Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:29][CH2:28]2)=[C:25]([CH:30]2[CH2:33][CH:32]([CH2:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH2:31]2)[O:24][N:23]=1)[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11].O.Br.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:28][CH2:29]2)=[C:25]([CH:30]2[CH2:31][CH:32]([CH2:34][CH:35]([CH2:38][CH3:39])[CH2:36][CH3:37])[CH2:33]2)[O:24][N:23]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:11]
Reactant: CCC(CC)CC1CC(c2onc(C(CC(=O)Nc3ccc(C)cc3Cl)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCC(CC)CC1CC(c2onc(C(CC(=O)O)CC(=O)Nc3ccc(C)cc3Cl)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
tert-Butyl 4-(2-chloro-4-methylphenylcarbamoyl)-3-{4-cyclopropyl-5-[3-(2-ethylbutyl)cyclobutyl]isoxazol-3-yl}butanoate (122 mg) and water (0.7 mL) were mixed. To the mixture was added a solution of 25 w/w % hydrogen bromide in acetic acid (1.4 mL) at ice temperature. After stirring at RT for 2 hr, aqueous 4 N sodium hydroxide (1.65 mL) was added to the reaction mixture at ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: methanol/chloroform/acetic acid=1/20/0.1) to give the title compound (56.7 mg). The title compound was analyzed using a chiral column. The retention time of the title compound was 8.2 min., and the optical purity thereof was 90.5% ee.
Reaction SMILES: C(Cl)(=O)C.[C:5]([C:7]1[CH:8]=[C:9]([C:22]#[C:23][CH2:24][C@H:25]([NH:30]C(OC(C)(C)C)=O)[C:26]([O:28][CH3:29])=[O:27])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])#[N:6].CO>C(OCC)(=O)C>[NH2:30][C@@H:25]([CH2:24][C:23]#[C:22][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:7]([C:5]#[N:6])[CH:8]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)[C@H](CC#Cc1ccc(OCc2ccccc2F)c(C#N)c1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CC(=O)Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)CC#Cc1ccc(OCc2ccccc2F)c(C#N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (225 ul, 248 mg, 3.16 mmol) was added dropwise to a solution of methyl (2S)-5-(3-cyano-4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-pentynoate (D70, 286 mg, 0.631 mmol), prepared with analogous procedure to that described hereinabove, in dry ethyl acetate (10 ml) and dry methanol (2 ml). After stirring at room temperature overnight the solvent was evaporated, water (10 ml) and dioxin (10 ml) were added and the pH was adjusted to 10 using 28% NH3 in water. The mixture was extracted with DCM. The combined organic layer was dried (Na2SO4), filtered and evaporated. The crude product was used in the next step. MS: (ES/+) m/z: 353 [MH+], C20H17FN2O3 requires 352.
Reaction SMILES: [CH3:1][C:2]([OH:16])([C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)=[O:5])[CH3:3].[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>>[CH3:3][C:2]([OH:16])([C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:8][CH:7]=1)=[O:5])[CH3:1].[CH2:19]([C:20]([O-:5])=[O:21])[CH2:18][C:17]([O-:22])=[O:23]
Reactant: O=C1CCC(=O)O1
Agent: CC(C)(O)C(=O)c1ccc(OCCO)cc1
Product: O=C([O-])CCC(=O)[O-]

Procedure:
As an illustrative example, a tri-functional compound can be prepared as follows. Irgacure 2959 (4-(2-hydroxyethoxy)phenyl-(2-hydroxy-2-propyl)ketone) can be reacted with succinic anhydride (reflux in triethylamine/Toluene) to obtain Irgacure 2959-monosuccinate. Norbloc (2-{3-(2H-Benxotriazol-2-yl)-4-hydroxyphenyl}ethyl methacrylate) is reacted with the obtained Irgacure 2959-monosuccinate in the presence of N,N-dicyclohexyl carbodiimide (DCC) and 4-(dimethylamino)pyridine (D-MAP) to obtain conjugated Irgacure 2959-Norbloc.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]1[CH2:8][CH:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[C:6](=[O:17])[N:5]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C[Si](C)(C)N[Si](C)(C)C.[Li].[C:36]([O:40][C:41]([N:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([CH2:52]Br)=[CH:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C@H:4]1[CH2:8][C@:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:12])[CH3:11])([CH2:52][C:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:43]([C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])[CH:44]=2)[C:6](=[O:17])[N:5]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)n1cc(CBr)c2ccccc21
Reactant: COC(=O)[C@H]1CC(O[Si](C)(C)C(C)(C)C)C(=O)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C[C@@](Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)(O[Si](C)(C)C(C)(C)C)C(=O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
1.45 g (3.9 mmol) of the above N-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-D-pyro-glutamic acid methyl ester were dissolved in 15 ml of anhydrous THF (tetrahydrofuran) in an atmosphere of argon gas. The resulting solution was cooled to −78° C., 2.8 ml (4.8 mmol; 1.7 mM/ml) of LHMDS (lithium hexamethyldisilazane) were added to it, and the mixture was stirred for an hour. A solution obtained by dissolving 1.30 g (4.2 mmol) of N-t-butoxycarbonyl-3-bromomethylindole in 4 ml of THF was added dropwise into the reacted solution and it was stirred at −78° C. for 25 minutes and then at room temperature for two hours. An aqueous solution of ammonium chloride was added to the reacted solution, and extraction was performed twice with 50 ml of ethyl acetate. The organic layer was washed with 50 ml of water and 50 ml of a saturated saline solution and was dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was refined by PTLC (preparative thin-layer chromatography) to yield 1.21 g (2.01 mmol) of N-t-butoxycarbonyl-(4R)-4-t-butyldimethylsilyloxy-4-(N-t-butoxycarbonyl-3-indolylmethyl)-D-pyroglutamic acid methyl ester. Its 1H-NMR spectrum showed a peak marked by a very small amount (several percent) of impurity beside the isomers of the compound.
Reaction SMILES: [Si]([O:8][C@H:9]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(C(C)(C)C)(C)C>O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:8][C@H:9]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:21]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3cccnc3)N2C(=O)OC(C)(C)C)cc1
Yield: 98.3 %

Procedure:
A solution of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(pyridin-3-yl)methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (11.0 g, 20.3 mmol) in 100 mL of 2 M tetrabutylammonium fluoride tetrahydrofuran solution was stirred at RT overnight. The mixture was then diluted with water and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated to afford 8.51 g (98%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 2H), 7.93 (d, J=8.0 Hz, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 3H), 6.36 (s, 1H), 4.54 (d, J=8.5 Hz, 1H), 4.18-4.09 (m, 2H), 3.92 (s, 3H), 3.23 (s, 1H), 3.13-3.10 (m, 1H), 2.61-2.52 (m, 1H), 1.78-1.60 (m, 2H), 1.49 (s, 9H). MS: m/z (ESI) 427 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:15][S:16]C.[Na]>>[CH2:13]([N:3]1[C:2]([S:16][CH3:15])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH3:14]
Reactant: CSC
Reactant: CCn1c(Cl)cc2ccccc2c1=O
Agent: [Na]
Product: CCn1c(SC)cc2ccccc2c1=O

Procedure:
By following the same procedure as in Example 1 using 0.6 g. of 3-chloro-2-ethyl-1-oxo-1,2-dihydroisoquinoline and 0.8 g. of an aqueous solution of 20% sodium methylsulfide, 0.31 g. of 2-ethyl-3-methylthio-1-oxo-1,2-dihydroisoquinoline was obtained (recrystallized from cyclohexane).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[CH3:11][C:12]1(C)[C:16](C)(C)OB(C(C)=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([C:12]([CH3:16])=[CH2:11])[CH:7]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=C(C)c1cnc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3,5-dichloropicolinonitrile (1.0 eq.), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (3.4 eq.) in toluene/ethanol (2:1, 0.04 M) was stirred at 100° C. for 2 hours, then 80° C. for 4 hours. After cooling to ambient temperature, the reaction content was diluted with ethyl acetate and water. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 3-chloro-5-(prop-1-en-2-yl)picolinonitrile as a white solid.
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].CCN(CC)CC.Br[C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][C@H:30]3[CH2:34][N:33]([C:35](=[O:51])[C@@H:36]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)[C@H:32]([C:52]([O:54][CH3:55])=[O:53])[CH2:31]3)[CH:23]=2)[CH:19]=[CH:20][CH:21]=1.CCOC(C)=O>CCO.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].C(Cl)Cl>[C:47]([O:46][C:44]([NH:43][C@@H:36]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:35]([N:33]1[CH2:34][C@H:30]([O:29][CH2:28][C:24]2[CH:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH:1]=[CH2:2])[CH:17]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:31][C@H:32]1[C:52]([O:54][CH3:55])=[O:53])=[O:51])=[O:45])([CH3:50])([CH3:48])[CH3:49]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](OCc2cccc(-c3cccc(Br)c3)c2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1cccc(-c2cccc(CO[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C4CCCCC4)C3)c2)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
Potassium vinyltrifluoroborate (2.0 eq.), Et3N (2.0 eq.) and PdCl2(dppf)-DCM adduct (0.05 eq.) were sequentially added to a 0.12 M solution of methyl (4R)-4-[(3′-bromobiphenyl-3-yl)methoxy]-1-{(2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylacetyl}-L-prolinate 106 in EtOH. The reaction mixture was stirred with heating at reflux for 3 h then it was cooled down to RT and diluted with H2O:EtOAc. The phases were separated and the organic layer was washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO2, PE:EtOAc=8:2) to afford the title compound 107 (72%) as a foam. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 7.75 (s, 1H), 7.71-7.61 (m, 2H), 7.59 (d, J 7.3, 1H), 7.56-4.43 (m, 3H), 7.39 (d, J 7.3, 1H), 6.94 (d, J 8.6, 1H), 6.86 (dd, J 17.7, 10.9, 1H), 5.98 (d, J 17.7, 1H), 5.36 (d, J 10.9, 1H), 4.66 (d, J 11.7, 1H), 4.58 (d, J 11.7, 1H), 4.36 (t, J 8.6, 1H), 4.32 (bs, 1H), 4.19 (d, J 10.9, 1H), 4.15-4.07 (m, 1H), 3.73-3.66 (m, 1H), 3.65 (s, 3H), 2.46-2.35 (m, 1H), 2.07-1.98 (m, 1H), 1.82-1.57 (m, 6H), 1.42-1.36 (m, 1H), 1.34 (s, 9H), 1.20-1.12 (m, 2H), 1.07-0.94 (m, 2H). MS (ES+) m/z 577 (M+H)+
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([O:26][CH2:27][CH3:28])[C:17]=2[CH3:29])=[C:13]([O:31]CC2C=CC=CC=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>O1CCOCC1.[Pd]>[OH:31][C:13]1[CH:12]=[CH:11][NH:10][C:9](=[O:8])[C:14]=1[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[C:18]([O:26][CH2:27][CH3:28])[C:17]=1[CH3:29]
Reactant: CCOc1c(S(C)(=O)=O)ccc(C(=O)c2c(OCc3ccccc3)ccnc2OCc2ccccc2)c1C
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOc1c(S(C)(=O)=O)ccc(C(=O)c2c(O)cc[nH]c2=O)c1C
Reaction time: 5 h
Yield: 101.6 %

Procedure:
To a solution of the product of step (c) (0.387 g) in 8 ml dioxane was added 110 mg of 10% palladium on carbon (Degussa type, water wet). The mixture was then shaken for 5 hours, filtered and the filter cake washed. The solvents were evaporated to yield 260 mg of 4-hydroxy-3-(3-ethoxy-2-methyl-4-methylsulfonylbenzoyl)pyrid-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]#[N:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:20][C:21]([CH2:23]Cl)=[CH2:22].[NH4+]=[S:26]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:23][C:21]([Cl:20])=[CH2:22])[C:10]([NH2:11])=[S:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N#CNc1cc(Cl)cc(Cl)c1
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cl)CN(C(N)=S)c1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Yield: 90 %

Procedure:
N-(3,5-dichlorophenyl)cyanamide (2.81 g) was dissolved in DMF (14.03 g), to which powdered potassium carbonate (3.11 g) and potassium iodide (0.26 g) were added at room temperature with stirring. Further, 2,3-dichloro-1-propene (2.00 g) was added dropwise at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 2.5 hours. After cooling to room temperature, DMF (9.00 g) and ammonium sulfide solution, yellow (8.00 g) having an S content of 6% were added dropwise to the reaction mixture at room temperature with stirring. The mixture was heated to 50° C. and stirred at the same temperature for 4 hour. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 4.00 g of N-(3,5-dichlorophenyl)-N-(2-chloro-2-propenyl)thiourea as a dark red solid (90% yield in appearance). The percentage area of liquid chromatography was 94%.
Reaction SMILES: [CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:24]([O:26]CC)=[O:25])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O.O.[OH-].[Li+].Cl>O1CCCC1>[CH2:1]([CH2:10][CH2:11][NH:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[CH:19][C:20]=2[Cl:22])[NH:15][C:14]=1[C:24]([OH:26])=[O:25])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCCC(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1
Yield: 55.3 %

Procedure:
Mix 3-[(phenacyl)ethylamino]-2-carbethoxy-4,6-dichloroindole (600 mg, 1.48 mmol), water (10 mL) and tetrahydrofuran (10 mL). Add lithium hydroxide monohydrate (0.22 g, 5.18 mmol) and stir at room temperature for 24 hours. Heat to reflux for 5 hours then pour into 1N hydrochloric acid (100 mL). Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo to give the crude product (0.72 g) as a white solid. Recrystallize (ethyl acetate/hexane) to give the title compound (0.32 g, 57%); mp 254°-6° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH2:6][CH2:5]2.[CH2:13](Br)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH2:5]2
Reactant: OC1=NCCc2cc(Br)ccc21
Reactant: BrCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: O=C1c2ccc(Br)cc2CCN1CCc1ccccc1
Temperature: 70 °C
Yield: 45.9 %

Procedure:
6-Bromo-1-hydroxy-3,4-dihydroisoquinoline (300 mg, 1.33 mmol, 1.0 equiv), tetrabutylammonium bromide (50 mg, 0.13 mmol, 0.10 equiv), and phenethyl bromide (220 uL, 1.6 mmol, 1.2 equiv) were combined in toluene (14 mL) and treated with 50% aq. NaOH (3 mL), and the resulting mixture stirred rapidly while heating to 70° C. After heating for 14 hours, the mixture was diluted with MTBE and washed with water, saturated NaHCO3, and brine. The organic phase was dried over Na2SO4. Addition of silica gel, concentration, and purification of the residue using flash silica gel chromatography (gradient of 3->18% ethyl acetate/hexanes) provided 6-bromo-2-phenethyl-3,4-dihydroisoquinolin-1-one (201 mg, 0.61 mmol, 46%) as a white solid. This isoquinolinone (201 mg, 0.61 mmol) was converted, via Methods 1 and 2, to compound 12 (90 mg, 50%) which was isolated as a white solid. Activity: A
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH2:49])=[CH:44][CH:43]=1>CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([C:8]([NH:49][CH2:48][C:45]2[CH:46]=[CH:47][C:42]([F:41])=[CH:43][CH:44]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(N)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(N)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 2-amino-4-methylthiazole-5-carboxylic acid (4.20 g, 26.0 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added 1-hydroxybenzotriazole (9.30 g, 69.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (6.60 g, 34.0 mmol), diisopropylethylamine (4.40 g, 34.0 mmol), and (4-fluorophenyl)methanamine (3.97 g, 32.0 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and N,N-dimethylformamide was removed in vacuo. The residue was dissolved in ethyl acetate (400 mL) and washed with saturated aqueous sodium bicarbonate (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford the title compound as a yellowish solid in 80% yield (5.60 g): 1H NMR (300 MHz, CDCl3) δ 7.39-7.17 (m, 2H), 7.01 (t, J=8.3 Hz, 2H), 5.78 (br s, 1H), 5.34 (br s, 2H), 4.50 (d, J=5.6 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 266.2 (M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:37][C@@H:36]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[NH:46][C:47](=[O:67])[C@H:48]([CH:54]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[NH:49][C:50]([O:52][CH3:53])=[O:51])[O:35][CH2:34][C@H:33]1[C:68](O)=[O:69])=[O:31])([CH3:28])([CH3:27])[CH3:26].[CH2:71]([NH2:78])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1.N1C(C)=CC=CC=1C>CN(C=O)C.CCOC(C)=O>[CH2:71]([NH:78][C:68]([C@H:33]1[N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:31])[CH2:37][C@@H:36]([CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[NH:46][C:47](=[O:67])[C@H:48]([CH:54]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[NH:49][C:50]([O:52][CH3:53])=[O:51])[O:35][CH2:34]1)=[O:69])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)CO1)C(c1ccccc1)c1ccccc1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)NCc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (1.4 eq) was added to a stirred mixture a solution of (3S,6R)-4-(tert-butoxycarbonyl)-6-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-3-carboxylic acid (Example 1, step 11) (1 eq), benzyl amine (1.2 eq) and 2,6-lutidine (2 eq) in DMF (0.05 M) and the mixture was stirred at room temperature for 16 hrs. The mixture was diluted in EtOAc, The organic layer was washed with aqueous saturated NH4Cl and brine. The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 10% to 100% of EtOAc/Hex to afford title compound.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:27])([C:23]([F:26])([F:25])[F:24])[CH2:14][CH2:15][CH2:16][S:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>C(Cl)Cl>[F:27][C:13]([F:12])([C:23]([F:24])([F:25])[F:26])[CH2:14][CH2:15][CH2:16][S:17]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[O:9]
Reactant: OCCCCSCCCC(F)(F)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(CCCCO)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
m-CPBA (64 mg, 0.37 mmol) was added to a cooled (0° C.) solution of 4-((4,4,5,5,5-pentafluoropentyl)thio)butan-1-ol (76 mg, 0.28 mmol) in DCM (3 mL) and it was stirred at 0° C. for 30 min. The reaction mixture was warmed to room temperature and was partitioned between a saturated solution of sodium bicarbonate and DCM. The organic layer was dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 10% MeOH/DCM to afford 52 mg of 4-((4,4,5,5,5-pentafluoropentyl)sulfinyl)butan-1-ol as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]#[N:20])([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.O1CCC[CH2:22]1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:11]([CH:10]1[CH2:9][C:8]([C:19]#[N:20])([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:14][CH2:15][C:16]1=[O:18])([O:13][CH3:22])=[O:12]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(F)cc1
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C1CC(C#N)(c2ccc(F)cc2)CCC1=O
Yield: 93 %

Procedure:
To a solution consisting of 42.71 gm. (0.139 mole) of the dimethyl ester of 4-(p-fluorophenyl)-4-cyanopimelic acid (prepared in Part A, above) and 900 ml. tetrahydrofuran is added 31.3 gm. (0.28 mole) potassium tert-butoxide. This reaction mixture is heated at the reflux temperature for 4 1/2 hours. It is allowed to cool. It is then chilled in ice and 225 ml. of 2.5 N aqueous acetic acid is added. The organic layer that forms is recovered and diluted with 750 ml. benzene. The benzene:tetrahydrofuran solution is washed successively with sodium bicarbonate, with water, and finally with brine. The solvents are then removed by evaporation under reduced pressure to give 35.6 gm. (93% yield) of 2-carbomethoxy-4-cyano-4-(p-fluorophenyl)cyclohexanone as a gum.