Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:43]=[CH:42][CH:41]=[CH:40][C:9]=2[CH2:10][CH2:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30]4)=[CH:25][CH:24]=3)[N:13]=2)[CH2:7][CH2:6]1)=O.O[Li].O.Cl.C1C=CC2N(O)N=[N:54]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CO.O.CCOC(C)=O>[C:3]([C:5]1([C:8]2[CH:43]=[CH:42][CH:41]=[CH:40][C:9]=2[CH2:10][CH2:11][C:12]2[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:30][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:32]4)=[CH:25][CH:24]=3)[N:13]=2)[CH2:6][CH2:7]1)(=[O:2])[NH2:54]
Reactant: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CN(C(=O)OC(C)(C)C)C4)cc3)ncc2C(F)(F)F)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cc2)C1
Temperature: 35 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
A solution of tert-butyl 3-(4-((4-(2-(1-(methoxycarbonyl)cyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A8) (347 mg, 0.582 mmol) and LiOH.H2O (293 mg, 6.98 mmol) in THF (7.0 mL), MeOH (7.0 mL) and H2O (2.0 mL) was stirred at room temperature for 3 days. LiOH.H2O (147 mg, 3.49 mmol) was added and the resulting mixture was heated at 35° C. for 16 hours. EtOAc (50 mL) and aqueous HCl (2 M, 50 mL) were added cautiously, then the layers were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine, dried (MgSO4) then evaporated to dryness. The residue was dissolved in THF (12 mL) and DMF (2.0 mL), to which HOBt (157 mg, 1.16 mmol), EDCl.HCl (223 mg, 1.16 mmol) and DIPEA (0.507 mL, 2.91 mmol) were added under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (280 mg, 2.91 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 16 hours, then 40° C. for a further 24 hours. The volatiles were removed in vacuo and EtOAc (20 mL) and saturated NaHCO3 (20 mL) were added. The layers were separated then the aqueous phase extracted with EtOAc (2×20 mL). The organic extracts were combined, washed with brine, dried (MgSO4) then evaporated to dryness. The residue was purified by silica gel column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 10-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound A9 as a white solid (179 mg, 53%); 1H NMR (400 MHz, d6-DMSO) δ 10.22 (s, 1H), 8.69 (s, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.37-7.27 (m, 5H), 7.26-7.19 (m, 1H), 6.98 (s, 1H), 5.99 (s, 1H), 4.23 (t, J=7.7 Hz, 2H), 3.88-3.70 (m, 3H), 3.21-3.14 (m, 2H), 3.14-3.07 (m, 2H), 1.44 (d, J=3.5 Hz, 2H), 1.40 (s, 9H), 0.97 (s, 2H). LCMS-A: rt 6.168 min; m/z 582 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[K+].C(COC)OC>O.CN(C)P(N(C)C)(N(C)C)=O>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:3]=1
Reactant: COc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Yield: 94.3 %

Procedure:
A mixture comprising 90.5 grams (0.5 mole) of 2-chloro-6-trifluoromethylpyridine, 65 grams (0.55 mole) of 4-methoxyphenol and 36.4 grams (0.55 mole) of 85 percent potassium hydroxide was stirred in 1 liter of a 1:1 mixture of monoglyme and hexamethylphosphoramide for 1 hour at room temperature and thereafter heated overnight at reflux. The resulting mixture was diluted with water and extracted with hexane. The hexane extract was washed with a dilute sodium hydroxide solution followed by water washing. The extract was dried and concentrated under reduced pressure to give 127 grams (94 percent of theoretical) of 2-trifluoromethyl-6-(4-methoxyphenoxy)pyridine.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: C1COCCN1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCN2CCOCC2)cc1

Procedure:
In a manner similar to that described in Example 207, 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and morpholine are converted to the named compound.
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9](I)=[C:4]2[CH:3]=1.[Si:13]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[CH:31]=[C:30](B(O)O)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Si:13]([O:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([N:27]2[CH:31]=[C:30]([C:9]3[CH:8]=[N:7][C:6]([NH2:11])=[C:5]4[O:12][C:2]([Cl:1])=[CH:3][C:4]=34)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(B(O)O)cn2)CC1
Reactant: Nc1ncc(I)c2cc(Cl)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-4-iodo-furo[2,3-c]pyridin-7-ylamine (2 g, 7 mmol), [1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]boronic acid (2.75 g, 8.49 mmol), (1,1′bis-(diphenylphosphino)-ferrocene)palladium dichloride (248 mg, 0.340 mmol) and potassium carbonate (2.35 g, 17.0 mmol) in 1,4-dioxane (20 mL) and water (9.5 mL) was heated to 70° C. for 22 h. The mixture was partitioned between ethyl acetate and water and the aqueous phase extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by ISCO chromatography (10% to 50% ethyl acetate:heptane) followed by trituration with ether:heptane afforded 2.0 g (60%) of the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.97 (s, 1 H), 7.76-7.69 (m, 1 H), 7.62 (s, 1 H), 6.73 (s, 1 H), 4.73 (s, 2 H), 4.17 (tt, J=3.9, 11.6 Hz, 1 H), 3.73 (tt, J=4.3, 10.5 Hz, 1 H), 2.23 (d, J=12.1 Hz, 2 H), 2.09-1.99 (m, 2 H), 1.91 (dq, J=3.5, 11.9 Hz, 2 H), 1.61-1.48 (m, 2 H), 0.92 (s, 9 H), 0.10 (s, 6 H); MS (ESI): 447.39, 449.35 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[C:22]1([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1ccc2ccc(-c3ccccc3)nc2n1
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3ccccc3)nc2n1)c1cccc(Cl)c1
Temperature: 4 °C
Yield: 57.6 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3-chlorobenzoic acid (1.6 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-phenyl-1,8-naphthyridine (1.6 g). The product obtained by precipitation in water (2.2 g; m.p. approximately 160° C.) is dissolved in boiling acetonitrile (200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Phenyl-1,8-naphthyridin-2-yl)-3-chlorobenzamide (1.5 g), m.p. 175° C., is obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH:25][C@@H:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:28]([CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH2:27]1.O>CN(C=O)C>[CH3:44][O:43][C:41](=[O:42])[CH2:40][CH2:39][C@@H:28]1[CH2:27][C@H:26]([O:25][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)=[C:9]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:31][CH2:30][N:29]1[C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33]
Reactant: COC(=O)CC[C@@H]1C[C@H](O)CCN1C(=O)OC(C)(C)C
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC[C@@H]1C[C@H](Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)CCN1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Dissolve 631.7 mg (1.87 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 490 mg (1.71 mmol) of tert-butyl(2R,4R)-4-hydroxy-2-(3-methoxy-3-oxopropyl)piperidine-1-carboxylate in 1 ml of DMF, cool to −10° C. and add 1.02 ml (2.05 mmol) of phosphazene base P2-t-Bu (approx. 2 M solution in THF). Stir the reaction mixture at 0° C. for 1 h and then add to water. Extract three times with dichloromethane, combine the organic phases, wash with satd. sodium chloride solution and dry over magnesium sulphate. After concentrating under reduced pressure, purify the product by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 20:1→3:1). 420 mg (38.1% of theory) of the target compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](=[O:28])[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1>Cl.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=5)=[O:28])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][NH:17][CH2:16][CH2:15]4)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2ccccn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(c1ccccn1)[C@@]12CNCCC1=Cc1c(cnn1-c1ccc(F)cc1)C2

Procedure:
(R)-tert-butyl 1-(4-fluorophenyl)-4a-picolinoyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (180 mg, 0.39 mmol) was dissolved in HCl-dioxan (4 M, 4 mL) and the resultant solution was stirred vigorously at room temperature for 1.5 hours. The reaction mixture was evaporated to afford (R)-(1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone as a yellow solid. LCMS (Method B, ESI): RT 0.30 and 2.01 min, m+H=375.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([F:24])[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])=[C:9]([C:12]([OH:14])=O)[CH:10]=2)[N:5]=[N:4][CH:3]=1.C1C=CC2N(O)[N:32]=[N:31]C=2C=1.CCN=C=NCCCN(C)C.NN>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([F:24])[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])=[C:9]([C:12]([NH:31][NH2:32])=[O:14])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: Nc1cnnc2c(F)c(Nc3ccc(Br)cc3F)c(C(=O)O)cc12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NNC(=O)c1cc2c(N)cnnc2c(F)c1Nc1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
To a solution of 4-amino-7-(4-bromo-2-fluorophenylamino)-8-fluoro-cinnoline-6-carboxylic acid (1.00 equiv.) and HOBt (3.00 equiv.) in DMF is added EDCI (3.00 equiv.) at room temperature. After stirring for 1 hour, hydrazine (3.00 equiv.) and TEA (3.00 equiv.) are added. The reaction mixture is stirred for 1 hour and diluted with EtOAc. The resulting mixture is washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3, and brine. The organic layer is dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is used directly without further purification.
Reaction SMILES: C([C:3]1([C:16]([O-:18])=O)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)C.O.[NH2:20][NH2:21]>C(O)C>[NH:20]([C:16]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:18])[NH2:21]
Reactant: NN
Reactant: CCC1(C(=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reaction time: 1 h

Procedure:
A mixture of 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (21 g), hydrazine monohydrate (40 mL), and ethanol (200 mL) was heated and refluxed for 22 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, to the residue were added saturated brine and ethyl acetate, and the organic phase was separated. The organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. To the residue was added diisopropyl ether, followed by stirring for 1 hour, and the resulting solid was collected by filtration and dried under reduced pressure to obtain tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (17.8 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[OH-].[Na+].O>C(O)C>[CH2:2]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(C(=O)O)cc1
Yield: 65.1 %

Procedure:
1-Bromobutane (22.6 g, 0.165 mol) was added dropwise at room temperature to a stirred mixture of 4-hydroxybenzoic acid (15.0 g, 0.11 mol) in ethanol (60 ml) and sodium hydroxide (10.60 g) in the minimum amount of water. The stirred mixture was heated under reflux overnight (tlc analysis revealed a complete reaction), and then the ethanol was distilled off and an equal volume of water was added. The mixture was boiled to give a solution, cooled, washed with ether and acidified with 36% hydrochloric acid. The cooled mixture was filtered, and the product was washed with water to give a colourless solid (13.9 g) which was recrystallised from ethanol to give colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[C:6]([CH3:9])=[CH:7][O:8][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:12][C:11]1[C:2]([N:1]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:3][C:4]2[O:8][CH:7]=[C:6]([CH3:9])[C:5]=2[CH:10]=1
Reactant: Cc1coc2cc(N)c(Cl)cc12
Reactant: BrCCCCBr
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1coc2cc(N3CCCC3)c(Cl)cc12

Procedure:
A mixture of 9.1 g (50 mmole) of 6-amino-5-chloro-3-methylbenzofuran, 11.8 ml (0.1 mole) of 1,4-dibromobutane, 17.1 ml (0.1 mole) of N-ethyldiisopropylamine and 60 ml of ethanol is boiled under reflux for 24 hours and then concentrated by evaporation in vacuo. The residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The crude product obtained after drying and concentration by evaporation of the methylene chloride is chromatographed with petroleum ether/ether over silica gel. Subsequent distillation in a bulb tube (150°/10-1 torr) yields 5-chloro-3-methyl-6-(pyrrolidin-1-yl)-benzofuran having a melting point of 50°-52°.
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:35](=[O:46])[CH2:36][N:37](C)[C:38](=O)OC(C)(C)C)[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.Cl>CC(C)=O>[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:35](=[O:46])[CH2:36][NH:37][CH3:38])[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)CN(C)C(=O)OC(C)(C)C)CC4)c4ncnc(N)c34)cc2F)c1
Agent: Cl
Solvent: CC(C)=O
Product: CNCC(=O)N1CCC(n2nc(-c3ccc(NC(=O)Nc4cccc(C)c4)c(F)c3)c3c(N)ncnc32)CC1
Temperature: 45 °C
Yield: 63 %

Procedure:
N-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea dihydrochloride salt (63 mg, 0.118 mmol) was dissolved in dichloromethane (7 mL) and N-ethyl-N-isopropylamine (0.113 mL), 2-[(tert-butoxycarbonyl)(methyl)amino]acetic acid (28mg, 0.147 mmol), 1-hydroxy-7-azabenzotriazole (16 mg, 0.118 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.147 mmol) were added to the reaction mixture. After 16 hours, the reaction mixture was diluted with dichloromethane (75 mL) then washed with water (75 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was isolated as a pale yellow solid (75 mg, 0.119 mmol). The crude tert-butyl N-{2-[4-(4-amino-3-{3-fluoro-4-[(3-toluidinocarbonyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidino]-2-oxoethyl}-N-methylcarbamate (75 mg, 0.119 mmol) was dissolved in acetone (5 mL) then aqueous hydrochloric acid (6N, 1 mL) was slowly added. The reaction mixture was heated at 45° C. for 2.5 hours then concentrated under reduced pressure. The remaining residue was triturated with dichloromethane (25 mL) to yield a light yellow solid. Purification by RP-HPLC (Waters PrepLC 4000, flow rate: 10 mL/min. λ=254 nm Gradient: 10% to 30% acetonitrile/0.1M aqueous ammonium acetate gradient over 40 minutes; Deltapak C18, 300A, 15 μm, 40×100 mm column) afforded N-[4-(4-amino-1-{1-[2-(methylamino)acetyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl]-N′-(3-methylphenyl)urea as a white solid (40 mg, 0.075 mmol). HPLC-RT: 12.22 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+)=532.1.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH:12]([Br:17])[C:13]3=[O:16])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH:12]([Br:17])[CH:13]3[OH:16])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2cc(-c3ccccc3)ccc2CC1Br
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: OC1c2cc(-c3ccccc3)ccc2CC1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.7 %

Procedure:
To a three-necked flask of 250 ml, fitted with a condenser, was added 3.55 g (12.4 mmol) of 6-phenyl-2-bromo-1-indanone, 100 ml of tetrahydrofuran (THF) and 100 ml of absolute ethanol. A dark red solution was formed and 0.40 g (10 mmol) of sodiumboronhydride was added in small portions. The mixture was stirred for 15 hours at room temperature. The mixture was poured onto ice and a 5% hydrochloric acid solution was added. The water layer was extracted 3 times with ether and the combined ether layer washed 2 times with a saturated NaCl solution. The ether was evaporated under reduced pressure yielding 2.57 g (8.89 mmol) of 6-phenyl-2-bromoindanol (72%).
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([S:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C[N:40]1CCOCC1.ClC(OCC(C)C)=O.N>C1COCC1>[C:32]([C:31]1[CH:35]=[CH:36][C:28]([S:25]([N:16]([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([C:6](=[O:7])[C:5]3[CH:37]=[CH:38][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])(=[O:26])=[O:27])=[CH:29][CH:30]=1)(=[O:33])[NH2:40]
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)S(=O)(=O)c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.7 %

Procedure:
In an atmosphere of argon and with cooling in an ice bath, 4-{[N-[2-[4-(4-fluorobenzoyl)piperidino]ethyl}-2-methoxyanilino]-sulfonyl}benzoic acid (63 mg, 0.117 mmol) was dissolved in THF (1 ml) to which were subsequently added dropwise N-methylmorpholine (14 μl, 0.13 mmol) and isobutyl chloroformate (16.8 μl, 0.13 mmol). After 15 minutes of stirring at room temperature, 28% liquid ammonia (0.5 ml) was added to the reaction solution which was cooled in an ice bath, followed by additional 10 minutes of stirring at room temperature. The reaction mixture was extracted with methylene chloride, and the resulting organic layer was dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation, and the resulting light yellow oily residue was purified by a silica gel column chromatography (ether-ethyl acetate-methylene chloride:methanol=10:1) to obtain 32 mg (50.9%) of the title compound in the form of light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[CH:9][CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.COC(=O)C1C=C(Cl)C=CC=1C(Cl)=O.O[NH:37][C:38](=[NH:40])[CH3:39]>C(Cl)Cl.CN(C=O)C.N1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]1[O:8][N:40]=[C:38]([CH3:39])[N:37]=1
Reactant: CC(=N)NO
Reactant: COC(=O)c1cc(OC)ccc1C(=O)O
Agent: COC(=O)c1cc(Cl)ccc1C(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(OC)ccc1-c1nc(C)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a mixture of crude 4-methoxy-phthalic acid 2-methyl ester (850 mg) in CH2Cl2 (25 mL) is added oxalyl chloride (3.0 mL) and DMF (1 drop). The reaction mixture is stirred at room temperature for 1 hour, and is concentrated under reduced pressure. To the freshly formed 5-chloro-2-chlorocarbonyl-benzoic acid methyl ester in pyridine (5.0 mL) is added N-hydroxy-acetamidine (350 mg, 4.72 mmol). The reaction mixture is heated at 100° C. for 16 hours. The reaction mixture is allowed to cool to room temperature, diluted with EtOAc (100 mL), and washed with H2O (75 mL×2). The organic layer is dried with Na2SO4 and is filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 35% EtOAc in heptanes as the eluent to afford 5-methoxy-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzoic acid methyl ester (600 mg, 60%).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>O1CCCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([B:24]([OH:29])[OH:25])[CH:18]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A cooled (−20° C.) solution of 2,2,6,6-tetramethylpiperidine (28 ml, 165 mmol) in tetrahydrofuran (400 ml) was treated with n-butyllithium (63 ml of a 2.5M solution in hexanes, 157.5 mmol). This mixture was then cooled to −78° C. 1-Bromo-4-fluorobenzene (16.5 ml, 150 mmol) was then added neat and dropwise over 10 min and stirring at −78° C. was continued for 3 h. Triisopropyl borate (40 ml, 172.5 mmol) was then added and stirring at −78° C. continued for 30 min before removing the cooling bath. When the internal temperature of the reaction reached −40° C., 5N hydrochloric acid was added (75 ml) and the mixture was stirred to ambient temperature. After stirring at ambient temp for 1 h the majority of the tetrahydrofuran was removed and the mixture partitioned between ether (500 ml) and 1N hydrochloric acid (500 ml). The organics were then extracted with 2N sodium hydroxide (400 ml) and the organics were discarded. The aqueous was cooled in an ice-water bath and 5N hydrochloric acid (150 ml) was added dropwise over 15 min. The resulting white solid was collected and dried under vacuum to afford 5-bromo-2-fluorobenzeneboronic acid (25 g, 76%).