Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:11]=1[CH3:12].[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]C)=[O:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][C:11]1[O:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH2:6][O:5][C:4]1[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=1[CH2:2][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
A mixture of 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (0.98 g), methyl 2-(4-hydroxyphenyl)acetate (0.51 g), anhydrous potassium carbonate (0.52 g), and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). To a mixture of the obtained oil, tetrahydrofuran (6 mL), and methanol (6 mL) was added a 1N aqueous sodium hydroxide solution (6 mL) and the mixture was stirred at room temperature for 2 hrs. Dilute hydrochloric acid was added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.00 g, 76%) of 2-[4-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH:12]([S:14](=[O:26])(=[O:25])[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1)[CH3:13])C1C=CC=CC=1>CO>[CH:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][S:14]([CH:12]([CH3:13])[CH2:11][NH2:10])(=[O:25])=[O:26])[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCC(NS(=O)(=O)C(C)CNC(=O)OCc2ccccc2)CC1
Solvent: CO
Product: CC(C)N1CCC(NS(=O)(=O)C(C)CN)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
255 mg (0.64 mmol) crude [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-propyl]-carbamic acid benzyl ester were dissolved in 10 ml MeOH. The solution was evacuated and rinsed with argon several times. 30 mg palladium on charcoal (10%) were added and again the mixture was evacuated and rinsed with argon several times. Finally argon was exchanged by hydrogen (balloon filled with hydrogen) and the mixture was stirred for 4 h at room temperature. The reaction mixture was filtered over “Celite” and the filter residue was washed with 10 ml MeOH. The filtrate was concentrated under vacuo to give crude 1-amino-propane-2-sulfonic acid (1-isopropyl-piperidin-4-yl)-amide as a colorless oil.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][N:7]([C:10]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[O:11])[CH2:6][CH2:5]2)OC1.[ClH:18].Cl.[NH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]([NH2:25])=[NH:24].Cl>C(O)C>[ClH:18].[NH2:25][C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][C:26]=2[F:30])[NH:20][C:4]2([CH2:5][CH2:6][N:7]([C:10]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[O:11])[CH2:8][CH2:9]2)[N:24]=1
Reactant: O=C(N1CCC2(CC1)OCCO2)n1ccnc1
Reactant: N=C(N)c1c(N)cccc1F
Agent: Cl
Solvent: CCO
Product: NC1=NC2(CCN(C(=O)n3ccnc3)CC2)Nc2cccc(F)c21
Temperature: 55 °C

Procedure:
1-(1H-Imidazol-1-ylcarbonyl)-4-piperidone ethylene ketal (Example EE, 156 mg., 0.66 mmol) was added to 2-amino-6-fluorobenzamidine dihydrochloride (150 mg, 0.66 is mmol) in ethanol (10 ml) together with an excess of HCl (1M in ether). This mixture was heated to 55° C. overnight, concentrated in vacuo and purified by flash column chromatography eluting with dichloromethane, increasing the gradient to dichloromethane/methanol (10:1), to give a solid which triturated from ethanol/ether to give yellow crystals, m.p. 260° C. (dec.).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH2:27]([S:34](Cl)(=[O:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][S:34]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: CC(C)CN([C@@H](CCCCNS(=O)(=O)Cc1ccccc1)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 24 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with benzylsulfonyl chloride under the conditions described in example 2 to yield 24% of the desired product.
Reaction SMILES: CO[C:3](=[O:29])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][CH2:16][CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:30]1([CH2:42][C:43]([NH2:45])=[O:44])[C:40]2=[C:41]3[C:36](=[CH:37][CH:38]=[CH:39]2)[CH2:35][CH2:34][CH2:33][N:32]3[CH:31]=1>>[C:30]1([C:42]2[C:43](=[O:44])[NH:45][C:3](=[O:29])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([CH2:15][CH2:16][CH2:17][O:18][Si:19]([CH:23]([CH3:24])[CH3:25])([CH:20]([CH3:22])[CH3:21])[CH:26]([CH3:27])[CH3:28])=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:40]2=[C:41]3[C:36](=[CH:37][CH:38]=[CH:39]2)[CH2:35][CH2:34][CH2:33][N:32]3[CH:31]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(CCCO[Si](C(C)C)(C(C)C)C(C)C)ccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: CC(C)[Si](OCCCc1ccc2c(C3=C(c4cn5c6c(cccc46)CCC5)C(=O)NC3=O)c[nH]c2c1)(C(C)C)C(C)C

Procedure:
Beginning with 6-((triisopropylsilyloxy)propyl)indole-3-glyoxylic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [H-].[Na+].CO[C:5](=O)[CH:6]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].IC[CH2:24][CH2:25][CH:26]([O:32]C(=O)C)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH3:20][S:17]([CH:6]([CH2:5][CH2:24][CH2:25][CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:18])=[O:19]
Reactant: COC(=O)CCCCCCC(C(=O)OC)S(C)(=O)=O
Reactant: CCCCCC(CCCI)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.3 %

Procedure:
A suspension of 57% sodium hydride/mineral oil (3.84 g., 0.091 mole) is washed by decantation with petroleum ether to remove the mineral oil. The residual solid is suspended in dry dimethylformamide (100 ml.) and treated with a solution of dimethyl-2-methylsulfonylazelate (23.5 g., 0.08 mole) in dry dimethylformamide (60 ml.) added dropwise at ambient temperature under a nitrogen atmosphere. The resulting solution is stirred for 1 hour at room temperature, cooled to ~10° C., and treated with 1-iodo-4-acetoxynonane (30 g., 0.096 mole) added at such a rate as to maintain an internal temperature less than 35° C. After 19 hours at ambient temperature, the reaction mixture is filtered. Collected sodium iodide (17.1 g.) is washed with ether. The combined filtrate and washings are concentrated in vacuo at ~100° C. yielding a residual oil which is partitioned between ether and dilute hydrochloric acid. The organic extract is washed with water and saturated brine, dried over magnesium sulfate and evaporated in vacuo leaving the title compound as a viscous oil (37.7 g., 98%), pmr (CDCl3) δ 2.0 (s, 3H), 3.0 (s, 3H), 3.65 (s, 3H), 3.81 (s, 3H) and 4.9 (b, H).
Reaction SMILES: [OH:1][C@@H:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]=1[C:12]1[NH:13][C:14]2[C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1.[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:35][C:21]([C:20]1[C:14]2[NH:13][C:12]([C:6]3[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=3[NH:4][CH2:3][C@@H:2]([OH:1])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1)=[O:22]
Reactant: NCc1cccc(F)c1
Reactant: O=C(O)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(F)c1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 mL round-bottomed flask, 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid (0.84 g, 2.15 mmol), 3-fluoro-benzylamine (296 mg, 270 μL, 2.37 mmol) and DIEA (612 mg, 827 μL, 4.73 mmol) were combined with DMF (10 mL) to give a black solution and to this was added HATU (982 mg, 2.58 mmol). The reaction was stirred at room temperature overnight. The next day, the reaction was dripped into water and the resulting precipitate was filtered and washed with water, ethyl ether, and hexanes. The purple solid was incompletely dissolved in minimal boiling ethanol and the resulting solid that formed upon cooling was filtered and washed with ethanol and hexanes yielding 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 3-fluoro-benzylamide as a light purple solid. LC/MS calcd for C28H24FN5O3 (m/e) 497.0, obsd 497.9 (M+H); 1H NMR (DMSO-d6-TFA) δ: 11.25 (br. s., 1H), 10.77 (br. s., 1H), 9.32 (t, J=5.8 Hz, 1H), 7.71-7.97 (m, 2H), 7.14-7.63 (m, 10H), 7.03-7.13 (m, 1H), 6.21 (d, J=7.5 Hz, 1H), 4.84 (br. s., 1H), 4.68 (br. s., 2H), 3.65 (d, J=12.5 Hz, 1H), 3.46 (d, J=7.0 Hz, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:14])=[O:13])=[CH:8][CH:7]=1.[Br:15]Br.Br>Cl>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:14])=[O:13])=[CH:8][C:7]=1[Br:15]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: BrBr
Agent: Br
Agent: Cl
Agent: [Al+3]
Product: CC(=O)c1ccc(C)c(Br)c1
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Anhydrous aluminum chloride (30 g, 225 mmol) was added to a 100 mL 2-neck round-bottom flask equipped with a magnetic stirrer, a septum, and a pressure-equalizer dropping funnel. The flask was flushed with nitrogen through the septum. 4-Methylacetophenone (13.3 mL, 100 mmol) was added to the flask via the dropping funnel over a period of 10 min. After the mixture was stirred for additional 30 min, bromine (5.7 mL, 110 mmol) was added dropwise over a period of 5 min. The reaction was completed when the reaction mixture solidified and no more hydrogen bromide was generated. The solidified mixture was transferred portionwise to a 3N aqueous HCl solution (250 mL). The dark oil at the bottom of the solution was extracted by ether (3×30 mL). The organic layer was then washed by a saturated NH4Cl aqueous solution (50 mL), dried over with anhydrous magnesium sulfate, and concentrated to get a crude product. The crude product was further purified by distillation under reduced pressure (118° C., 3 mm Hg) to give 18.53 g (87% yield) of the desired product. m.p. 94–95° C.; 1H NMR (300 MHz, CDCl3) δ 2.46 (3H, s), 2.58 (3H, s), 7.33 (1H, d, J=4.7 Hz), 7.79 (1H, dd, J=4.7, 0.99 Hz), 8.12 (1H, d, J=0.99 Hz); 13C NMR (75 MHz, CDCl3) δ 23.19, 26.52, 123.21, 127.08, 130.87, 132.32, 136.46, 143.53, 196.4; IR (neat) 3024 (s), 1684 (s), 1599 (m), 1383 (m), 1521 (s), 1039 (m), 958 (w), 907 (m), 831 (w) cm−1; MS m/z 212 (M+), 199, 197, 171, 169, 89; HRMS calcd.: C9H9OBr 211.9837, found: 211.9840.
Reaction SMILES: [C:1]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]=1[CH2:22][O:23][CH3:24])=[CH:18][C:17]([OH:25])=[CH:16][CH:15]=3)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1.C(O)(=O)C>CS(C)=O.C(OCC)(=O)C>[C:1]([C:9]1[N:10]=[CH:11][C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:21]=1[CH2:22][O:23][CH3:24])=[CH:18][C:17]([O:25][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1)=[CH:16][CH:15]=3)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3ccc(O)cc3c12
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3ccc(Oc4ccc(Br)cn4)cc3c12

Procedure:
332 mg of 3-benzoyl-6-hydroxy-4-methoxymethyl-beta-carboline and 130 mg of potassium hydroxide powder were mixed in 3 ml of dimethyl sulfoxide under argon with 285 mg of 2,5-dibromopyridine in 1 ml of dimethyl sulfoxide and heated for 1 hour to 90°-95° C. The reaction mixture was poured on ice water, acidified with 1N-acetic acid to pH 5 and shaken out with ethyl acetate. The ethyl acetate phase was washed with saturated common salt solution, dried on magnesium sulfate and concentrated by evaporation. After chromatography on silica gel with dichloromethane/ethyl acetate 1:1 as eluant and recrystallization from the main fraction from ethyl acetate/petroleum ether, the title compound with melting point 193°-194° C. was obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2.[CH3:14][C:15]1[CH:16]=[C:17]([Mg]Br)[CH:18]=[C:19]([CH3:21])[CH:20]=1>CCOCC.Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:15]1[CH:16]=[C:17]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]3)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Cc1cc(C)cc([Mg]Br)c1
Reactant: CC(C)C1=Cc2c(Cl)cccc2C1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: Cc1cc(C)cc(-c2cccc3c2C=C(C(C)C)C3)c1

Procedure:
4-chloro-2-isopropylindene (10.0 g, 54 mmol) and NiCl2(PPh3)2 (1.8 g, 2.8 mmol) were dissolved in 150 mL of Et2O. 3,5-dimethylphenylmagnesium bromide (54 mmol) as a Et2O solution was added under vigorous stirring and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq), neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 5.5 g (39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:8][C:9](=[O:20])[C@H:10]([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]1[CH2:7][CH2:6]1.[C:22](NC(CC)C(O)=O)(OC(C)(C)C)=O>>[CH3:1][O:2][C:3](=[O:21])[CH:4]([NH:8][C:9](=[O:20])[CH:10]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:19][CH3:22])[CH:5]1[CH2:6][CH2:7]1
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C1CC1
Product: CCC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)OC)C1CC1

Procedure:
Following the procedure for the preparation of methyl{[N-(tert-butoxycarbonyl)-L-alanyl]amino}(cyclopropyl)acetate but substituting N-Boc-alpha-aminobutyric acid and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.40–0.62, 0.94–0.99, 1.09–1.12, 1.46, 1.63–2.06, 3.77, 4.04, 5.02, 6.54.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1
Reactant: COc1ccc(Cc2cc(I)ccc2Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.4 %

Procedure:
1-chloro-4-iodo-2-(4-methoxybenzyl)benzene (10.0 g, 27.9 mmol) was dissolved in methylene chloride (150 mL). To the resulting mixture was added dropwise boron tribromide (21 g, 83.7 mmol) under cooling in an ice-water bath. After the completion of dropwise addition, the mixture was warmed up to room temperature, and stirred for 3 hr. The mixture was quenched with a saturated sodium bicarbonate solution, was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (150 mL×2). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under a reduced pressure. The resulting crude product was purified with a silica-gel column chromatography (ethyl acetate:petroleum ether=0-1:20) to produce 8.5 g of a product in a yield of 88%.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[C:13]([C:23]([O:25][CH2:26][CH2:27][C:28]#[N:29])=[O:24])=[C:14]([CH2:20][CH2:21][CH3:22])[NH:15][C:16]=1[CH2:17][CH2:18][CH3:19])=[O:10])C1C=CC=CC=1.C(O)=O.CO>C(Cl)(Cl)Cl.[Pd]>[C:28]([CH2:27][CH2:26][O:25][C:23]([C:13]1[CH:12]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[C:11]([C:9]([OH:10])=[O:8])=[C:16]([CH2:17][CH2:18][CH3:19])[NH:15][C:14]=1[CH2:20][CH2:21][CH3:22])=[O:24])#[N:29]
Reactant: CCCC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(CCC)N1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: O=CO
Solvent: CO
Product: CCCC1=C(C(=O)O)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(CCC)N1
Reaction time: 1 h

Procedure:
A solution of 5-benzyloxycarbonyl-3-(2-cyanoethoxy) carbonyl-1,4-dihydro-4-(4-nitrophenyl) -2,6-dipropylpyridine (10.6 g, 20.4 mmol) in 200 ml of 4.4% (w/w) formic acid/MeOH mixture was stirred with Pd/C (10%, 3.50 g) at room temperature. After 1 hr, the reaction was quenched by addition of 50 ml of CHCl3. The mixture was filtered and concentrated to give a yellow powder, which was dissolved in CHCl3 (250 ml), washed with 0.5N aqueous HCl (100 ml) and brine (100 ml), then dried over Na2SO4. After filtration and evaporation of solvent, 3-(2-cyanoethoxy)carbonyl-1,4-dihydro-4-(4-nitrophenyl)-2,6-dipropylpyridine-5-carboxylic acid was obtained as a yellow powder (8.04 g, 92%).
Reaction SMILES: C([NH:11][C:12](=[N:47]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]([C:34]([NH:36][C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[CH3:38])=[O:35])[NH:18][C:19](=[O:33])[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C=CC=CC=1)=O.[ClH:58].CO>CC(O)=O.[Pd]>[ClH:58].[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]([NH:18][C@@H:17]([C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[CH3:38])=[O:35])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:11])[NH2:47])=[O:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reaction time: 4 h

Procedure:
(R)-Nω,Nω '-bis(Cbz)-N2 -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]-arginine amide (5.40 g; 7.10 mmol; from step (f) above) in HOAc (300 mL) was flushed with nitrogen prior to the addition of 10% Pd/C (w/w; 1.10 g). The heterogeneous solution was briefly flushed with hydrogen and then stirred under 1 atmosphere of hydrogen for 4 hours. When the deprotection was complete, as determined by TLC analysis, the solution was filtered through a pad of Celite to remove the catalyst. The filtrate was evaporated at reduced pressure to give the crude product. The crude acetate salt was dissolved in HCl/MeOH, treated with activated carbon, filtered, concentrated, and dried under vacuum at 55-60° C. for 5 hours to give the sub-title compound as an off-white solid (3.47 g).
Reaction SMILES: [Si](CC1CCC(C[C@H](NC(N2CCC[C@@H]([C@@](C3C=CC=C(Cl)C=3F)(O)CCCCOC)C2)=O)CN(C)C(=O)OCC[Si](C)(C)C)CC1)(C(C)(C)C)(C)C.[N+](CC)(CC)(CC)CC.[F-].[Cl:64][C:65]1[C:66]([F:100])=[C:67]([C@:71]([C@@H:79]2[CH2:84][CH2:83][CH2:82][N:81]([C:85]([NH:87][C@H:88]([CH2:97][NH:98][CH3:99])[CH2:89][C@H:90]3[CH2:95][CH2:94][C@H:93]([OH:96])[CH2:92][CH2:91]3)=[O:86])[CH2:80]2)([OH:78])[CH2:72][CH2:73][CH2:74][CH2:75][O:76][CH3:77])[CH:68]=[CH:69][CH:70]=1.ClC1C(F)=C([C@]([C@@H]2CCCN(C(N[C@H](CNC)C[C@H]3CC[C@@H](O)CC3)=O)C2)(O)CCCCOC)C=CC=1>CC#N>[Cl:64][C:65]1[C:66]([F:100])=[C:67]([C@:71]([C@@H:79]2[CH2:84][CH2:83][CH2:82][N:81]([C:85]([NH:87][C@H:88]([CH2:97][NH:98][CH3:99])[CH2:89][CH:90]3[CH2:91][CH2:92][CH:93]([OH:96])[CH2:94][CH2:95]3)=[O:86])[CH2:80]2)([OH:78])[CH2:72][CH2:73][CH2:74][CH2:75][O:76][CH3:77])[CH:68]=[CH:69][CH:70]=1
Reactant: CNC[C@H](C[C@H]1CC[C@H](O)CC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCOC)c2cccc(Cl)c2F)C1
Agent: CC[N+](CC)(CC)CC
Agent: CNC[C@H](C[C@H]1CC[C@@H](O)CC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCOC)c2cccc(Cl)c2F)C1
Agent: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCC(C[Si](C)(C)C(C)(C)C)CC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Solvent: CC#N
Product: CNC[C@H](CC1CCC(O)CC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCOC)c2cccc(Cl)c2F)C1

Procedure:
A solution of 2-(trimethylsilyl)ethyl (S)-3-(4-((tert-butyldimethylsilyl)methyl)cyclohexyl)-2-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)propyl(methyl)carbamate (79 mg, 0.0991 mmol) and Et4NF (36.9 mg, 0.248 mmol) in dry CH3CN (8 mL) was heated under reflux for 2 h. After the reaction was completed by analysis of HPLC, the mixture was concentrated in vacuo. The product was purified by preparative HPLC to give two isomeric compounds: (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S)-1-(trans-4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide (16 mg, 0.0295 mmol) 1H NMR (400 MHz, CD3OD): 2.14 (m, 1H), 2.71 (s, 3H), 3.25 (s, 3H), 3.44-3.49 (m, 1H), 3.94-3.98 (m, 1H), 4.12 (m, 1H), 4.33-4.37 (m, 1H), 7.16-7.11 (t, 1H), 7.33-7.39 (m, 1H), 7.50-7.55 (m, 1H). MS (E/Z): 542 (M+H+) and (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((2S)-1-(cis-4-hydroxycyclohexyl)-3-(methylamino)propan-2-yl)piperidine-1-carboxamide (10 mg, 0.0185 mmol) 1H NMR (400 MHz, CD3OD): 2.14 (m, 1H), 2.71 (s, 3H), 3.25 (s, 3H), 3.94-4.02 (m, 1H), 4.12 (m, 1H), 4.33-4.37 (m, 1H), 7.16-7.11 (t, 1H), 7.34-7.39 (m, 1H), 7.50-7.54 (m, 1H). MS (E/Z): 542 (M÷H+).