Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][CH3:15])[N:3]=1.[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.[OH-].[Na+]>CC#N.O.O>[CH3:15][NH:14][C:4]1[N:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=[C:2]([NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]2)[N:3]=1
Reactant: CNc1nc(Cl)nc(-c2ccccc2)n1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(-c2ccccc2)n1
Temperature: 80 °C
Reaction time: 36 h

Procedure:
To a mixture of 4-chloro-N-methyl-6-phenyl-1,3,5-triazin-2-amine (1.0 g, 4.5 mmol) in CH3CN:H2O (1:1, 5 mL) was added trans-4-aminocyclohexanecarboxylic acid (973 mgs, 6.80 mmol). The solution was treated with 1 N NaOH to maintain a pH of 9-10 and stirred at 80° C. for 36 h. The resulting mixture was diluted with water and filtered to provide the crude product, which was purified by HPLC to afford 300 mg (20% yield) of the desired product. MS (ES+): m/e 328.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:6]2[CH2:11][CH:12]([CH3:14])[CH3:13].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:24][C@H:25]1[O:27][CH2:26]1)(=O)=O.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>>[OH:27][C@@H:25]([CH2:26][N:50]1[CH2:51][CH2:52][CH:47]([C:38]2[CH:39]=[CH:40][C:41]3[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:37]=2)[CH2:48][CH2:49]1)[CH2:24][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:6]2[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Reactant: CCOC(=O)c1cc2c(O)cccc2n1CC(C)C
Product: CCOC(=O)c1cc2c(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2n1CC(C)C
Yield: 81.7 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 25 using ethyl 4-hydroxy-1-(2-methylpropyl)indole-2-carboxylate (5.0 g) obtained in Starting Material Synthesis Example 12, (S)-glycidyl nosylate (4.5 g) and 4-(naphthalen-2-yl)piperidine (5.3 g), ethyl (S)-4-(2-hydroxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-1-(2-methylpropyl)indole-2-carboxylate (7.5 g) was obtained. This was dissolved in ethanol (40 ml) and water (30 ml) and potassium hydroxide (4.0 g) were added. The mixture was refluxed for 2.5 hr. From the obtained reaction mixture, ethanol was evaporated under reduced pressure and 1N aqueous hydrochloric acid solution (30 ml) was added under ice-cooling. The mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and isopropyl ether was added to the obtained oil. The obtained crystals were collected by filtration to give the title compound (6.7 g) as pale-yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:17]([OH:19])=O)[CH2:12][CH:11]1[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:26]C=2C=1.CN1CCOCC1.C(Cl)CCl>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([C:17](=[O:19])[NH2:26])[CH2:12][CH:11]1[CH2:13][CH:14]([CH3:16])[CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)CC1CC1(CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isobutyl-cyclopropanecarboxylic acid (5.2 g, 19.2 mmol) in dry THF (190 mL) was added HOBt (2.85 g, 21.1 mmol), NMM (2.32 mL, 21.1 mmol) and EDC (4.0 g, 21.1 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours and quenched with concentrated ammonium hydroxide (16 mL). The reaction mixture was stirred at room temperature overnight. Excess of solvent was removed in vacuo and the residue was dissolved in EtOAc (200 mL). The organic layer was washed with 1N HCl, aqueous NaHCO3, brine and dried over Na2SO4. Evaporation of excess of solvent gave 3.5 g (69%) of (1-carbamoyl-2-isobutyl-cyclopropylmethyl)-carbamic acid tert-butyl ester as a colorless oil: 1H NMR (300 MHz, CD3OD) & 0.61 (dd, J=4.2, 6.5 Hz, 1H), 0.94 (d, J=5.0 Hz, 3H), 0.96 (d, J=5.0 Hz, 3H), 1.20 (m, 1H), 1.29 (dd, J=3.9, 8.7 Hz, 1H), 1.44 (s, 9H), 1.51 (m, 2H), 1.65 (m, 1H), 3.20 (d, J=15.2 Hz, 1H), 3.54 (d, J=15.2 Hz, 1H); 13C (75 MHz, CD3OD) δ 21.5, 23.2, 23.6, 27.4, 29.3, 30.3, 30.4, 39.3, 41.8, 80.9, 159.3, 179.9; MS (APCI) m/z271 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13].C(O)(=O)C.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>O>[N+:19]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([CH3:12])([CH3:11])[CH:3]([CH3:13])[C:2]2([CH3:14])[CH3:1])([O-:21])=[O:20]
Reactant: CC1C(C)(C)c2ccccc2C1(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC1C(C)(C)c2ccc([N+](=O)[O-])cc2C1(C)C
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
Into a 500 ml reaction vessel equipped with stirrer, thermometer, reflux condenser, addition funnel and cooling bath is placed 50 grams of 1,1,2,3,3-pentamethyl indane having the structure: ##STR36## in admixture with 100 grams of acetic acid. While maintaining the reaction mass at 25° C., 40 grams of fuming nitric acid is added over a period of 0.5 hour. The reaction mass is then stirred for a period of 6 minutes. Over a period of 10 minutes while maintaining the reaction mass at 20°-22° C., 10 grams of concentrated sulfuric acid is added to the reaction mass. The reaction mass is then heated to a temperature in the range of 26°-30° C. with stirring and maintained at that temperature for a period of four hours. At the end of the four hour period, the reaction mass is added to water and a solid is formed which precipitates out. The resulting crystals are washed with two 500 ml portions of water. The crystals melt at 99.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([NH:24][CH3:25])=[CH:22][C:21]=1[C:28]([F:31])([F:30])[F:29]>>[CH3:25][N:24]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)[CH:5]=[CH:4][N:3]=1)[C:23]1[CH:26]=[CH:27][C:20]([F:19])=[C:21]([C:28]([F:31])([F:29])[F:30])[CH:22]=1
Reactant: CNc1ccc(F)c(C(F)(F)F)c1
Reactant: Fc1ccc(-c2ccnc(Cl)n2)cc1C(F)(F)F
Product: CN(c1ccc(F)c(C(F)(F)F)c1)c1nccc(-c2ccc(F)c(C(F)(F)F)c2)n1
Temperature: 126 °C
Reaction time: 8 h
Yield: 41.5 %

Procedure:
A round-bottom flask was charged with 1.03 g of 2-chloro-4-(4-fluoro-3-trifluoromethylphenyl)-pyrimidine and 0.82 g of 4-fluoro-3-trifluoromethyl-N-methylaniline and heated to 126° C. for 1.5 h. The reaction mixture melted and subsequently thickened. After standing overnight, the mixture was partitioned between 20 mL of EtOAc and 20 mL of NaHCO3. The organic phase was separated, dried, filtered and evaporated. The crude product was adsorbed onto silica gel and eluted with 50% EtOAc/heptane to yield 0.67 g of an oil which solidified on standing: m.p. 83-84° C.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:11][N:12]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[S:13]1(=[O:15])=[O:14].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([C:1]([O:9][CH2:11][N:12]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:13]2(=[O:14])=[O:15])=[O:8])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccncc1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CBr
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(OCN1C(=O)c2ccccc2S1(=O)=O)c1ccncc1
Yield: 35.3 %

Procedure:
A mixture of isonicotinic acid (0.98 g, 0.008 mol), 2-bromomethylsaccharin (2.11 g, 0.008 mol), triethylamine (0.81 g, 0.008 mol) and xylene (25 ml) were refluxed for 1 hour. The solvent was removed in vacuo and the residue was partitioned between water and methylene chloride. The organic layer was separated and the solvent removed in vacuo. The solid residue was recrystallized from CH3CN to afford 0.9 g (37%) of 2-saccharinylmethyl pyridine-4-carboxylate as a yellow solid, m.p. 145°-146° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1.Br[CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>COCCOC>[CH3:10][O:9][C:3](=[O:8])[CH:4]([CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:5](=[O:6])[CH3:7]
Reactant: BrCCOCc1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C(CCOCc1ccccc1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (2.0 g, 60% in mineral oil) in DME (50 ml) at 0° C. is added dropwise a solution of methyl acetoacetate (5.8 g, 50 mmol) in DME (10 mL). The solution is stirred at room temperature for 30 minutes. Nal (7.5 g) is added in one portion and then benzyl bromoethyl ether (10.7 5 g, 50 mmol). The mixture is stirred at 70–80° C. overnight. After the formed solid is removed, the solvent is removed. The residue is purified by column with 4:1 of hexane to ethyl acetate to a colorless oil (159).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:41]=[CH:40][C:20]([C:21]([N:23]([CH3:39])[C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=4[O:31]CC4C=CC=CC=4)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:41]=[CH:40][C:20]([C:21]([N:23]([CH3:39])[C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=4[OH:31])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccc(C)cc3OCc3ccccc3)cc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccc(C)cc3O)cc2)cc1
Reaction time: 5 h
Yield: 93.3 %

Procedure:
A solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-benzyloxy-4-methylphenyl)benzamide (2.2 g), 10% palladium hydroxide (220 mg) in methanol (50 ml) was stirred under atmospheric pressure of hydrogen at ambient temperature. After 5 hours, the reaction mixture was filtered through a bed of Celite, and then concentrated to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-hydroxy-4-methylphenyl]benzamide (1.71 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([OH:14])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[C:23]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:15])[C:12]([O:14][CH3:23])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1c(O)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-ol (52 mg, 0.17 mmol) in DMF (2 mL) was added Cs2CO3 (65 mg, 0.2 mmol) and the mixture was stirred at RT for 10 minutes. A solution of methyl iodide in DMF (0.2 mL, 0.2 mmol, 1 M) was added and the reaction solution was stirred at RT for 2 h. The reaction was quenched with EtOAc (5 mL) and H2O (5 mL). The organic layer was separated, dried with sodium sulfate and concentrated in vacuo to give the title compound (35 mg, 65%) as a yellow solid.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][OH:16])[CH2:13][C@@H:12]([NH:17]C(OC(C)(C)C)=O)[C@@H:11]1[O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34].O1CCOCC1>>[ClH:34].[C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][OH:16])[CH2:13][C@@H:12]([NH2:17])[C@@H:11]1[O:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reaction time: 0.58 h
Yield: 90 %

Procedure:
(1R,2S,3R,5R)-3-[(tert-Butoxycarbonyl)amino]-5-(hydroxymethyl)-cyclopentane-1,2-diyl dibenzoate (1.42 g, 3.11 mmol) was treated with a 4.00 M solution of HCl in 1,4-dioxane (17.0 mL, 69.3 mmol) and the reaction was stirred for 35 min. The reaction mixture was concentrated in vacuo and Et2O was added to precipitate the product, which was washed with Et2O to afford the title compound as a white solid (1.05 g, 90%). LC/MS: Rt=1.06 min, ES+ 356 (FA standard).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2(O)[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7][CH2:6]1)=[O:4].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:9]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(C2(O)ON=C(c3ccc(OC)cc3)C2c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1(c2onc(-c3ccc(OC)cc3)c2-c2ccccc2)CC1
Temperature: 64 °C
Reaction time: 6.5 h
Yield: 39.7 %

Procedure:
To a solution consisting of 1-[5-hydroxy-3-(4-methoxy-phenyl)-4-phenyl-4,5-dihydro-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (2354 g) in toluene (8 L) is added p-toluenesulfonic acid monohydrate (40.8 g.) The mixture is stirred at 64° C. for 6.5 hours and is subsequently filtered over Celite filter aid. The Celite cake is washed with toluene (2×1 L) and the filtrate is diluted with a mixture of isopropanol (6 L) and heptane (6 L) to form a precipitate. The precipitate is triturated to afford a solid. The solid is triturated in a mixture of isopropanol (6 L) and heptane (2 L) for 3.5 hours and is subsequently collected by filtration. The solid is dried to afford the synthetic intermediate 1-[3-(4-methoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (889 g.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([C:20](O)=[O:21])=[CH:18][C:17]([O:23][CH2:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])=[N:16]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:12])[F:14])=[CH:4][C:3]=1[N:15]1[C:19]([CH2:20][OH:21])=[CH:18][C:17]([O:23][CH2:24][C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])=[N:16]1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C(=O)O)cc1SCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2CO)cc1SCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.1 %

Procedure:
3.97 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole-5-carboxylic acid was dissolved in 60 mL of dichloromethane, and 0.93 mL of oxalyl dichloride and N,N-dimethylformamide in a catalytic amount were added, followed by stirring at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, the resulting product was dissolved in 50 mL of tetrahydrofuran, and 1.56 g of sodium borohydride was added, followed by cooling to −20° C. 20 mL of water was slowly dropwise added, and then, stirring was carried out for 12 hours while the temperature was slowly increased to room temperature. Then, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 3.01 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-hydroxymethyl-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@H:10]([CH3:25])[NH:11][C:12](=[O:24])[C@H:13]([CH3:23])[N:14](C(OC(C)(C)C)=O)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[C@H:10]([CH3:25])[NH:11][C:12](=[O:24])[C@H:13]([CH3:23])[NH:14][CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 17 g (0.0466 mole) of Boc-N-methyl-L-alanyl-L-alanine benzyl ester in 150 ml of dry dichloromethane, cooled at -10° C., was added 100 ml trifluoroacetic acid, which was previously cooled at -10° C. The reaction mixture was stirred for 16 hours at -5° C., then poured carefully with good stirring into a mixture of 177 g of sodium bicarbonate, ice, and 150 ml of dichloromethane. The organic layer was separated and the aqueous layer was further extracted with another 60 ml of dichloromethane. The combined organic layers were washed with 3×50 ml of saturated sodium bicarbonate solution, dried over manesium sulfate, and evaporated to give 11.6 g (91% of theory) of crude product which was used in step 3 without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[CH:26](=O)[CH2:27][CH3:28].[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:26][CH2:27][CH3:28])[CH2:12][CH2:13]2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: NC(=O)c1cccc2nc(-c3ccc(C4CCNCC4)cc3F)oc12
Reactant: [H][H]
Reactant: CCC=O
Agent: [Pd]
Solvent: CO
Product: CCCN1CCC(c2ccc(-c3nc4cccc(C(N)=O)c4o3)c(F)c2)CC1
Yield: 9.7 %

Procedure:
A solution of 2-(2-fluoro-4-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (70 mg, 0.2 mmol), 10% Pd/C (30 mg) and propanal (5 mL, 2 mmol) in methanol (10 mL) was purged with hydrogen at room temperature for 2 days. The resulting solution was filtered and the filtrate was concentrated, the residue was purified by prep-HPLC to obtain 2-(2-fluoro-4-(1-propylpiperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (7.4 mg, yield 10%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.03-1.08 (m, 3H), 1.80-1.86 (m, 2H), 2.01-2.04 (m, 2H), 2.20-2.24 (m, 2H), 3.07-3.18 (m, 5H), 3.72-3.75 (m, 2H), 7.32-7.37 (m, 2H), 7.52-7.56 (t, J=7.6 Hz, 1H), 7.94-7.97 (t, J=7.6 Hz, 2H), 8.30-8.34 (t, J=7.6 Hz, 1H); LC-MS (ESI) m/z: 382 (M+1)+.
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:32]1[CH2:36][C@@H:35]([O:37][CH2:38][CH2:39][CH3:40])[CH2:34][N:33]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:30])[NH2:29])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.[CH2:48](O[C@H]1CN(C(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H]([C@@H](O)[C@@H](NC(=O)C2C=CC=C(C(N(CCC)CCC)=O)C=2)CC2C=C(F)C=C(F)C=2)C1)[CH:49]=[CH2:50].[CH2:100](N(CCC)C(C1C=C(C=CC=1)C(O)=O)=O)[CH2:101][CH3:102].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=CC=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C>ClCCl>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:29]([CH2:100][CH2:101][CH3:102])[CH2:48][CH2:49][CH3:50])=[O:30])[CH:23]=2)[C@H:9]([OH:8])[C@H:32]2[CH2:36][C@@H:35]([O:37][CH2:38][CH2:39][CH3:40])[CH2:34][NH:33]2)[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N(CCC)CCC)c2)N(C(c2ccccc2)c2ccccc2)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(N)=O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N(CCC)CCC)c2)C1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
Step 4 (A): N1-((1S,2S)-1-((2R,4R)-4-(allyloxy)-1-benzhydrylpyrrolidin-2-yl)-3-(3,5-difluorophenyl)-1-hydroxypropan-2-yl)-N3,N3-dipropylisophthalamide. To a solution of 3-(dipropylcarbamoyl)benzoic acid (31 mg, 0.12 mmol) in dichloromethane (3 mL) were added Hunig's base (43 mg, 0.33 mmol) and HATU (54 mg, 0.143 mmol). After stirring for 20 min, the reaction mixture was added (1S,2S)-1-((2R,4R)-4-(allyloxy)-1-benzhydrylpyrrolidin-2-yl)-2-amino-3-(3,5-difluorophenyl)propan-1-ol (Preparation (C), 54 mg, 0.11 mmol) and the reaction mixture was stirred at rt overnight. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 50% EtOAc/Hexane step gradient) to give 70 mg of the title compound (89% yield): 1H NMR (CDCl3, 500 MHz) δ 0.74 (3H, brd s), 1.00 (3H, brd s), 1.53 (2H, brd s), 1.73 (2H, brd s), 2.02-2.09 (1H, m), 2.17 (1H, d, J=10 Hz), 2.26 (1H, dd, J=5, 10 Hz), 2.68 (1H, d, J=10 Hz), 2.84 (1H, dd, J=5, 15 Hz), 2.96 (1H, dd, J=5, 15 Hz), 3.09 (1H, d, J=10 Hz), 3.16 (2H, brd s), 3.25 (1H, d, J=10 Hz), 3.49 (2H, brd s), 3.91-3.93 (2H, m), 3.96-4.11 (3H, m), 4.50 (1H, s), 4.91 (1H, d, J=10 Hz), 5.22 (1H, dd, J=5, 10 Hz), 5.31 (1H, m), 5.90-5.98 (1H, m), 6.64-6.69 (3H, m), 6.91-6.97 (3H, m), 7.15-7.20 (3H, m), 7.22-7.25 (2H, m), 7.34 (2H, d, J=5 Hz), 7.47-7.57 (4H, m). MS (ESI) (M+H)+ 710.37.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][O:24][CH2:25][CH3:26]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][O:24][CH2:25][CH3:26])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: CCOCCBr
Product: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2cccnc21
Yield: 101.3 %

Procedure:
This compound was prepared following the procedure described in example 24, part C, starting with 2.8 g (10 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester and 1.7 ml (15 mmol) of 2-bromoethylethyl ether. After standard work-up and purification, 3.5 g of 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.