Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N#N.[C:36]([O:40][C:41](=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([C:48]#[CH:49])=[CH:44][CH:43]=1)([CH3:39])([CH3:38])[CH3:37]>C(#N)C.[Cu]I.CCN(CC)CC>[C:1]([O:5][C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:49]#[C:48][C:45]2[CH:46]=[CH:47][C:42]([C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:50])=[CH:43][CH:44]=2)=[CH:9][CH:8]=1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Cu]I
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2ccc(C(=O)OC(C)(C)C)cc2)cc1
Reaction time: 8 h

Procedure:
4-Bromo-benzoic acid tert.-butyl ester, 5.1 g of triphenylphosphine and 375 ml of NEt3 are introduced into 1 l of absolute acetonitrile under nitrogen and N2 is passed through the solution for 20 minutes. 10.5 g of (Pφ3)2PdCl2 and 1.5 g of copper(I)iodide are then added and 166.5 g of 4-ethinyl-benzoic acid tert.-butyl ester dissolved in 1 l of absolute acetonitrile are slowly added dropwise under reflux and the reaction mixture is stirred overnight. The resulting reaction mixture is then suction filtered after cooling, stirred up in water, again suction filtered, dissolved in CH2Cl2 and filtered after the addition of a small quantity of Tonsil, and the solvent is then evaporated off under vacuum. 225 g of 4,4'-Tolan-dicarboxylic acid-di-tert.-butyl ester are obtained.
Reaction SMILES: [C:1]1([S:7][C:8]([CH:22]2[CH2:27][O:26][C:24](=[O:25])[CH:23]2[C:28](=[O:43])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:30]=2)([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:44][C:45](OC(C)=O)=[O:46].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[C:45]([O:43][C:28](=[C:23]1[CH:22]([C:8]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:27][O:26][C:24]1=[O:25])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=1)(=[O:46])[CH3:44]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1OCC(C(Sc2ccccc2)(Sc2ccccc2)c2ccccc2)C1C(=O)c1cccc(OCc2ccccc2)c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)OC(=C1C(=O)OCC1C(Sc1ccccc1)(Sc1ccccc1)c1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the ketone from Step 1 (1.91 g) in CH2Cl2 (20 mL) was added Ac2O (1.5 mL), Et3N (2.3 mL) and DMAP (40 mg). The reaction mixture was stirred at r.t. for 18 hr then diluted with Et2O and a saturated solution of NH4Cl. The organic phase was extracted, washed with H2O, brine, dried over MgSO4, and the solvent evaporated to afford the title product as a foam which was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[C:5]=1[NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14].[H-].[Na+].Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14]
Reactant: COC(=O)c1ccc(Br)c(C)c1NC(=O)OC(C)C
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN(C(=O)OC(C)C)c1c(C(=O)OC)ccc(Br)c1C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Add a solution of 2-Isopropoxycarbonylamino-4-bromo-3-methyl-benzoic acid methyl ester (3.36 g, 10.18 mmol) in DMF (37 mL) to a suspension of sodium hydride 60% dispersion mineral oil (407 mg, 10.18 mmol) in DMF (37 mL) at 0° C. under an atmosphere of nitrogen and allow to reach room temperature over 1 h. Add ethyl 4-bromobutyrate (2.2 mL, 15.27 mmol) and stir at room temperature for 14 h. Dilute with ethyl acetate, wash with 1M HCl, water and brine. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to provide the titled compound (3.47 g, 77%): MS (ES+): 445 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C(Cl)Cl>[CH2:46]([NH:53][C:23]([CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[N:17]1)=[O:24])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)NCc3ccccc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.15 mmol) was added to the solution at 0° C. After 1 h, benzylamine (12 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-[1-(2-benzylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (19 mg, 32%) as a white solid: ESI-LRMS m/e calcd for C28H33ClN4O4S [M+] 556.2, found 557.4 [M+H+]; 1H NMR (400 MHz, CDCl3), δ ppm 1.04-1.22 (m, 2H, CH2), 1.42-1.93 (m, 8H, 4×CH2), 2.13-2.29 (m, 1H, CH), 2.67 (t, J=6.2 Hz, 2H, COCH2), 3.25 (s, 3H, SO2CH3), 3.52 (t, J=7.6 Hz, 1H, CH), 4.31 (t, J=6.2 Hz, 2H, NCH2), 4.36 (d, J=5.5 Hz, 2H, NCH2Ar), 5.91 (t, J=5.5 Hz, 1H, NH), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.06-7.13 (m, 2H, Ar), 7.21-7.26 (m, 3H, Ar), 7.28 (d, J=2.3 Hz, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1 h, Ar), 8.67 (s, 1H, NH), 8.06 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][N:21]=4)[N:16]=[CH:15][CH:14]=3)=[N:9][N:10]=2)[N:7]=1.[CH2:25]([Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[C:28]#[CH:29])[CH3:26].C(N(CC)CC)C>C(#N)C.[Cu]I>[CH3:24][O:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:12][CH2:11][C:8]3[N:6]4[N:7]=[C:2]([C:26]#[C:25][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[CH:14][CH:15]=[N:16]2)=[N:21][CH:20]=1
Reactant: C#C[Si](CC)(CC)CC
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC[Si](C#Cc1ccc2nnc(CNc3ccnc4cc(OC)cnc34)n2n1)(CC)CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an argon flushed pressure vial (15 mL) was added copper (I)iodide (0.0070 g, 0.037 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.012 g, 0.015 mmol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (0.050 g, 0.15 mmol), and triethyl(ethynyl)silane (0.13 ml, 0.73 mmol) in acetonitrile (2 mL) followed by triethylamine (0.61 ml, 4.4 mmol). The vial was sealed and stirred at room temperature overnight The solution was concentrated and purified by MPLC (eluted with 0-10% (90:10:1 DCM:MeOH:NH4OH)) to yield the product as a light yellow solid. MS m/z=446.1 [M+1]+. Calc'd for C23H27N7OSi: 445.2.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12])C1C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2cccnc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2cccnc2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-3-yl)benzamido)-4-phenylbenzoate (0.14 g) in ethyl acetate (1 mL) and methanol (1 mL), 10% palladium-carbon (14 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. To the reaction mixture, 10% palladium-carbon (14 mg) was added. The resulting mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. Acetic acid (2 mL) and 10% palladium-carbon (0.11 g) were added to the reaction mixture, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. Ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Trifluoroacetic acid (5 mL) was added to the obtained residue, followed by stirring at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and water and ethyl acetate were added to the residue. After adjusting the pH to 5 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.070 g of 2-(2-hydroxy-5-(pyridin-3-yl)benzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([N:14]=[C:15]=[S:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(C)=O>[C:6]([N:14]=[C:15]=[N:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:6]([NH:14][C:15]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[S:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)N
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Product: CC(C)(C)N=C=NC(=O)c1ccccc1
Product: CC(C)(C)NC(=S)NC(=O)c1ccccc1
Reaction time: 2 h
Yield: 52 %

Procedure:
N-Benzoyl-N'-(t-butyl)carbodiimide was prepared by the method of O. Misunobu et al (Bull. Chem. Soc. Japan, 45, p. 3607, 1972) in two steps from t-butylamine, benzoyl isothiocyanate, diethylazodicarboxylate and triphenylphosphine. The initial reaction combined equimolar amounts (0.04 m) of benzoyl isothiocyanate and t-butylamine in 125 ml of dry acetone. After two hours at ambient temperature and 0.5 hour at 40° C., the solution was evaporated to dryness and the precipitate washed with petroleum ether and recrystallized from acetonitrile to yield N-benzoyl-N'-(t-butyl)thiourea (52%), mp 128.5°-130° C. To this was added an equivalent of diethylazodicarboxylate in 100 ml of tetrahydrofuran, and the solution was allowed to stir three days. After the addition of triphenylphosphine the solution stirred an additional ten days, the solvent was evaporated and the residue was extracted with petroleum ether, dried over sodium sulfate and then distilled to yield 38% of N-benzoyl-N'-(t-butyl)carbodiimide, bp 94 (0.04 torr), lit. bp 110° C. (0.55 m).
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=4[Cl:25])[CH2:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>>[Cl:25][C:18]1[CH:19]=[C:20]([CH2:23][OH:24])[CH:21]=[N:22][C:17]=1[N:14]1[CH2:13][CH2:12][N:11]([C:9]2[NH:8][C:7]3[C:2]([C:33]4[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([F:30])[CH:32]=4)=[CH:3][C:4]([C:26]([F:29])([F:27])[F:28])=[CH:5][C:6]=3[N:10]=2)[CH2:16][CH2:15]1
Reactant: OCc1cnc(N2CCN(c3nc4cc(C(F)(F)F)cc(Br)c4[nH]3)CC2)c(Cl)c1
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncc(CO)cc5Cl)CC4)[nH]c23)cc1F

Procedure:
(6-{4-[7-Bromo-5-(trifluoromethyl)-1H-benzimidazol-2-yl]piperazin-1-yl}-5-chloropyridin-3-yl)methanol from step (a) above (98 mg, 0.2 mmol) and 3-fluoro-4-methoxyphenylboronic acid (43 mg, 0.25 mmol, Aldrich) reacted under the conditions of Example 51 to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 536 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[S:13]1[C:17]([C:18]2[C:19]([O:28][CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[CH:23]=O)=[CH:16][C:15]2[CH:30]=[CH:31][CH:32]=[CH:33][C:14]1=2.[OH-].[Na+]>CN(C)C=O.O>[S:13]1[C:17]([C:18]2[C:19]([O:28][CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22](/[CH:23]=[CH:2]/[C:1]([C:4]3[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=3)=[O:3])[CH:25]=2)=[CH:16][C:15]2[CH:30]=[CH:31][CH:32]=[CH:33][C:14]1=2
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of 4-acetylbenzoic acid (1.50 g, 9.1 mmol) and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from Ex-3A (3.27 g, 11.0 mmol) in N,N-dimethylformamide (76 mL) was added a solution of sodium hydroxide (5 M, 7.3 mL, 36.5 mmol). The reaction mixture was allowed to stir at room temperature for 2 h and was then diluted with water to a volume of 150 mL. The solution was washed with dichloromethane and acidified with concentrated sulfuric acid to pH=3. The resulting solution was then extracted with dichloromethane. The dichloromethane extract was washed with brine, dried over sodium sulfate and concentrated. The resulting oily product solidified in ethanol. The solid was further stirred in ethanol for one day and collected by filtration. The solid was washed with ethanol, then dried in vacuo to afford the title compound as a yellow solid (2.2 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.21 (d, 2H), 8.07 (m, 3H), 7.93 (m, 3H), 7.82 (d, 1H), 7.32 (m, 2H), 6.86 (s, 1H), 4.08 (s, 3H), 4.00 (s, 3H). Anal. Calculated for C26H20O5S·1/6H2O: C, 69.78; H, 4.58; S, 7.17; found: C, 69.95; H, 4.69; S, 7.15. HPLC purity: 97.9% (area percentage).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][CH2:22][N:21](C(OCC4C=CC=CC=4)=O)[CH2:20]3)[C:16]2=[O:35])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:16]2=[O:35])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC3(CCCN(C(=O)OCc4ccccc4)C3)C2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC3(CCCNC3)C2=O)CC1
Reaction time: 20 h

Procedure:
To a solution of benzyl 2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (18.0 g, 35.9 mmol) in methanol (150 mL) was added 10% palladium on carbon (Aldrich, cat #: 520888) (1.8 g, 1.5 mmol) under the atmosphere of nitrogen. The reaction mixture was hydrogenated and shaken at 50 psi for 20 h. The reaction mixture was filtered through a pad of Celite and then washed with methanol (300 mL). The filtrate was concentrated under reduced pressure to give the desired product as a white solid in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]#[N:24])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[CH:3]=1.[N:34]([Si](C)(C)C)=[N+:35]=[N-:36].C([Sn](=O)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:22][C:23]2[NH:36][N:35]=[N:34][N:24]=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH2:25][C:26]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=2[F:33])[CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc(S(=O)(=O)N(CC#N)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Agent: CCCC[Sn](=O)CCCC
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2nnn[nH]2)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Yield: 74 %

Procedure:
To 8.7 g of N-[4-chloro-2-(2,6-difluorobenzyl)phenyl]-N-(cyanomethyl)-3,4-dimethoxybenzenesulfonamide (compound 211), obtained in Example 18, dissolved in 100 ml of THF are added, at room temperature, 10 g of azidotrimethylsilane and 2.29 g of dibutyltin oxide, and the mixture is refluxed for 8 hours. The reaction medium is concentrated and the residue is chromatographed on a column of silica gel, eluting with a 99/1 (v/v) dichloromethane/methanol mixture to give 7 g of the expected product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]3([OH:44])[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17]C(OCC4C=CC=CC=4)=O)=[C:13]([O:28][CH3:29])[CH:12]=3)[C:3]=12>[Pd].C(O)C.O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]3([OH:44])[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:35][CH2:36]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:28][CH3:29])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 1000 %

Procedure:
A mixture of tert-butyl 4-{[4-amino-3-(4-{[(benzyloxy)carbonyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.1 g, 0.000017 mol) and palladium on carbon (0.01 g) in ethanol (2.5 mL) and tetrahydrofuran (2.5 mL) was stirred under atmosphere of hydrogen at room temperature for 18 hours. The mixture was filtered and additional palladium on carbon (0.01 g) was added. The mixture was stirred under atmosphere of hydrogen at room temperature for 18 hours. The mixture was filtered through celite and the solvents were removed under reduced pressure to give tert-butyl 4-{[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.08 g, 0.00017 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 8.8 min. MS: MH+ 470.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[F:22].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:11][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][OH:10])=[CH:7][C:2]=2[F:1])=[CH:15][C:14]=1[F:22]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: OCCc1ccc(O)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: OCCc1ccc(Oc2ccc(Cl)c(F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.9 %

Procedure:
To a solution of 2-fluoro-4-(2-hydroxyethyl)phenol (22.41 mmol, 3.5 g) and (4-chloro-3-fluorophenyl)boronic acid (45 mmol, 7.82 g) in dry CH2Cl2 (150 mL) were added copper (II) acetate (4.5 mmol 0.81 g), pyridine (45 mmol, 3.55 g), and 4 A molecular sieves in turn. The mixture was stirred at room temperature under N2 for 72 hours. The reaction mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by silica gel chromatography to provide the desired product (1.4 g, 20%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1CCN(Cc2ccccc2)CC1)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC1CCN(C(=O)CC2CCN(Cc3ccccc3)CC2)CC1
Temperature: 66 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
To a mixture of 4.75 g (0.015 mol) of 1-(1-benzyl-4-piperidylacetyl)-4-hydroxypiperidine [1], 51 g of toluene, 1.68 g (0.017 mol) of triethylamine, 1.87 g (0.016 mol) of mesyl chloride was added dropwise at a temperature in the range of 0 to 10° C. and the reaction was allowed to proceed for 2 hours at the temperature in the range. Thereafter, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium chloride. The resultant organic layer was dried with anhydrous magnesium sulfate and concentrated under a reduced pressure. To the concentrated residue, 7 g of 2-propanol and 43 g of diisopropyl ether were added and the temperature of the mixture was increased. The mixture was stirred for 0.3 hours at a reflux temperature of 66° C. Thereafter the mixture was cooled to room temperature and subjected to filtration. The resultant wet crystal was dried under a reduced pressure, whereby 5.01 g of the title compound in the state of white powder was obtained (the yield was 84.7%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:7][CH:8]=1)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2ncn(-c3ccc(SC)cc3)c2c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2ncn(-c3ccc(S(C)=O)cc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of methyl 1-[4-(methylthio)phenyl]-1H-benzimidazole-6-carboxylate (4.44 g, 14.88 mmol) in dichloromethane (50 mL) was added m-chloroperbenzoic acid (3.07 g, 12.40 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 30 min. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 15 min. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/1-0/1) to give the title compound (3.89 g, yield 83%) as colorless crystals.