Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[C@@H:7]([NH:13][C:14]([NH:16][C@@H:17]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])[CH2:8][CH2:9][C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[S:40]([NH2:50])(=[O:49])([C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1)=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:39])[C@@H:7]([NH:13][C:14](=[O:15])[NH:16][C@@H:17]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1)[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:8][CH2:9][C:10](=[O:12])[NH:48][C:45]1[CH:46]=[CH:47][C:42]([S:40](=[O:49])(=[O:41])[NH2:50])=[CH:43][CH:44]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)[C@H](CCCCNC(=O)c1cccc(I)c1)NC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H](CCCCNC(=O)c1cccc(I)c1)NC(=O)N[C@@H](CCC(=O)Nc1ccc(S(N)(=O)=O)cc1)C(=O)OC(C)(C)C

Procedure:
(S)-2-(3-((S)-1-carboxy-4-oxo-4-(4-sulfamoylphenylamino)butyl) reido)-6-(3-iodobenzamido)hexanoic acid. A solution of (S)-5-tert-butoxy-4-(3-((S)-1-tert-butoxy-6-(3-iodobenzamido)-1-oxohexan-2-yl)ureido)-5-oxopentanoic acid (98 mg, 0.148 mmol), sulfanilamide (34.4 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol), and DIPEA (0.50 mL) in DMF (5 mL) was stirred at 50° C. overnight. The solvents were evaporated under reduced pressure to give a residue, which was purified utilizing a Biotage SP4 with a gradient of 10-100% EtOAc in hexane to give (S)-tert-butyl 2-(3-((S)-1-tert-butoxy-1,5-dioxo-5-(4-sulfamoylphenylamino)pentan-2-yl)ureido)-6-(3-iodobenzamido)hexanoate. A solution of the above isolated material was dissolved in a mixture of TFA (2.0 mL)/DCM (2.0 mL) and stirred at room temperature for 3 h. The solvents were removed under reduced pressure to give a residue, which was purified by HPLC to give the title compound (20 mg, 19% over 2 steps) as a white solid. ESMS m/z: 704.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][OH:15].CN(C=O)C>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][OH:15])=[C:4]([CH3:9])[CH:3]=1
Reactant: OCCBr
Reactant: Cc1cc(I)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1OCCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 2.34 g (10 mmol) of 4-iodo-2-methylphenol was added batchwise to a suspension of 0.48 g (11 mmol) of NaH in 50 mL of THF cooled to 0° C. and the mixture was stirred for a further 30 minutes at this temperature. Then 0.85 mL (12 mmol) of 2-bromoethanol dissolved in 5 mL of THF was added dropwise and the mixture was stirred for 18 hours at RT. 5 mL of DMF was added and the reaction mixture was heated to 70° C. for 8 hours. It was evaporated down in vacuo, the residue was taken up in water, extracted exhaustively with EtOAc and dried over sodium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography on silica gel (cyc/EtOAc 7:3). Yield: 0.39 g (14% of theoretical); C9H11IO2 (M=278.091); calc.: molpeak (M+H)+: 279; found: molpeak (M+H)+: 279; Rf value: 0.28 (silica gel, cyc/EtOAc 2:1).
Reaction SMILES: [Si](I)(C)(C)C.C[O:7][C:8]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[O:21])[CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1.CO>C(Cl)(Cl)Cl>[OH:7][C:8]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:27][CH:28]=3)=[O:21])[CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COc1ncccc1-c1cncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(-c2cccnc2O)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
TMSI (100 μL, 0.734 mmol) was added to a solution of 2′-methoxy-N-(4-(trifluoromethoxy)phenyl)-[3,3′-bipyridine]-5-carboxamide (Example 62, 79 mg, 0.203 mmol) in CHCl3 (4 mL) and the RM was stirred at 60° C. overnight. The RM was cooled to RT, poured into MeOH and the solvent was evaporated off under reduced pressure. The residue was treated with aq. 5% NH3 and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the product which was recrystallized from hot EtOAc to afford the title compound as beige crystals. UPLC-MS (Condition 2) tR0.87 min, m/z=376.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 6.38 (t, J=6.65 Hz, 1H) 7.40 (d, J=8.99 Hz, 2H) 7.51 (d, J=6.26 Hz, 1H) 7.86-7.96 (m, 3H) 8.61-8.66 (m, 1H) 9.00-9.04 (m, 1H) 9.09-9.13 (m, 1H) 10.63 (s, 1H) 12.03 (br. s, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:17][CH2:16][C@H:15]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C@H:14]2[OH:28])(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Li+]>CN(C)C=O>[N:29]([CH2:12][C@@H:13]1[O:17][CH2:16][C@H:15]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C@H:14]1[OH:28])=[N+:30]=[N-:31]
Reactant: COc1ccc(CS[C@H]2CO[C@@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H]2O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2CO[C@@H](CN=[N+]=[N-])[C@@H]2O)cc1
Temperature: 70 °C
Reaction time: 65 h
Yield: 32.6 %

Procedure:
A mixture of 2.0 g of product from Example 324, 0.460 g of lithium azide and 2 ml of N,N-dimethylformamide is stirred at 70° C. for 65 hours. The reaction mixture is concentrated in vacuo. The residue is purified by chromatography (Silica gel: 30% ethyl acetate/hexane). to give 0.454 g of the desired product.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=S(Cl)[Cl:22]>C(Cl)Cl>[ClH:22].[Cl:22][CH2:2][C:3]1[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)CCn1ccc(-c2ncccc2CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCn1ccc(-c2ncccc2CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To methyl 3-(3-(3-(hydroxymethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate (51 mg, 0.20 mmol) in DCM (5 mL) was added SOCl2 (1.0 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give methyl 3-(3-(3-(chloromethyl)pyridin-2-yl)-1H-pyrazol-1-yl)propanoate hydrochloride (63 mg) as an off-white solid, which was used for next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH:36]2[CH2:38][CH2:37]2)=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH:36]3[CH2:38][CH2:37]3)=[N:22][C:23]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
In analogy to the procedure described in example 29A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) to give the title compound as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:10]=2[C:11]2[CH:16]=[CH:15][C:14](SC)=[CH:13][CH:12]=2)[CH:7]=1.O[O:27][S:28]([O-:30])=O.[K+].[CH3:32]C(C)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([S:28]([CH3:32])(=[O:30])=[O:27])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2c(-c3ccc(F)cc3)nn3cc(Br)ccc23)cc1
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(Br)ccc23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58 %

Procedure:
To a solution of 6-bromo-2-(4-fluorophenyl)-3-[4-(methylsulfanyl)phenyl]pyrazolo[1,5-a]pyridine (0.26 g 0.63 mmol) in acetone (30 ml) was added a solution of oxone (1.16 g 1.9 mmol) in water (10 ml). The reaction was stirred at room temperature for 20 hours, further oxone (1 g 1.7 mmol) in water (10 ml) was added and stirring was continued for 6 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (3×30 ml). The combined extracts were washed with water (30 ml), brine (30 ml) and dried. Removal of solvent gave a solid which was purified by biotage chromatography. Elution with cyclohexane ethyl acetate gave the title compound as a white solid (0.13 g 58%). MH+: 445, 447. NMR: (CDCl3) δ 3.13 (3H, s) 7.07 (2H, t) 7.29 (1H, dd) 7.45-7.55 (5H, m) 7.96 (2H, d) 8.67 (1H, s).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[C:19]([CH2:23]O)[CH:20]=[N:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1>ClCCl>[Cl:3][CH2:23][C:19]1[CH:20]=[N:21][CH:22]=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([Cl:10])[CH:12]=2)[CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(-c2cccc(Cl)c2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cncc(-c2cccc(Cl)c2)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
271 mg (0.165 ml, 2.28 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.2 ml N,N-dimethylformamide (DMF) and 250 mg (1.14 mmol) [5-(3-Chloro-phenyl)-pyridin-3-yl]-methanol in 20 ml dichloromethane and stirred for 3 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase was extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (248 mg, 84%) used without further purification.
Reaction SMILES: [O-][Mn](=O)(=O)=O.[K+].[CH3:7][C:8]1[CH:9]=[C:10]([B:14]([OH:16])[OH:15])[CH:11]=CC=1.[OH-:17].[Na+].[CH3:19][CH2:20][OH:21]>O>[C:20]([C:19]1[CH:11]=[C:10]([B:14]([OH:16])[OH:15])[CH:9]=[CH:8][CH:7]=1)([OH:17])=[O:21]
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1cccc(B(O)O)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cccc(B(O)O)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of KMnO4 (3.7 g, 23.4 mmol) in water (100 mL) was slowly added to a solution of (3-methylphenyl)boronic acid (1.5 g, 11 mmol) and NaOH (1 g, 25 mmol) in water (60 mL), while the temperature was maintained between 30° C. and 40° C. using a water bath. The resulting brown suspension was heated at 55° C. for 2 h and allowed to cool to room temperature. EtOH (1 mL) was added, the resulting slurry was filtered and the filtrate concentrated to 100 mL under reduced pressure. The resulting mixture was acidified with conc. HCl (1.5 mL) and kept at 5° C. overnight. The white suspension was filtered to give (3-carboxyphenyl)boronic acid (1.44 g, 79%) as a white solid: 1H NMR (D2O) δ 7.51 (m, 1H), 7.99 (m, 1H), 8.07 (m, 1H), 8.4 (s, 1H).
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([C:8]1[CH:9]=[C:10]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)[C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=O)([CH3:7])([CH3:6])[CH3:5].C([O-])(=O)C.[Na+]>C(O)C>[C:4]([C:8]1[CH:9]=[C:10]([C:17]2[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)[C:11]([OH:16])=[C:12]([CH:15]=1)[CH:13]=[N:2][OH:3])([CH3:7])([CH3:6])[CH3:5]
Reactant: NO
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(C=NO)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
Following the patent procedure of C. G. Luca (US 20050137168), hydroxylamine hydrochloride (355 mg, 5.11 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (from Example 47, Step 1) (1.5 g, 4.64 mmol) and sodium acetate (419 mg, 5.11 mmol) in ethanol (15 mL). The reaction was stirred at room temperature for 16 hours. The mixture was partitioned between water and ethyl acetate and the organic phase separated, dried (Na2SO4), filtered and the solvent removed under reduced pressure. The residue was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde oxime (1.3 g, 83% yield).
Reaction SMILES: [CH:1]1[N:6]=[C:5]([NH2:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][O:17][P:18]([OH:21])([OH:20])=[O:19])[C@@H:13](O)[C@H:12]3[OH:23])[C:3]=2[N:2]=1.C1C(N)=CC=C(SC#N)C=1>>[CH:1]1[N:6]=[C:5]([NH2:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@@H:14]4[CH2:16][O:17][P:18]([OH:20])([O:21][C@H:13]4[C@H:12]3[OH:23])=[O:19])[C:3]=2[N:2]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: N#CSc1ccc(N)cc1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Reaction time: 0.08 h

Procedure:
The adenylate cyclase activity induced by each of Analogs I-V was also measured in SaOS-2 B10 cells as described previously (Rodan et al. 1983 J. Clin. Invest. 72;1511; Goldman et al. 1988 Endocrinology 123, 1468). Confluent SaOS-2 B10 cells in 24 wells plates were incubated 0.5 μCi[3H]adenine (26.9 Ci/mmol, New England Nuclear, Boston, Mass.) in fresh medium at 37° C. for 2 hrs, and washed twice with Hank's solution. The cells were treated with 1 mM IBMX [isobutylmethylxanthine, Sigma, St. Louis, Mo.] in fresh medium for 15 min, and a tested PTH analog was added to the medium to incubate for 5 min. The reaction was stopped by the addition of 1.2M TCA followed by sample neutralization with 4N KOH. Cyclic AMP was isolated by the two-column chromatographic method (see Salomon et al. 1974 Anal. Biochem. 58;541). The radioactivity was counted in a scintillation counter (Liquid scintillation counter 2200CA, PACKARD, Downers Grove, Ill.). The EC50 's (half maximal stimulation of adenylate cyclase) were calculated for the five PTH analogs and are shown below:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([CH2:23][CH2:24][CH3:25])=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[C:32](O)=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37].C1(N=C=NC2CCCCC2)CCCCC1.O>C(OCC)(=O)C>[F:26][C:27]1[C:28]([F:37])=[C:29]([F:36])[C:30]([F:35])=[C:31]([F:34])[C:32]=1[O:21][C:20]([C:17]1[N:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)=[C:15]([CH2:23][CH2:24][CH3:25])[CH:16]=1)=[O:22]
Reactant: CCCc1cc(C(=O)O)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.4 %

Procedure:
5-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-4-propyl picolinic acid (134 mg, 0.307 mmol) was dissolved in ethyl acetate (6.2 mL). At room temperature, pentafluorophenol (68 mg, 0.368 mmol) and N,N′-dicyclohexylcarbodiimide (76 mg, 0.368 mmol) were added sequentially, and the mixture was stirred at room temperature overnight. The reaction solution was added water under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (189 mg (yield >99%)) was obtained as a yellow brown crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]1[C:12]([CH2:13]O)=[CH:11][CH:10]=[C:9]([O:15][C:16](=[O:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>ClCCl>[C:1]([O:5][C:6](=[O:27])[C:7]1[C:12]([CH2:13][Br:48])=[CH:11][CH:10]=[C:9]([O:15][C:16](=[O:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc(CO)c(C(=O)OC(C)(C)C)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Oc1ccc(CBr)c(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of 650 mg of 3-(tert-butoxycarbonylaminoacetoxy)-6-hydroxymethylbenzoic acid tert-butyl ester and 580 mg of triphenylphosphine was added 848 mg of carbon tetrabromide, and the mixture was stirred for 2 h at room temperature. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Column chromatography on silica gel gave 322 mg of 3-(tert-butoxycarbonylaminoacetoxy)-6-(bromomethyl)benzoic acid tert-butyl ester as a colourless oil; 1H-NMR(CDCl3) δ1.34(9H,s), 1.51 (9H,s), 4.08(2H,br.d,J=5.6 Hz), 4.80(2H,s), 4.95(1H,br.s), 7.12(1H,dd,J=8.6,2.6 Hz), 7.34(1H,d,J=8.6 Hz), 7.51(1H,d,J=2.6 Hz)
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.CC(N1[C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=3)[NH:32][CH:31]=[C:30]4[CH:39]3[CH2:44][CH2:43][N:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])[CH2:41][CH2:40]3)=[CH:23][CH:22]=2)=[O:18])=[CH:15][C:14](C)=[N:13]1)(C)C.CC(N1C(C(NCC2C=CC(B(O)O)=CC=2)=O)=CC(C)=N1)(C)C>>[CH2:48]([S:45]([N:42]1[CH2:41][CH2:40][CH:39]([C:30]2[C:29]3[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=[C:27]([C:24]4[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:17]([C:16]5[CH:15]=[CH:14][N:13]=[CH:3][CH:2]=5)=[O:18])=[CH:26][CH:25]=4)[CH:28]=3)[NH:32][CH:31]=2)[CH2:44][CH2:43]1)(=[O:47])=[O:46])[CH3:49]
Reactant: O=C(O)C(F)(F)F
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5cc(C)nn5C(C)(C)C)cc4)cc23)CC1
Agent: Cc1cc(C(=O)NCc2ccc(B(O)O)cc2)n(C(C)(C)C)n1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5ccncc5)cc4)cc23)CC1
Yield: 45.8 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (4-{[(4-pyridinylcarbonyl)amino]methyl}phenyl)boronic acid (124 mg, 0.480 mmol) for {4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid to afford 30 mg of the title compound (45.8%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.C1COCC1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CCOC(C)=O>[F:14][C:9]([F:15])([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:3][CH:4]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: FC(F)(F)C(F)(F)Oc1ccc(Br)cc1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To an oven-dried 500-mL round bottom flask equipped with a stirring bar was added 1-bromo-4-(perfluoroethoxy)benzene (9.35 g, 32.1 mmol) and anhydrous THF (200 mL). The flask was placed under nitrogen and cooled in an ice bath for 10 min. A solution of 1.3 M isopropylmagnesium chloride-lithium chloride complex (30 mL, 38.6 mmol) was added over 15 min. The ice bath was removed after 1 hour, and the reaction was warmed to room temperature and stirred overnight. GC/MS showed the presence of starting material. The reaction was cooled in an ice bath and 1.3 M isopropylmagnesium chloride-lithium chloride complex (5 mL) was added. The ice bath was removed after 20 min and stirred at room temperature for 9 hours. Ethyl chloroformate (3.4 mL, 35.3 mmol) was added in a slow, steady stream. The reaction was warmed slightly during the addition and was stirred at room temperature overnight. The reaction was diluted with EtOAc and washed with saturated aqueous ammonium chloride. The aqueous layer was extracted three times with EtOAc. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow liquid, which was purified by flash chromatography (0-0, 0-4, 4-10% EtOAc/hexanes) to provide ethyl 4-(perfluoroethoxy)benzoate as a yellow liquid (4.58 g, 50%): 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 4.39 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −86.05, −87.84; ESIMS m/z 284 ([M+11]+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1>C1COCC1>[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH:30][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=2)=[N:26]1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: Cn1ccc(N)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccn(C)n1
Yield: 81.3 %

Procedure:
To a solution of 800 mg of ethyl 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate in 20 mL of THF, 890 mg of DIPEA and 368 mg of 1-methyl-1H-pyrazol-3-amine were added, and the resulting mixture was stirred under reflux for 2 hours, and then, the solvent was distilled off. The thus obtained crude product was purified by silica gel column chromatography, whereby 820 mg the title compound was obtained.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[O:19][CH2:20][C:21]([NH:23][NH2:24])=[O:22])([CH3:15])[CH3:14]>O1CCCC1.C(OCC)(=O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[O:19][CH2:20][C:21]1[O:22][C:1](=[O:2])[NH:24][N:23]=1)([CH3:12])[CH3:14]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)c1cc(OCC(=O)NN)cc(C(C)(C)C)c1O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(OCc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
A 12.5% solution of phosgene in toluene (2.4 mL, 2.7 mmol) is added dropwise to a -78° C. of [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]-acetic acid hydrazide (0.40 g, 1.36 mmol) in tetrahydrofuran (25 mL). The reaction mixture is stirred for 30 minutes, diluted with ethyl acetate, and washed three times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a pale yellow oil which is crystallized from ethyl acetate/hexane yielding 0.34 g (79%) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenoxy]methyl-1,3,4-oxadiazol-2(3H)-one; mp 138.0°-140.0° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)#[CH:20]>CCCCCCC.CCOC(C)=O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[C:20][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[CH:6][N:5]=2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(C)ncn2)cc1
Reactant: C#Cc1ccc(OC)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(C#Cc2cc(C)ncn2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 6-methyl-pyrimidin-4-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (52 mg, 46%); 1H NMR δ (CDCl3): 8.99 (s, 1H), 7.32 (d, J=8.60 Hz, 2H), 7.22 (s, 1H), 7.17 (d, J=8.43 Hz, 2H), 3.83 (s, 3H), 2.51 (s, 3H); LCMS m/z: 224.