Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:35])[CH3:34].O>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:1].[CH3:20][C:19]1[N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=[CH:16][C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:3]2[C:2]([C:41]3[CH:42]=[CH:43][C:38]([CH2:37][NH:36][C:33](=[O:35])[CH3:34])=[CH:39][CH:40]=3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9][CH2:10]1
Reactant: CC(=O)NCc1ccc(B(O)O)cc1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)NCc1ccc(-c2nccnc2N2CCN(Cc3cnn(-c4ccccc4)c3C)CC2)cc1
Product: Cl
Yield: 89.6 %

Procedure:
Combine 3′-chloro-4-(5-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.290 g, 0.786 mmol), potassium carbonate (0.261 g, 1.89 mmol), (4-acetamidomethylphenyl)boronic acid (0.182 g, 0.943 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol) in N,N-dimethylacetamide (1.6 mL). Add water (790 μL), and reflux reaction for 18 hr. Add DCM and wash with water. Extract water layer three times with DCM. Dry combined organics (magnesium sulfate) and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes then 10:90 to 20:80 methanol:ethyl acetate), to give the free base of the title compound (365 mg, 96%). Dissolve the free base (0.363 g, 0.754 mmol) in acetonitrile (904 μL) and add aq. 1 N HCl solution (904 μL, 0.904 mmol). Shake for 15 min. at ambient temperature. Freeze dry to give the title compound (392 mg, 100%). MS (ES): m/z=482 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][CH2:2][CH2:3][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][CH:5]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: NCCc1cccc2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(NCCc1cccc2ccccc12)c1ccc(Cl)cc1

Procedure:
Prepared from 1-(2-aminoethyl)naphthalene and 4-chlorobenzenesulphonic acid chloride analogously to Example 1a. The crude product was purified by column chromatography on silica gel using ethylene chloride/cyclohexane (2:1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.[Br:13]C1CC(=O)NC1=O.C([O-])([O-])=O.[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>C(Cl)Cl.CN(C=O)C>[Br:13][C:3]1[C:4](=[O:12])[NH:5][C:6]2[C:11]([C:2]=1[O:1][CH2:30][C:29]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:28]=1[F:27])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: O=C1CC(Br)C(=O)N1
Reactant: O=c1cc(O)c2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2c(OCc2ccc(F)cc2F)c1Br
Reaction time: 1 h

Procedure:
To a room temperature solution of 4-hydroxy-1,2-dihydroquinolin-2-one (500 mg, 3.10 mmol) in CH2Cl2 (10.0 mL) was added portion-wise solid N bromosuccinimide (551.5 mg, 3.10 mmol). The reaction was stirred vigorously for 1.0 h, followed by the sequential addition of K2CO3 (540 mg, 3.90 mmol), DMF (4.0 mL), and 2,4-difluorobenzyl bromide (0.430 mL, 3.30 mmol). The resulting suspension was stirred for 4.5 hours until complete formation of desired product was seen by LCMS analysis. The reaction was then diluted with ethyl acetate (400 mL) and brine washed (3×200 mL). The resulting organic extract was Na2SO4 dried, filtered, and concentrated in vacuo to a residue that was subjected to SiO2 chromatography with ethyl acetate/hexanes/methanol (60:35:5) to furnish a solid (529 mg, 47%). 1H NMR (300 MHz, d6-DMSO) δ 12.23 (s, 1H), 7.68 (app q, J=7.5 Hz, 1H), 7.64 (app q, J=8.5 Hz, 1H), 7.54 (app q, J=8.3 Hz, 1H), 7.38-7.27 (m, 2H), 7.20 (app t, J=7.4 Hz, 1H), 7.13 (app dt, J=8.4, 2.6 Hz, 1H), 5.25 (s, 2H); LC/MS C-18 column, tr=2.64 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 366 (M+H). ES-HRMS m/z 365.9967 (M+H calcd for C16H11BrF2NO2 requires 365.9936).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)[CH:7]=1.[C@H:50]12[CH2:56][C@H:53]([NH:54][CH2:55]1)[CH2:52][N:51]2C(OC(C)(C)C)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[F:81][C:82]([F:87])([F:86])[C:83]([OH:85])=[O:84]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:51]3[CH2:52][C@@H:53]4[CH2:56][C@H:50]3[CH2:55][NH:54]4)[CH:9]=2)[CH:7]=1.[C:83]([OH:85])([C:82]([F:87])([F:86])[F:81])=[O:84]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(C=O)c3)c2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-[(5-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (40 mg, 0.059 mmol) and 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.68 mg, 0.059 mmol) were dissolved in 1,2-dichloroethane (DCE) (1 mL) in a 1 dram vial and acetic acid (3.71 μL, 0.065 mmol) was added. The mixture was stirred for 30 min and then MP-Triacetoxyborohydride (126 mg, 0.294 mmol) was added. The mixture was stirred overnight. The mixture was filtered through glass fibre filter paper and washed 2× with 0.3 mL of DCE. Trifluoroacetic acid (0.18 mL, 2.336 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and taken up in 1.1 mL of DMSO and purified on a Gilson HPLC eluting at 20 mL/min with a linear gradient running from 10% CH3CN/H2O (0.1% TFA) to 90% CH3CN/H2O (0.1% TFA). The desired fractions were concentrated to give the desired product as a TFA salt. This was converted to the free base by taking up the residue in EtOAc (30 mL) and 2.5 N NaOH (5 mL). The organic phase was washed with 2.5 N NaOH (3×5 mL) and then with brine (2×5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and dried under 50° C. to give N-({5-chloro-3′-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl]-3-biphenylyl}methyl)-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (25.8 mg, 57.5%) as a white solid. LC-MS m/z 762 (M+H)+; mp 130-133° C.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.[C:18](ON1C(=O)CCC1=O)(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(O)(=O)C>O>[C:18]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCCC[C@H](N)C(=O)O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Reaction time: 4 h
Yield: 86 %

Procedure:
To the solution of L-lysine (1 mmol) in water (2 ml) and triethylamine (0.27 ml, 2 mmol) 1 mmol of succinimidyl palmitate (suspended in 2 ml of acetone) was added at room temperature under stirring. Stirring of the reaction mixture was continued for 4h. Triethylamine was removed under reduced pressure, the precipitate was collected by filtration, washed with water and ethanol, crystallized from glacial acetic acid giving an 86% yield of the title compound. Analysis data are given in Table 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[N:6][C:7]=1[Cl:8].C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:12])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(CBr)cnc1Cl
Yield: 130 %

Procedure:
5,6-dichloro-3-pyridinemethanol (1.0 eq.) was taken up in dichloromethane and stirred overnight with carbon tetrabromide (1.5 eq.) and 1,3-bis(diphenylphosphino)propane (0.75 eq.) Ether was added to the solution and filtration followed by concentration of the filtrate afforded the 5,6-dichloro-3-bromomethylpyridine in 130% yield.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:6][CH2:5]1.[H-].[Na+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[O:18]=[C:10]1[C:7]2([CH2:8][CH2:9][N:4]([CH2:3][C:2]([F:1])([F:19])[F:20])[CH2:5][CH2:6]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]1[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1Nc2ccccc2C12CCN(CC(F)(F)F)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidin]-2-one from Step A (3.30 g, 11.6 mmol) in DMF (10 mL) was added sodium hydride (697 mg of a 60% dispersion in mineral oil, 17.4 mmol) at 0° C. The mixture was stirred at 0° C. for 45 min, then tert-butyl bromoacetate (1.88 mL, 12.8 mmol) was added and stirring was continued at room temperature for 72 h. The reaction mixture was quenched with H2O. The aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 80:20, to provide the title compound. MS: m/z=399 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].[CH2:23]([O:30][C@@H:31]1[CH2:36][C@@H:35]([CH2:37]I)[O:34][C@@H:33]([O:39][CH3:40])[CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:3]1([S:9]([CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:37][C@H:35]2[O:34][C@@H:33]([O:39][CH3:40])[CH2:32][C@H:31]([O:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:36]2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CO[C@H]1C[C@H](OCc2ccccc2)C[C@@H](CI)O1
Reactant: O=S(=O)(Cc1ccc(Cl)cc1Cl)c1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@H](OCc2ccccc2)C[C@@H](CC(c2ccc(Cl)cc2Cl)S(=O)(=O)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.5 %

Procedure:
To a stirred suspension of sodium hydride (0.030 g of 50% NaH in mineral oil) in dry DMF (0.5 ml) under nitrogen is added 2,4-dichlorobenzyl phenyl sulfone (0.18 g; 0.6 mmole) as the crystalline solid all at once. The reaction mixture is stirred at room temperature under nitrogen until hydrogen evolution ceases (50 min.) A solution of (2R,4R,6S)-4-benzyloxy-6-iodomethyl-2-methoxy-3,4,5,6-tetrahydro-2H-pyran (0.109 g; 0.3 mmole) in dry DMF (0.4 ml) is added by syringe through a septum. The reaction is stirred for 2.5 hours at room temperature and then partitioned between ether (100 ml) and water (20 ml). The ether layer is extracted with water (4×20 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo to leave 0.24 g of crude product. Flash chromatography of this product on silica gel with a 30 mm×130 mm column, eluting with 2% (by volume) acetone in methylene chloride, gives 40 mg of the major diastereoisomer and 10 mg of the minor diastereoisomer and 60 mg of a mixture of the two with a total of 110 mg of 1-(2,4-dichlorophenyl)-2-(4(R)-benzyloxy-2(R)-methoxy-3,4,5,6-tetra-hydro-2H-pyran-6(S)-yl)ethyl phenyl sulfone.
Reaction SMILES: [O:1]1[C@H:3]2[CH:4]=[C:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][CH2:36][CH2:37][CH2:38][NH2:39].C(O)CCC>COC(C)(C)C>[CH3:17][C@@H:10]([C@@H:9]1[C@@:18]2([CH3:29])[CH2:19][CH2:20][C@@H:21]3[C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C@:2]4([OH:1])[C@H:3]([NH:39][CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH2:30])[CH:4]=[C:5]3[C@@H:6]2[CH2:7][CH2:8]1)[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16]
Reactant: NCCCCNCCCN
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C[C@@H](NCCCNCCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 58 %

Procedure:
5,6α-epoxicholest-7-en-3β-ol (8.9 g, 22.1 mmol, 1 eq) and spermidine (6.4 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give Dendrogenin B (5α-Hydroxy-6β-[4-(3-aminopropylamino)-butylamino]-cholest-7-en-3β-ol) as a white solid (7.0 g, 58%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 14% yield.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[CH2:12][CH:13]=[O:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCO)c1ccc2ncccc2c1
Solvent: ClCCl
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: CC(CC=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 3-quinolin-6-ylbutan-1-ol (0.060 g, 0.30 mmol) in methylene chloride (3.0 mL) was added 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (0.005 g, 0.03 mmol) and iodobenzene diacetate (0.10 g, 0.33 mmol). The reaction was stirred overnight at RT. The mixture was purified by chromatography on silica gel with EtOAc in hexanes (0-40%) to afford the desired product (0.050 g, 84%). LCMS: (M+H)=200.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](Br)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[C:41](B(O)O)=[CH:40][CH:39]=[N:38]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([C:41]5[NH:37][N:38]=[CH:39][CH:40]=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccn[nH]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(Br)ccc4c3=O)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Temperature: 150 °C
Yield: 45 %

Procedure:
{1-[4-(7-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (81 mg, 0.15 mmol), 1H-pyrazole-5-boronic acid (22 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol) and sodium carbonate (32 mg, 0.30 mmol) were suspended in DME (2 mL) and water (1 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The mixture was heated in a microwave at 150° C. for 25 min. The resulting mixture was partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases were separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 40% ethyl acetate in cyclohexane) to give the title compound as a pale brown oil (36 mg, 45%). LCMS (Method B): RT=4.82 min, [M+H]+=534.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[ClH:26].[OH:27][CH:28]1[CH2:33][CH2:32][CH2:31][N:30]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:11]=[CH:10][C:9]3[O:8][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:29]1
Reactant: ClCCCCCCBr
Reactant: OC1CCCNC1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCCN3CCCC(O)C3)cc12

Procedure:
The compound was prepared by a method similar to Example 3 from 6-hydroxyflavone, 1-bromo-6-chlorohexane, and 3-hydroxypiperidine: mp 197°-202° C.
Reaction SMILES: [OH-:1].[Li+].C[O:4][C:5](=[O:39])[CH:6](O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)[N:8]=1.O>O.CO>[OH:1][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:4])=[O:39])=[N:8][C:9]=1[C:13]1[CH:14]=[C:15]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:16]2=[N:17][CH:18]=1
Reactant: [OH-]
Reactant: COC(=O)C(O)c1cccc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)n1
Agent: [Li+]
Solvent: O
Solvent: CO
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3nc(CC(=O)O)ccc3O)cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.4 %

Procedure:
4 N aqueous lithium hydroxide (17 μl, 0.66 mmol) was added to hydroxy-{6-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid methyl ester (286 mg, 0.55 mmol) in water/methanol(3:1) (5 ml) and stirred at room temperature for 3 days. Water was added and the mixture was extracted with ethyl acetate (3×), the combined organic layers were dried over magnesium sulfate and purified by silica gel chromatography to give 5-hydroxy-{6-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridin-2-yl}-acetic acid (174 mg, 61% yield) as an off white powder. MS: m/z 507.6 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[F:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=O.N>>[F:13][C:14]1[C:15]([C:16]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)=[CH:19][CH:20]=[CH:21][N:22]=1
Reactant: N#Cc1cccc(C(N)=NO)c1
Reactant: O=C(Cl)c1cccnc1F
Agent: N
Product: N#Cc1cccc(-c2noc(-c3cccnc3F)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 4B using 3-cyano-N′-hydroxybenzimidamide (Example 4A) and 2-fluoronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.87 (m, 1 H), 7.95 (m, 1 H), 8.17 (m, 1 H), 8.17 (m, 1 H), 8.43 (m, 1 H), 8.6 (m, 1 H), 8.8 (m, 1 H) ppm; MS (DCI/NH3) m/z 267 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]#[N:14])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-]>C1COCC1.O>[C:13]([C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:14]
Reactant: COC(=O)c1cc(C#N)cc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(C#N)cc(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
Methyl 3,5-dicyanobenzoate (400 mg, 2.1 mmol) was dissolved in THF—H2O (7:3 v/v, 30 mL), the solution was cooled to 0° C. and LiOH (51 mg, 2.1 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 1 h. THF was removed under reduced pressure and the aqueous layer was washed with EtOAc, acidified to pH ˜2-3 using 1.5N HCl, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 20% MeOH in CHCl3) to get pure product 3,5-dicyanobenzoic acid (100 mg, yield 28%): 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.50 (s, 2H). MS (ESI) m/z: Calculated for C9H4N2O2: 172.03. found: 171.2 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:27]>C(Cl)Cl.CO>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:25])=[N:39][CH:40]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(Cl)c(OC)cc(OC)c4Cl)c4cccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1; purified by silica gel column chromatography), and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 580.1 [M+H]+; tR=3.80 min (System 1); TLC: Rf=0.27 (DCM/MeOH/NH3aq, 94:5:1).