Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[C:40]1(B2OC(C)(C)C(C)(C)O2)[CH2:44][CH2:43][CH2:42][CH:41]=1>>[NH2:32][C:4]1[S:3][C:2]([C:40]2[CH2:44][CH2:43][CH2:42][CH:41]=2)=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Product: Cn1ncc(NC(=O)c2nc(C3=CCCC3)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane gave 333. 1H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 7.85 (s, 1H), 7.34 (s, 2H), 6.20-6.15 (m, 1H), 4.80 (dd, J=10.4, 3.7 Hz, 1H), 4.50-4.29 (m, 1H), 4.27-4.16 (m, 1H), 4.12-3.95 (m, 1H), 3.74 (s, 3H), 2.79-2.69 (m, 2H), 2.07-1.99 (m, 1H), 1.97-1.86 (m, 2H), 1.81-1.66 (m, 4H). LCMS (ES+) m/z 421 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[CH2:5])=[O:3].C(O[CH:9](OCC)[CH2:10][CH2:11][CH2:12][NH2:13])C.Cl>C(OCC)C>[CH2:11]1[CH:12]2[N:13]([CH2:5][CH2:4][C:2](=[O:3])[CH2:1]2)[CH2:9][CH2:10]1
Reactant: C=CC(C)=O
Reactant: CCOC(CCCN)OCC
Agent: Cl
Solvent: CCOCC
Product: O=C1CCN2CCCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
Methylvinyl ketone (18.0 g, 256 mmol) was added dropwise to a solution of the 4,4-diethoxybutylamine (24.8 g, 154 mmol) in diethyl ether at 0° C. and stirred for one hour. The reaction was allowed to warm to room temperature and stir for 2 hours. The reaction was poured into 350 ml of 2N hydrochloric acid and the layers were separated. The aqueous layer was heated on a steam bath for 1 hour and then allowed to stir at 40° C. for 18 hours. The reaction was made basic with a sodium hydroxide solution and then extracted with methylene chloride. The extracts were dried over sodium sulfate and concentrated to give 20 g of an orange oil. This oil was distilled in vacuo at 74-84° C./5 mmHg to give 6.68 g of racemic product. (31%). MS(FD) (m/e): 139. 1H-NMR.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=[CH:5][CH:4]=1.[C:15]([N:18]1[CH2:22][C:21](=O)[N:20]=[CH:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=[CH:5][CH:4]=1)(=[O:17])[CH3:16]
Reactant: Nc1ccnn1-c1ccccc1Cl
Reactant: CC(=O)N1C=NC(=O)C1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1ccnn1-c1ccccc1Cl

Procedure:
5-Amino-1(2-chlorophenyl) pyrazole hydrochloride (Farmaco, 22, 68, 1967) (20.5 g.) and 1-acetyl-2-imidazolinone (12.6 g.) were reacted as described in Example I to give 17.11 g. product mp 179°-181° (crystallized from CH3CN)
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH2:6]([O:13][C@H:14]([C@@H:17]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:19]=[CH2:20])[CH:15]=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[CH2:6]([O:13][C@H:14]([C@@H:17]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@@H:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:19]=[CH2:20])[CH:15]([OH:16])[CH2:3][CH:2]=[CH2:1])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=CC[Mg]Br
Reactant: C=C[C@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](C=O)OCc1ccccc1
Solvent: C1CCOC1
Product: C=CCC(O)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](C=C)OCc1ccccc1
Reaction time: 4 h

Procedure:
Allyl magnesium bromide (1.0 M in Et2O, 1.44 mL, 1.44 mmol) was added dropwise over 5 min to a solution of aldehyde 47 (200 mg, 0.48 mmol) in THF (10 mL) at −78° C. The reaction mixture was left stirring at this temperature for 4 h before being quenched with NH4Cl solution (30 mL). The resulting layers were separated and the aqueous layer was extracted with EtOAc (3×25 mL). The combined organic layers were washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography (0-4% EtOAc in hexanes, gradient) to give product 53 as a mixture of two diasteroisomers.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>O1CCCC1>[NH2:1][C:2]1[C:7]([CH:8]=[CH:22][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1nc(Nc2ccccc2)ncc1C=O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cnc(Nc2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a room temperature solution of 4-amino-2-phenylamino-pyrimidine-5-carboxaldehyde (2.89 g, 13.50 mmol) in 120 mL of tetrahydrofuran was added (carbethoxymethylene)triphenylphosphorane (11.00 g, 31.60 mmol). The reaction mixture was heated at reflux for 9 hours then stirred at room temperature overnight. The solution was concentrated in vacuo and treated with ethyl acetate and hexane to give a yellow solid. The solid was collected by filtration and purified by flash chromatography to give 1.55 g (40%) of ethyl 3-(4-amino-2-phenylamino-pyrimidin-5-yl)acrylate, mp 190-192° C.
Reaction SMILES: [CH2:1]([N:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br)[CH3:2].[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:22]=1[NH2:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.[Cu]>[CH2:1]([N:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:23][C:22]1[C:21]([Cl:20])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28])[CH3:2]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CCN(C(=O)Cc1ccccc1Br)c1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCN(C(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl)c1ccccc1
Yield: 77.4 %

Procedure:
A mixture of 6.36 g (0.02 mole) of N-ethyl-N-phenyl-(o-bromophenyl)acetamide having a boiling point of 185° to 190° C. under 2 mmHg, 6.48 g (0.04 mole) of 2,6-dichloroaniline, 3.0 g (0.02 mole) of anhydrous potassium carbonate, 2.0 g of copper powder and 2.0 g of cuprous bromide was reacted in 100 ml of xylene in the same manner as in Example 22 to obtain 6.1 g of a colorless prism having a melting point of 121° to 123° C. The yield was 77.4%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@@H:10]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[C:34]([O:38][C:39]([NH:41][C:42]([CH3:47])([C:44](O)=[O:45])[CH3:43])=[O:40])([CH3:37])([CH3:36])[CH3:35].Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl.O>[C:34]([O:38][C:39]([NH:41][C:42]([CH3:47])([CH3:43])[C:44]([NH:11][C@H:10]([CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22])=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Crude D-tryptophan benzyl ester (1.0 g, 3.40 mmol), 1-hydroxybenztriazole hydrate (0.63 g, 4.1 mmol) and t-butoxycarbonyl-α-methylalanine (0.84 g, 4.11 mmol) were stirred together at room temperature in chloroform (20 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (980 mg, 5.11 mmol) was added to this mixture in a single portion. The reaction mixture was stirred at room temperature for 4 hours and worked up by pouring into water (50 mL). The chloroform layer was separated and washed with 5% aqueous citric acid solution (25 mL) and 5% aqueous sodium bicarbonate solution (25 mL). The chloroform layer was dried over magnesium sulfate, filtered and evaporated under vacuum to afford a thick oily foam. Chromatography on silica gel using ethyl acetate/hexanes (2:3 v/v) afforded a yellow foam (0.822 g 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][N:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[N:13]3)=[CH:4][C:3]=1[O:22]C.B(Br)(Br)Br.CO.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14](=[N:13][C:12]([C:18]([F:19])([F:20])[F:21])=[CH:11][CH:10]=3)[N:15]=[CH:16][CH:17]=2)=[CH:4][C:3]=1[OH:22]
Reactant: COc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Temperature: 0 °C

Procedure:
To 5-(4-fluoro-3-methoxyphenyl)-2-trifluoromethyl[1,8]naphthyridine (prepared as described in Example 34; 1.00 g, 3.1 mmol) in dichloromethane (20 mL) was added boron(III) bromide (9.31 mL of a 1 M solution in dichloromethane, 9.3 mmol) dropwise with stirring at 0° C., and the resulting mixture was stirred at 0° C. for 1 h. Methanol (2 mL) was added dropwise at 0° C. with stirring—Care! Large exotherm observed!—then the mixture was poured into saturated sodium hydrogencarbonate solution (50 mL). Effervescence was observed, and a yellow solid was precipitated, which was separated by filtration, washed with water and dried in a drying pistol at 60° C. This was 2-fluoro-5-(7-trifluoromethyl-[1,8]naphthyridin-4-yl)phenol (881 mg, 92%). δH (400 MHz, DMSO) 7.01-7.04 (1H, m), 7.16 (1H, dd, J 2.3 and 8.2), 7.40 (1H, dd, J 8.2 and 11.3), 7.74 (1H, d, J 4.3), 8.09 (1H, d, J 8.6), 8.66 (1H, d, J 8.6), 9.27 (1H, d, J 4.3), 10.30 (1H, s). m/z (ES+) 309 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Br[CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13]>>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C@H:11]([C:12]([OH:14])=[O:13])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(Cl)cc1F
Product: CC(C)[C@H](Nc1ccc(Cl)cc1F)C(=O)O

Procedure:
Following the procedure of Example 17, N-(2-fluoro-4-chlorophenyl)valine (0.79 g) is reacted with α-ethynyl-m-phenoxybenzyl bromide (0.39 g) to yield the α-ethynyl-m-phenoxybenzyl ester of N-(2-fluoro-4-chlorophenyl)valine, MS m/e 451 (M+). N-(2-fluoro-4-chlorophenyl)valine is prepared from 2-fluoro-4-chloroaniline and α-bromoisovaleric acid using the procedure of Example 17.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:16]N(C=O)C>>[CH3:16][S:3][C:4]1[S:5][C:6]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:7]=2[N:8]=1
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc2nc(S)sc2c1
Agent: [H-]
Agent: [Na+]
Product: CSc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydride (containing by 60%, 6.15 g) was suspended in DMF (120 mL) and 2-mercapto-6-nitrobenzothiazole (20 g) was added thereto under ice-cooling. After completion of bubbling, methyl iodide (26.4 mL) was added thereto. The mixture was stirred at room temperature for 18 hr. Water (800 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration to give 2-methylthio-6-nitrobenzothiazole (21.2 g) as a pale-yellow powder.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=O)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:8]1[NH:9][C:10]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cccc(F)c2[nH]1
Product: Fc1cccc2nc(Cl)[nH]c12
Temperature: 25 °C
Yield: 94.3 %

Procedure:
3-Fluorobenzene-1,2-diamine (0.600 g, 4.76 mmol) was dissolved in THF (14.82 ml) and 1,1′-carbonyldiimidazole (0.848 g, 5.23 mmol) was added at RT. The reaction mixture was stirred overnight at RT and then heated for 24 hours at 50° C. The mixture was cooled to RT and ammonia in MeOH (1.5 ml) was added and the mixture stirred for 30 minutes. The mixture was diluted with water (40 ml) and the resultant brown solid was collected by filtration, washed with water and then dried in vacuo to afford 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.700 g, 97%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 6.81 (2H, ddd), 6.88-6.95 (1H, m), 10.82 (1H, s), 11.08 (1H, s); m/z: (ES-) M-H−, 151.19. b) A solution of 4-fluoro-1H-benzo[d]imidazol-2(3H)-one (0.7 g, 4.60 mmol) in phosphorus oxychloride (14.11 ml, 151.39 mmol) was heated at 100° C. for 18 hours. The reaction mixture was cooled to RT and excess phosphorus oxychloride was evaporated in vacuo. The residue was neutralized slowly (Care: exotherm) with saturated sodium bicarbonate solution (10 ml), and the mixture was then extracted with EtOAc (3×20 ml). The combined organic layers were washed with saturated brine and then dried over Na2SO4, filtered and evaporated to afford 2-chloro-7-fluoro-1H-benzo[d]imidazole (0.740 g, 94%) which was used in the next step without further purification; 1H NMR (400 MHz, DMSO-d6) 7.01-7.11 (1H, m), 7.23 (1H, td), 7.32 (1H, s), 13.59 (1H, s); m/z: (ES+) MH+, 171.20. c) 2-Chloro-7-fluoro-1H-benzo[d]imidazole (1.7 g, 9.97 mmol) was charged to a high pressure autoclave PV10832 (Parr 160 ml) with methylamine (40% EtOH solution, 50 ml, 9.97 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The mixture was evaporated and the residue dissolved in MeOH and then added to an SCX column. The column was eluted with 7N ammonia in MeOH and fractions containing product were evaporated to leave a brown oil. The oil was was purified by flash chromatography on silica, eluting with a gradient of 5 to 20% MeOH in DCM. Pure fractions were evaporated to afford 7-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (1.230 g, 75%); 1H NMR (400 MHz, DMSO-d6) 2.88 (3H, d), 6.54 (1H, bs), 6.67-6.73 (1H, m), 6.81 (1H, dd), 6.95 (1H, d); m/z: (ES+) MH+, 166.00.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>O.CO>[CH3:1][O:2][C:3]1([CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC(=O)CCSC(c1ccccc1)C1(OC)CCOCC1
Solvent: O
Solvent: CO
Product: COC1(C(SCCC(=O)O)c2ccccc2)CCOCC1
Yield: 103.6 %

Procedure:
A solution of methyl 3-[[(4-methoxy)tetrahydropyran-4-yl]phenyl-methyl-thio]propionate (Step 1) (0.91 g, 2.8 mmol) and LiCH (0.29 g, 7.01 mmol) in 10% water and methanol (10 mL) was stirred for 18 h at room temperature. The solvents were removed at reduced pressure, and the concentrated residue was partitioned between ethyl acetate (200 mL) and 1 N HCl (100 mL). The organic layer was separated and washed with saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was vacuum dried to give 0.9 g of 3-[[(4-methoxy)tetrahydropyran-4-yl]phenylmethyl-thio]propionic acid as a clear, colorless oil: HRMS calcd for C16H22O4S 310.1239, found 310.1241.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=2[N+:15]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCOC(C)=O>[CH:1]1([NH:7][C:8]2[C:9]([NH2:15])=[CH:10][CH:11]=[C:12]([F:14])[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccc(F)cc1NC1CCCCC1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
(Cyclohexyl-(5-fluoro-2-nitrophenyl)amine (2.4 g, 10.0 mmol) was dissolved in EtOAc (40 mL) and the flask evacuated and flushed with nitrogen gas. 10% Pd/C (0.24 g) was added and the reaction mixture stirred under an atmosphere of hydrogen gas, at RT overnight. The resultant mixture was filtered through Celite® and the filtrate was concentrated in vacuo to afford the title compound as a dark red oil (1.9 g, 92%). 1H NMR (CDCl3, 400 MHz): δ 6.61 (1H, dd, J=8.35, 5.74 Hz), 6.35 (1H, dd, J=11.23, 2.77 Hz), 6.27 (1H, td, J=8.43, 2.76 Hz), 3.23-3.11 (1H, m), 2.11-2.00 (2H, m), 1.83-1.72 (2H, m), 1.70-1.60 (1H, m), 1.47-1.12 (5H, m)
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH:12]([CH2:17][CH3:18])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6].C([BH3-])#N.[Na+]>CO>[C:5]([N:10]1[CH2:15][CH2:14][CH:13]([NH:4][CH:1]2[CH2:3][CH2:2]2)[CH:12]([CH2:17][CH3:18])[CH2:11]1)([O:7][CH2:8][CH3:9])=[O:6]
Reactant: NC1CC1
Reactant: CCOC(=O)N1CCC(=O)C(CC)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(NC2CC2)C(CC)C1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Cyclopropylamine (14.25 g, 250 mmol) was added to the stirred solution of 1-carbethoxy-3-ethyl-4-piperidone (10 g, 50 mmol) in methanol (100 ml) and stirring was continued for 12 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (3.9 g, 62 mmol) was added to it. Cooling was removed after 10 min. and stirring was continued for 12 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH ˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford crude 1-carbethoxy-4-cyclopropylamino-3-ethyl piperidine. The obtained crude 1-carbethoxy-4-cyclopropylamino-3-ethylpiperidine was suspended in 7 M NaOH solution (30 ml), stirred at 130° C. for 160 hr, cooled and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to afford 4-cyclopropylamino-3-ethyl-piperidine. Yield 5.7 g (67%), C10H20N2, m/z 169, (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([N:37]([CH3:42])[CH2:38][C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:39](=[O:40])[CH2:38][N:37]([CH3:42])[C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:33])[CH3:31])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.054 g, 0.00014 mol), 2-[(tert-butoxycarbonyl)(methyl)amino]acetic acid (0.0033 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-oxoethyl)-N-methylcarbamate. The solid was dissolved in dichloromethane (2 mL) and 25% trifluoroaceticacid in dichloromethane (4 mL) was slowly added into the reaction at 0° C. The reaction mixture was stirred for 5 hours at room temperature. The solvent was removed under reduced pressure. To the residue a 5 N aqueous solution of sodium hydroxide was addded to pH 11 at 0° C. The water phase was extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (1×60 mL) and brine (1×60 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-(methylamino)-1-ethanone acetate (0.010 g, 0.00002 mol).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:46])[F:45])[CH:42]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCOc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCCOc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
Ethyl 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenoxy)-butyrate (115 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 4 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 4-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenoxy)-butyric acid (108 mg). MS (m/z): 667 [M+H]+
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1O.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH:11]=[C:10]([CH2:13][O:14][C:17]2[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH:21][C:16]=2[Br:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Reactant: OCC1=CCN(Cc2ccccc2)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(OCC2=CCN(Cc3ccccc3)C2)c(Br)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
(1-Benzyl-2,5-dihydro-1H-pyrrol-3-yl)methanol (14.0 g) obtained in Example 50(2), 2-bromo-4-trifluoromethylphenol (19.0 g), DEAD (13.5 g) and triphenylphosphine (23.3 g) were dissolved in tetrahydrofuran (450 mL). The reaction solution was stirred under a nitrogen atmosphere at 50° C. overnight. Tetrahydrofuran was evaporated under reduced pressure, and the residue was purified by silica gel column (20% diethyl ether/petroleum ether to 33% diethyl ether/petroleum ether) to give the object product as a pale-yellow oil (10 g, 33%).