Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13](C=O)=[CH:14][CH:15]=1.[CH:19]([O:24][CH3:25])([O:22][CH3:23])OC.[Cl-].[NH4+]>CO>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH:19]([O:22][CH3:23])[O:24][CH3:25])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCCCc1ccc(C=O)o1
Reactant: COC(OC)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CCCCCCCc1ccc(C(OC)OC)o1

Procedure:
32.8 g of 8-(5-formyl-2-furyl)-octanoic acid methyl ester, 15.5 g of trimethyl orthoformate, 16 ml of methanol and 0.3 g of ammonium chloride were mixed and refluxed for 4 hours. The solution was concentrated to dryness on a water bath. The residue was then absorbed in ether, washed with water, dried and distilled. Boiling point 136°-138° C at 0.2 mm Hg.
Reaction SMILES: CN(C)C=O.Cl.Cl[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[NH2:16][C:17](=[O:49])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([OH:33])=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH2:47]C)=[O:19].[Na]>O>[NH2:16][C:17](=[O:49])[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH2:30][C:31]([O:33][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:32])[N:22]([CH2:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:38]=[CH:39][CH:40]=2)[C:21]=1[CH3:47])=[O:19]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1cccc(-c2ccccc2)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)OCCN3CCOCC3)cccc2n1Cc1cccc(-c2ccccc2)c1
Temperature: 60 °C

Procedure:
In a flask containing 10 ml of dimethylformamide is added with stirring 133 mg. of 4-(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3) and 231 mg. of CsCO3 and 300 mg. of ((3-(2-amino-1,2-dioxoethyl)-1-((1,1′-biphenyl)-3-ylmethyl)-2-ethyl-1H-indol-4-yl)oxy)acetic acid, sodium salt. The slurry is heated to 60° C. until a solution formed. Heating is continued overnight until reaction is complete. 20 ml of H2O is added to the flask and the organic soluble phase is extracted with three 20 ml. portions of ethyl acetate. The ethyl acetate solution is washed with water and dried over Na2SO4.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[CH:28]=[N:29][N:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=34)[CH:24]=[CH:23][N:22]=2)=[C:13]([O:36][CH3:37])[CH:12]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[C:13]([O:36][CH3:37])[CH:12]=2)[CH2:6]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: CN(C)C1CNC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 85 °C
Yield: 71.7 %

Procedure:
N,N-Dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 227 mg, 1.31 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.755 mL, 4.36 mmol) in DMA (3.2 mL) and the mixture was heated at 85° C. for 1 h. The mixture was part-purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 0-7% CH3OH in CH2Cl2 gave the title compound (360 mg, 72%) as an orange solid; 1H NMR: 2.15 (6H, s), 3.12-3.19 (1H, m), 3.74-3.78 (2H, m), 3.95 (3H, s), 4.04-4.09 (2H, m), 6.29 (1H, s), 7.08 (1H, td), 7.28 (1H, d), 7.36-7.41 (1H, m), 8.26 (1H, s), 8.35 (1H, d), 8.45-8.49 (2H, m), 8.78 (1H, s), 8.80 (1H, d); m/z: ES+ MH+ 461.33.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[C:14]=2[CH3:15])=[CH:5][CH:4]=1.C(Cl)Cl.B(Br)(Br)Br.B(Cl)(Cl)Cl>C(Cl)(Cl)Cl.C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[C:14]=2[CH3:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C)c(=O)cc(-c3ccccc3)n2-c2ccccc2)cc1
Agent: BrB(Br)Br
Agent: ClB(Cl)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(-c2ccc(O)cc2)n(-c2ccccc2)c(-c2ccccc2)cc1=O

Procedure:
For example, when 2-(4-methoxyphenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone is either dissolved or suspended in a suitable solvent, e.g., methylene chloride, benzene or chloroform, and a Lewis acid such as boron tribromide, boron trichloride or the like is then added to the resulting solution to conduct a reaction, 2-(4-hydroxyphenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone is produced.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].C(OC(C)C)(C)C.C(N(CC)CC)C.Cl[C:21]([C:23]([F:34])([F:33])[CH:24]([O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:25][CH3:26])=[O:22]>>[CH2:1]([O:5][C:21]([C:23]([F:33])([F:34])[CH:24]([O:27][C:28](=[O:32])[C:29]([CH3:31])=[CH2:30])[CH2:25][CH3:26])=[O:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)Cl
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OCCCC
Temperature: 0 °C
Yield: 91.1 %

Procedure:
Into a 1 L glass flask with a dropping funnel, 62.8 g (0.847 mol, 1.2 eq) of n-butanol, 510 g of diisopropyl ether, 100 g (0.988 mol, 1.4 eq) of triethylamine and 1 g of antioxidant “Nonflex MBP” (manufactured by Seiko Chemical Co., Ltd.) were added. The resulting solution was cooled to 0° C. and stirred, followed by dropping thereto 170 g (purity: 99%, 0.706 mol) of methacrylic acid 1-chlorocarbonyl-1,1-difluoro-2-butyl ester. The thus-obtained reaction solution was stirred for 1 hour at room temperature. The completion of the reaction was confirmed by 19F NMR. The reaction-completed solution was separated into an organic layer and an aqueous layer by the addition of 500 mL of water. The organic layer was dehydrated with magnesium sulfate, filtrated, and then, concentrated under a reduced pressure. The concentration residue was subjected to distillation under a reduced pressure. With this, 179 g of methacrylic acid 1-(n-butoxycarbonyl)-1,1-difluoro-2-butyl ester was obtained as a colorless transparent liquid (yield: 91%, purity: 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CO[C:12]([CH3:15])([CH3:14])[CH3:13]>[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[C:12]([C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:9])=[CH:5][C:6]=1[F:8])([CH3:15])([CH3:14])[CH3:13]
Reactant: Oc1cc(F)cc(F)c1
Reactant: COC(C)(C)C
Agent: [Zr+4]
Agent: [Cl-]
Product: CC(C)(C)c1c(F)cc(O)cc1F
Temperature: 55 °C
Reaction time: 12 h
Yield: 54.2 %

Procedure:
A mixture of 3,5-difluorophenol (TCl, 14 g, 107 mmol), tert-butyl methyl ether (12.8 ml, 108 mmol) and zirconium(IV) chloride (25 g, 107 mmol) was stirred for 12 hours at 55 ° C., followed by addition of tert-butyl methyl ether (6.4 ml, 54 mmol). The additional injection of tert-butyl methyl ether (6.4 ml, 54 mmol), was repeated 8 times at intervals of 24 hours and then the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution. The whole was extracted with DCM, washed with brine, and dried over magnesium sulfate. The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography, eluting with gradually from hexane only to hexane/EtOAc (10:1), to give the title compound (10.8 g, 54%) as white solids.
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:2]([C:10]([NH:12][C@H:13]([C:21](O)=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:34][C@H:35]([C:40]([NH:42][C@H:43]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:65]([NH2:67])=[O:66])[CH2:59][C:60]1[N:64]=[CH:63][NH:62][CH:61]=1)=[O:56])[C@H:51]([CH2:53][CH3:54])[CH3:52])=[O:48])[CH:44]([CH3:46])[CH3:45])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CO.O>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:34][C@H:35]([C:40]([NH:42][C@H:43]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:65]([NH2:67])=[O:66])[CH2:59][C:60]1[N:64]=[CH:63][NH:62][CH:61]=1)=[O:56])[C@H:51]([CH2:53][CH3:54])[CH3:52])=[O:48])[CH:44]([CH3:45])[CH3:46])=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 69 mg of Z-Phe-Arg-OH, 50 mg of H-Leu-Val-Ile-His-NH2, 16 mg of HOBt and 40 mg of DCCI, the title compound is obtained in the form of a colourless powder after flash chromatography (45 g of silica gel 60, 40-63 μm, eluant system methylene chloride/methanol/water/glacial acetic acid 330:100: 19:2). Rf (S3)=0.16.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[N:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[N:11][C:10]=2[NH:18][C:19]2[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=2)[CH:3]=1.[CH3:28][Mg]Br.C(OCC)C>O1CCCC1.[NH4+].[Cl-]>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[N:14]=[C:13]([C:15]([OH:17])([CH3:28])[CH3:16])[CH:12]=[N:11][C:10]=2[NH:18][C:19]2[CH:20]=[N:21][C:22]([O:26][CH3:27])=[C:23]([F:25])[CH:24]=2)[CH:3]=1
Reactant: COc1ncc(Nc2ncc(C(C)=O)nc2-c2cc(N)nc(C)n2)cc1F
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)(C)O)nc2-c2cc(N)nc(C)n2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
A mixture of 1-(6-(6-amino-2-methylpyrimidin-4-yl)-5-(5-fluoro-6-methoxypyridin-3-ylamino)pyrazin-2-yl)ethanone (11 mg, 0.030 mmol) and methylmagnesium bromide, 3.0 M solution in diethyl ether (10.65 μL, 0.089 mmol, Aldrich, St. Louis, Mo.) in tetrahydrofuran (1 mL) was stirred at 0° C. for 30 min. The reaction mixture was diluted with saturated NH4Cl (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic extracts were washed with saturated NaCl 5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 5% MeOH/CH2Cl2 to give 2-(6-(6-amino-2-methylpyrimidin-4-yl)-5-(5-fluoro-6-methoxypyridin-3-ylamino)pyrazin-2-yl)propan-2-ol (8.5 mg, 0.022 mmol, 74.1% yield). 1H NMR (300 MHz, CDCl3) δ 1.63 (s, 6H) 2.66 (s, 3H) 3.66 (s, 1H) 4.03 (s, 3H) 5.01 (s, 2H) 7.45 (s, 1H) 8.11 (d, J=1.90 Hz, 1H) 8.22 (dd, J=12.13, 2.05Hz, 1H) 8.39 (s, 1H) 12.66 (s, 1H). m/z (ESI, +ve ion) 386.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](F)[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CS(C)=O.[Cl-].[Na+].O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:32][C@H:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:21])([F:33])[F:34])=[CH:29][CH:28]=2)[CH3:31])[N:15]=1)[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)c1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1ccnc(F)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)n1)c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C

Procedure:
To a suspension of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-fluoropyrimidin-4-yl)oxazolidin-2-one (30.0 mg, 0.106 mmol) and (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (38.4 mg, 0.159 mmol) in DMSO (0.53 mL), was added DIEA (64.7 ul, 0.371 mmol) in a microwave vial. The vial was capped and the reaction mixture heated in a preheated oil bath at 100° C. for 3 hr. The mixture was diluted with dilute brine and extracted with EtOAc two times. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, concentrated and dried on house vacuum to afford crude (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one as a clear colorless oil which was used without further purification (yield assumed quantitative). LCMS m/z 469.3 (M+H)+, Rt 0.98 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=2[CH3:21])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H][H]>CN(C)C=O.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:10])=[C:13]([CH3:21])[CH:14]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)Nc1cccc(F)c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc(N)ccc1NC(=O)Nc1cccc(F)c1

Procedure:
A solution of EXAMPLE 100A (1.28 g, 4.43 mmol) in 12 mL of N,N-dimethylformamide was degassed and hydrogenated under an atmosphere of hydrogen (balloon) in the presence of catalytic amount of 10% Pd on carbon for 24 hours. The mixture was filtered and the filtrate was extracted with ethyl acetate. The organic extract was washed with brine, dried with MgSO4 and concentrated to provide EXAMPLE 100B. MS (ESI(+)) m/e 260 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([C:12]#[N:13])[C:9]2[N:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[S:16][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].Cl>C[O-].[Na+].CO.O>[C:17]([C:15]1[S:16][C:8]2[C:7]([OH:21])=[C:6]([C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5])[N:11]=[C:10]([C:12]#[N:13])[C:9]=2[N:14]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2nc(C(C)(C)C)sc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nc2c(C#N)nc(C(=O)NCC(=O)O)c(O)c2s1
Yield: 53.4 %

Procedure:
A suspension of 2-tert-butyl-4-cyano-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (85 mg, 0.28 mmol) and glycine (188 mg, 2.5 mmol) in 4.4 mL of 0.5 N NaOMe in methanol was heated at reflux temperature for 25 h. The reaction mixture was diluted with water, acidified with 1 N HCl, and extracted with ethyl acetate. The organic fraction was concentrated to a residue and purified by reverse phase chromatography on a C-18 column, eluting the desired product with a gradient of 10-90% acetonitrile in water+0.1% formic acid. The lyophilized material fractions provided 50 mg of white solid. MS (ESI−): m/z 333.0 (M−1).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:28][C:13]3=[N:14][CH:15]=[C:16]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([O:23]C)=[O:22])[CH:17]=[C:12]3[C:11]=2[C:29](=[O:32])[NH:30][CH3:31])=[CH:6][CH:5]=1>CO.CCOC(C)=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:28][C:13]3=[N:14][CH:15]=[C:16]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([OH:23])=[O:22])[CH:17]=[C:12]3[C:11]=2[C:29](=[O:32])[NH:30][CH3:31])=[CH:6][CH:5]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)OC)c3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)O)c3)cc12
Reaction time: 8 h
Yield: 94.9 %

Procedure:
NaOH (0.297 mL, 0.297 mmol, 1M aq.) was added to a stirring solution of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoate (24 mg, 0.059 mmol) in MeOH (2 mL) at room temperature. It was allowed to stir overnight. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the expected product 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)benzoic acid (22 mg, 0.056 mmol, 95% yield) consistent by LCMS. LC-MS retention time: 0.90 min; m/z (MH+): 391. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][CH:26]=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Nc1cc[nH]n1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1C(F)(F)F
Yield: 85.1 %

Procedure:
A mixture of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (2.17 g, 7.28 mmol) and commercially available 3-aminopyrazole (0.73 g, 8.78 mmol) in acetic acid (15 ml) was refluxed for 4 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/heptane) to yield 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (2.14 g, 85%) as a yellow solid. MS (EI) 345.1 [(M)+]; mp 87° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][CH2:17][C:18](Cl)=[O:19].C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:18](=[O:19])[CH2:17][Cl:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: O=C(Cl)CCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)CCl)C1
Reaction time: 8 h

Procedure:
3-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester 1c (5.0 g, 23.4 mmol) in 20 mL CH2Cl2 was added dropwise to a cold (−10→0° C.) solution of chloroacetylchloride (2.8 mL, 35 mmol, 1.5 equiv) and diisopropylethylamine (6.1 mL, 35 mmol, 1.5 equiv) in 60 mL CH2Cl2 under N2. After being left overnight (−10° C.→rt), the mixture was diluted with ethyl acetate and washed briefly with water and brine, dried (Na2SO4), and concentrated to give 3-[(2-chloroacetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester 1d as a dark brown oil. The crude product was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([N+:14]([O-])=O)[NH:12][CH:13]=2)[CH2:4][CH2:3]1.CO.C1COCC1.CO.[CH3:26][C:27]1[C:28]([C:32]2[C:41]3[N:40]=[CH:39][CH:38]=[N:37][C:36]=3[C:35]([C:42](O)=[O:43])=[CH:34][CH:33]=2)=[CH:29][S:30][CH:31]=1>[Ni].C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:42]([C:35]3[C:36]4[N:37]=[CH:38][CH:39]=[N:40][C:41]=4[C:32]([C:28]4[C:27]([CH3:26])=[CH:31][S:30][CH:29]=4)=[CH:33][CH:34]=3)=[O:43])[NH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: Cc1cscc1-c1ccc(C(=O)O)c2nccnc12
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Agent: [Ni]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cscc1-c1ccc(C(=O)Nc2nc(CN3CCN(C)CC3)c[nH]2)c2nccnc12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but stirring the reaction mixture for 16 h at 60° C., using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3, Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid (Example 67) in Step 14.1. Title compound: ESI-MS: 448.0 [M+H]+; tR=3.00 min (System 1); TLC: Rf=0.14 (DCM/MeOH, 9:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[C:15](Cl)([N:17]=[C:18]=[O:19])=[O:16]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[O:14][C:18](=[O:19])[NH:17][C:15](=[O:16])[C:10]=3[CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:13][CH2:12][CH2:11][CH:10]=[C:9]2[O:14][C:18](=[O:19])[NH:17][C:15]3=[O:16])=[CH:6][CH:7]=1
Reactant: O=C1CCCCC1c1ccc(F)cc1
Reactant: O=C=NC(=O)Cl
Product: O=C1NC(=O)C2(c3ccc(F)cc3)CCCC=C2O1
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)cc1)CCC2
Yield: 35.3 %
Yield: 19.62 %

Procedure:
2-(4-fluorophenyl)cyclohexanone and carbonisocyanatidic chloride (0.966 mL, 12 mmol) was reacted as in Intermediate AC(1) to provide 8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.689 mmol, 19.62% yield) as white solid and 4a-(4-fluorophenyl)-4a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (746.4 mg, 3.04 mmol, 35.3% yield) as white solid. 8-(4-fluorophenyl)-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione. LC-MS (M+H)+=262.1. 1H NMR (500 MHz, CDCl3) δ ppm 9.61 (1H, br s), 7.10 (2H, dd, J=5.0, 8.5 Hz), 6.98 (2H, app t, J=8.5 Hz), 3.77 (1H, t, J=4.9 Hz), 2.38-2.53 (2H, m), 2.16-2.07 (1H, m), 1.87-1.62 (3H, m).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[OH:54][CH2:55][CH2:56][NH:57][CH2:58][CH2:59][NH-:60].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([NH:48][C@H:49]([C:51]([OH:53])=[O:52])[CH3:50])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:54][CH2:55][CH2:56][NH:57][CH2:58][CH2:59][NH-:60]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCNCCO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](C)C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 88 mg of Z-Phe-His-OH, 60 mg of H-Leu-Val-Ala-2-(2-hydroxyethylamino)-ethyl amide, 31 mg of HOBt and 48 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B11). Rf (B11)=0.24.