Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@@H:44]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:43]([C@@H:44]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:45][N:46]2[CH2:47][CH:48]([OH:50])[CH2:49]2)[CH3:42])=[O:17])=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CCCC[C@@H](CN1CC(O)C1)NC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 29.6 %

Procedure:
DIPEA (0.275 mL, 1.58 mmol) was added to a stirred suspension of 4-chlorobenzoic acid (0.082 g, 0.53 mmol) and TBTU (0.169 g, 0.53 mmol) in DCM (1 mL) at rt. The suspension was stirred for 5 min. A solution of (S)-1-(2-(methylamino)hexyl)azetidin-3-ol (Compound G2.2) (0.11 g, 0.53 mmol) in DCM (1 mL) was added and the reaction was stirred at rt overnight. The reaction mixture was washed with an 8% aq. sol. of NaHCO3 (2 mL). The organic layer was dried through a phase separator and the solvent was removed in vacuo. Purification by preparative HPLC afforded the title compound (51 mg, 30%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.75-0.80, 0.82-0.87, 0.91-0.99, 1.02-1.46, 2.31-2.39, 2.44-2.62, 2.65-2.73, 3.16-3.53, 3.99-4.17, 4.36-4.48, 5.23, 7.30-7.33, 7.35-7.39, 7.45-7.49. Total number of protons in spectrum: 25. HRMS (M+H)+: calculated 325.1683. found 325.169
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>>[Br:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCCBr)cc1
Yield: 99 %

Procedure:
Methyl 4-hydroxybenzoate (5.0 g, 32.86 mmol) was combined with 1,2-dibromoethane (35 mL) and potassium carbonate (6.8 g, 49.23 mmol, 1.5 eq.) then heated at reflux for 18 h. The reaction mixture was concentrated under reduced pressure then the residue partitioned between ethyl ether (500 mL) and water (200 mL). The ether was extracted with 2 N sodium hydroxide (5×50 mL). The solvent was removed under reduced pressure to give the desired product as a white solid (8.47 g, 99%).
Reaction SMILES: C(OC(CC1C=CC(O)=C(C)C=1)C(O)=O)C.[CH2:17]([O:24][C:25](=[O:45])[CH:26]([O:42][CH2:43][CH3:44])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH2:35]C2C=CC=CC=2)[CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25](=[O:45])[CH:26]([O:42][CH2:43][CH3:44])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Agent: CCOC(Cc1ccc(O)c(C)c1)C(=O)O
Product: CCOC(Cc1ccc(O)c(C)c1)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid (0.71 g, 3.15 mmol) in the same manner as described for 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid benzyl ester. The crude product was purified by column chromatography using n-heptane/EtOAc (3:2) as the eluent and the title compound was obtained as an oil (0.51 g, 51.6%). 1H NMR (400 MHz, CDCl3): δ 7.26-7.38 (m, 5H), 6.96 (s, 1H), 6.97-6.91 (d, 1H), 6.65-6.67 (d, 1H), 5.16 (s, 2H), 4.08-4.12 (t, 1H), 3.61-3.66 (m, 1H), 3.39-3.44 (m, 1H), 2.96-2.99 (d, 2H), 2.20 (s, 3H), 1.17-1.22 (t, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](O)(=[O:10])[CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:8]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[CH3:9]
Reactant: Oc1ccccc1
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccccc1
Yield: 90 %

Procedure:
Toluene (100 ml), phenol (8.94 g, 95 mmol) and acetic acid (6.05 g, 100 mmol) were added into a 200-ml flask in this order at room temperature and then p-toluenesulfonic acid monohydrate (2.85 g, 15 mmol) was charged thereto. The solution was gently heated and subjected to reflux dehydration for 3 to 5 hours. After reflux dehydration, the solution was cooled to around room temperature, added with triethylamine (2.40 g, 25 mmol) at room temperature, stirred and then added with silica gel. After continuing to stir for a while, the silica gel was filtered off. After the solvent of the filtrate was removed in vacuum distillation, phenyl acetate (11.64 g, 90%) was isolated in distillation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[C:18]([O:22][C:23](=[O:26])[CH2:24][Zn+])([CH3:21])([CH3:20])[CH3:19].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Cc1cc(OCc2ccccc2)ccc1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OCc2ccccc2)ccc1CC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of 5-benzyloxy-2-bromotoluene (1 g, 3.61 mmol) in THF (10 ml) was added 2-tert-butoxy-2-oxoethylzinc chloride (18.04 ml, 9.02 mmol). Nitrogen gas bubbled through the mixture for 10 min. then Pd2(dba)3 (0.165 g, 0.180 mmol) and X-PHOS (0.172 g, 0.361 mmol) were added and the resulting mixture heated at 60° C. for 50 min. The mixture was cooled, diluted with ethyl acetate (20 mL), washed with aqueous ammonium chloride (saturated, 1×15 mL), dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 50M, using a gradient eluant of EtOAc/Hexane (0-20%) %) to afford the title compound. LC/MS (m/z): 335(M+Na)+.
Reaction SMILES: C(O[C@H]1C2C(=CC(Br)=CC=2)[C@@H](NC[C@@H](O)[C@@H](N)CC2C=C(F)C=C(F)C=2)C1)C=C.[CH3:30][N:31]([C@@H:39]([CH2:43][CH:44]=[CH2:45])[C:40]([OH:42])=O)[C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[CH2:46]([O:49][CH:50]1[C:58]2[C:53](=[CH:54][C:55]([O:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:56][CH:57]=2)[CH:52]([NH:66][CH2:67][C@@H:68]([O:78][Si:79]([C:82]([CH3:85])([CH3:84])[CH3:83])([CH3:81])[CH3:80])[C@@H:69]([NH2:77])[CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:51]1)[CH:47]=[CH2:48]>>[CH2:46]([O:49][CH:50]1[C:58]2[C:53](=[CH:54][C:55]([O:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:56][CH:57]=2)[CH:52]([NH:66][CH2:67][C@@H:68]([O:78][Si:79]([C:82]([CH3:85])([CH3:84])[CH3:83])([CH3:80])[CH3:81])[C@@H:69]([NH:77][C:40](=[O:42])[C@@H:39]([N:31]([CH3:30])[C:32](=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:43][CH:44]=[CH2:45])[CH2:70][C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)[CH2:51]1)[CH:47]=[CH2:48]
Reactant: C=CCOC1CC(NC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)Cc2ccccc2)c2cc(Oc3ccccc3)ccc21
Reactant: C=CC[C@@H](C(=O)O)N(C)C(=O)CCCCC
Agent: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(Br)ccc21
Product: C=CCOC1CC(NC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)[C@H](CC=C)N(C)C(=O)CCCCC)c2cc(Oc3ccccc3)ccc21
Yield: 65.1 %

Procedure:
Step EW (1): (S)-2-(N-Methylhexanamido)pent-4-enoic acid (420 mg, 1.8 mmol) and (2R,3S)-N1-(3-(allyloxy)-6-phenoxy-2,3-dihydro-1H-inden-1-yl)-2-(tert-butyldimethylsilyloxy)-4-phenylbutane-1,3-diamine (1.0 g, 1.8 mmol, from Preparation BC) were coupled using a procedure analogous to Step CA (1) to afford 900 mg (65% yield) of N-((2S)-1-((2S,3R)-4-(3-(allyloxy)-6-phenoxy-2,3-dihydro-1H-inden-1-ylamino)-3-(tert-butyldimethylsilyloxy)-1-phenylbutan-2-ylamino)-1-oxopent-4-en-2-yl)-N-methylhexanamide. LC-MS (M+H)+=768.65; 1H NMR (300 MHz, CDCl3) δ ppm 0.0 (m, 6H) 0.7-0.9 (m, 12H) 1.0-1.4 (m, 6H) 1.4-1.7 (m, 3H) 1.7-2.3 (m, 4H) 2.4 (s, 3H) 2.5-3.0 (m, 4H) 3.5-3.8 (m, 1H) 4.0-4.4 (m, 4H) 4.7-4.8 (m, 1H) 4.8-5.4 (m, 4H) 5.5-6.1 (m, 2H) 6.8-7.4 (m, 13H).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.CCOC(/N=N/C(OCC)=O)=O.C(O)(C)C.[Br:36][C:37]1[CH:38]=[C:39]([OH:44])[C:40]([Cl:43])=[CH:41][CH:42]=1>C(Cl)Cl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([O:44][CH:1]([CH3:6])[CH3:2])[CH:38]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1cc(Br)ccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Oc1cc(Br)ccc1Cl
Reaction time: 0.17 h

Procedure:
To 1.70 g (6.5 mmol) of triphenylphosphine in 25 mL of CH2Cl2 at 0° C. was added 1.14 g (6.5 mmol) of diethylazodicarboxylate. After 10 minutes, 390 mg (6.5 mmol) of isopropanol was added, followed rapidly by 1.03 g (5.0 mmol) of 3-Bromo-6-chlorophenol. The reaction was complete within three hours, and was partitioned between ether and water. The phases were separated, and the ether phase was diluted with hexanes and washed twice with 10% aqueous methanol and once with brine. The ether/hexanes phase was dried over Na2SO4, filtered, and concentrated in vacuo to yield product as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])[S:5][CH:6]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:32]=2)[CH:3]=1)(=[O:11])=[O:10]
Reactant: CC(C)CN(Cc1cc(Br)cs1)S(=O)(=O)c1ccccc1Cl
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CN(Cc1cc(-c2cccc(S(C)(=O)=O)c2)cs1)S(=O)(=O)c1ccccc1Cl

Procedure:
In analogy to example 1, step 3, N-(4-bromo-thiophen-2-ylmethyl)-2-chloro-N-isobutyl-benzenesulfonamide was reacted with (3-methylsulfonylphenyl)-boronic acid, Na2CO3 and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct in dioxane/water to give 2-chloro-N-isobutyl-N-[4-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a light yellow oil. MS: 514.9 ([M+NH4]+)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](Br)=[CH:5][N:6]=[CH:7]2.[CH3:13][S-:14].[Na+]>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([S:14][CH3:13])=[CH:5][N:6]=[CH:7]2
Reactant: Nc1cccc2cncc(Br)c12
Reactant: C[S-]
Agent: [Na+]
Product: CSc1cncc2cccc(N)c12

Procedure:
5-Amino-4-bromoisoquinoline (prepared according to the process described by Gordon et al., J. Het. Chem,, 4, 410 (1967)) was allowed to react with sodium thiomethoxide according to the procedure of Massie, Iowa State Coll. J. Sci., 21, 41 (1946) (Ca. 41: 3044 g) to give 5-amino-4-methylthioisoquinoline. This material was coupled with 2-hexylthiodecanoic acid (prepared by the procedures described in Examples 1 and 3) using the procedure described in Example 25 to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:22][C:23]([OH:25])=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[C:23](=[O:25])[CH2:22][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH3:27]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccc(C(C)C)cn1
Reactant: CCNCC
Product: CCN(CC)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-(2-methoxy-phenyl)-amino]-acetic acid with diethylamine
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[O:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O1CCOCC1>[CH2:13]([NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:5]=2[N:11]=[CH:10][N:9]=1)[C:14]1[O:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CNCCN1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4ccco4)ncnc23)CC1
Solvent: C1COCCO1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4ccco4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-furfurylamino-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 203°-205° C.) and piperazine in dioxane at 80° C.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH3:31][N:32](C)C=O.[OH-].[Li+]>O1CCCC1.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:31]([C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([NH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)#[N:32]
Reactant: COC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2Br)C2CCCCC2)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2oc(C(Nc3ccc(C(=O)O)cc3)C3CCCCC3)c(C#N)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of methyl 4-{[(3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoate (1.46 g) synthesized above, zinc cyanide (362 mg) and N,N-dimethylformamide (30 mL) was added tetrakis(triphenylphosphine)palladium (0) (357 mg), and after deaeration, the mixture was stirred under argon atmosphere at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to give a yellow solid. To a solution (10 mL) of the obtained solid in tetrahydrofuran was added 1N lithium hydroxide aqueous solution (2.88 mL), and the mixture was stirred overnight with heating under reflux. Ethanol (10 mL) and water (10 mL) were added to the reaction mixture, and the mixture was stirred with heating under reflux for 3 hr. 1N lithium hydroxide aqueous solution (1.44 mL) was additionally added, and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (4.35 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (547 mg, 94%) as a pale-yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH2:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34].[N:35]1([C:40](N)=[NH:41])C=CC=N1.C(N(CC)CC)C.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:34].[C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]([NH:10][C@@H:11]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[CH3:20])=[O:17])[CH2:12][CH2:13][CH2:14][NH:15][C:40](=[NH:35])[NH2:41])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](NC(=O)[C@@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c1ccccc1)c1ccccc1)c1ccc(Br)cc1
Yield: 63.6 %

Procedure:
Prepared according to the method described in Example 2(f) above from (R)-N2 -(diphenylacetyl)-(R)-N-[1-(4-bromophenyl)ethyl]ornithine amide (free base, 0.42 g; 0.83 mmol; from step (d) above), 1H-pyrazole-1-carboxamidine mono hydrochloride (0.13 g; 0.83 mmol), triethylamine (0.17 g; 1.66 mmol; instead of DiPEA) and DMF (4 mL), 18 hours reaction time. The solution was concentrated under vacuum and the crude product chromatographed on silica gel using MeOH:CHCl3 :ammonium hydroxide (3:6:1). Conversion to the hydrochloride salt afforded the title compound as a white solid (0.31 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH3:20])=[C:15]([O:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:14]=[CH:13]2.[C:35](Cl)(=[O:40])[CH2:36][CH2:37][CH2:38][CH3:39].[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:20][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:2]3[O:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]=3[C:35](=[O:40])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[O:21][CH:22]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3cc4ccccc4o3)ccc2c1C
Reactant: CCCCC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCC(=O)c1c(-c2ccc3c(C)c(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a mixture of ethyl 2-{[6-(1-benzofuran-2-yl)-1-methyl-2-naphthyl]oxy}-3-phenylpropanoate (0.944 g, 2.10 mmol) in methylene chloride (4.2 mL) at −78° C. was added valeryl chloride (0.25 mL, 2.1 mmol), and tin (IV) chloride (0.25 mL, 2.1 mmol). The reaction mixture was stirred for 2 hours and 20 minutes. It was diluted with extra methylene chloride and poured into excess sodium bicarbonate solution. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The compound was purified by flash chromatography using 100% hexane and 0.5-3% ethyl acetate in hexane. It was dried at 60° C. for 30 minutes to afford ethyl 2-{[1-methyl-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}-3-phenylpropanoate as a yellow gum (0.553 g). Mass spectrum (+ESI, [M+H]+) m/z 5351HNMR (500 MHz, DMSO-d6): δ8.35 (d, 1H, J=1.7 Hz), 8.1 (d, 1H, J=9.0 Hz), 8.05 (dd, 1H, J=7.6 Hz and 1.0 Hz), 7.9 (d, 1H, J=9.2 Hz), 7.85 (dd, 1H, J=8.9 Hz and 1.8 Hz), 7.75 (d, 1H, J=8.1 Hz), 7.25-7.45 (m, 8H), 5.3-5.35 (m, 1H), 4.1 (q, 2H, J=6.9 Hz), 3.25-3.35 (m, 2H), 2.75 (t, 2H, J=7.3 Hz), 2.5 (s, 3H), 1.5-1.6 (m, 2H), 1.05-1.2 (m, 5H), and 0.7 ppm (t, 3H, J=7.4 Hz). Elemental Analysis for C35H34O5: Calculated: C, 78.63; H, 6.41; N, 0.00. Found: C, 78.70; H, 6.30; N, 0.00.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:14])[CH2:12][CH3:13]>CCO>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:14][CH2:11][CH2:12][CH3:13])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCCN
Solvent: CCO
Product: CCCNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-3-nitro-pyridine (18.0 g, 114 mmol) in EtOH(300 ml) is added n-propylamine(46.9 ml, 568 mmol) slowly at 0° C. and the resulting yellow mixture is warmed to room temp. After stirring for 2 h, the reaction is concentrated in vacuo. The residue is purified by flash chromatography (eluent 50% Hex/EtOAc) to give (3-nitro-pyridin-4-yl)-propyl-amine as a yellow solid. 1H NMR (CDCl3) δ 9.16 (s, 1H), 8.25 (d, J=6 Hz, 1H), 8.15 (br s, 1H), 6.68 (d, J=6 Hz, 1H), 3.29 (q, J=6.8 Hz, 2H), 1.74 (sextet, J=7.2 Hz, 2H), 1.02 (t, J=7.6 Hz, 3H). LRMS calcd 181.19, found 182.5 (MH+).
Reaction SMILES: [OH-].[Na+].[CH:3]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:7][C:6]=1[OH:21])=[O:4].C(Cl)(Cl)Cl.CO>CO>[CH:3]([C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:7][C:6]=1[OH:21])=[O:4]
Reactant: CCOC(=O)CCCCOc1ccc(C=O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(OCCCCC(=O)O)cc1O
Yield: 97.7 %

Procedure:
2 N aqueous NaOH (10 mL) was added to ethyl 5-(4-formyl-3-hydroxyphenoxy)valerate (1.5 g, mw 266.3, 5.8 mmol; prepared as in Example 16) dissolved in methanol (20 mL) and the solution stirred at 25° C. for 1 hour, at which point TLC (CHCl3 -methanol, 99:1) indicated the reaction was complete. Methanol was removed under reduced pressure and the reaction diluted with water (50 mL), washed with ethyl acetate (3×15 mL, discarded), acidified to pH 4 with 6 N aqueous HCl, and extracted with ethyl acetate (4×25 mL). The combined organic extracts were washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated to yield 1.35 g (98%) of a white solid. A portion of the solid was purified by flash chromatography on silica (CHCl3 -methanol, 45:1) and recrystallized from boiling ethyl acetate-hexane to provide NMR and TLC (Rf origin) pure title product; 1H NMR (500 MHz, CDCl3, 294 K) δ 11.47 (s), 9.71 (s), 7.42 (d, J=8.6; 1H), 6.53 (dd, J=2.3, 8.6; 1H), 6.41 (d, J=2.3; 1H), 4.04 (t, J=5.8; 2H), 2.46 (t, J=7.0; 2H), 1.86 (m; 4H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[O:8][CH:9]([CH:25]([CH:32]2[CH2:36][O:35][C:34]([CH3:38])([CH3:37])[O:33]2)[O:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:10]([NH:21][C:22](=[O:24])[CH3:23])[CH:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:12]=1)=[O:6]>C1COCC1>[C:22]([NH:21][CH:10]1[CH:9]([CH:25]([O:26][CH2:27][C:28]([OH:30])=[O:29])[CH:32]2[CH2:36][O:35][C:34]([CH3:37])([CH3:38])[O:33]2)[O:8][C:7]([C:5]([OH:6])=[O:4])=[CH:12][CH:11]1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])(=[O:24])[CH3:23]
Reactant: COC(=O)COC(C1COC(C)(C)O1)C1OC(C(=O)OC)=CC(O[Si](C)(C)C(C)(C)C)C1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)NC1C(O[Si](C)(C)C(C)(C)C)C=C(C(=O)O)OC1C(OCC(=O)O)C1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
Sodium hydroxide (5 mL, 0.1 M, 0.5 mmol) was added slowly to a stirred solution of 28 (100 mg, 0.19 mmol) in THF (5 mL). The resulting mixture was stirred for 2 h at room temperature. The organic solvent was evaporated and the aqueous solution was acidified with HCl to pH=2, extracted with ethyl acetate, and extract was concentrated to give 29 as a white solid (66 mg, 70%). mp 130° C. [α]D26+35.1° (c 1.2, CH3OH). 1H NMR (CD3OD, 500 MHz) 60.11 (s, 3H, CH3), 0.14 (s, 3H, CH3), 0.91 (s, 9H, 3CH3), 1.32 (s, 3H, CH3), 1.39 (s, 3H, CH3), 2.0 (s, 3H, NAc), 3.66 (s, 2H, OCH2), 3.98 (m, 2H), 4.14 (t, J=8.0 Hz, 1H), 4.20 (t, J=8.0 Hz, 1H), 4.27 (m, 1H, H-6), 4.33 (m, 1H), 4.63 (m, 1H, H-4), 5.84 (s, 1H, H-3). 13C NMR (CD3OD, 125 MHz) δ −4.65, −4.45, 18.81, 23.19, 25.43, 26.18, 26.61, 30.89, 51.97, 66.47, 68.13, 68.79, 70.76, 77.71, 78.38, 78.68, 109.35, 113.37, 144.93, 164.97, 173.24, 173.61. ESIMS calcd for C22H37NO10SiNa [M+Na]+ 526.3. Found 526.3. Anal. Calc. for C22H37NO10Si: C, 52.47; H, 7.41; N, 2.78. Found: C, 52.38; H, 7.48; N, 2.64.