Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)=[N:12][N:13]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][N:29]1[CH2:32][CH:31]([C:33]([O:35]C)=[O:34])[CH2:30]1)[CH3:2].[OH-].[Na+].Cl>C(O)(C)C.O>[CH2:1]([C:3]1[C:8]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)=[N:12][N:13]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][N:29]1[CH2:30][CH:31]([C:33]([OH:35])=[O:34])[CH2:32]1)[CH3:2]
Reactant: CCc1c(CN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of methyl 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)methyl]-3-azetidinecarboxylate (D8) (64 mg) in isopropanol (3 mL) and water (3 mL) was added sodium hydroxide (50 mg). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with 2N HCl till pH ˜6.0. The mixture was extracted with EA/THF for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated and the residue was purified by Mass Directed AutoPrep to give 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)methyl]-3-azetidinecarboxylic acid (E2) (35 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.10 (3H, t), 1.33 (6H, d), 2.85 (2H, m), 3.23 (3H, m), 3.42 (2H, m), 3.67 (2H, s), 4.93 (1H, m), 7.33 (1H, t), 7.50 (3H, m), 8.23 (2H, m). δF (DMSO-d6, 376 MHz): −61.3. MS (ES): C25H26F3N3O3S requires 505. found 506.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[C@@H:9]([CH3:12])[C@H:8]([C:13]([OH:15])=O)[CH2:7]1.[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:13]([C@H:8]1[C@H:9]([CH3:12])[C:10](=[O:11])[N:6]([CH2:5][C:4]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:3]=2[O:2][CH3:1])[CH2:7]1)=[O:15])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1ccc(CN2C[C@@H](C(=O)O)[C@H](C)C2=O)c(OC)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C[C@@H](C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)[C@H](C)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of the crude product of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (14.0 g) in chloroform (60 ml) were sequentially added (R)-4-benzyl-2-oxazolidinone (8.15 g), WSC.HCl (9.70 g), 4-dimethylaminopyridine (2.81 g), and the mixture was stirred overnight at room temperature. This reaction solution was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1 to 1/3) to give the titled compound (low-polarity component 11.4 g, high-polarity component 10.1 g).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([O-:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(O)CO>O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)(=[O:13])=[O:12])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=S([O-])c1cccc2cnccc12
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: O=[N+]([O-])c1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Yield: 19.1 %

Procedure:
A mixture of sodium 5-isoquinolinesulfinate 100 mg (0.5 mmol), 4-fluoronitrobenzene 70 mg (0.5 mmol), ethylene glycol 0.1 ml and ethyleneglycoldiethylether 0.1 ml was heated and refluxed for 3.5 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate, the organic layer washed with a saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was recrystallized from methanol to give 5-(4-nitrophenylsulfonyl)isoquinoline 30 mg (20.3%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)[CH:5]=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1>C1(C)C=CC=CC=1.O>[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]4)[CH:5]=[CH:4][C:3]=2[C:28]([F:31])([F:30])[F:29])=[CH:48][CH:47]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C(F)(F)F)c(Cl)n3)ccc21
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C(F)(F)F)c(-c4ccc(OC)cc4)n3)ccc21
Temperature: 80 °C

Procedure:
To a solution of ethyl [(1S)-5-(3-{[6-chloro-5-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 303, 0.06 g, 0.14 mmol) in a mixture of toluene (3.75 mL), 1,4-dioxane (0.75 mL), and water (0.88 mL) were added Na2CO3 (0.15 g, 1.38 mmol), 4-methoxyphenyl boronic acid (0.08 g, 0.55 mmol), and PdCl2(dppf)CH2Cl2 (0.02 g, 0.03 mmol). The mixture was heated at 80° C. for 4 h, and then concentrated under reduced pressure. The product (0.11 g, 94%) was purified by silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, 1H), 7.39 (t, 1H), 7.33 (d, 2H), 7.04 (d, 1H), 6.94 (dd, 2H), 6.74 (d, 1H), 6.65 (dd, 1H), 6.50 (d, 1H), 4.08 (q, 2H), 3.97 (t, 2H), 3.79 (s, 3H), 3.45-3.30 (m, 3H), 2.76-2.68 (m, 3H), 2.35 (dd, 1H), 2.30-2.20 (m, 1H), 1.95 (qt, 2H), 1.70-1.58 (m, 1H), 1.19 (t, 3H).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.[F:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[CH:25]=[C:26]([F:29])[C:27]=1O>>[CH:16]1([C:8]2[C:7]([CH2:6][O:5][C:27]3[C:26]([F:29])=[CH:25][C:24]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:23][C:22]=3[F:21])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CS(=O)(=O)OCc1c(C2CCCC2)nsc1C(F)(F)F
Product: O=C(O)CCc1cc(F)c(OCc2c(C3CCCC3)nsc2C(F)(F)F)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-cyclopentyl-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CD3OD) δ6.89-6.96 (m, 2H), 5.26 (s, 2H), 3.57 (m, 1H), 2.89 (t, J=7.6 Hz, 2H), 2.61 (t, J=7.6 Hz, 2H), 2.06-2.12 (m, 2H), 1.81-1.97 (m, 4H), 1.69-1.79 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C19H15F5NO3S, 436.1 (M+H). found 436.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]#[N:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2>C1COCC1.C(O)C.[Ni].O.[NH4+].[OH-]>[NH2:25][CH2:24][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: Cc1cc(C#N)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(CN)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 7-methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile (0.104 g, 0.3 mmol) in THF (1 mL) and ethanol (4 mL) was treated with a suspension of Raney nickel in water (1 mL) and aqueous NH4OH (0.5 mL). The mixture was stirred at ambient temperature for 12 h under hydrogen atmosphere (1 atm.). After this time GC-MS indicated that all the starting material was consumed. The reaction mixture was filtered and concentrated to afford the desired product. The material was used without purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH2:20])=[O:19]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([NH2:20])=[O:19])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(I)cc1
Reactant: NC(=O)c1sccc1N
Product: NC(=O)c1sccc1NC(=O)Cc1ccc(I)cc1

Procedure:
This compound was prepared from 2-(4-iodophenyl)acetic acid and 3-aminothiophene-2-carboxamide using protocol B. Method[1], MS (ESI) 387.0, Retention time=1.777 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]([NH:14][CH3:15])=[O:13])[CH2:3]1.[O:17]1[CH2:22][CH2:21][N:20]([S:23]Cl)[CH2:19][CH2:18]1.Cl.N1C=CC=CC=1.O>N1C=CC=CC=1>[CH3:15][N:14]([S:23][N:20]1[CH2:21][CH2:22][O:17][CH2:18][CH2:19]1)[C:12](=[O:13])[O:11][C:8]1[C:9]2[O:10][C:2]([CH3:16])([CH3:1])[CH2:3][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: ClSN1CCOCC1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CN(SN1CCOCC1)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A mixture of 6.6 g of carbofuran and 4.8 g of morpholinosulfenyl chloride in 40 ml of pyridine was allowed to stand at room temperature for about 18 hours. The mixture, which contained solid pyridine hydrochloride, was poured into water and the aqueous mixture extracted with diethyl ether. The ether extract was washed with dilute acid, then with water and with saturated sodium chloride solution and dried. Evaporation of the ether gave 6.1 g of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (methyl)(morpholinosulfenyl)carbamate, m.p. 75° -78° . Recrystallization from hexane-diethyl ether increased the melting point to 89° .
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=2)[N:8]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[NH2:65][C@@H:66]([CH2:80][C:81]1[CH:86]=[C:85]([F:87])[CH:84]=[C:83]([F:88])[CH:82]=1)[C@H:67]([OH:79])[CH2:68][NH:69][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[C:73]([CH2:77][CH3:78])[CH:72]=1.Cl>C(Cl)Cl.CO>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH:65][C@@H:66]([CH2:80][C:81]3[CH:82]=[C:83]([F:88])[CH:84]=[C:85]([F:87])[CH:86]=3)[C@H:67]([OH:79])[CH2:68][NH:69][CH2:70][C:71]3[CH:76]=[CH:75][CH:74]=[C:73]([CH2:77][CH3:78])[CH:72]=3)=[O:17])[CH:13]=2)[N:8]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCN1CCN(S(C)(=O)=O)c2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1CCN(S(C)(=O)=O)c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 8 h
Yield: 45.2 %

Procedure:
A solution of 4-butyl-1-(methylsulfonyl)-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (99 mg), HATU (181 mg), HOBt (64 mg), and diisopropylethylamine (100 μL) was stirred in methylene chloride (1.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (129 mg) and diisopropylethylamine (100 μL) in methylene chloride (1.0 mL) was added and the mixture was stirred overnight. The mixture was diluted with methylene chloride, washed with 1 N hydorchloric acid (10 mL), saturated sodium bicarbonate (10 mL), and brine. The organic layer was then dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purificatio by flash column chromatography (silica, 1:9 methanol/chloroform) provided a clear solid. The solid was dissolved in methanol (1 mL), and treated with hydrochloric acid (0.5 mL, 1.0 M diethyl ether). The resulting precipitate was collected by filtration to provide 90 mg of the title compound: ESI MS m/z 629 [M+H]+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([NH2:17])[CH2:15][CH3:16].CS(C)=O>O>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:17][CH2:14][CH2:15][CH3:16])[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: CCCN
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: O
Solvent: CS(C)=O
Product: CCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 7.1 parts of 4-fluoro-3-nitrobenzoic acid, 9.1 parts of 1-propanamine and 25 parts of dimethyl sulfoxide is stirred for 3 hours at 60° C. The reaction mixture is poured onto 150 parts of water. The precipitated product is filtered off, washed with water and dried, yielding 8.8 parts of 3-nitro-4-(propylamino)benzoic acid; mp. 208° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[O:21][C:22]4[C:27]([C:28](=[O:37])[C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[O:21][C:22]4[C:27]([C:28](=[O:37])[C:29]=3[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(Cc3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1cccc(O)c1)nn2Cc1oc2ccccc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.1 %

Procedure:
To a solution of example 54 (0.200 g, 0.383 mmoles) in dichloromethane (30 ml), BBr3 (1M in dichloromethane, 2.0 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as off-white solid (0.070 g, 36% yield). MP: 280-283° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.69(s,1H), 8.20(s,1H), 8.06(dd, J=8.2,1.7 Hz, 1H), 7.80(m,1H), 7.51(m 2H), 7.39(m,2H), 7.17(m, 2H), 7.11(dt, J=8.7,2.2 Hz, 1H), 7.02(d, J=8.6 Hz, 1H), 7.00(s,1H), 6.86 (dd, J=7.7,1.8Hz, 1H), 5.5 (s, 2H). Mass: 479.88(M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1cccc(Sc2ccc(Br)cc2)c1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cccc(Cl)c3)cc2)c1C
Yield: 26.2 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(3-chlorophenylsulfanyl)-benzene (0.159 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(3-chloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.065 g, 26%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[P:61]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])([O:63][CH2:64][C:65]([NH2:68])([CH3:67])[CH3:66])=[O:62].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[C:70]([O:69][P:61]([O:63][CH2:64][C:65]([NH:68][C:20]([C:19]1[CH:23]=[CH:24][C:16]([S:15][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:14][CH:13]=2)=[C:17]([NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:18]=1)=[O:21])([CH3:67])[CH3:66])([O:74][C:75]([CH3:77])([CH3:76])[CH3:78])=[O:62])([CH3:73])([CH3:72])[CH3:71]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: CC(C)(N)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 61.6 %

Procedure:
To a solution of the product of Example 89E (100 mg, 0.19 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate [TBTU] (72 mg, 0.22 mmol), the product of Example 95C (65 mg, 0.23 mmol) in DMSO (1 mL) was added N,N-diisopropylethylamine (0.065 mL, 0.37 mmol) dropwise at room temperature under N2. The mixture was stirred at room temperature for 12 hours under N2. The reaction was diluted with ethyl acetate and the organic layer was washed sequentially with water (3×) and brine, dried over MgSO4, and concentrated. The residue was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate in dichloromethane (0-100%) to give the title compound (93 mg, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:24]([CH3:27])([CH3:26])[CH3:25])(=O)C.Cl(O)(=O)(=O)=O>O>[C:24]([O:18][C:17](=[O:19])[C@H:15]([CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[NH2:16])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(=O)OC(C)(C)C
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](N)CCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
Nδ -(Benzyloxycarbonyl)-L-ornithine tert-butyl ester was prepared according to a general published procedure (Bodanszky, M.; Bodanszky, A.; The Practice of Peptide Synthesis; Spring Verlag: New York, 1984). Specifically, Nδ -(benzyloxycarbonyl)-L-ornithine (10.0 gm, 37.6 mmol, Sigma Chemicals, Inc.) was mixed with tert-butyl acetate (564 ml) and perchloric acid (5.91 ml, 69-72% aqueous solution) at room temperature. The reaction mixture became homogenous after 15 minutes and was stirred at room temperature for 2 days. Water (300 ml) was added to the reaction mixture, and the two layers obtained were separated. The organic layer was extracted twice (2×200 ml) with water, and the combined aqueous layers were adjusted to pH 9.5-10.0 with 50% NaOH. The aqueous layer was then filtered to remove a small amount of insoluble material, and the filtrate was extracted with ethyl acetate (3×300 ml). The combined ethyl acetate extracts were dried over MgSO4 and were concentrated by rotary evaporation at reduced pressure to yield 7.5 g of Nδ -(benzyloxycarbonyl)-L-ornithine tert-butyl ester as an oil (65% yield). 1H NMR (DCCl3) δ 1.44 (s,9H), 1.5-1.9 (m,4H), 3.23 (t,2H), 3.31 (t,1H), 5.09 (s,2H and s,1H broad), 7.35 (s,5H).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH:19]3[CH2:28][CH2:27][C:22]4([O:26][CH2:25][CH2:24][O:23]4)[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[CH:6]=1)C.[OH-].[Na+].Cl>C(O)C>[O:23]1[C:22]2([CH2:21][CH2:20][CH:19]([CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][N:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:4]([OH:29])=[O:3])[CH2:16][CH2:15]3)[CH2:28][CH2:27]2)[O:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Yield: 106.2 %

Procedure:
To a solution of 3.75 g (9.3 mmol) of 3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}benzoic acid ethyl ester in 20 mL of ethanol are added 10.2 mL of an aqueous 1N sodium hydroxide solution. Stirring is maintained overnight. The mixture is cooled and 2.55 mL (10.2 mmol) of 4N hydrochloric acid solution are added. After evaporation under reduced pressure, the solid is taken off with ethyl acetate, filtered and dried at 50° C. under vacuum to give 3.7 g of crude 3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}benzoic acid.
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)[CH:2]=[CH2:3].[NH2:14][C@H:15]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)[C@H:16]([OH:30])[CH2:17][NH:18][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=2)[CH2:21][CH2:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([S:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:14][C@@H:15]([CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)[C@H:16]([OH:30])[CH2:17][NH:18][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=2)[CH2:21][CH2:20]1)=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCSc1cccc(C(=O)O)c1
Reactant: CCc1cccc(C2(NC[C@@H](O)[C@H](N)Cc3cc(F)cc(F)c3)CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCSc1cccc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNC2(c3cccc(CC)c3)CC2)c1
Yield: 176.8 %

Procedure:
3-(Allylthio)benzoic acid (717 mg, 3.69 mmol), (2R,3R)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethylphenyl)cyclopropyl]amino}butan-2-ol (247mg, 0.685 mmol), and HATU (Aldrich, 2.1 g, 5.54 mmol) were dissolved in dichloromethane (35 mL), at ambient temperature, and treated with diisopropylethylamine (1.6 mL, 9.225 mmol). Upon completion, the reaction mixture was concentrated and chromatographed (SiO2, 2:1 to 1:1 Hexanes: EtOAc) to give the desired compound (650 mg). (LRMS (M+H) m/z=537.8)