Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.CN1CCCC1=O.[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21](F)[CH:20]=1.CC([O-])(C)C.[K+]>CCCCCCC>[Br:18][C:19]1[CH:26]=[C:25]2[C:22]([CH:23]=[N:10][N:9]2[C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)=[CH:21][CH:20]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCCCCC
Solvent: CN1CCCC1=O
Product: Fc1ccc(-n2ncc3ccc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.4 %

Procedure:
A flask was charged with (4-fluorophenyl)hydrazine hydrochloride (25.0 g, 154 mmol), 1-methyl-2-pyrrolidinone (500 mL) and 4-bromo-2-fluorobenzaldehyde (31.2 g, 154 mmol). The mixture was stirred at rt for about 14 h then potassium 2-methylpropan-2-olate (18.98 g, 169 mmol) was added. The mixture was stirred for about 1 h then a second portion of potassium 2-methylpropan-2-olate (17.25 g, 154 mmol) was added. The mixture was stirred for about 15 min then warmed in an oil bath heated to about 160° C. for about 24 h. The mixture was cooled to rt then about 250 mL solvent was removed under reduced pressure. The mixture was diluted with about 750 mL water then allowed to stand overnight. The supernatant was decanted and the resulting residue was stirred with EtOAc (350 mL) for about 1 h. The solids were collected by filtration. The filtrate was concentrated then stirred in a mixture of DCM (350 mL), water (250 mL) and 6 N HCl (25 mL) for about 3 h. The layers were separated then the organic layer was dried over MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified on silica gel (330 g) using a gradient of 0-10% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to give a solid which was treated with heptane (100 mL) and stirred overnight at room rt. The solids were collected by filtration and washed with heptane (25 mL). The solids from the initial EtOAc trituration and the material from the column and heptane trituration were combined to yield 6-bromo-1-(4-fluorophenyl)-1H-indazole (1, R1=4-fluorophenyl) (23.94 g, 54%); LC/MS, method 3, Rt=2.83 min, MS m/z 291, 293 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 7.97 (s, 1H), 7.88-7.79 (m, 3H), 7.46-7.42 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18](S(O)(=O)=O)=[CH:17][CH:16]=1.[C:26]1(C)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:10][CH2:9][CH:8]([CH:25]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:5][O:14]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1ccc(Cl)cc1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C1(c2ccc(Cl)cc2)OCC(C2c3ccccc3-c3ccccc32)CO1

Procedure:
The product is obtained by reacting the above diol with ethyl 2-(4-chlorophenyl)-2-oxoacetate according to the method already described, by refluxing in toluene in the presence of para-toluenesulphonic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[O:11][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: OC1CCc2c(Br)cccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2,3-dihydro-1H-inden-1-ol INT-28 (2.56 g, 12.0 mm) in DMF (5 mL) were added TBDMSCl (2.17 g, 14.4 mmol) and imidazole (2 g, 30.0 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture was diluted with Inter and extracted with EA. The organic layers were washed with water and brine, and dried over MgSO4. The crude product was purified by chromatography (EA/hexane) to afford (4-bromo-2,3-dihydro-1H-inden-1-yloxy)(tert-butyl)dimethylsilane INT-29 (3.3 g, 84%) as a clear oil. LCMS-ESI (m/z) calculated for C15H23BrOSi: 327.3; found 195.0 [M−OTBS]+, tR=3.07 min. 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J=7.8 Hz, 1H), 7.06 (d, J=7.4 Hz, 1H), 6.92 (t, J=7.7 Hz, 1H), 5.13 (t, J=7.0 Hz, 1H), 2.85 (ddd, J=16.4, 9.1, 2.9 Hz, 1H), 2.57 (dt, J=16.5, 8.3 Hz, 1H), 2.36-2.17 (m, 1H), 1.76 (dtd, J=12.8, 8.8, 7.1 Hz, 1H), 0.83-0.72 (m, 9H), 0.05-0.06 (m, 6H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:28]1[O:38][C:31]2([CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]2)[O:30][CH2:29]1.[Cl-].[NH4+]>O1CCCC1.ClCCl>[CH2:13]([O:20][C:21]1[CH2:26][CH2:25][CH:24]([C:34]2([OH:37])[CH2:35][CH2:36][C:31]3([O:38][CH2:28][CH2:29][O:30]3)[CH2:32][CH2:33]2)[C:23](=[O:27])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C1C=C(OCc2ccccc2)CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1C=C(OCc2ccccc2)CCC1C1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 88.2 %

Procedure:
To a flask equipped with magnetic stirrer was added tetrahydrofuran (600 ml) and diisopropylamine (38.1 ml, 272 mmol). The stirred solution was cooled to −78° C. and n-butyl lithium (113.4 ml, 272 mmol, 2.4 M in hexanes) was added dropwise via syringe. The resulting yellow solution was stirred for 35 min at −78° C., then 3-(benzyloxy)-2-cyclohexen-1-one (50.0 g, 248 mmol) was added as a solution in tetrahydrofuran (100 ml). The solution was stirred for 1 hr prior to the addition of cyclohexane-1,4-dione monoethylene ketal (38.7 g, 248 mmol) as a solution in anhydrous tetrahydrofuran (100 ml). The solution was stirred for 2 hr at −78° C., then allowed to warm slowly to room temperature over 1 hr. Saturated aqueous ammonium chloride (80 ml) was added, followed by dichloromethane (700 ml) and the mixture stirred until no solids remained. The layers were separated and the aqueous phase extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine (50 ml), dried over magnesium sulfate, then concentrated in vacuo. Trituration of the resulting solid with methanol afforded the title compound (78.4 g, 88%). m/z (ES+) 359 (M+H+).
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18][CH2:17][N:16]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[CH2:15][CH2:14][CH2:13][N:12]([CH3:32])[CH2:11][CH2:10]1)([O:3]C(C)(C)C)=[O:2].CCOCC>C(C(O)=O)(F)(F)F.C(Cl)Cl>[C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]([CH3:23])[CH2:18][CH2:17][N:16]([CH2:24][C:25]([OH:27])=[O:26])[CH2:15][CH2:14][CH2:13][N:12]([CH3:32])[CH2:11][CH2:10]1)([OH:3])=[O:2]
Reactant: CN1CCCN(CC(=O)OC(C)(C)C)CCN(C)CCCN(CC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CCCN(CC(=O)O)CCN(C)CCCN(CC(=O)O)CC1
Yield: 99.2 %

Procedure:
Compound (33) (1.46 g, 3.19 mmol) was dissolved in a mixture of CF3CO2H (TFA) and CH2Cl2 (1:1 (v/v), 50 ml). The resultant mixture was stirred at an ambient temperature for 24 hours. The solvent was removed under reduced pressure to give an oily residue, which was then treated with Et2O to obtain a white solid of compound (34) (1.09 g, 99% yield). HRMS (FAB) calculated for C16H33N4O4: 345.2502 [(M+H)+], measured value: 345.2506 [(M+H)+].
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C(=O)([O-])[O-:13].[K+].[K+].[CH3:18][C:19]([CH3:21])=[O:20]>O>[OH:13][CH2:11][C:1]1[CH:2]=[C:21]2[C:4]([CH2:3][CH2:18][C:19]2=[O:20])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Agent: [K+]
Solvent: O
Product: O=C1CCc2ccc(CO)cc21

Procedure:
A solution of Example 28 (8.0 g, 38.7 mmol) and p-toluenesulfonic acid (7.4 g, 38.7 mmol) in a mixture of water (20 mL) and acetone (85 mL) was heated to reflux for about 1 hour. The mixture was concentrated under vacuum, diluted with water, and neutralized by careful addition of potassium carbonate (2.7 g, 19.4 mmol). The precipitate was collected by filtration, washed with minimal water and diethyl ether, and dried under vacuum to provide the desired product. MS (DCI-NH3): m/z 180 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[C:27]([C:26]([F:25])([F:34])[F:35])[CH:28]=3)=[O:20])=[CH:23][CH:24]=2)[N:10]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 30 %

Procedure:
To a solution of methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol) in dry toluene was added 3-trifloromethyl aniline (0.070 g, 0.43 mmol) followed by addition of trimethyl aluminium (2M solution in toluene) (0.5 mL). The reaction mixture was refluxed for 1 h. The reaction mass was quenched in water and acidified with dilute HCl and extracted in DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford crude product, which was column purified to afford 0.040 g of desired product. 1H NMR (DMSO-d6): δ 7.45-7.54 (m, 2H), 7.59 (m, 2H), 7.72 (q, J=6.3 Hz, 1H), 8.05-8.12 (m, 5H), 8.25 (s, 1H), 10.58 (br s, 1H), 12.77 (br s, 1H); MS (m/z): 477.08 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:11](=[O:12])[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:28][CH2:29][CH3:30])[N:8]3[N:31]=[CH:32][N:33]=[C:7]23)[CH2:3]1.[N+](=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[N-]>C([O-])(=O)C.[Rh+].C1(C)C=CC=CC=1>[C:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:10]2[C:11](=[O:12])[N:6]([C@H:4]3[CH2:5][C@H:2]([O:1][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:3]3)[C:7]3[N:8]([N:31]=[CH:32][N:33]=3)[C:9]=2[CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=1)#[N:27]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](O)C2)c2ncnn12
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](OCC(=O)OCC)C2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[4-(trans-3-hydroxycyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.28 g), rhodium(I) acetate (0.0028 g) and toluene (10 mL) was added dropwise ethyl diazoacetate (0.62 mL) at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.056 g, 17%).
Reaction SMILES: [CH2:1]([CH:4]([N:8]1[C:12]2[N:13]=[C:14]([CH3:27])[N:15]=[C:16]([NH:17][C:18]3[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])[C:11]=2[N:10]=[N:9]1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C)C=O.O>[CH2:30]([N:17]([C:18]1[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=1[CH3:24])[C:16]1[C:11]2[N:10]=[N:9][N:8]([CH:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[C:12]=2[N:13]=[C:14]([CH3:27])[N:15]=1)[CH3:31]
Reactant: CCCC(CCC)n1nnc2c(Nc3c(C)cc(C)nc3C)nc(C)nc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCC)n1nnc2c(N(CC)c3c(C)cc(C)nc3C)nc(C)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The product from Example 47, Part B (400 mg, 1.09 mmol) was treated with sodium hydride (40 mg, 1.31 mmol, 80%) and ethyl iodide (0.130 ml, 1.63 mmol) in dry dimethylformamide (10 ml) and stirred at room temperature for 15 hours. The reaction was diluted with 150 ml water, and extracted with 3×30 ml ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (20 g, 1/3 hexanes/ethyl acetate) afforded the desired product, 373 mg (87%) as a clear viscous oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:19][C:20]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:10]=[CH:9][S:8][N:7]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCSCc1ccsn1
Product: O=C(NC(=S)NCCSCc1ccsn1)c1ccccc1

Procedure:
By the procedure of Example 18. 3-[(2-aminoethyl)thiomethyl]isothiazole is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(3-isothiazolylmethylthio)ethyl]thiourea.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: Clc1ccc(Br)cc1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(Oc2ccc(Cl)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 21.3 %

Procedure:
To a solution of (S)-2-tert-Butoxycarbonylamino-3-[4-hydroxy-phenyl]-propionic acid methyl ester (2 g, 6.8 mmol, 1 eq.) in dioxane (20 ml) was added 4-bromochlorobenzene (1.95 g, 10 mmol, 1.5 eq.), CuI(I) (140 mg, 0.7 mmol, 0.1 eq.), N,N-dimethylglycine (220 mg, 2.1 mmol, 0.3 eq.) and cesium carbonate (4.6 g, 14 mmol, 3 eq.). The resulting mixture was stirred under Ar at reflux overnight. After cooling to room temperature, the volatile material was removed under reduced pressure to give a residue, which was partitioned between water and ethyl acetate. The ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (2×20 ml). The combined ethyl acetate layers were dried over anhydrous MgSO4. Evaporation of solvent under reduced pressure gave a residue, which was purified by chromatography on silica gel using dichloromethane/MeOH (50:1) as eluent to give the desired product (587 mg, 21% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26]O)=[CH:20][N:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][O:14][C:10]2[C:11]([CH3:13])=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][C:9]=2[CH3:15])=[CH:20][N:19]=1
Reactant: Cc1nc(-c2cc(C)c(O)c(C)c2)no1
Reactant: COc1ccc(CCCO)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCOc2c(C)cc(-c3noc(C)n3)cc2C)cn1
Yield: 72.6 %

Procedure:
To a suspension of 0.81 g (3.9 mmol) of 4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 0.8 g (1.2 eq) of 2-methoxy-5-(3-hydroxypropyl)-pyridine, 1.4 g (1.2 eq) of triphenylphosphine in 70 ml of methylene chloride under nitrogen at 5° C. was added in portions 0.88 g (1.2 eq) of DEAD. The mixture was concentrated in vacuo, the residue was triturated with ether, filtered, and the crude product was purified by MPLC (50 id,Kieselgel 60 column, hexane/ethyl acetate, 2:1) and recrystallization from isopropyl acetate/hexane to afford 1 g (71.4%) of 2-methoxy-5-[3-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine, as a white powder, m.p. 71°-73° C.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.FC1C(O)=C(F)C(F)=C(F)C=1F.[C:25]([N:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:33][C:34]([OH:36])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C.Cl.[CH3:52][O:53][C:54](=[O:64])[C@H:55]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[NH2:56]>C(Cl)Cl>[CH3:52][O:53][C:54](=[O:64])[C@H:55]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[NH:56][C:34](=[O:36])[CH2:33][N:32]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a stirring suspension of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol) in reagent grade CH2Cl2 (20 mL) was added a solution of pentafluorophenol (1.5 g, 8.1 mmol) in CH2Cl2 (10 mL) followed by a solution of N-Boc-N-Benzyl glycine 3 [Naylor 1993] (1.32 g, 5.0 mmol) in CH2Cl2 (20 mL). The solution was stirred at ambient temperature for 1 h then triethylamine (2.5 mL, 18 mmol) was added with additional CH2Cl2 (10 mL). The (±)-phenylalanine methyl ester hydrochloride (1.32 g, 5 mmol) was then added in small portions. The final solution was stirred for 20 h at ambient temperature and then was washed with aqueous sodium carbonate (1 M, 100 mL), aqueous citric acid (1 M, 100 mL) and water (50 mL). The organic phase was dried (K2CO3) and concentrated to afford the crude product. Column chromatography of the crude material (silica gel, EtOAc:hexanes, gradient 1:3 3:2) to provided 5 as a clear viscous oil (2.17 g, 102%, solvent heavy). 1H NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 2.99-3.16 (bm, 2H), 3.72 (s, 3H), 3.79 (bd, J=16.1 Hz, overlapped with bm, 2H), 4.30-4.50 (bm, 2H), 4.85 (m, 1H), 6.27 (bs, 0.3H), 6.63 (bs, 0.3H), 7.05-7.11 (bm, 2H), 7.17-7.34 (m, 8H); 13C NMR (100 MHz, CDCl3): δ 28.2, 37.8, 50.2, 51.2 (v. broad), 52.3, 52.8 (broad), 81.1, 127.1, 127.6, 128.1 (broad), 128.6, 129.1, 135.6, 136.9, 155.3 (broad), 168.9 (broad), 171.5.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27](C)([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.CCN(CC)CC.ClC(OC(C)C)=O>C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Agent: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (53 mg, 0.118 mmol) in CH2Cl2 (1.0 mL) was added TFA (0.5 mL) dropwise. The reaction mixture was stirred for 1 h and evaporated under reduced pressure. The residue was then dissolved in CH2Cl2 (1.5 mL) followed by addition of Et3N (82 μL, 0.59 mmol) and isopropyl chloroformate (0.295 mL, 0.295 mmol, Aldrich). The resulting mixture was stirred at room temperature for 30 min, quenched with H2O (0.2 mL) and then evaporated to dryness. The crude product was purified by preparative HPLC (C18 column; 10-100% methanol in water containing 0.05% trifluoroacetic acid) to give Example 3 (44.5 mg, white solid, 87%) upon lyophilization. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J=8.80 Hz, 2 H), 7.61 (d, J=8.25 Hz, 2 H), 7.30 (d, J=7.70 Hz, 1 H), 6.28 (d, J=2.20 Hz, 1 H), 6.19 (dd, J=7.70, 2.20 Hz, 1 H), 4.86-5.00 (m, 1 H), 4.51-4.63 (m, 1 H), 3.77 (app brs, 2 H), 3.33-3.44 (m, 2 H), 3.11 (s, 3 H), 1.96-2.11 (m, 2 H), 1.73-1.86 (m, J=7.15 Hz, 2 H), 1.26 (d, J=6.05 Hz, 6 H). MS (ESI) 435 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:45][S:42]([CH:39]3[CH2:41][CH2:40]3)(=[O:44])=[O:43])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc3c(C(=O)O)cnn23)c1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 84.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.130 g, 0.251 mmol) obtained in step 2 and cyclopropanesulfonamide (0.155 g, 0.125 mmol), the title compound (0.066 g, 42%) was obtained.
Reaction SMILES: [Si](O[C@H]1CC(=O)N([C:15]2[C:16]([C:23]([F:26])([F:25])[F:24])=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[C@H]1CC)(C(C)(C)C)(C)C.[CH2:29]([OH:31])[CH3:30].Cl.[C:33](=[O:36])([O-])O.[Na+]>O1CCCC1>[CH2:17]([C@H:18]1[C@@H:29]([OH:31])[CH2:30][C:33](=[O:36])[N:19]1[C:22]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:23]([F:24])([F:25])[F:26])[CH:15]=1)[CH3:16]
Reactant: CC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1cccc(C#N)c1C(F)(F)F
Reactant: CCO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
To a solution of 4-[((2S,3S)-3-(tert-butyldimethylsilyloxy)-2-ethyl-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (7.76 g) in tetrahydrofuran (60 mL)-ethanol (30 mL) was added 6 mol/L hydrochloric acid (60 mL), and the mixture was stirred at room temperature for 18 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/4), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound as a colorless solid (yield: 2.36 g, 42%).