15 minutes, then cooled back to 0° C. To the suspension was added dropwise a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (300 mg, 1.75 mmol, in 2 mL of tetrahydrofuran), prepared using procedures similar to those described in Reference 3. The suspension was stirred at room temperature for 1 hour. The reaction mixture was quenched by adding 20% aqueous citric acid, and then was partitioned with ethyl acetate. The aqueous portion was extracted twice using ethyl acetate and the combined organic portion was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a colorless oil that was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes, the isolated product was concentrated in vacuo to afford 250 mg, 1.02 mmol (58%) of 1,1-dimethylethyl 3-hydroxy-3-(1-nitroethyl)azetidine-1-carboxylate as a colorless oil. 1H NMR (400 MHz, DMSO): 6.46 (s, 1H), 5.01 (q, 1H), 4.24-3.97 (m, 2H), 3.77-3.60 (m, 2H), 1.41 (d, 3H), 1.39 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:16][CH3:17])C(=O)OC(C)(C)C)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].Cl>O1CCOCC1>[CH2:16]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:18]([O-:20])=[O:19])[CH:4]=1)[CH3:17]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Solvent: C1COCCO1
Product: CCNc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The tert-butyl 4-amino-3-nitrophenyl(ethyl)carbamate from the previous step was dissolved in dioxane (35 mL) and hydrogen chloride (35 mL of a 4M solution in dioxane) was added. The mixture was stirred at room temperature for 18 hr and then the solvent was evaporated. The residue was dissolved in water (200 mL) and the solution adjusted to pH10 with 5M sodium hydroxide solution. The solution was extracted with EA (3×100 mL), and the combined EA extracts were washed with brine, dried over magnesium sulfate, and concentrated to give N1-ethyl-3-nitrobenzene-1,4-diamine as a purple solid (1.68 g).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>>[CH:1]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: Oc1ccccc1
Product: c1ccc(C2CCCCC2)cc1

Procedure:
In the embodiment illustrated in FIG. 7, phenol process 700 comprises: Step 710: treating hydrogen stream 702 and recycle stream 704 to at least partially remove at least one impurity and form stream 708; optional Step 720: treating benzene stream 706 to at least partially remove at least one impurity to form stream 711; Step 730: hydroalkylating streams 708 and 711 to form at least some cyclohexylbenzene in stream 733; Step 740: oxidizing at least a portion of the cyclohexylbenzene in stream 733 to form cyclohexylbenzene peroxide in stream 744; Step 750: cleaving the cyclohexylbenzene peroxide in stream 744 to form at least some phenol and cyclohexanone in stream 755; and Step 760: dehydrogenating at least a portion of the cyclohexanone in stream 755 to form at least some additional phenol in stream 766 and at least some hydrogen in recycle stream 704.
Reaction SMILES: [C:1]([CH:4]([N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH2:7]1)[CH3:5])([OH:3])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([CH:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH:8]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH2:7]1)[CH3:5])([OH:3])=[O:2]
Reactant: [H][H]
Reactant: CC(C(=O)O)N1CCC=C(c2nnn[nH]2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C(=O)O)N1CCCC(c2nnn[nH]2)C1
Yield: 68.7 %

Procedure:
To a solution of 5 (14.9 g, 0.078 mol) in ethyl acetate (160 ml) acetic acid (25 ml) and 5% palladium on charcoal (1.25 g) were added. The mixture was shaken for 24 hours with 3.5 atm. of hydrogen pressure. The mixture was filtered and evaporated to yield the title compound as an oil (12.07 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[C:13]1([CH:19]2[CH2:24][C:23](=[O:25])[CH:22]=[C:21]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:22]3[C:23](=[O:25])[CH2:24][CH:19]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:20][C:21]=3[N:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)[C:10](=[O:11])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C=NC(Cl)c1ccc(Br)cc1
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CC(c2ccccc2)C1
Solvent: ClCCl
Product: O=C1CC(c2ccccc2)CC2=C1C(c1ccc(Br)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (201 mg, 0.815 mmol) in dichloromethane (3 mL) is added to a solution of 5-phenyl-3-(3-(trifluoromethyl)phenyl-amino)cyclohex-2-enone (intermediate 14, 270 mg, 0.815 mmol) in dichloromethane (7 mL), and the mixture is heated at reflux for 4 h and cooled to room temperature. After 2 d the mixture is concentrated under reduced pressure and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 90:10 to 60:40). Yield: 195 mg; ESI mass spectrum: [(79Br)-M+H]+=541, [(81Br)-M+H]+=543; Retention time HPLC: 1.42 min, 1.44 min (1:1 mixture of diastereomers) (Z002—002).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][O:46][CH2:47][CH2:48]O>CN(C=O)C>[CH3:45][O:46][CH2:47][CH2:48][O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A solution of N-(carbobenzyloxy)-L-phenylalanine (10.0 g, 33.4 mmol) in DMF (75 mL) was treated with HOBT (6.8 g, 50.1 mmol), N-(3-dimethylaminopropyl)-N ′-ethylcarbodiimide hydrochloride (7.7 g, 40.1 mmol), 2-methoxyethanol (2.8 g, 36.8 mmol) and a catalytic amount of 4-N,N-dimethylaminopyridine. The reaction was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue taken up in ethyl acetate and washed with 1M hydrochloric acid, saturated sodium hydrogen carbonate and brine. The solution was dried over sodium sulphate, filtered and concentrated under reduced pressure to provide N-(carbobenzyloxy)-L-phenylalanine 2-methoxy-ethyl ester as a yellow foam (8.8 g, 74%). 1H-NMR; δ (CDCl3), 7.44-7.12 (10H, m), 5.27 (1H, d), 5.11 (2H, s), 4.72 (1H, dd), 4.26 (2H, m), 3.57 (2H, t), 3.38 (3H, s) and 3.15 (2H, m).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13](=[O:36])[CH:14]([CH3:35])[C:15]([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[CH:31]=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:16])(C)(C)C>ClCCl>[CH3:35][CH:14]([C:15]([NH:17][CH:18]1[C:24](=[O:25])[N:23]([CH3:26])[C:22]2[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=2[C:20]2[CH:31]=[CH:32][CH:33]=[CH:34][C:19]1=2)=[O:16])[C:13]([OH:36])=[O:12]
Reactant: CC(C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TFA (3 ml) was added to a solution of 2-methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid tert-butyl ester (920 mg, 2.33 mmol) in dichloromethane (3 ml) and the mixture was stirred at r.t. overnight. The mixture was then taken up in more dichloromethane, washed with water, and dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=339.3 (M+H+), (580 mg, 73%) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C@@:8]3([C@@H:17]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=4[F:25])[C@H:16]([C:26]([NH:28][C@H:29]4[CH2:34][O:33][C@H:32]([C:35]([O:37]C)=[O:36])[CH2:31][CH2:30]4)=[O:27])[NH:15][C:14]43[CH2:43][CH2:42][C:41]([CH3:45])([CH3:44])[CH2:40][CH2:39]4)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.Cl>CO>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C@@:8]3([C@@H:17]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[C:19]=4[F:25])[C@H:16]([C:26]([NH:28][C@H:29]4[CH2:34][O:33][C@H:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]4)=[O:27])[NH:15][C:14]43[CH2:39][CH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][CH2:43]4)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1
Reactant: COC(=O)[C@@H]1CC[C@@H](NC(=O)[C@@H]2NC3(CCC(C)(C)CC3)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2ccnc(Cl)c2F)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)N[C@@H]1CC[C@@H](C(=O)O)OC1)[C@H](c1ccnc(Cl)c1F)[C@]21C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
1N sodium hydroxide solution (3 ml) was added to a methanol (10 ml) solution of the compound (1.00 g, 1.58 mmol) obtained in Example 173 and the resulting mixture was stirred at room temperature for 18 hours. 1N hydrochloric acid was added to the reaction mixture to adjust its pH to approximately 6 to 7, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 577 mg (60%) of the title compound as a solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C:23]1[C:32]2[C:27](=[C:28]([O:35][CH3:36])[CH:29]=[CH:30][C:31]=2[O:33][CH3:34])[N:26]=[CH:25][CH:24]=1)=[N+]=[N-]>C1COCC1.O>[NH2:20][C:23]1[C:32]2[C:27](=[C:28]([O:35][CH3:36])[CH:29]=[CH:30][C:31]=2[O:33][CH3:34])[N:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(OC)c2c(N=[N+]=[N-])ccnc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC)c2c(N)ccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 g (45.8 mmol) of triphenylphosphine are added in a single portion to a solution of 8.7 g (37.8 mmol) of 4-azido-5,8-dimethoxyquinoline in a THF/H2O mixture (110 mL/110 mL). The reaction medium is stirred at ambient temperature for 2 hours and then concentrated on a rotary evaporator. The residue is acidified with 200 mL of 1N HCl and extracted with ether (3 times 500 mL). The aqueous phase is then basified with 250 mL of 1N NaOH and re-extracted with CHCl3 (3 times 250 mL). After drying over MgSO4 and evaporating off the solvent on a rotary evaporator, the expected amine is obtained quantitatively in the form of brown powder, which decomposes before melting.
Reaction SMILES: [N:1]#[C:2]Br.[NH:4]1[CH2:8][CH2:7][N:6]=[C:5]1[C:9]1[C:14]([NH2:15])=[C:13]([O:16][CH3:17])[C:12]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:11][CH:10]=1>C(Cl)Cl>[CH3:17][O:16][C:13]1[C:14]2[N:15]=[C:2]([NH2:1])[N:4]3[CH2:8][CH2:7][N:6]=[C:5]3[C:9]=2[CH:10]=[CH:11][C:12]=1[O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: N#CBr
Reactant: COc1c(OCCCN2CCOCC2)ccc(C2=NCCN2)c1N
Solvent: ClCCl
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyanogen bromide (10.9 g, 102.9 mmol) was added to a mixture of 6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholin-4-ylpropoxy)aniline (Step 4, 17.2 g, 51.4 mmol) and TEA (15.6 g, 154.3 mmol) in DCM (200 mL) precooled to 0° C. After 1 h the reaction mixture was concentrated under reduced pressure and the resulting residue stirred with EtOAc (300 mL) overnight at rt. The resulting slurry was filtered to generate the title compound contaminated with triethylamine hydrobromide (26.2 g, 71%): HPLC MS RT=0.17 min, MH+=360.2.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[C:25]2[C:30]([CH:31]=[C:32]3[C:37]=1[CH:36]=[CH:35][CH:34]=[CH:33]3)=[C:29]1[CH:38]=[CH:39][CH:40]=[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:28]1=[CH:27][CH:26]=2.[CH:48]([C:50]1[CH:55]=[CH:54][C:53](B(O)O)=[CH:52][CH:51]=1)=[O:49].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[C:42]1([C:41]2[C:28]3=[CH:27][CH:26]=[C:25]4[C:30]([CH:31]=[C:32]5[C:37]([CH:36]=[CH:35][CH:34]=[CH:33]5)=[C:24]4[C:53]4[CH:54]=[CH:55][C:50]([CH:48]=[O:49])=[CH:51][CH:52]=4)=[C:29]3[CH:38]=[CH:39][CH:40]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: Brc1c2ccccc2cc2c1ccc1c(-c3ccccc3)cccc12
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2c3ccccc3cc3c2ccc2c(-c4ccccc4)cccc23)cc1

Procedure:
913 mg (3 mmol) of tri-o-tolylphosphine and then 112 mg (0.5 mmol) of palladium(II) acetate are added to a well-stirred suspension of 15.3 g (40 mmol) of 7-bromo-4-phenylbenz[a]anthracene, 7.5 g (50 mmol) of 4-formylphenylboronic acid and 25.5 g (120 mmol) of tripotassium phosphate in a mixture of 300 ml of toluene, 100 ml of dioxane and 400 ml of water, and the mixture is subsequently heated under reflux for 16 h. After cooling, the precipitated solid is filtered off with suction, washed three times with 50 ml of toluene, three times with 50 ml of ethanol:water (1:1, v:v), three times with 100 ml of ethanol and finally dried. Recrystallisation from DMF. Yield: 14.3 g (35 mmol), 88%.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:8][CH:9]([CH3:24])[CH2:10][CH2:11][CH2:12][CH:13](C(OCC)=O)[C:14]([O:16]CC)=[O:15])[CH2:4][CH2:5][CH2:6][CH3:7]>O>[CH2:3]([O:8][CH:9]([CH3:24])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCOC(C)CCCC(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCOC(C)CCCCC(=O)O
Yield: 84.5 %

Procedure:
Then, 18.6 g of water was added to 18.6 g of 85% KOH, and under stirring, 25.8 g of the above diester was dropped in 30 min. at 20°-23° C. After the addition, the mixture was stirred for 4 hours at the temperature and extracted with benzene. The benzene layer was washed with 5% NaOH aqueous solution and added to the aqueous layer. The aqueous layer was acidified to pH 1 with 6N-hydrochloric acid and extracted with ether. The ether layer was washed with saturated NaCl aqueous solution and dried, followed by distilling-off of the ether to obtain 21.1 g of a slightly yellowish liquid. The liquid was stirred for 3 hours at 160°-170° C., and after cooling, water was added thereto, followed by extraction with benzene. The benzene layer was washed with 5% NaOH aqueous solution and added to the aqueous layer. The aqueous layer was acidified to pH 1 and extracted with ether, followed by washing with saturated NaCl aqueous solution, drying and distilling-off of the solvent to obtain 14.9 g of 6-pentyloxyheptanoic acid in the form of a yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][S:13]([C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18])(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][OH:37])[CH3:30]>N1C=CC=CC=1>[CH2:29]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][C:17]([C:16]([S:13]([CH2:12][CH:11]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:14])=[O:15])([CH3:21])[CH3:20])=[O:18])[CH3:30]
Reactant: CC(C)(C(=O)Cl)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCOCCOCCO
Solvent: c1ccncc1
Product: CCOCCOCCOC(=O)C(C)(C)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
In an analogous manner to that of Example 2, paragraph (c), by reacting (RS)-2-[[2-[(benzyloxy)carbonyl]-3-phenylpropyl]sulfonyl]-2-methylpropionyl chloride and diethylene glycol monoethyl ether in pyridine there was obtained benzyl rac-α-[[[1-[[2-(2-ethoxyethoxy)ethoxy]carbonyl]-1-methylethyl]sulfonyl]methyl]hydrocinnamate as a colourless oil, MS: 385 (M-COObenzyl)+.