Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](Cl)=[N:10][OH:11].[CH3:13][C:14]([CH3:26])([CH3:25])[C:15]#[C:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[O:18].C(=O)(O)[O-].[Na+].[Cl-]>C(O)(C)C.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:16]([C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[C:15]([C:14]([CH3:26])([CH3:25])[CH3:13])[O:11][N:10]=1
Reactant: ON=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)C#CC(=O)c1cccnc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: CC(C)(C)c1onc(-c2ccc(Cl)cc2Cl)c1C(=O)c1cccnc1
Temperature: 55 °C
Reaction time: 20 h
Yield: 76.6 %

Procedure:
A mixture of 72 mg (0.32 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 60 mg (0.32 mmol) of 4,4-dimethyl-1-(3-pyridyl)-2-pentyn-1-one, and 32 mg (0.38 mmol, 1.2 equivalents) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. for 16 hrs on a rotary table shaker. A second addition of 25 mg of carboximidoyl chloride and 10 mg of sodium bicarbonate was followed by another 20 hrs at 55° C. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 92 mg of oily product, 3-(2,4-dichlorophenyl)-5-(1,1-dimethylethyl)-4-[(3-pyridyl)carbonyl]isoxazole. 1H NMR (CDCl3): δ 1.47 (s, 9), 7.90 (m, 1), 7.60 (br s, 1) and 8.72 ppm (br s, 1). MS m/z: 375.0 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH:13]S(C)(=O)=O)=[C:5](I)[CH:4]=1)#[N:2].[C:19]([Si:23]([O:26][C:27]([CH3:31])([CH3:30])[C:28]#[CH:29])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].CCN(CC)CC.O>CN(C=O)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>[C:19]([Si:23]([CH3:25])([CH3:24])[O:26][C:27]([C:28]1[NH:13][C:6]2[C:5]([CH:29]=1)=[CH:4][C:3]([C:1]#[N:2])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:7]=2)([CH3:30])[CH3:31])([CH3:22])([CH3:21])[CH3:20]
Reactant: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c(C#N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(O[Si](C)(C)C(C)(C)C)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
N-(4-Cyano-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (1.95 g, 5.0 mmol), tert-Butyl-(1,1-dimethyl-prop-2-ynyloxy)-dimethyl-silane (992 mg, 5.0 mmol), PdCl2(PPh3)2, (175 mg, 0.25 mmol), CuI (95 mg, 0.5 mmol), NEt3 (1.4 mL, 10.0 mmol), was mixed in DMF (15 mL) and stirred at room temperature for 16 hours. Water was added and the mixture was extracted twice with ethyl acetate. The organic layers were washed with 10% LiCl solution, dried over magnesium sulfate, filtered, evaporated to a brown oil. The brown oil was purified by column chromatography eluting with 1, 3, and 10% ethyl acetate/hexanes. The product was obtained as a white solid (306 mg, 16%). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.92 S, 1H), 7.67 (s, 1H), 6.27 (d, J=1.2 Hz, 1H), 1.58 (s, 6H), 0.85 (s, 9H), 0.3 (s, 6H). MS (m/z): 405 (MNa+), 381 (MH−).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](Br)[C:3]=1[Cl:10].C(=[NH:24])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[NH2:24]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Fc1cc(Br)c(Cl)c(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Nc1cc(F)cc(Br)c1Cl
Temperature: 85 °C

Procedure:
To a sealable glass tube was charged 1,3-dibromo-2-chloro-5-fluorobenzene (12.52 g, 43.4 mmol), benzophenone imine (8.26 g, 45.6 mmol), sodium tert-butoxide (6.26 g, 65.1 mmol), and toluene (100 mL). The resulting mixture was thoroughly sparged with Argon, followed by the addition of Pd2(dba)3 (0.398 g, 0.434 mmol) and (S)-BINAP (0.81 g, 1.3 mmol), and follow by another Argon sparge. The reaction tube was sealed and heated to 85° C. in an oil bath and maintained overnight. The reaction was allowed to cool to room temperature and quenched with water (20 mL). The resulting layers were partitioned and separated. The organic phase was concentrated and assayed to be a mixture of mono- and bis-aminated products (˜4:1 by HPLC area at 220 nm). The residue was dissolved in THF (70 mL), treated with aqueous 3.0 M HCl (20 mL) at room temperature for 1 hour and basified with saturated aqueous Na2CO3 solution (40 mL). The reaction mixture was allowed to partition and the layers were separated. The organic portion was separated, washed with brine, concentrated and the resulting residue was purified by flash chromatography (SiO2, 0-15% EtOAc in heptane) and 3-bromo-2-chloro-5-fluoroaniline was obtained as a light yellow solid (6.82 g, 30.4 mmol): LCMS(m/z): not ionized (MH+), tR=0.95 minute; 1H NMR (CDCl3, 300 MHz) δ 4.32 (br s, 2H), 6.44 (dd, J=9.8, 2.8 Hz, 1H), 6.77 (dd, J=7.9, 2.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O.O.NN.Cl.[C:24]([C:28]1[CH:37]=[CH:36][C:31]([CH2:32][N:33]=[C:34]=[S:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>CO.O1CCCC1.CN(C)C=O.ClCCl.C(N(CC)CC)C>[C:24]([C:28]1[CH:37]=[CH:36][C:31]([CH2:32][NH:33][C:34]([NH:9][CH2:8][CH2:7][C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])=[S:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1ncsc1CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncsc1CCNC(=S)NCc1ccc(C(C)(C)C)cc1
Reaction time: 20 h
Yield: 20.7 %

Procedure:
2-[2-(4-methylthiazol-5-yl)ethyl]isoindol-1,3-dione (3 g) was dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml) and to the solution was added dropwise hydrazine hydrate (610 mg), followed by stirring for 20 hours. To the obtained solution was added 2 N aqueous hydrochloric acid solution (6 ml), and the mixture was stirred for 3 hours and concentrated under reduced pressure to obtain reaction mixture (3.5 g) as a yellow solid. The obtained mixture (140 mg) was dissolved in dimethylformamide (5 ml) and to the solution were added 4-t-butylbenzylisothiocyanate (0.2 g) and a small amount of triethylamine, followed by stirring at room temperature for 21 hours. The resulting mixture was diluted with dichloromethane, washed with water, dried, concentrated under reduced pressure, and then purified by column-chromatography (hexane/ethyl acetate=1/1) to yield the compound 14-6 (0.07 g) as a liquid.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[O:7])=[CH:4][N:3]=1.[SH2:19].[Na]>CN(C=O)C.C(OCC)(=O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:8]([CH3:9])[C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([SH:19])=[N:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: CN(C(=O)c1ccc(Cl)nc1)c1ccc(F)cc1
Reactant: S
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(S)nc1)c1ccc(F)cc1
Yield: 71.9 %

Procedure:
6-Chloro-N-(4-fluoro-phenyl)-N-methyl-nicotinamide (396 mg, 1.5 mmol) was dissolved in anhydrous DMF (6 mL) under nitrogen. Sodium hydrogen sulfide (181 mg, 1.5 mmol) was added and the solution was refluxed for 70 minutes. After cooling, the solution was diluted with ethyl acetate and washed with water. The water was washed with ethyl acetate, and the combined aqueous layers were acidified with 1 N HCl and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, saturated sodium bicarbonate, water, and brine, dried over sodium sulfate, filtered, and dried in vacu to yield N-(4-Fluoro-phenyl)-6-mercapto-N-methyl-nicotinamide as a yellow solid (283 mg, 72%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]1[O:12][CH:13]=[C:14]([CH2:16][C:17]#[N:18])[N:15]=1)([CH3:10])([CH3:9])[CH3:8].[Cl:19][C:20]1[C:24]([C:25](Cl)=[O:26])=[C:23]([Cl:28])[N:22]([CH3:29])[N:21]=1>C1COCC1>[C:7]([C:11]1[O:12][CH:13]=[C:14]([C:16](=[C:25]([C:24]2[C:20]([Cl:19])=[N:21][N:22]([CH3:29])[C:23]=2[Cl:28])[OH:26])[C:17]#[N:18])[N:15]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Reactant: CC(C)(C)c1nc(CC#N)co1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nc(Cl)c(C(O)=C(C#N)c2coc(C(C)(C)C)n2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
2.87 g of potassium tert-butoxide was suspended in 20 ml of THF, and a solution of 2.00 g of 2-tert-butyl-4-cyanomethyloxazole and 2.37 g of 3,5-dichloro-1-methylpyrazole-4-carbonyl chloride as dissolved in 10 ml of THF was dropwise added thereto with cooling with ice, and then stirred overnight at room temperature. The reaction mixture was poured into ice water, extracted with ethyl acetate, and washed with a small amount of water. After the resulting product was dried with anhydrous sodium sulfate, the solvent was evaporated out under reduced pressure. The residual product was purified through column chromatography (silica gel; n-hexane:ethyl acetate=4:1) to obtain 3.26 g of the intended compound.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:17]([N:24]1[C:28](=[O:29])[CH:27]=[CH:26][C:25]1=[O:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O.C(Cl)Cl>[CH2:17]([N:24]1[C:28](=[O:29])[CH:27]2[CH:26]([C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)([OH:5])[C:3]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=3[CH2:1]2)[C:25]1=[O:30])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1ccc(C)c(C(=O)c2ccccc2)c1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(O)(c1ccccc1)C1C(=O)N(Cc3ccccc3)C(=O)C1C2
Yield: 52.9 %

Procedure:
A solution of 35 g of 2,5-dimethylbenzophenone and 31.5 g of N-benzylmaleimide in 500 cc of acetone or methylene chloride is irradiated with a mercury high pressure lamp through a pyrex filter, until all the material has reacted (20 to 130 hours), filtration and concentration by evaporation are then effected. After crystallization from ether, the residue yields 35 g of 2-benzyl-3a,4,9,9a-tetrahydro-6-methyl-4-phenyl-benz[f]isoindolin-4-ol-1,3-dione, having a M.P. of 162-164°, which are dissolved in 170 cc of trifluoroacetic acid. The solution is stirred at 25° for 3 hours and concentrated by evaporation. After crystallization from methylene chloride/methanol, the residue yields 30 g of (9aRS)-2-benzyl-9,9a-dihydro-6-methyl-4-phenyl-benz[f]isoindoline-1,3-dione, having a M.P. of 156°-158°.
Reaction SMILES: [CH2:1]([O:4][C:5](Cl)=[O:6])[CH:2]=[CH2:3].[NH2:8][CH2:9][C:10]([OH:12])=[O:11]>O.[OH-].[Na+]>[CH2:1]([O:4][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: NCC(=O)O
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCOC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12 ml of chloroformic acid allyl ester are added dropwise at 0° to a solution of 7.51 g of glycine in 20 ml of water and 44 ml of 5N NaOH solution. The suspension is then stirred for 16 hours at room temperature. After removal of the insoluble material by filtration, the filtrate is diluted with 100 ml of water and washed twice with CH2Cl2. The aqueous phase is adjusted to pH 2 with 4N HCl and extracted twice with CH2Cl2. The combined organic extracts are washed once with brine, dried over MgSO4 and concentrated by evaporation to form the white crystals of the title compound. IR in CH2Cl2 : 3450, 1715 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[NH:12][CH2:11][CH2:10][N:9]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:8]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+].Br[C:65]1[CH:70]=[CH:69][C:68]([C:71]([OH:80])([C:76]([F:79])([F:78])[F:77])[C:72]([F:75])([F:74])[F:73])=[CH:67][CH:66]=1>C1(C)C=CC=CC=1.[NH4+].[Cl-].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]>[F:73][C:72]([F:74])([F:75])[C:71]([C:68]1[CH:67]=[CH:66][C:65]([N:12]2[CH2:11][CH2:10][N:9]([S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[CH2:8][CH:7]2[CH2:6][C:5]2[CH:21]=[CH:22][CH:23]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:70][CH:69]=1)([OH:80])[C:76]([F:77])([F:79])[F:78]
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reactant: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cccc(CC2CN(S(=O)(=O)c3cccs3)CCN2c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a 50-mL round-bottomed flask was added 3-(3-methoxybenzyl)-1-(thiophen-2-ylsulfonyl)piperazine (48 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium (0) (6 mg, 6.81 μmol, Strem, Newburyport, Mass.), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (RuPhos) (13 mg, 0.027 mmol, Strem Chemicals, Newburyport, Mass.), sodium tert-butoxide (33 mg, 0.34 mmol) and 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (53 mg, 0.16 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009) in toluene (2 mL). The reaction mixture was stirred at 100° C. for 18 h. The mixture was cooled to room temperature and then diluted with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc in hexanes to give 1,1,1,3,3,3-hexafluoro-2-(4-(2-(3-methoxybenzyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-2-propanol (41 mg) (racemic mixture) as a colorless tar.
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:21][CH:22]([CH3:26])[CH2:23][C:24]#[CH:25].ClC(OC)=O>C(OCC)(=O)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.C(N(CC)CC)C.CN(C=O)C>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([C:25]#[C:24][CH2:23][CH:22]([CH3:26])[CH3:21])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Reactant: C#CCC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCC(C)C)cc1C1CCCC1
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To 4-bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (100 mg, 0.29 mmol), Pd(PPh3)2Cl2 (4 mg, 0.006 mmol), and CuI (1 mg, 0.006 mmol) was added DMF (600 μL), triethylamine (750 μL), and 4-methylpent-1-yne (72 mg, 103 μL, 0.87 mmol). The reaction mixture was stirred under N2 atmosphere for 20 min, resulting in product formation with partial loss of the carbonate group. The reaction was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over Na2SO4 and filtered through a plug of silica. The filtrate was treated with triethylamine (29 mg, 40 μL, 0.29 mmol) and then dropwise with methyl chloroformate (14 mg, 11 μL, 0.14 mmol). The reaction mixture was stirred for 10 min, and was then dried down, diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, 0.5 M HCl, and brine. The solution was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-cyclopentyl-4-(4-methylpent-1-ynyl)-5-nitrophenyl methyl carbonate as an orange oil (75 mg, 75% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.77 (s, 1H), 4.00 (s, 3H), 3.25-3.18 (m, 1H), 2.46 (d, J=6.3 Hz, 2H), 2.00-1.88 (m, 3H), 1.79-1.75 (m, 2H), 1.73-1.55 (m, 4H), 1.06 (d, J=6.6 Hz, 6H).
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][S:9]([N:12]([CH2:14][C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH3:13])(=[O:11])=[O:10]>C(C(C)=O)C>[F:23][C:15]([F:24])([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:14][N:12]([CH3:13])[S:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][I:1])(=[O:11])=[O:10]
Reactant: CN(CC(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)CCCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CN(CC(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)CCCCCI
Yield: 96.6 %

Procedure:
300 mg of sodium iodide were added to a solution of 355 mg of the product of Step A in 3 ml of methyl ethyl ketone and the mixture was refluxed for 4 hours. After evaporation of the solvent, the residue was taken up in water and extracted with ethyl acetate. The extracts were washed with an aqueous solution of sodium thiosulfate, then of sodium chloride, and evaporated to dryness under reduced pressure to obtain 425 mg of the expected product in the form of a colourless oil which slowly crystallized.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][C:11](=[O:13])[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:39][C:40]1[N:41]=[CH:42][NH:43][CH:44]=1)[C:19]([NH:21][C@@H:22]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:23]([OH:31])[CH2:24][C@@H:25]([CH:28]([CH3:30])[CH3:29])[CH:26]=[CH2:27])=[O:20].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl-].[NH4+]>CN(C)C=O.C(#N)C>[CH2:1]([NH:8][C@H:9]([CH2:10][C:11](=[O:13])[NH2:12])[C:14]([NH:17][C@@H:18]([CH2:39][C:40]1[N:41]=[CH:42][NH:43][CH:44]=1)[C:19]([NH:21][C@@H:22]([CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C@@H:23]([OH:31])[CH2:24][C@@H:25]([CH:28]([CH3:29])[CH3:30])[CH:26]=[CH2:27])=[O:20])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C[C@@H](NCc1ccccc1)C(=O)O
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(N)=O)NCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.5 %

Procedure:
A mixture of 100 mg (0.45 mmol) of N-benzyl-3-carbamoyl-D-alanine, 187 mg (0.45 mmol) of (S)-α-amino-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy 4-isopropyl-5-hexenyl]imidazole-4-propionamide 0.093 ml of Hunig base and 202 mg of BOP in 10 ml of a 2:1 mixture of acetonitrile and dimethylformamide was stirred at room temperature for 18 hours. Thereafter, the reaction mixture was poured into aqueous ammonium chloride solution, extracted with ethyl acetate, the extracts were washed with sodium carbonate solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue on silica gel with 10% methanol in methylene chloride as the eluting agent yielded 87 mg (32%) of (S)-α-[(R)-2-(benzylamino) 3-carbamoylpropionamido]-N-[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]imidazole-4-propionamide as a resin. MS: 595 (M+H)+.
Reaction SMILES: OS(O)(=O)=O.[C:6]([CH:8]([C:14]([CH3:23])([CH3:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:7]>[NH4+].[OH-]>[NH2:7][C:6]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][C:14]([CH3:22])([CH3:23])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C#N)C(C)(C)Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)C1=C(N)c2ccccc2CC1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.4 %

Procedure:
Concentrated H2SO4 (2.35 mL, 44.0 mmol) was added dropwise to ethyl 2-cyano-3,3-dimethyl-4-phenylbutanoate (1.08 g, 4.4 mmol) at 0° C. to give an orange solution. The reaction was allowed to warm to room temperature and was stirred for 24 h. Ice water (10 mL) was added to the deep red reaction to give an opaque yellow mixture. The reaction was basified with NH4OH (20 mL) and extracted with ether (3×10 mL). The organic extracts were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give bright yellow oil. Purified by flash column chromatography (20% ethyl acetate in hexanes, Rf=0.30) afforded the title compound as bright yellow crystalline solid (392.4 mg, 36.4% yield). 1H NMR (500 MHz, CDCl3) δ 7.39 (d, J=7.5 Hz, 1H), 7.31-7.28 (m, 2H), 7.18 (d, J=7.2 Hz, 1H), 6.33 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 2.65 (s, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.20 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:35].Cl>CCOC(C)=O>[ClH:1].[NH2:35][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:33])=[C:19]([NH:23][S:24]([C:27]3[N:31]([CH3:32])[N:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: Cn1nccc1S(=O)(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1nccc1S(=O)(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(N)n2)c1F

Procedure:
N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-5-sulfonamide (530 mg, 1.04 mmol) and ammonium hydroxide (26%, 15 ml) was heated in a steal reactor to 100° C. for 3 h. The reaction mixture was cooled and concentrated under reduced pressure, the residue was dissolved in methanol, and purified by Pre-HPLC (A=10 m MNH4HCO3/H2O, B=Acetonitrile), then the white solid obtained was dissolved in EtOAc, treated with HCl (g) for 30 min. The mixture was concentrated under reduced pressure, and then the residue was suspended in ether (20 ml), treated with ultrasonic for 3 min, filtered, the solid was suspended in ether (20 ml) again, treated with ultrasonic for 3 min, filtered to afford the title compound was obtained as a white solid (142 mg, 26%). 1HNMR (MEOD-d4): δ ppm 8.05 (br s, 1H), 7.61-7.65 (ddd, J1=7.7 Hz, J2=1.6 Hz, 1H), 7.42-7.46 (m, 2H), 7.32-7.36 (t, J=8.0 Hz, 1H), 6.70-6.71 (d, J=2.0 Hz, 1H), 6.25-6.27 (d, J=6.4 Hz, 1H), 4.04 (s, 3H), 1.50 (s, 9H). MS: 488.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[N:23]([CH3:22])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: CNc1ccccc1
Product: CN(C(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)c1ccccc1
Yield: 70 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using N-methylaniline (23 μL, 0.21 mmol) as the coupling partner. Concentration (no chromatography) yielded 45 mg (70%) of the titled compound. ESI-MS m/z 381 (MH+), 379 (M−H−).