Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16](=O)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:9]=1)[C:4]([OH:6])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)[CH:9]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(Cc1ccc(OC)c(C(=O)CCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CCC(Cc1ccc(OC)c(CCCc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Yield: 85.6 %

Procedure:
A solution of 2-ethyl-3-[3-[3-[4-(trifluoromethyl)phenyl]propionyl]-4-methoxyphenyl]propanoic acid (224 mg, 0.548 mmol) in ethanol (30 mL) was hydrogenated for 7 hours with 10% palladium on carbon (250 mg) at room temperature under a hydrogen pressure of 392 kPa. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by means of thin layer silica gel column chromatography (eluent: n-hexane: ethyl acetate:acetic acid=200:100:2 v/v/v) to afford 185 mg (86%) of the title compound as a yellow oil.
Reaction SMILES: CCCCCC.C([Li:11])CCC.CC(C)([O-])C.[K+].[F:18][C:19]1[C:20]([F:28])=[C:21]([F:27])[C:22]([F:26])=[C:23]([F:25])[CH:24]=1>C(OCC)C>[F:18][C:19]1[C:24]([Li:11])=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[C:20]=1[F:28]
Reactant: Fc1cc(F)c(F)c(F)c1F
Reactant: [Li]CCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1c(F)c(F)c(F)c(F)c1F
Temperature: -65 °C
Yield: 95.9 %

Procedure:
Inside of a 100 ml volume glass three-neck flask equipped with a 50 ml volume glass dropping funnel, temperature resistor and septum rubber was sufficiently replaced with nitrogen. Into the flask, 15.5 g (29.8 mmol) hexane solution of 15.5 wt. % butyllithium, 3.3 g (29.8 mmol) potassium tertbutoxide and 15 ml diethyl ether were charged, of which solution was cooled to -65° C. Thereafter, 5 g (29.8 mmol) pentafluorobenzene and 15 ml diethyl ether charged into the dropping funnel were added dropwise while making the inner temperature not to exceed -55° C. After the completion of dropwise addition, the reaction mixture was kept at a temperature of -65°~-55° C. with stirring to give pentafluorophenyllithium.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].Cl[C:12]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17](Cl)[C:13]=1[C:14]([OH:16])=[O:15].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[C:13]([C:14]([OH:16])=[O:15])=[CH:17][C:18]([N+:24]([O-:26])=[O:25])=[CH:19][C:20]=2[N+:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C(O)c1c(Cl)c([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: CCOc1ccc(N)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Nc2c(C(=O)O)cc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 10.5 g of 4-ethoxyaniline in 250 ml acetonitrile was added over a 1.5 hour period to a solution of 20 g of 2,6-dichloro-3,5-dinitrobenzoic acid and 11 g of N,N-diisopropylethylamine in 400 ml of acetonitrile and stirred at room temperature for five hours. After the solvent was removed in vacuo, the residue was dissolved in 500 ml of chloroform and extracted with several portions of 5% ammonium hydroxide. The aqueous extracts were washed with chloroform and acidified with dilute acid. The resulting solid was collected by filtration and was washed with water to provide 2-chloro=6-[(4-ethoxyphenyl)amino]-3,5-dinitrobenzoic acid, mp 202°-206° C.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH:27]([CH2:28][N:29]([C@@H:37]([C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.O>CS(C)=O>[C:32]([O:31][C:30]([N:29]([CH2:28][CH:27]1[CH2:26][CH2:25][N:24]([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:23][CH:22]1[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=1)[C@@H:37]([C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][CH:40]=1)[CH3:38])=[O:36])([CH3:33])([CH3:34])[CH3:35]
Reactant: COC(=O)c1ccc2nc(Cl)[nH]c2c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(N3CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c4cccc5ccccc45)C(c4cccc(F)c4)C3)[nH]c2c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A solution of 313 mg of methyl 2-chloro-1H-benzimidazole-6-carboxylate and 100 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate in 2.00 mL of DMSO was stirred at 130° C. for 9 hours. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 48 mg of methyl 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1H-benzimidazole-6-carboxylate as a pale yellow solid. ESI+: 637
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:41])[CH2:6][C@H:7]([NH:17][CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[CH2:30][CH2:29][CH2:28][NH:27][C:26]=2[N:25]=1)[C:8]1[CH:16]=[CH:15][C:11]2[CH2:12][CH2:13][O:14][C:10]=2[CH:9]=1)[CH3:3]>O1CCOCC1>[CH2:2]([O:4][C:5](=[O:41])[CH2:6][C@@H:7]([C:8]1[CH:16]=[CH:15][C:11]2[CH2:12][CH2:13][O:14][C:10]=2[CH:9]=1)[NH:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[CH2:30][CH2:29][CH2:28][NH:27][C:26]=2[N:25]=1)[CH3:3]
Reactant: CCOC(=O)C[C@H](NCCN(CCCc1ccc2c(n1)NCCC2)C(=O)OC(C)(C)C)c1ccc2c(c1)OCC2
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](NCCNCCCc1ccc2c(n1)NCCC2)c1ccc2c(c1)OCC2
Reaction time: 0.5 h

Procedure:
HCl gas was rapidly bubbled through a solution of 2-10 (4.0 g, 7.2 mmol) in dioxane (160 ml) at 0° C. for 10 minutes. After 30 minutes, the solution was purged with argon for 30 minutes. The solution was concentrated to give the amine 2-11 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.40 (d, J=7.0 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.10 (m,2H), 6.56 (d, J=6.1 Hz, 1H), 4.58 (m, 2H), 4.04 (m,2H), 3.49 (m, 4H), 3.19 (m, 4H), 2.90 (m, 2H), 2.79 (m, 2H), 2.30 (m, 2H), 1.98(m, 2H), 1.85 (m, 5H), 1.15 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:2]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:26])[CH3:25]
Reactant: CCOC(=O)CCN
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN([Si](C)(C)C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 39 h
Yield: 89.6 %

Procedure:
About 7.23 g of ethyl 3-aminopropionate hydrochloride, 15.71 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 23.00 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 39 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 3-[bis(trimethylsilyl)amino]propionate (3-BTMSAEP) as a colorless oil (11.03 g, 90% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 3.91 (quartet, 2H, OCH2 protons), 3.21 (multiplet, 2H, NCH2CH2 protons), 2.36 (multiplet, 2H, NCH2CH2 protons), 0.91 (triplet, 3H, CH3 protons), 0.07 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: O[Li].O.CO.[NH:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:7]([C:9]([NH:11][C@H:12]([C:14]([O:16]C)=[O:15])[CH3:13])=[O:10])[CH3:8].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[NH:6]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@H:7]([C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH3:8]
Reactant: COC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of LiOH.H2O (275 mg, 6.56 mmol) in a mixture of solvents MeOH:H2O (10.9 mL:3.6 mL) was added Boc-Ala-Ala-OMe (1.2 g, 4.38 mmol) and stirred for 4 hours at r.t. The solution was acidified to pH 2 with saturated aqueous solution of citric acid and the mixture was extracted with EtOAc (3×20 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum to give the desired product Boc-Ala-Ala-OH as a highly viscous and hygroscopic oil in quantitative yields (1.14 g). The product was taken for further reactions directly without any purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7]NC1C=CC(C2OC3C(C(=O)C=2)=C(O)C(OC)=C(O)C=3)=CC=1)[CH2:4][CH3:5])[CH3:2].[CH2:30]1[O:42][C:41]2[CH:40]=[C:39]3[C:34]([C:35](=[O:50])[CH:36]=[C:37]([C:43]4[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=4)[O:38]3)=[C:33]([OH:51])[C:32]=2[O:31]1>>[CH2:1]([N:3]([CH2:6][CH2:7][O:49][C:46]1[CH:45]=[CH:44][C:43]([C:37]2[O:38][C:39]3[C:34]([C:35](=[O:50])[CH:36]=2)=[C:33]([OH:51])[C:32]2[O:31][CH2:30][O:42][C:41]=2[CH:40]=3)=[CH:48][CH:47]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCNc1ccc(-c2cc(=O)c3c(O)c(OC)c(O)cc3o2)cc1
Reactant: O=c1cc(-c2ccc(O)cc2)oc2cc3c(c(O)c12)OCO3
Product: CCN(CC)CCOc1ccc(-c2cc(=O)c3c(O)c4c(cc3o2)OCO4)cc1

Procedure:
Similar to the preparation of 4′-[2-(N,N-diethylamino)ethylamino]-5,7-dihydroxy-6-methoxyflavone (discussed above), the title compound is prepared starting from 6,7-methylenedioxy-5,4′-dihydroxyflavone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:29]=[C:30]=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH2:23]([NH:29][C:30]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCCCCCN=C=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in N,N-dimethylformamide (3 ml), hexyl isocyanate (0.2 ml) was added, and the admixture was stirred at 60° C. for 15 hours. After the addition of water, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 63 mg of the title compound (yield: 84%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:29][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[O:9])=[CH:4][C:3]=1[O:41][CH3:42].[N:43]1([C@@H:49]2[CH2:54][CH2:53][CH2:52][CH2:51][C@H:50]2O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH3:42][O:41][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[C:11]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:29][C:12]=3[S:13][C:14]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:19][CH:20]=2)=[O:9])[CH:6]=[CH:7][C:2]=1[O:1][C@@H:50]1[CH2:51][CH2:52][CH2:53][CH2:54][C@H:49]1[N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: O[C@@H]1CCCC[C@H]1N1CCCCC1
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1O
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1O[C@@H]1CCCC[C@H]1N1CCCCC1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield by essentially following the procedures outlined in Example 20, Part B, from 6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 4-hydroxy-3-methoxyphenyl ketone (Example 81, Part F) and (±)-trans-2-(1-piperidyl)cyclohexanol (Example 20, Part A).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].[CH3:12][C:13]([CH3:21])([CH3:20])[C:14]#[C:15]/[CH:16]=[CH:17]/[CH2:18]Br.C(OCC)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:9])[CH:4](/[CH:18]=[CH:17]/[CH2:16][C:15]#[C:14][C:13]([CH3:21])([CH3:20])[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(C)(C)C#C/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)C(/C=C/CC#CC(C)(C)C)C(=O)OC
Reaction time: 1 h

Procedure:
4.05 ml of malonic acid dimethyl ester is dissolved in 40 ml of dimethylformamide, 1.29 g of 60% oily sodium hydride and 6.5 g of (E)-6,6-dimethyl-2-hepten-4-ynyl bromide (containing about 5% Z-form) are added gradually, and the mixture is stirred at that temperature for 1 hour. Saturated saline and ethyl ether are added to the reaction solution to form two liquid phases, the ether layer is taken, washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography [Wako gel C-200, 400 g; hexane/ethyl acetate=19/1→9/1] to obtain 6.26 g of (E)-6,6-dimethyl-2-hepten-4-ynylmalonic acid dimethyl ester as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)CCBr
Reactant: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1ccc(O)c(-c2cc(CCCC(=O)OC)ccc2OCCC(C)C)c1
Yield: 83.8 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl and 0.646 ml (5.181 mmol) of isopentyl bromide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 5 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate., The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 15 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 50/1) to obtain 1908 mg (0.4342 mmol, 84%) of 2-isopentyloxy-2'-hydroxy-5,5'-bis (3-methoxycarbonylpropyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 0.86 (6H, d, 2CH3), 1.0-2.2 (7 H, m, CH, 3CH2), 2.35 (4H, t, 2CH2), 2.64 (4H, t, 2CH2), 3.66 (6H, s, 2CH3), 4.04 (2H, t, CH2), 6.58 (1H, s, OH), 6.8-7.3 (6H, m, arom-H) MS (FAB): 455 (M-H)-
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([O:31]CC)=O)[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:36][CH3:35])=[O:31])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCC2=O)c1=O
Reactant: CN
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-pyrrolidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methylamine (8 M in ethanol) employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.04 (m, 1 H), 8.55 (s, 1 H), 7.41 (s, 1 H), 7.17 (dd, J=8.5, 5.3 Hz, 2 H), 7.02 (t, J=8.6 Hz, 2 H), 4.16-4.11 (m, 4 H), 3.41-3.37 (m, 4 H), 3.01 (d, J=4.9 Hz, 3 H), 2.39 (t, J=8.0 Hz, 2 H), 2.05 (m, 2 H), 1.83 (m, 2 H); HRMS C24H25FN4O4 (M+H)+ calcd 453.1938, found 453.1945.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[C:22]([Cl:37])=[CH:21][N:20]=1.Cl.O1CCOCC1.[Na]>O>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:17][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]2[CH2:16][CH:14]3[CH2:15][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6]2)=[N:20][CH:21]=1
Reactant: COCCN1CC2CC(C1)c1cc(N)ccc12
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CC3CN(CCOC)C2)ncc1Cl
Temperature: 120 °C
Yield: 52.3 %

Procedure:
10-(2-Methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (45 mg, 0.19 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (65 mg, 0.19 mmol) and 4N HCl in dioxane (53 μl, 0.21 mmol) were combined in a microwave tube. The reaction was heated to at 120° C. for 40 minutes in the microwave. The reaction was poured into water (50 ml) and saturated sodium bicarb (90 ml) and extracted 3 times with 25 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a brown oil. The crude reaction was purified on a 12 g Isco silica gel column using 0-15% methanol in methylene chloride as the eluent to yield 2-[5-chloro-2-(10-(2-methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide (52.57 mg, 43%) as a white foam. MP: 92-94° C., 1H-NMR (CDCl3) δ 9.10 (s, 1H), 8.50 (d, J=7.5 Hz, 1H), 8.13 (s, 1H), 7.96 (d, J=7.8 Hz, 1H), 7.58 (m, 1H), 7.35 (s, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.95 (s, 1H), 4.61-4.53 (m, 1H), 3.36 (t, J=5.9 Hz, 2H), 3.29 (s, 3H), 3.08 (br s, 1H), 3.02 (br s, 1H), 2.85 (m, 2H), 2.64 (d, J=5.3 Hz, 3H), 2.57-2.45 (m, 4H), 2.27 (m, 1H), 1.71 (d, J=10.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=4)=[O:19])=[C:13]([F:28])[CH:12]=3)[C:3]=12.[ClH:42].[Cl:43]CCl>CC(C)=O>[ClH:43].[ClH:42].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[C:13]([F:28])[CH:12]=3)[C:3]=12
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3nn(C4CCN(C(=O)OC(C)(C)C)CC4)c4ncnc(N)c34)cc2F)c1
Reactant: ClCCl
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)Nc2ccc(-c3nn(C4CCNCC4)c4ncnc(N)c34)cc2F)c1
Temperature: 0 °C

Procedure:
tert-Butyl 4-(4-amino-3-{3-fluoro-4-[(3-toluidinocarbonyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (117 mg, 0.209 mmol) was suspended in acetone (7 mL) and cooled to 0° C. Aqueous hydrochloric acid (6N, 1.6 mL) was slowly added to the reaction mixture. The reaction mixture was warmed to room temperature then heated at 50° C. for 4 hours. Concentration of the reaction mixture under reduced pressure followed by trituration with dichloromethane (25 mL) afforded N-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea dihydrochloride salt as an off-white solid (111 mg, 0.241 mmol). HPLC-RT: 11.98 min. (flow rate: 1 mL/min λ=254 nm Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300A, 5 μm, 150×3.9 mm column); m/z (MH+)=461.3.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:8]2[CH2:12][C@H:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Br:23][CH2:24][CH2:25][CH2:26]Br>O1CCCC1>[Br:23][CH2:24][CH2:25][CH2:26][C@@:11]1([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:12][C@H:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:9]=[CH:10]1
Reactant: BrCCCBr
Reactant: Cc1ccc(C)n1C1C=C[C@@H](C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Product: Cc1ccc(C)n1[C@@H]1C=C[C@](CCCBr)(C(=O)OCc2ccccc2)C1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of Example 48A (21.94 g, 74.4 mmol) in tetrahydrofuran (200 ml) was added dropwise lithium hexamethyl bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 119 mL) at −50° C. The reaction mixture was stirred for 1 hour at the same temperature. 1,3-dibromopropane (150 g, 744 mmol) was added dropwise over 1 hour. The reaction mixture was allowed to warm to −20° C. and stirred at the same temperature for 1 hour. LCMS showed that the reaction was complete. The reaction mixture was quenched with an aqueous ammonium chloride solution (6%, 600 mL), and extracted with ethyl acetate. The organic fraction was washed with aqueous ammonium chloride (6%), brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:1) to give the title compound.