Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].C([O:18][CH2:19][CH2:20][O:21][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])(=O)CCC([O-])=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH3:25][C:23]([C:22]([O:21][CH2:20][CH2:19][OH:18])=[O:26])=[CH2:24]
Reactant: C=C(C)C(=O)OCCOC(=O)CCC(=O)[O-]
Agent: COC(=O)C1CCOCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCO
Temperature: 80 °C

Procedure:
A 1 L three neck flask equipped with a mechanical stirrer, condenser, thermocouple, and addition funnel was charged with THPE GE (112.5 g), mono-2-(methacryloyloxy)ethyl succinate (218.3 g), triethylamine (1.2 g), and Prostab® 5415 (0.2 g,). The mixture was heated to 80° C. for 7.5 hr to obtain a pale yellow mixture. The mixture was dissolved in 1250 mL of ethyl acetate, extracted with 500 mL of water followed by 500 mL of saturated sodium bicarbonate solution. The solution was dried with anhydrous sodium sulphate, then added to 1 liter of silica gel (Merck silica gel 60), and the solvent was removed. The silica gel containing the compound was then added to a column with 2500 g of silica gel and was eluted with a mixture of hexanes and ethyl acetate to isolate a purified fraction of the desired compound, THPE GE Su HEMA. 1H NMR (500 MHz, CDCl3) δ 1.93 (s, 9H), 2.08 (s, 3H), 2.61-2.7 (m, 12H), 3.84-4.2 (m, 15H), 4.3-4.4 (m, 12H), 5.6 (m, 3H), 6.1 (m, 3H), 6.75 (m, 6 H), 6.98 (m, 6H).
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[C:7](=[O:15])[O:6][C:5]=1[NH:16][C@@H:17]([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)(=[O:3])[CH3:2].[OH-:28].[Na+]>O1CCCC1.CO>[CH:25]1([C@H:17]([NH:16][C:5]([CH:4]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([F:14])[C:8]=2[C:7]([OH:6])=[O:15])[C:1](=[O:3])[CH3:2])=[O:28])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)c1c(N[C@H](c2cccc(F)c2)C2CC2)oc(=O)c2c(F)cccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)C(C(=O)N[C@H](c1cccc(F)c1)C1CC1)c1cccc(F)c1C(=O)O
Temperature: 20 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
4-Acetyl-3-{[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-amino}-8-fluoro-2-benzopyran-1-one (14.30 g, 38.72 mmol) was dissolved in a mixture of tetrahydrofuran (50 mL) and methanol (50 mL) and placed on an ice/water bath with stirring. NaOH (1 M in H2O, 100 ml) was added and stirring continued for 1 hour. The cold bath removed and the mixture was allowed to warm to r.t. (20° C.) during 1 hour. The reaction mixture was poured into ice-water mixture (200 g+200 ml), followed by slow addition of 2 M aq. HCl (200 mL) and extracted with ethyl acetate (200 mL), washed with sat. aq. NaCl, dried (Na2SO4), filtered and evaporated to give the title compound (14.65 g, yield 97.7%) as a pale brown foam. The crude product was used in the next step without further purification. LC-MS (m/z) 388.3 (MH+); tR=1.2. 1H NMR (500 MHz, DMSO-d6): a mixture of tautomers and diastereoisomers.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](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.[Cu]I>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:23])([F:22])[F:13])=[CH:16][CH:17]=2)=[C:6]([CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: C#Cc1ccc(N)c(C#N)c1C
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1c(C#Cc2ccc(C(F)(F)F)cc2)ccc(N)c1C#N
Yield: 72.7 %

Procedure:
A solution of 3.5 grams (0.022 mole) of 2-amino-5-ethynyl-6-methylbenzonitrile, 8.4 grams (0.031 mole) of 4-trifluoromethylphenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper(I)iodide in 100 mL of acetonitrile was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was partitioned between ethyl acetate and aqueous 1N hydrochloric acid. The two-layered mixture was filtered to remove a solid. The aqueous layer and the organic layer were separated, and the aqueous layer was washed with ethyl acetate. The ethyl acetate wash was combined with the organic layer, and the combination was washed with an aqueous solution of 10% lithium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was triturated with methylene chloride and filtered. The filtrate was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.8 grams of 2-amino-6-methyl-5-[(4-trifluoromethylphenyl)ethynyl]benzonitrile, mp 136°-138° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[C:4](=[O:20])[C:5]1[CH:6]=[N:7][CH:8]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:10]=1.Br[C:24]1[CH:25]=[C:26]2[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[CH:31][NH:30][C:27]2=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].O=[N-]>C(#N)C>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]1[C:26]2[C:27](=[N:28][CH:29]=[C:24]([C:9]3[CH:10]=[C:5]([C:4](=[O:20])[C:3]([N:2]([CH3:1])[CH3:22])=[O:21])[CH:6]=[N:7][CH:8]=3)[CH:25]=2)[NH:30][CH:31]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Reactant: CN(C)C(=O)C(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [N-]=O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(=O)C(=O)N(C)C)c3)cc12
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
Crude N,N-dimethyl-2-oxo-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)acetamide (592 g, 1.32 mol) from the boronic ester synthesis and 5-bromo-3-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine 7 (398.5 g, 1.32 mol) were stirred in acetonitrile (5 L) in 10 L reaction vessel. The solution was stirred and purged with N2 for 30 min. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (34 g, 40.8 mmol) and Na2CO3(aq) (312.8 g dissolved in 1.36 L H2O) were added. Stirring and purging with N2 continued for 30 min. Thereafter, the solution was heated to 75° C. and stirred under N2 for two days. After the conversion was confirmed to be complete by NMR, H2O (1700 ml) was added and stirring was continued for 10 min. Then heating was stopped and the reaction mixture was filtered over a pad of Celite®. The Celite® pad was washed with a 1:1 mixture of acetonitrile/H2O (3×1000 ml). The filtrate was concentrated until almost acetonitrile had evaporated and a brownish precipitate formed. The concentrated mixture was then extracted with CH2Cl2 (1×3.6 L, 2×1000 ml). The organic layers were combined and dried over Na2SO4, after which the solvent was evaporated in vacuo. The residue was treated with 1800 ml MeOH and sonicated for 15 minutes. The yellowish solid is filtered off and dried in vacuo. This solid is dissolved in a mixture of 10% MeOH in CH2Cl2 and filtered over a SiO2 plug, and washed off using 10% MeOH in CH2Cl2 (±15 L). Yielding after evaporation of the solvent in vacuo ketoamide (380 g, 0.95 mol, 72% over two steps).
Reaction SMILES: [CH3:1][N:2](C)CC1C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C#N>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([C:1]#[N:2])=[O:18])=[CH:15][CH:14]=1
Reactant: CN(C)Cc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: C#N
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)C#N)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
A solution of 135 g (1 mole) of dimethylbenzylamine in 100 ml of toluene was added dropwise, at -20° C, while cooling, in the course of 30 minutes to a mixture of 170 g (1 mole) of para-methoxybenzoyl chloride and 50 g of anhydrous hydrocyanic acid in 400 ml of toluene at such a rate that the internal temperature did not rise above -20° C during the addition. When the addition was complete, the mixture was stirred for a further 10 minutes at -20° C and excess hydrocyanic acid was then distilled, under a waterpump vacuum, into a cooled receiver. The residue was recrystallized from a mixture of benzene and ligroin. In this way 128 g (77% of theory) of para-methyoxybenzoyl cyanide with a melting point of 63° C were obtained.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8](C)(C1C=CC=C(C(C)(C)O)C=1)O.C(OC=C)(=O)C.[OH:27][C:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([CH3:42])([O:39][CH:40]=[CH2:41])[CH3:38])[CH:32]=1)([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[CH3:38][C:37]([C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:28]([O:27][CH:7]=[CH2:8])([CH3:30])[CH3:29])[CH:32]=1)([O:39][CH:40]=[CH2:41])[CH3:42]
Reactant: CC(C)(O)c1cccc(C(C)(C)O)c1
Reactant: C=COC(C)(C)c1cccc(C(C)(C)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C=COC(C)=O
Product: C=COC(C)(C)c1cccc(C(C)(C)OC=C)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene) diiridium(I) [Ir(cod)Cl]2 (67 mg, 0.1 mmol) and sodium carbonate (640 mg, 6 mmol) in toluene (5 ml) were added α,α,α′,α′-tetramethyl-1,3-benzenedimethanol (5 mmol) and vinyl acetate (2.15 g, 25 mmol), followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that 1-(1-hydroxy-1-methylethyl)-3-(1-methyl-1-vinyloxyethyl)benzene and 1,3-bis(1-methyl-1-vinyloxyethyl)benzene were formed in yields of 8% and 70%, respectively, with a conversion from α,α,α′,α′-tetramethyl-1,3-benzenedimethanol of 98%.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[C:20]3[NH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].C([N+]([CH2:29][CH3:30])(CC)CC)C>CC(C)=O.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>[C:30]1([C:9]2[CH:10]=[CH:11][C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:19][C:20]=3[C:8]=2[C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH:29]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CC[N+](CC)(CC)CC
Reactant: Ic1cccc(-c2cccc3c2[nH]c2ccccc23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [OH-]
Solvent: CC(C)=O
Product: c1ccc(-c2ccc3c([nH]c4ccccc43)c2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
91 g (242 mmol) of 3-iodophenylcarbazole 18 and 91 g (246 mmol) of phenylcarbazoleboronic ester 19 are suspended in acetone, and a 350 ml of 20% tetraethylammonium hydroxide solution (493 mmol) are added, the mixture is carefully degassed using argon. 4.6 g (4 mmol) of tetrakistriphenylphosphinepalladium are subsequently added. The reaction is heated to 70° C. The progress of the reaction is followed by means of thin-layer chromatography. When the reaction is complete, the batch is cooled to room temperature, and the precipitated product is filtered off with suction. The crude product is recrystallised from acetonitrile, giving a beige solid.
Reaction SMILES: CCCC[Si](CC)CC.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:18]=[CH:19][C:20]1C=C[C:23](C=C)=[CH:22][CH:21]=1.[SiH4].COC1C=CC=CC=1C(N1CCC[C@H]1CO)=O>C(Cl)Cl>[CH:16]1[C:17]2[C:12](=[CH:11][C:10]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=1
Reactant: C=Cc1ccc(C=C)cc1
Reactant: C=Cc1ccccc1
Agent: CCCC[Si](CC)CC
Agent: COc1ccccc1C(=O)N1CCC[C@H]1CO
Agent: [SiH4]
Solvent: ClCCl
Product: c1ccc2cc3ccccc3cc2c1
Reaction time: 3 h
Yield: 99.3 %

Procedure:
We were able to successfully load representative primary alcohols to silane resin VIIIa and cleave the resins to afford high yields of alcohol products (Scheme 13). In a typical experiment, 200 mg PS-DES-silane resin was combined with a DCM solution of 1.7 mg of Rh2 (pfb)4 in 10 mL round bottle flask under argon. Then 66 mg of (s)-(-)-1-(2-methoxybenzoyl)-2-pyrrolidinemethanol was added at room temperature and the reaction was monitored by IR. After 3 hrs, the reaction was complete (as evidenced by the disappearance of the Si-H stretch at 2100 cm-1), the reaction mixture was filtered, and washed with 3×DCM, 2×toluene, 2×THF/H2O (1:1), 3×THF. The product was dried under vacuum in a dessicator. This product was then treated with AcOH/THF/H2O (6:6:1) for 12 hrs and the filtrate was concentrated by speedvac (rt, 80 mins) to obtain alcohol with 99.3% yield (GC, anthracene as internal standard).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].[OH-].[K+].[C:13](=S)=[S:14].C>O.C(O)C>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]2[N:1]=[C:13]([SH:14])[NH:10][C:3]=2[CH:4]=1
Reactant: Nc1cc(F)c(Cl)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1cc2nc(S)[nH]c2cc1Cl
Reaction time: 4 h
Yield: 575.7 %

Procedure:
The procedure of Van Allan and Deacon, Org. Synth. Coll. Vol. IV, 569, was adapted. A mixture of 1,2-diamino-4-chloro-5-fluorobenzene (528 mg, 3.29 mmol, Aldrich), potassium hydroxide (202 mg, 0.36 mmol), carbon disulfide (280 mg, 0.36 mmol), 95% ethanol (3 mL) and water (0.45 mL) was heated under reflux for 3 h. Activated charcoal (120 mg) was then added cautiously, and after the mixture has been heated at the refluxing temperature for 10 min the activated charcoal was removed by filtration. The filtrate was heated to 60°-70° C., warm water (3 mL) was added, and then acetic acid (0.25 mL) in water (0.5 mL) was added with good stirring for 4 h. The mixture was placed in a refrigerator overnight to give a mixture of brown and white crystals. The brown crystals were removed by washing with chloroform (5 mL). Recrystallization from hot EtOH/H2O gave pure title compound (420 mg, 63.5%, purity >99.57% by HPLC) as a white cubic crystals; top: 294°-6° C. (sub. from 250° C.). IR (KBr, cm-1): 3443, 3131, 3075, 1618, 1506, 1487, 1462. 1H NMR (DMSO-d6): δ 7.169 (d, J=9 Hz, 1H); 7.245 (d, J=6.6 Hz, 1H); 12.758 (s, 2H). HRMS: calcd for C7H4ClFN2S (M+) m/z: 201.9766, Found: 201.9779.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][CH:10]([OH:13])[C:11]#[CH:12].N(C(C)C)C(C)C>ClCCl.[Cu]I.Cl[Pd](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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]#[C:11][CH:10]([OH:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: Clc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(O)C#Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To a solution of 4-chloro iodobenzene (10 g, 42 mmol), 3-butyn-2-ol (6.6 mL, 84 mmol, 2 eq.), and iPr2NH (14.8 mL, 105 mmol, 2.5 eq.) in 200 mL dichloromethane was added CuI (1.6 g, 8.4 mmol, 0.2 eq.) followed by Pd(PPh3)2Cl2 (1.5 g, 2.1 mmol, 5 mol %). The mixture was stirred for 1.5 hr at room temperature, concentrated and diluted with ether. The insoluble components of the mixture were filtered off and the filtrate washed with 1N HCl and brine, dried over MgSO4, filtered, concentrated and chromatographed with 20% ethyl acetate-hexane to provide 7.6 g of 4-(4-chloro-phenyl)-but-3-yn-2-ol.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]([O:13][CH3:14])[CH2:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.[CH3:18][C:19]1[C:20]([NH2:24])=[N:21][O:22][N:23]=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:7]2[CH:8]([O:13][CH3:14])[CH2:9][S:10](=[O:11])(=[O:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]([NH:24][C:20]1[C:19]([CH3:18])=[N:23][O:22][N:21]=1)=[O:17]
Reactant: Cc1nonc1N
Reactant: COC1CS(=O)(=O)c2ccc(C(=O)O)c(Cl)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CS(=O)(=O)c2ccc(C(=O)Nc3nonc3C)c(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (3.14 mmol) of 4-chloro-3-methoxy-2,3-dihydro-1-benzothiophene-5-carboxylic acid 1,1-dioxide and 0.33 g (3.15 mmol) of 4-methyl-1,2,5-oxadiazol-3-yl-amine were dissolved at room temperature (RT) in 35 ml of CH2Cl2, 3.02 g (4.74 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) were added and the mixture was stirred at RT for 1 h. Subsequently, 2.18 ml (15.64 mmol) of triethylamine and 75 mg (0.61 mmol) of 4-dimethylaminopyridine (DMAP) were added and the whole mixture was stirred at RT for 16 h. This was followed by washing with water and twice with 6N hydrochloric acid, drying of the organic phase over Na2SO4 and filtration with suction through silica gel, washing through with 1:2 heptane/ethyl acetate and concentration. Yield 708 mg (63%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[CH3:18])(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[CH2:16]([O:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]([NH2:7])=[C:9]([CH3:18])[CH:10]=1)[CH3:17].[C:22]([OH:24])([C:21]([F:26])([F:25])[F:20])=[O:23]
Reactant: CCOc1cc(C)c(NC(=O)OC(C)(C)C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(C)c(N)cc1C
Reaction time: 2 h

Procedure:
To a solution of 36 (950 mg, 3.6 mmol) in 10 mL dichoromethane, trifloroacetic acid (5 mL) was added. The reaction mixture was stirred for 2 h. At this point, LC-MS showed the reaction to be complete. The reaction flask was concentrated to remove the solvent and most of the TFA. The residue was then dried further in a high vacuum oven over 24 h to give the title compound 37 as TFA salt.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([S:11]([CH2:14][C@H:15]([NH:19][C@@H:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:21]([F:24])([F:23])[F:22])[C:16](O)=[O:17])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:57][C@@H:58]([CH2:67][CH3:68])[CH:59]([OH:66])[C:60]([NH:62][CH:63]1[CH2:65][CH2:64]1)=[O:61].CCN(C(C)C)C(C)C>ClCCl>[CH:63]1([NH:62][C:60](=[O:61])[CH:59]([OH:66])[C@@H:58]([NH:57][C:16](=[O:17])[C@@H:15]([NH:19][C@@H:20]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:21]([F:23])([F:24])[F:22])[CH2:14][S:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)(=[O:13])=[O:12])[CH2:67][CH3:68])[CH2:64][CH2:65]1
Reactant: CC[C@H](N)C(O)C(=O)NC1CC1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)C[C@H](N[C@@H](c2ccc(F)cc2)C(F)(F)F)C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](NC(=O)[C@H](CS(=O)(=O)c1cccc(S(C)(=O)=O)c1)N[C@@H](c1ccc(F)cc1)C(F)(F)F)C(O)C(=O)NC1CC1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 89.9 %

Procedure:
A solution of (R)-3-((3-(methylsulfonyl)phenyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-amino)propanoic acid (7.3 g; 15 mmol) and HATU (6.84 g; 18.0 mmol; 120 mole %) in anhydrous dichloromethane (200 mL) was stirred at ambient temperature for 5 minutes, then (3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide hydrochloride (35.0 mmol; 233 mole %) was added and the mixture stirred for 5 minutes. The reaction mixture was then cooled to 0-5° C. and treated with the dropwise addition of DIPEA (7.8 mL; 5.8 g; 45 mmol; 300 mol %). After the addition was complete, the cooling bath was removed and the reaction was stirred for 2.5 h at ambient temperature. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed in sequence with a solution of 10% aqueous potassium hydrogensulfate, water, 10% aqueous sodium bicarbonate, water, and finally saturated aqueous sodium chloride. The organic phase was dried (MgSO4), and concentrated almost to dryness. The residue was triturated with diethyl ether then some hexane was added. The resulting solid was filtered and washed with hexane to give 8.6 g (96%) of (3S)—N-cyclopropyl-2-hydroxy-3-((R)-3-((3-(methylsulfonyl)phenyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)amino)propanamido)pentanamide as an off-white solid. LC-MS, positive ion mode: m/z=638 [M+H]+ (100%); negative ion mode: m/z=636 [M−H]− (100%). Methods for the preparation of starting materials are disclosed in U.S. Pat. No. 7,488,848.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.[C:8](Cl)(=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1(C)C=CC=CC=1.CCCCCC>[C:8]([NH:1][C:2]1[C:6]([NH:7][C:8](=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:5][S:4][CH:3]=1)(=[O:24])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Nc1cscc1N
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCC(=O)Nc1cscc1NC(=O)CCCCCCCCCCCCCCC
Yield: 70 %

Procedure:
This compound was prepared in a yield of 70% of theory starting from 3,4-diaminothiophene and palmitoyl chloride (boiling point 141° C. at 1.4 mbar) in a similar manner to above. The melting point was 107-109° C. (from toluene-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:13][C:14]1[CH:20]=[C:19]([C:21]([F:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:18]=[C:17]([Cl:31])[C:15]=1[NH2:16]>N1C=CC=CC=1.O>[Cl:13][C:14]1[CH:20]=[C:19]([C:21]([F:30])([C:26]([F:27])([F:28])[F:29])[C:22]([F:25])([F:24])[F:23])[CH:18]=[C:17]([Cl:31])[C:15]=1[NH:16][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(Cl)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
4-Nitrobenzoyl chloride (4.55 g) was dissolved in a pyridine (30 ml) solution of 2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)aniline (2.7 g). The solution was refluxed under heating for 3 hours. After cooling to room temperature, the solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined and dried over magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml), and an aqueous solution (5 ml) containing sodium hydroxide (2.0 g) was added, and then stirred at room temperature for 4 hours. The reaction solution was extracted twice with ethyl acetate. The organic phases were combined, washed with 1 N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The drying agent (i.e., anhydrous magnesium sulfate) was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain N-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-4-nitrobenzamide (3.27 g, yield 83.4%).