Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]12[CH2:18][CH2:17][C:16](=[O:19])[CH:15]=[C:14]1[C:13]1[C:8](=[CH:9][C:10]([O:20][CH3:21])=[CH:11][CH:12]=1)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+].[Br:27]Br>C(Cl)(Cl)(Cl)Cl>[Br:27][C:15]1[C:16](=[O:19])[CH2:17][CH2:18][C:5]2([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]=1[C:13]1[C:8](=[CH:9][C:10]([O:20][CH3:21])=[CH:11][CH:12]=1)[CH2:7][CH2:6]2
Reactant: BrBr
Reactant: CCCCC12CCC(=O)C=C1c1ccc(OC)cc1CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)cc1CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 10a-butyl-7-methoxy-1,9,10,10a-tetrahydro-3(2H)-phenanthrenone (31 mg, 0.109 mmol) and NaHCO3 (46 mg, 0.545 mmol) in CCl4 (0.25 mL) was stirred at room temperature while Br2 (0.0056 mL, 0.109 mmol) was added by syringe. A gummy precipitate formed which slowly dissolved. After stirring at room temperature for 15 minutes, the mixture was partitioned between EtOAc (4 mL) and aqueous Na2SO3 (4 mL). The organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to an oil. The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 5% EtOAc in CH2Cl2. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 4-bromo-10a-butyl-7-methoxy-1,9,10,10a-tetrahydro-3(2H)-phenanthrenone as an oil.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][CH2:29][CH3:30])[N:18]=[C:17]([NH2:31])[N:16]=2)=[CH:10][CH:9]=1)C.[OH-].[Na+].[Cl-].[Na+].Cl>C(OCC)(=O)C.C(O)C>[NH2:31][C:17]1[N:16]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:9][CH:10]=2)[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH2:29][CH3:30])[N:18]=1
Reactant: CCOC(=O)CCCc1ccc(Nc2cc(-c3cc(Cl)ccc3OCC)nc(N)n2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(CCCC(=O)O)cc2)nc(N)n1
Reaction time: 18 h
Yield: 66 %

Procedure:
A mixture of 4-{4-[2-amino-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-butyric acid ethyl ester (350 mg, 0.71 mmol), sodium hydroxide (150 mg, 3.8 mmol) and ethanol (5 ml) was stirred for 18 hours. Ethyl acetate (100 ml), saturated aqueous sodium chloride solution (100 ml) and concentrated hydrochloric acid (1 ml) were added and the mixture was stirred for 10 minutes. The organic layer was concentrated under reduced pressure. The residual solid was treated with water (25 ml) and stirred vigorously. Suction filtration afforded the title compound (200 mg 61% yield) as a white powder. 1H NMR (DMSO-d6) δ 1.38 (m, 3H, CH3), 1.83 (m, 2H, CH2), 2.23 (m, 2H, CH2), 2.61 (m, 2H, CH2), 4.17 (m, 2H, CH2), 6.60 (s, 1H, Ar), 7.20-7.29 (m, 3H, Ar), 7.61-7.71 (m, 4H, Ar), 10.76 (s, 1H, NH), 12.48 (s, 1H).
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH:8][C:7]([CH3:14])([CH3:13])[CH2:6]1)[CH2:2][CH3:3].[C:15]1(O)[C:19](=[O:20])[C:17](=O)[C:16]=1[OH:21]>C(C(O)CCCCC)C>[CH2:1]([N:4]([C+:15]1[C:16]([O-:21])=[C:17]([N:4]([CH:5]2[CH2:6][C:7]([CH3:14])([CH3:13])[NH:8][C:9]([CH3:11])([CH3:12])[CH2:10]2)[CH2:1][CH2:2][CH3:3])[C+:19]1[O-:20])[CH:5]1[CH2:6][C:7]([CH3:13])([CH3:14])[NH:8][C:9]([CH3:12])([CH3:11])[CH2:10]1)[CH2:2][CH3:3]
Reactant: CCCNC1CC(C)(C)NC(C)(C)C1
Reactant: O=c1c(O)c(O)c1=O
Solvent: CCCCCC(O)CC
Product: CCCN(c1c([O-])[c+](N(CCC)C2CC(C)(C)NC(C)(C)C2)[c+]1[O-])C1CC(C)(C)NC(C)(C)C1
Reaction time: 5 h
Yield: 75.2 %

Procedure:
Under agitation, 363.0 g (1.83 moles) of 4-n-propylamino-2,2,6,6-tetramethylpiperidine, 10.8 g (0.095 mole) of quadratic acid, and 150 cc of ethylhexanol were heated in a 1-liter agitated flask with attached water trap for five hours under reflux to boiling; the sump temperature was 205° C., and 3.0 cc of water was removed from the cycle. After concentration of the reaction solution, 33.9 g of crystals was precipitated. Yield: 75.2%, mp 198°-199° C. (from cyclohexane). Extinction (g/l.cm) at 278 nm: 27; at 335 nm: 95.
Reaction SMILES: C([O:8][C:9](=[O:58])[C@H:10]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:11][C:12](=[O:50])[CH2:13][CH:14]([O:30][C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:48])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45](=[O:47])[CH3:46])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[C:45]([NH:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:38]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:31]([O:30][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][C:12]([NH:11][C@H:10]([C:9]([OH:58])=[O:8])[CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)=[O:50])=[O:49])=[O:48])(=[O:47])[CH3:46]
Reactant: CCCCCCCCCCCCCCCC(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OC(=O)CCCCCNC(=O)CCCCCNC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(CC(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC(=O)CCCCCNC(=O)CCCCCNC(C)=O
Yield: 76.8 %

Procedure:
1.80 g of the above ester compound was treated with 8 ml of TFA to convert the ester to free carboxylic acid and after adding thereto 5 ml of methylenechloride, 1.20 g of L-phenylalanine benzyl ester TsOH salt, 0.4 ml of TEA and 590 mg of DCC, the mixture was trated in the same manner as in Example 14-(ii) to provide 740 mg of N-[3-[6-(6-acetamidohexanamido)hexanoyloxy]octadecanoyl]-L-phenylalanine benzyl ester. 660 mg of the ester compound thus were dissolved in a mixture of 30 ml of tetrahydrofuran and 15 ml of methanol and after carrying out catalytic reduction by using 100 mg of 10% Pd-C and treating in the same manner as in Example 23-(iv), 450 mg of N-[3-[6-(6-acetamidohexanamido)hexanoyloxy]octadecanoyl]-L-phenylalanine was obtained.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:42])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:39][CH3:40])[CH2:25][N:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[C:5]1=[O:41])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:42])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:39][CH3:40])[CH2:25][N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]2)[C:5]1=[O:41])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 4-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)piperazine-1-carboxylate (Example 95, Step A) (187 mg, 0.304 mmol in DCM (2.4 mL) was added TFA (600 μL, 7.79 mmol). The reaction mixture was stirred at room temperature for 16 hours before concentrating under reduced pressure. The residue was taken up in DCM (15 mL) and washed with sat. sodium bicarbonate solution (10 mL) and saturated sodium chloride solution (10 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford the title compound as a white foam.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])(OCC1C=CC=CC=1)OCC1C=CC=CC=1>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc2ccccc12
Reactant: Nc1ccccc1
Agent: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 195 °C
Yield: 85 %

Procedure:
288 parts of α-naphthol, 205 parts of aniline and 10 parts of dibenzyl phosphite are mixed and heated to 195° C. The elimination of water commences at this temperature and has ended when the internal temperature is 235° C. 33 parts of water are removed in the course of 4 hours. After distilling off excess α-naphthol and aniline, 374 parts of phenyl-α-naphthylamine, boiling at 202° - 204° C/5 mm Hg, are obtained; the product has a melting point of 55° - 58° C and corresponds to a yield of 85% of theory.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[CH3:16])[C:8](=[O:17])[NH:7][C:6]1=[O:18].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>C1COCC1>[CH3:16][C:15]1[CH:14]=[CH:13][S:12][C:11]=1[C:9]1[C:8](=[O:17])[NH:7][C:6](=[O:18])[N:5]([CH2:4][CH2:3][CH:2]=[O:1])[CH:10]=1
Reactant: Cc1ccsc1-c1cn(CCCO)c(=O)[nH]c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccsc1-c1cn(CCC=O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.5 %

Procedure:
1-(3-Hydroxy-propyl)-5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep 28.36 mg, 0.13 mmol) was dissolved in dry THF (5 mL), the solution was cooled to 0° C. and then Dess-Martin periodinane (97 mg, 0.22 mmol) was added under nitrogen. The mixture was stirred at room temperature for 1.5 hours. Ethyl acetate was added and the solution was washed with aqueous saturated NaHCO3 solution. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (7-3) to give 17 mg of the title compound (50% yield).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[NH:8][C:7](=[O:9])[CH:6]([CH2:10][C:11]2[CH:42]=[CH:41][C:14]([O:15][CH2:16][C:17]3([CH3:40])[CH2:26][C:25](=[O:27])[C:24]4[C:19](=[C:20]([CH3:39])[C:21]([CH3:38])=[C:22]([O:29][CH2:30][C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])[C:23]=4[CH3:28])[O:18]3)=[CH:13][CH:12]=2)[S:5]1.Cl>CO>[O:3]=[C:4]1[NH:8][C:7](=[O:9])[CH:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]3([CH3:40])[CH2:26][CH:25]([OH:27])[C:24]4[C:19](=[C:20]([CH3:39])[C:21]([CH3:38])=[C:22]([O:29][CH2:30][C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[O:32])[C:23]=4[CH3:28])[O:18]3)=[CH:41][CH:42]=2)[S:5]1
Reactant: COCCOC(=O)COc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COCCOC(=O)COc1c(C)c(C)c2c(c1C)C(O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.5 g of sodium borohydride were added, whilst ice-cooling, to a mixture of 1.2 g of 2-methoxyethyl α-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxymethyl]-2,5,7,8-tetramethyl-4-oxochroman -6-yloxy}acetate (prepared as described in Example 35) and 20 ml of methanol, and the mixture was stirred for 60 minutes. The reaction mixture was then poured into ice-water, neutralized with 10% w/v aqueous hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound as a pale yellow powder.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([OH:23])=[O:22])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:27]1([C:33]([CH:35](Br)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C.S(=O)(=O)(O)O>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=1)[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([O:23][CH:35]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22])=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CCO
Product: O=C(c1ccccc1)C(OC(=O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Temperature: 70 °C
Reaction time: 48 h
Yield: 28.4 %

Procedure:
Sodium (54 mg) was dissolved in ethanol (8.0 ml), and then 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylic acid (665 mg), conc. sulfuric acid (1 drop), and desyl bromide (539 mg) was successively dissolved thereto. The resulting mixture was stirred at 70° C. for 2 days, cooled to room temperature, and partitioned between ethyl acetate and 1N HCl. The organic layer was washed with 1N HCl, aqueous sodium bicarbonate, and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 2-oxo-1,2-diphenylethyl 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylate (297 mg) as a pale yellow oil. (+) APCI-MS (m/z): 534 (M+ +1) IR (Nujol): 1735, 1690, 1630, 1225 cm-1
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([N:13]1[CH2:17][C:16]([O:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[CH:15][C:14]1=[O:27])[CH2:5][CH:6]1[CH2:11][CH:10]2[CH2:12][CH:7]1[CH2:8][CH2:9]2.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:7]12[CH2:12][CH:10]([CH2:9][CH2:8]1)[CH2:11][CH:6]2[CH2:5][CH:4]([N:13]1[CH2:17][C:16]([O:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])=[CH:15][C:14]1=[O:27])[C:3]([OH:28])=[O:2]
Reactant: COC(=O)C(CC1CC2CCC1C2)N1CC(Oc2c(F)cccc2F)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC1CC2CCC1C2)N1CC(Oc2c(F)cccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
In a flask was placed 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (87 mg, 0.22 mmol) dissolved in tetrahydrofuran (3 mL). To this mixture at 25° C. was added a solution of lithium hydroxide monohydrate (19 mg, 0.44 mmol) in water (3 mL) and stirred for 1 h at 25° C. The mixture was then treated with a 1N aqueous hydrochloric acid solution to pH=2 and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-bicyclo[2.2.1]hept-2-yl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (73 mg, 87%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[NH:15][C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[O:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl.O>O1CCOCC1>[OH:11][C:10]1[C:17]2[C:13](=[CH:12][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:16])[NH:15][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(C2=COc3ccccc3C(=O)N2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2[nH]c(=O)c3ccccc3c2O)c1
Temperature: 100 °C
Yield: 82 %

Procedure:
To a suspension of 1 g (3.74 mmol) of 3-(3-Methoxy-phenyl)-4H-benzo[f][1,4]oxazepin-5-one in dioxane (20 mL), 0.225 g (5.6 mmol) of sodium hydride (60% dispersion in mineral oil) were added under strictly oxygen-free atmosphere and the mixture was heated at 100° C. for 45 min. After cooling to room temperature, 2N hydrochloric acid was added till pH 1 then water was added until complete precipitation of the product was reached. The solid was filtered, washed with water and dried in vacuo, affording 0.82 g of the title compound (82%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][O:11][C:7]1[C:6]([Br:12])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[CH:9][C:8]=1[Br:10]
Reactant: BrCCCBr
Reactant: CC(=O)c1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(OCCCBr)c(Br)c1

Procedure:
A stirred mixture of 3,5-dibromo-4-hydroxyacetophenone (3.0 g, 10.1 mmol), K2CO3 (2.8 g, 20.3 mmol), 1,3-dibromo-propane (4.0 g, 19.8 mmol) in acetonitrile (100 ml) was heated at reflux for 5 hours. The solvent was removed. The crude product was extracted into dichloromethane (150 ml) and the insoluble inorganics were filtered off. The solution was concentrated to dryness again. Purification was carried out by flash chromatography on silica gel (45 g, SiO2 ; eluted with 1:1 hexane:dichloromethane). The material thus obtained (2.8 g) was recrystallized twice from isopropyl ether to give analytically pure 1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone, m.p.=87-88° C.
Reaction SMILES: [F-].[CH2:2]([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:41]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([O:52][Si](C(C)(C)C)(C)C)[CH:47]=2)=[O:43])[CH:39]=[C:38]([Cl:60])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([OH:37])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:60][C:38]1[CH:39]=[C:40]([C:42]([NH:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([OH:52])[CH:47]=2)=[O:43])[CH:41]=[C:20]([Cl:19])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:2])=[O:36])[CH2:26][NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])=[O:23]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CNC(=O)c2cc(Cl)c(C(=O)N[C@@H](CNC(=O)c3cccs3)C(=O)O)c(Cl)c2)c1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
Tetra-n-butylammonium fluoride (1 M in tetrahydrofuran; 3.94 mL, 3.94 mmol) was added to a solution of N-[2,6-dichloro-4-[[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine (2.38 g, 3.6 mmol) in tetrahydrofuran (30 mL). The solution was stirred at room temperature for 3 h, then diluted with ethyl acetate and concentrated. The residue was chromatographed (50-100% ethyl acetate/hexanes then 10% methanol/ethyl acetate) to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(thiophene-2-carbonyl)amino]-L-alanine, methyl ester (1.68 g, 85%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br.[I-:13].[Na+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][I:13]
Reactant: COC(=O)C#CCCCCCBr
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C#CCCCCCI
Yield: 98.6 %

Procedure:
To a solution of 4.05 g of 8-bromo-2-octynoic acid methyl ester (prepared as described hereafter) in 24 ml of acetone was added 3.9 g of sodium iodide, the mixture was refluxed with heating for one hour, and concentrated under reduced pressure. The residue was dissolved in water, extracted with diethyl ether, the extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure to give 4.80 g of the title compound having the following physical characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@H](C(O)=O)CC1C=CC=CC=1)=O)(C)(C)C.[N+:39]([C:42]1[CH:62]=[CH:61][C:45]([CH2:46][NH:47][C:48](=[O:60])[C@H:49]([CH3:59])[NH:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:57])[CH3:56])[NH2:53])=[CH:44][CH:43]=1)([O-:41])=[O:40].C(Cl)Cl>C(OCC)(=O)C>[N+:39]([C:42]1[CH:62]=[CH:61][C:45]([CH2:46][NH:47][C:48](=[O:60])[C@H:49]([CH3:59])[NH:50][C:51](=[O:58])[C@H:52]([CH2:54][CH:55]([CH3:56])[CH3:57])[NH:53][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:44][CH:43]=1)([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCc1ccc([N+](=O)[O-])cc1
Yield: 71 %

Procedure:
Parallel syntheses for the D-isomer (R1 =H, R2 =benzyl) and L-isomer (R1 =benzyl, R2 =H) were performed. The following procedure was used for each. The procedure of Example 2, Section B was followed, using t-butoxycarbonyl-D-phenylalanine for one isomer and t-butoxycarbonyl-L-phenylalanine for the other, and using L-leucyl-L-alanine 4-nitrobenzylamide of the formula ##STR28## instead of (-)N-(L-2-hydroxy-4-methylpentanoyl)-L-alanine 4-nitrobenzyl amide. The reaction was carried out on a 2.0 mmol scale, using methylene chloride (10 mL) instead of dimethylformamide as the solvent. After the extractions, the crude product was purified by silica gel chromatography, eluting with 7:3 methylene chloride:ethyl acetate to afford the products as white solids (D-isomer: 0.83 g, 1.42 mmol, 71% yield; L-isomer: 0.77 g, 1.3 mmol, 62% yield). Verification of the structures was as follows:
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([CH:42]=O)[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:42][C@H:39]1[CH2:38][CH2:37][C@H:36]([C:33]2[CH:32]=[CH:31][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1
Reactant: CCCCCc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCc1ccc([C@H]2CC[C@H](C=C(Br)Br)CC2)cc1
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
A solution of 5.0 g of tetrabromomethane in 60 ml of methylene chloride was placed a -10° C. in a sulphonation flask under argon gasification and treated within 5 minutes with a solution of 7.9 g of triphenylphosphine in 20 ml of methylene chloride. The resulting clear orange solution was stirred at -10° C. for a further 1 minute and then a solution of 1.95 g of trans-4-(p-pentylphenyl)cyclohexanecarboxaldehyde in 20 ml of methylene chloride was added dropwise within 3 minutes. The mixture was subsequently left to stand at -18° C. overnight, then poured into 600 ml of hexane and the separated precipitate was filtered off (rinsing with hexane). The concentrated filtrate was digested with 300 ml of hexane, left to stand at -18° C. for 30 minutes, filtered (rinsing with hexane) and the filtrate was concetrated. Low-pressure chromatography (0.5 bar) of the residue (1.87 g) on silica gel with hexane gave 503 mg of 1-[trans-4-(2,2-dibromovinyl)cyclohexyl)-4-pentylbenzene as colourless crystals (purity 95.8%); m.p. 35°-37.7° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:12]1C[O:15][CH2:14][CH2:13]1.BrCCCO>C(OCC)(=O)C>[OH:15][CH2:14][CH2:13][CH2:12][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCNC1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CCOC(C)=O
Product: OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
Potassium carbonate (269 g) and pyrrolidine (200 mL) were added in that order to a THF solution (500 mL) of 3-bromopropanol (200 g) at 0° C. The reaction liquid was stirred at room temperature for 15 hours, then ethyl acetate (500 mL) was added to it, and further stirred at room temperature for 1 hour. The obtained reaction liquid was filtered through Celite, and the solid on the Celite was washed with ethyl acetate. The wash liquid and the filtrate were concentrated under reduced pressure, and ethyl acetate (500 mL) was added to the resulting residue, then stirred for 1 hour and filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified through distillation (boiling point: 62° C., 1 mmHg) to obtain (3-hydroxypropyl)pyrrolidine (156 g, yield 95%).