Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:49])[C@H:6]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([C:41]2[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:42]=2[Cl:48])=[O:40])=[CH:34][CH:33]=1)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)=[N:19][N:18]=[N:17]2)=[CH:12][C:11]=1[Cl:30])=[O:9]>CO.C1COCC1.O>[Cl:47][C:46]1[CH:45]=[CH:44][CH:43]=[C:42]([Cl:48])[C:41]=1[C:39]([NH:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][C@@H:6]([C:5]([OH:49])=[O:4])[NH:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=4)=[N:19][N:18]=[N:17]3)=[CH:12][C:11]=2[Cl:30])=[O:9])=[CH:37][CH:36]=1)=[O:40]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(-n2nnnc2NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)C(=O)O)c1ccc(-n2nnnc2NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
An aqueous 1N lithium hydroxide solution (0.33 mL) was added to a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[5-[[(3-hydroxyphenyl)methyl]amino]-1H-tetrazol-1-yl]phenyl]carbonyl]-L-phenylalanine methyl ester (75 mg; 0.108 mmol) in methanol (0.66 mL) and THF (0.66 mL) and the mixture was stirred at room temperature for 90 min. After the solvents were stripped under reduced pressure, the residue was dissolved in water (20 mL) and extracted with diethyl ether (3×5 mL). The aqueous layer was filtered through Celite, then acidified with 1 N HCl (0.35 mL). The resulting colorless solid was filtered off, washed with water, and dried in vacuo to give 57 mg of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-chloro-4-[5-[[(3-hydroxyphenyl)methyl]amino]-1H-tetrazol-1-yl]phenyl]carbonyl]-L-phenylalanine. FAB HRMS: (C31H24Cl3N7O5) Obs. Mass 680.0981 Calcd. Mass 680.0983 (M+H).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[C:10]([Br:15])[C:11]2=[O:14])=[CH:7][CH:6]=1)(=O)C.C(OC1C=C2C(C(C3C=CC=CC=3)=C(Br)C2=O)=CC=1)(=O)C>>[Br:15][C:10]1[C:11](=[O:14])[C:12]2[C:8]([C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])=[CH:7][CH:6]=[C:5]([OH:4])[CH:13]=2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1F
Agent: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1
Product: O=C1C(Br)=C(c2ccccc2F)c2ccc(O)cc21
Yield: 93 %

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 2-bromo-3-(2-fluorophenyl)-1-oxo-1H-inden-6-yl acetate obtained in Step 4 as a starting material instead of 2-bromo-1-oxo-3-phenyl-1H-inden-6-yl acetate to obtain the title compound (93%).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:10](=[O:28])[NH:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][N:11]3[CH2:12][C@H:8]([C:6]([OH:7])=[O:5])[NH:9][C:10]3=[O:28])=[CH:15][CH:16]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of (4R)-1-[4-(4-fluorophenoxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid tert-butyl ester (810 mg, 1.56 mmol) in CH2Cl2 (8 mL) was treated with trifluoroacetic acid (8 mL). The reaction mixture was stirred at room temperature for 2.5 hours and concentrated to leave an oil. The title compound, a white solid (297 mg, 58%), was collected by filtration, after triturating the oil with a mixture of warm diethyl ether and hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-:19])=[O:18])=[C:11]([CH:14]=[CH:15][CH:16]=1)[N:12]([C:32](=[O:33])[CH2:31][O:30][CH3:29])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: CNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: COCC(=O)N(C)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 3-benzyloxy-2-nitro-N-methylaniline (400 mg) and N,N-dimethylaniline (1 ml) was added methoxyacetyl chloride (310 μl) under nitrogen atmosphere, and the mixture was stirred for 2.5 hours at 90° C. After cooling, ethyl acetate was added to the reaction mixture, and the mixture was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1, v/v) to give 3-benzyloxy-2-nitro-N-methoxyacetyl-N-methylaniline (474.2 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].[Na+].[Cl-]>N1C=CC=CC=1>[CH2:18]([O:17][C:15]([N:12]=[S:10]([CH3:13])([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:11])=[O:16])[CH3:19]
Reactant: CCOC(=O)Cl
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)N=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
8.50 g (4.5 mmol) (RS)—S-(4-nitrophenyl)-S-methylsulfoximide in 400 ml pyridine are treated dropwise at room temperature with 18.8 ml (197.2 mmol) ethyl chloroformate. The mixture is stirred at room temperature for 4 hours and then poured into dilute NaCl solution. It is extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated. The remaining residue is chromatographically purified (hexane/ethyl acetate 1:1). 8.94 g (32.8 mmol, corresponding to 77% of theor.) of the product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[NH:12]C(=O)C>Cl>[NH2:12][C:3]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CC(=O)Nc1c(Cl)cc(O)cc1[N+](=O)[O-]
Agent: Cl
Product: Nc1c(Cl)cc(O)cc1[N+](=O)[O-]

Procedure:
1.00 g (4.24 mmol) N-(2-chloro-4-hydroxy-6-nitrophenyl)acetamid were refluxed in 10 mL semiconcentrated hydrochloric acid for 2 h. The reaction mixture was evaporated down i.vac. and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[C:14]([Cl:15])=[N:13][S:12][N:11]=2)=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@H:24]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:16]([O:20][C:21]([NH:23][C@H:24]([CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([NH:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:10]1[C:14]([Cl:15])=[N:13][S:12][N:11]=1)=[O:30])=[O:26])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: NCc1cc(Cl)ccc1-c1nsnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1nsnc1Cl)C1CCCCC1

Procedure:
To a stirred solution of 1-[5-chloro-2-(4-chloro-1,2,5-thiadiazol-3-yl)phenyl]methanamine (28.1 mg, 0.11 mmol), 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-proline (prepared by standard peptide coupling protocols, 38.3 mg, 0.11 mmol) and HOAt (19.1 mg, 0.14 mmol) in DMF (1.0 mL) was added EDC (26.9 g, 0.14 mmol). After 16 h the mixture was partitioned between EtOAc and water. The organic phase was washed with brine dried (Na2SO4) and reduced in vacuo. The residue was purified by HPLC (C18 eluting with an acetonitrile/water/0.1% TFA gradient). 1-{(2R)-2-[(tert-Butoxycarbonyl)amino]-2-cyclohexylethanoyl}-N-[5-chloro-2-(4-chloro-1,2,5-thiadiazol-3-yl)benzyl]-L-prolinamide was obtained as a solid. LCMS m/z=596.5.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[O:8].C[Si](C)(C)[C:11]([F:14])([F:13])[F:12].Cl>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([OH:8])[C:11]([F:14])([F:13])[F:12]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=CCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(CCCCCBr)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.9 %

Procedure:
Subsequent treatment of 6-bromo-hexanal with trimethyl(trifluoromethyl)silane in the presence of a catalytic amount of tertrabutyl ammonium fluoride (TBAF) resulted in the nucleophilic addition to the carbonyl and afforded the corresponding α-trifluoromethyl alcohol in a single step, a modification of Krishnamurti et al., J. Org. Chem. 1991, 56, 984. A 1.12 g sample of 6-bromo-hexanal (6.26 mmol) was combined with 8 mL freshly distilled THF and trimethyl(trifluoromethyl)silane (1.07 g, 7.51 mmol), all in a 50 mL round bottomed flask under a nitrogen atmosphere. The solution was allowed to stir for 20 min at rt and then cooled to 0° C. for 15 min prior to the addition of 20 mg of TBAF. After observation of initial yellow color formation, the ice bath was removed and solution allowed to warm to room temperature and stirred overnight. Disappearance of the carbonyl band of the starting material was confirmed by FTIR. The resulting reaction mixture was hydrolyzed upon addition of 1 mL of 5 M HCl followed by stirring at rt for 5 hr. The resulting reaction mixture was extracted with Et2O (3×75 mL), washed with di-H2O (50 mL), washed with brine (50 mL) and dried over MgSO4. The resulting organic layer was concentrated to afford the desired product (1.48 g). FTIR: 3283, 2946, 2862, 1633, 1463, 1379, 1272, 1161, 1118, 841 cm−1; 19F NMR—79.93 δ (d, J=7, CF3); 1H NMR: 4.09 (t, J=6, 1H), 3.43 (t, J=7, 2H), 2.35 (bs, 1-OH), 1.91 (t, J=7, 2H), 1.87–1.41 δ (m, 6H); 13C NMR: 121.7 (q, CF3), 82.3, 34.7, 28.7, 25.4, 23.0, 20.8 δ. Anal. Calcd for C7H12BrF3O: C, 33.76; H, 4.86. Found: C, 33.91; H, 4.57.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:31][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: Cc1ccccc1-c1ccc(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)s1
Yield: 41 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and o-tolylboronic acid (8 mg, 0.06 mmol). The title compound was obtained in 41% yield (8.1 mg). MS (ESI+) calcd mass for C18H15N5O2S2 397.066716, found 397.066896.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([N:26]([CH2:32][C@H:33]1[C@@H:37]([F:38])[CH2:36][N:35](C(OCC2C=CC=CC=2)=O)[CH2:34]1)[C:27](=[O:31])[C@@H:28]([OH:30])[CH3:29])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([N:26]([CH2:32][C@H:33]1[C@@H:37]([F:38])[CH2:36][NH:35][CH2:34]1)[C:27](=[O:31])[C@@H:28]([OH:30])[CH3:29])[C:22]([CH3:25])([CH3:23])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@H](O)C(=O)N(C[C@@H]1CNC[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 590.1 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)-2-hydroxypropanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (6.5 mg, 0.8 μmol) in degassed ethanol (980 μL, 0.01 M solution) was added Pd/C (5.0 mg) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for 30 min. The reaction mixture was filtered through Celite® pad that was washed with methanol and EtOAc. The volatile organic filtrate was removed in vacuo to give the crude amine, which was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative TLC to yield (S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide (2.5 mg, 48.2%) as the free amine. LC/MS (uplc): MH+ 530.3, 0.94 min.
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31]>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: COc1ccccc1N
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccccc1NC1c2cc(NC(=O)CC(C)(C)C)c(C)c(C)c2OC1(C)C
Yield: 75 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 235 and (2-methoxyphenyl)amine, the title compound was synthesized in the same manner as in Example 297. Yield: 75%. Melting point: 184-185° C. (ethyl acetate-hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O.C(=O)(O)[O-].[Na+].[C:16](Cl)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[CH2:19]([O:18][C:16]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To piperidine-4-carboxylic acid (25 g) in THF (75 ml) there was added water (75 ml), followed by sodium bicarbonate (30.8 g). The mixture was cooled to 0° C., and Cbz chloride (38.9 ml) was added dropwise. The reaction mixture was then stirred for 5 h at room temperature (TLC monitoring). When the reaction was complete, the organic solvent was distilled off and the residue was taken up in water (200 ml) and washed with ethyl acetate (2×150 ml). The aqueous phase was acidified with dilute aqueous HCl solution and extracted with ethyl acetate. The organic phase was dried (Na2SO4) and concentrated under vacuum. Yield: 48.5 g (96%)
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[F:31][C:32]([F:39])([F:38])[CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:35]3[CH2:36][CH2:37][CH:33]([C:32]([F:39])([F:38])[F:31])[CH2:34]3)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: FC(F)(F)C1CCNC1
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N3CCC(C(F)(F)F)C3)c21
Temperature: 150 °C

Procedure:
Under an argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was put in 4 ml of absolute NMP and 671 mg (4.82 mmol) of 3-(trifluoromethyl)pyrrolidine was added. The mixture was heated in the microwave at 150° C. for 5 h. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 65 mg (49% of theor.) of the target compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Yield: 39.6 %

Procedure:
2-Chloroquinoline (0.04 moles, 6.54 g), 4-aminothiophenol (0.04 moles, 5.0 g) and potassium carbonate (0.04 moles, 5.52 g) were stirred at room temperature in 200 ml of ethanol for 18 hr. The reaction mixture was concentrated, ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with ethyl acetate/hexane to yield 2-(4-aminophenylthio)quinoline 4.0 g, 40%. Mass Spec (FD) 252. Calculated for C15H12N2S: C, 71.40; H, 4.79, N, 11.10. Found: C, 71.11; H, 4.98N, 11.20.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH3:31][O-:32].[Na+].O>CO>[CH3:31][O:32][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1
Reactant: C[O-]
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 8.0 ml of methanol were added 60.79 mg (1.124 mmol) of sodium methoxide, and then the reaction mixture was stirred under reflux for 18 h. The reaction mixture was admixed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 32.0 mg (31% of theory)
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH:6]([CH3:8])[CH2:5][NH:4][C:3]1=[O:9].C(N(CC)CC)C.[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][C:25]([N:7]1[CH:6]([CH3:8])[CH2:5][NH:4][C:3](=[O:9])[C@@H:2]1[CH3:1])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC1CNC(=O)[C@H](C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CNC(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of (3S, 5RS)-3,5-dimethyl-piperazin-2-one (24.3 mmol) in 100 mL of methylenechloride is added triethylamine (8.45 mL, 60.75 mmol) and N-(benzyloxycarbonyloxy)succinimide (12.1 g, 48.6 mmol). After stirring overnight, the CH2Cl2 is removed, and the crude mixture is chromatographed (50% EtOAc/Hexane). (2S, 6RS)-2,6-Dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (3.3 g, 52% yield over three steps) is isolated as a white powder. MS C14H18N2O3 MS m/z: 263.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[C:27](OC(=O)C)(=O)[CH3:28]>CN(C=O)C.O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]2[CH:10]([OH:20])[C:3]3[C:2](=[C:7]([CH3:8])[C:6]([OH:9])=[CH:5][CH:4]=3)[O:1][C:27]=2[CH3:28])=[CH:13][CH:14]=1
Reactant: COc1ccc(CC(=O)c2ccc(O)c(C)c2O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(C)Oc3c(ccc(O)c3C)C2O)cc1
Reaction time: 5 h

Procedure:
To a solution of 1-(2,4-dihydroxy-3-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone (1 eq) in anhydrous DMF was added K2CO3 (3 eq). Acetic anhydride (3 eq) was added dropwise to the solution, which was then refluxed, under nitrogen whilst stirring for 5 h. The solution was taken up in water and extracted using ethyl acetate, dried over MgSO4 and concentrated in vacuo to give 3-(4-methoxy-phenyl)-2,8-dimethyl-4H-chromene-4,7-diol as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23]C)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30].OC1C=C2C(=CC=1)NC=C2CC(O)=O.C(NC1C(Cl)=CC(CN)=CC=1Cl)(=O)C>>[Cl:27][C:4]1[CH:5]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[NH:16][CH:15]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:28][C:29](=[O:31])[CH3:30]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: CC(=O)Nc1c(Cl)cc(CN)cc1Cl
Agent: O=C(O)Cc1c[nH]c2ccc(O)cc12
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3ccc(O)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-hydroxy-1H-indol-3-yl)acetic acid in step 14 (A) and 4-acetamido-3,5-dichloro-benzylamine (preparation B) in step 14 (B), the title compound was prepared. MS (ESI) (M+H)+=448.05 1H-NMR (500 MHz, CD3OD) δ 7.41 (s, 2 H), 7.15-7.30 (m, 2 H), 6.93 (d, J=2.44 Hz, 1 H), 6.73 (dd, J=8.70, 2.29 Hz, 1 H), 4.47 (s, 2 H), 3.88 (s, 2 H), 2.19 (s, 3 H).
Reaction SMILES: [CH2:1]([C:4]1([NH2:20])[CH2:11][CH2:10][CH2:9][CH:8]([O:12][Si](C(C)(C)C)(C)C)[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]>CO.[Pd]>[NH2:20][C:4]1([CH2:1][CH2:2][CH3:3])[CH2:11][CH2:10][CH2:9][CH:8]([OH:12])[CH2:7][CH2:6][CH2:5]1
Reactant: C=CCC1(N)CCCC(O[Si](C)(C)C(C)(C)C)CCC1
Agent: [Pd]
Solvent: CO
Product: CCCC1(N)CCCC(O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A solution of 895 mg (4.88 mmol) of 1-allyl-5-(tert-butyl-dimethyl-silanyloxy)-cyclooctylamine (63) in 15 mL of methanol was treated with 52 mg of 10% palladium on activated carbon and the mixture was stirred overnight under a hydrogen atmosphere (1 atm) at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo to give 0.794 g of the title compound (64). Rt=0.56 min, 0.62 min min (Method C). Detected mass: 186.3 (M+H+).