Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1.NCC[NH:25][C:26](=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>CN1CCCC1>[CH3:19][C:12]1[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:10]1[C:9]([CH3:20])=[N:8][N:7]2[C:2]([NH:25][C:26](=[O:36])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)=[CH:3][C:4]([CH3:21])=[N:5][C:6]=12
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)cc(C)nc23)c(C)c1
Reactant: COc1ccc(CC(=O)NCCN)cc1
Agent: CN1CCCC1
Product: COc1ccc(CC(=O)Nc2cc(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn23)cc1
Temperature: 80 °C
Yield: 80.6 %

Procedure:
Dissolve 7-chloro-2,5-dimethyl-3-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine (0.26 g, 8.69×10−4 mol) in 2 mL N-methylpyrrolidine, and add N-(2-aminoethyl)-2-(4-methoxyphenyl)acetamide (0.75 g, 3.6 mmol). Heat to 80° C. overnight under N2. Partition between EtOAc (50 mL) and H2O (50 mL), then separate layers and wash EtOAC layer successively with 0.1 N NaOH (25 mL), H2O (25 mL), and brine. Pool aqueous layers and extract with EtOAc (25 mL). Pool EtOAc layers, dry over Na2SO4, filter and concentrate to yellow oil. Chromatograph on silica gel eluting with EtOAc and evaporate to obtain 0.30 g of N-(3-(2,4,6-trimethylphenyl)-2,5-dirnethyl-pyrazolo[1,5-a]pyrimidin-7yl)-2-(4-methoxyphenyl)acetamide as a clear pale yellow oil. LCMS=472.3 (MH+); 470.2 (M−). 1H-NMR (CDCl3): 7.10 (d, 2H, J=10.2 Hz); 6.39 (s, 2H); 6.81 (d, 2H, J=10.2 Hz); 6.46 (t, 1H, J=6.0 Hz); 6.16 (t, 1H, J=6.0 Hz); 5.79 (s, 1H); 3.76 (s, 3H); 3.45-3.50 (m, 6H); 2.38 (s, 3H); 2.30 (s, 3H); 2.20 (s, 3H); 2.02 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1([C:16]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:20][C:19]3[CH:21]=[CH:22][C:23]([CH2:25][C:26](Cl)=[O:27])=[CH:24][C:18]=3[O:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:29]1([C:16]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:20][C:19]3[CH:21]=[CH:22][C:23]([CH2:25][C:26]([C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[O:27])=[CH:24][C:18]=3[O:17]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)Cc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Product: O=C(Cc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)c1c[nH]c2ccccc12

Procedure:
The title compound was prepared by a similar method to that of Preparation 4 using indole and (2,2-diphenyl-1,3-benzodioxolan-5-yl)acetyl chloride (prepared from the corresponding carboxylic acid [see Preparation 7] by a similar method to that of Preparation 3) as the starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[C:6]2[CH2:19][C:20]([O:22][CH3:23])=[O:21].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[C:6]2[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1c(-c2ccc(F)cc2)[nH]c2ccc(OC)cc12
Product: COC(=O)Cc1c(-c2ccc(F)cc2)n(Cc2ccccc2)c2ccc(OC)cc12

Procedure:
Prepare by a method similar to Example 48 using methyl [5-methoxy-2-(4-fluorophenyl)-indol-3-yl]-acetate and benzyl bromide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:27])[C:23]([F:26])([F:25])[F:24].[F-].Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:27])([F:21])[C:23]([F:26])([F:25])[F:24])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cccc(F)c1OC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)(CC(C)(C)c1cccc(F)c1OC)C(F)(F)C(F)(F)F
Temperature: -25 °C
Reaction time: 4.5 h
Yield: 115.9 %

Procedure:
1.0 g (3.54 mmol) of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate and 0.98 g (5.1 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixed with 65 mg (0.7 mmol) of tetramethylammonum fluoride at −40° C. The reaction mixture is heated to −25° C. and stirred at this temperature. After 4.5 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. 1.65 g of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate is obtained as a crude product. The ester is mixed in 80 ml of diethyl ether at 0° C. with 300 mg (8 mmol) of lithium aluminum hydride and stirred for 3.5 more hours at room temperature. A little water is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is filtered by Cellite, and the precipitate is rewashed thoroughly with ethyl acetate. The filtrate is dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 800 mg of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diol is obtained. 1.8 ml (13 mmol) of triethylamine and, in portions over 10 minutes, 1.6 g (10 mmol) of pyridine SO3 complex are added to 800 mg (2.2 mmol) of diol in 25 ml of dichloromethane and 8.9 ml of DMSO. It is stirred for 2.5 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and the desired aldehyde is obtained quantitatively.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:20]([O:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[CH3:1])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2ccccc2c1O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C)ccc2ccccc12
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A solution of 9.48 g (60 mmole) of 2-methyl-1-naphthol and 8.10 g (80 mmole) of triethylamine in 50 mL of ethyl acetate was cooled to below 5° C. in an ice-bath. 5.50 g (70 mmole) of acetyl chloride was added at a rate such that the temperature did not rise about 5° C. The reaction mixture was stirred for an additional one hour, diluted with 50 mL of ethyl acetate, and washed with water then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to give an oily residue. Crystallization in hexane yielded 7.58 g (63% yield) of the title compound with a melting point of 81°-83° C. and an 1HNMR as follows: (300 MHz, DMSO-d6) δ 2.26 ) (s, 3H), 2.48 (s, 3H), 7.42 (d, 1H, J=9 Hz), 7.46-7.55 (m, 2H), 7.47-7.81 (m, 2H), 7.92 (d, 1H, J=9 Hz). The mass spectrum showed a molecular ion at m/z 200.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].CC1(C)[O:14][C:13](=O)[CH:12]=[C:11]([CH3:16])[O:10]1>CC(C)=O>[C:13]([O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])(=[O:14])[CH2:12][C:11]([CH3:16])=[O:10]
Reactant: C[Si](C)(C)CCO
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: CC(C)=O
Product: CC(=O)CC(=O)OCC[Si](C)(C)C

Procedure:
A mixture of 6.70 g of 2-trimethylsilylethanol (56.7 mmol) and 8.05 g of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (56.7 mmol) was placed in a round bottom flask equipped with a short distillation apparatus and heated to to drive off acetone. The calculated amount of acetone was collected, and the residue was distilled under reduced pressure. The fraction boiling at 106-110° C. (5-10 mmHg) was collected (8.52 g, 74%). The product was used in the next step after spectral characterization.
Reaction SMILES: [C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2].[NH2:33][CH2:34][C@H:35]([OH:37])[CH3:36]>>[C:1]([N:4]([CH3:32])[CH2:5][CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:15]=2)[C:10]([OH:25])=[C:9]([C:26]([NH:33][CH2:34][C@H:35]([OH:37])[CH3:36])=[O:27])[C:8]1=[O:31])(=[O:3])[CH3:2]
Reactant: C[C@@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(C)=O)c1=O
Product: CC(=O)N(C)CCn1c(=O)c(C(=O)NC[C@@H](C)O)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-{2-[acetyl(methyl)amino]ethyl}-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-1-amino-2-propanol using methods similar to Example 574: step 2 to provide an off-white solid: 1H NMR (400 MHz, DMSO-d6@90° C.) δ ppm 1.14 (d, J=6.17 Hz, 3 H), 1.84 (s, 3 H), 2.91-2.98 (m, 3 H), 3.23-3.33 (m, 1 H), 3.40-3.50 (m, 1 H), 3.54 (t, J=6.72 Hz, 2 H), 3.85-3.88 (m, 1 H), 4.18 (s, 2 H), 4.37 (d, J=7.55 Hz, 2 H), 4.65 (d, J=5.90 Hz, 1 H), 7.12 (t, J=8.51 Hz, 2 H), 7.36-7.43 (m, 2 H), 8.07 (s, 1 H), 8.55 (s, 1 H), 10.35 (s, 1 H), 16.97-17.20 (m, 1 H); ES+ MS: 471 (M+H+).
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][O:14][C:15]=2[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)=[CH:7][C:6]=1[N+:28]([O-])=O.C1COCC1.[ClH:36]>CO.[Pd]>[ClH:36].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][O:14][C:15]=2[C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)=[CH:7][C:6]=1[NH2:28]
Reactant: [H][H]
Reactant: COc1ccc(-c2cnoc2-c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cnoc2-c2cc(OC)c(OC)c(OC)c2)cc1N

Procedure:
A 200-mL round-bottom flask equipped with T-bore stopcock connected to a balloon with hydrogen was charged with 4 (4.44 g, 11.5 mmol) and THF (40 mL), and a mixture was stirred to dissolve a substrate. Methanol (22 mL), solution of HCl in methanol (1M, 22 mL) and palladium, 10 wt % on activated carbon (532 mg, 12 wt %) were added to the flask, the system was evacuated and stirred under atmosphere of hydrogen for 2 hours. TLC indicated completion of reaction (Hexane/EtOAc, 2:1, developed two times). Catalyst was filtered out and washed with methanol (15 mL×3). Filtrate was diluted with 2-propanol (20 mL) and concentrated under reduced pressure to ˜20 mL volume. A resulted suspension was diluted with EtOAc (20 mL), a solid was filtered out, washed with EtOAc (20×2) and dried to give crude amine hydrochloride 5 as a yellow solid, 3.3 g (80%), LC purity 97.1%. The solid was refluxed in ethanol (50 mL) for 15 min to dissolve colored impurities. A cooled suspension was filtered out, washed with EtOAc (20×2) and vacuum-dried to obtain a creamy-colored solid, 2.9 g (70%), LC purity 99.1%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Sn](C)(C)C)=[CH:5][N:4]=1.FC(F)(F)S(O[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=2)(=O)=O.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=3)=[CH:5][N:4]=1
Reactant: COc1ccc([Sn](C)(C)C)cn1
Reactant: COc1cc2cc(OS(=O)(=O)C(F)(F)F)cnc2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc3cc(OC)c(OC)cc3c2)cn1

Procedure:
A mixture of 800 mg (2.94 mmol) of 2-methoxy-5-trimethylstannyl-pyridine, mg (2.94 mmol) of 6,7-dimethoxyquinolin-3-yl trifluoromethane sulfonate, 374 mg (8.82 mmol) of anhydrous lithium chloride and 170 mg (0.147 mmol) of Pd(PPh3)4 in 15 mL of anhydrous dioxane is flushed thoroughly with nitrogen and refluxed for 6 hours. The mixture is diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (75 mL), dried (Na2SO4) and evaporated. The resulting residue is chromatographed on silica gel (eluting with chloroform) to give a solid material which is recrystallized from ethyl acetate to give 3-(2-methoxypyrid-5-yl)-6,7-dimethoxyquinoline (m.p. 170.5°-171.5° C.).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[NH:19][CH2:18][CH:15]1[CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:20])([F:1])[F:21])[CH:4]=3)[C:17]=2[O:16]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2O1)OCc1ccccc1
Yield: 97.1 %

Procedure:
Treatment of (±)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (1.67 g, 5.06 mmol) with diisopropylethylamine (0.98 g, 7.59 mmol) followed by benzyl chloroformate (1.04 g, 7.59 mmol) generally according to the procedure described for Intermediate 12 provided 2.1 g (97%) of (±)-benzyl({7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate as a colorless oil. Anal. calcd. for C24H20F3NO3: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.08; H, 5.05; N, 3.22. Chiral HPLC separation of (±)-benzyl ({7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (Chiralpak OJ, isopropanol:carbon dioxide 15:85) provided two fractions. Fraction 1 (Rt=6.12 min, Chiralpak OJ, isopropanol:carbon dioxide 15:85); Fraction 2 (Rt=7.17 min, Chiralpak OJ, isopropanol:carbon dioxide 15:85).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:34])/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30]C(=O)C)[CH:23]=1>C1COCC1>[ClH:3].[Cl:3][C:4]1[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:34])/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([OH:30])[CH:23]=1
Reactant: COc1ccc(/C=C/C(=O)Nc2cccc(OCc3ccncc3)c2Cl)cc1OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)Nc2cccc(OCc3ccncc3)c2Cl)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 195.7 %

Procedure:
A 3N methanolic solution of hydrochloric acid (10 ml, 30 mmols) is added to a solution of (E)-N-[2-chloro-3-(pyridin-4-ylmethoxy)-phenyl]-3-(3-acetoxy-4-methoxy-phenyl)-acrylamide hydrochloride (240 mg, 0.53 mmol) in THF (5 mL). The resulting mixture was stirred at RT for 16 hrs, concentrated under reduced pressure, taken up with solvent an re-evaporated (3 times with MeOH and once with acetone) to give a light yellow residue that was triturated with ethyl ether. After filtration and drying, 232 mg of the title (E)-N-[2-chloro-3-(pyridin-4-ylmethoxy)-phenyl]-3-(3-hydroxy-4-methoxy-phenyl)-acrylamide hydrochloride were obtained as a light yellow powder.
Reaction SMILES: [H][H].[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1>CO.[Pd]>[CH:3]1([N:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(OC2CCN(C3CCC3)CC2)cc1
Yield: 95.6 %

Procedure:
Hydrogen gas was bubbled through a solution of 1-Cyclobutyl-4-(4-nitrophenoxy)piperidine (94.9 g, 0.344 moles, obtained in above step) over 10% Pd/C (95 g) in methanol (2 L) at room temperature, for 5 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated under vacuum to obtain the title compound 81 g (Yield: 95.7%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:37])[CH:12]=[CH:13][CH:14]([N:28](C(OC(C)(C)C)=O)[CH3:29])[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:37])[CH:12]=[CH:13][CH:14]([NH:28][CH3:29])[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:9]
Reactant: CCOC(=O)C=CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C=CC(NC)C(c1ccccc1)c1ccccc1

Procedure:
22 ml (0.28 mol) of trifluoroacetic acid are added dropwise to a solution of 14.2 g (34.7 mmol) of 4-(tert-butoxycarbonyl-methyl-amino)-5,5-diphenyl-pent-2-enoic acid ethyl ester in 100 ml of methylene chloride. After 5 hours the reaction mixture is concentrated by evaporation and then twice toluene is added and the mixture concentrated by evaporation. The residue is dissolved in methylene chloride, washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and again concentrated by evaporation. The title compound is obtained in the form of a yellow oil. TLC: methylene chloride/methanol (95:5) Rf =0.26; Rt (HPLC)=12.5 min; 1H-NMR (300 MHz, CDCl3, RT) d 7.38-7.15 (m, 10H), 6.66 (dd, 1H), 5.84 (d, 1H), 4.12 (q, 2H), 3.97 (d, 1H), 3.81 (m, 1H), 2.31 (s, 3H), 1.33 (br, 1H), 1.24 (t, 3H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CN(C)C=O.C(O)(=O)C>[CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N:25]3[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc(CN3CCC(O)CC3)cc2)cc1
Yield: 58.8 %

Procedure:
To a solution of 4-(4-methylsulfonylaminophenoxy)benzaldehyde (2.50 g) in dimethyl formamide (25 mL) were added 4-hydroxypiperidine (1.74 g) and acetic acid (2.5 mL), and the solution was stirred. To the reaction solution was added sodium triacetoxyborohydride (2.18 g) and the solution was stirred for 2 days. After finishing the reaction, the reaction solution was neutralized with 2N aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (methylene chloride:methanol=10:1) to give the title compound (1.90 g) having the following physical data.
Reaction SMILES: [Si]([O:18][C:19]1[CH:57]=[CH:56][C:22]([O:23][CH2:24][C@@H:25]([OH:55])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:54]=[CH:53][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH2:45][CH2:46][CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH:47]1([CH2:46][CH2:45][CH2:44][NH:43][C:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:55])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:57][CH:56]=4)=[CH:54][CH:53]=3)[CH2:40][CH2:39]2)=[O:42])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCCCC4CCCCC4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCCCC1CCCCC1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 68.4 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-N-(3-cyclohexylpropyl)-1-piperidinecarboxamide (0.23 g, 0.291 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.11 g, 0.199 mmol).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)OC)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)c1cccc(OC)c1
Yield: 82 %

Procedure:
Methyl 2-methoxyimino-2-(3-methoxyphenyl)acetate (syn isomer) (1.6 g.) and a 2 N aqueous solution of sodium hydroxide (4 ml.) were treated according to a similar manner to that of Preparation (5-3) (c) to give oil of 2-methoxyimino-2-(3-methoxyphenyl)acetic acid (syn isomer) (1.23 g.).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:23]=[CH:24][C:25]=1[F:26]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:22]3[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(F)c(Cl)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(F)c(Cl)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(3-chloro-4-fluoro-phenyl)-acrylic acid.
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: FC(F)(F)C1CCNC1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
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.