Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1(F)[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1O.C(C1C(C(C)(C)C)=NC=CC=1)(C)(C)C.CC[O:28]CC>Cl([O-])(=O)(=O)=O.[Ag+]>[O:9]1[C@H:8]([CH2:10][OH:28])[C@H:6]([OH:7])[C@H:4]([OH:5])[CH:2]=[CH:1]1
Reactant: C[C@@H]1OC(F)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: CCOCC
Agent: [Ag+]
Agent: CC(C)(C)c1cccnc1C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: OC[C@H]1OC=C[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To 2.00 g (2.47 mmol) of lactal carbonate 8c was added 4.44 g (9.86 mmol) of fucosyl fluoride 9c. The mixture was azeotroped 5 times with benzene and placed under high vacuum for two hours. Under an argon atmosphere 2.77 mL (12.33 mmol) of di-tert-butyl pyridine and 16 mL of dry ether were added. 2.0 g of freshly activated 4 Å molecular sieves were added and the mixture stirred one hour at room temperature. In an argon glove bag, 2.34 g (12.33 mmol) of stannous chloride (SnCl2) and 2.56 g (12.33 mmol) of silver perchlorate (AgClO4) were added. The flask was equipped with a reflux condenser and the reaction brought to reflux for 72 hours. The reaction was quenched with 5 mL of saturated bicarbonate and filtered through a pad of celite. Diluted with 50 mL ethyl acetate and washed 2 times with saturated bicarbonate, 2 times with sat. copper sulfate and 2 times with sat. brine. The organics were dried over MgSO4 and concentrated. Flash chromatography in 20% ethyl acetate/hexanes afforded 2.10 g (51%) of a white foam 10 c:
Reaction SMILES: Cl[C:2]1[C:3]2([C:13]([CH3:15])([CH3:14])[CH:12]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]2[C:9]([C:10]=1[Cl:11])=[CH:8][CH:7]=[CH:6][CH:5]=2.CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[Cl:11][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]([CH3:14])([CH3:15])[CH:12]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:2]=1
Reactant: CCOC(=O)C1C(C)(C)C12C(Cl)=C(Cl)c1ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)C1C(C)(C)C12C=C(Cl)c1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of 2',3'-dichloro-3,3-dimethyl-spiro[cyclopropane-1,1'-indene]-2-carboxylic acid-, ethyl ester (19 g as is, containing iodobenzene) in t-butanol (50 ml) is added to a 0.1 M solution of potassium-t-butoxide in t-butanol (450 ml; 0.045 mole) and the mixture allowed to stir overnight at room temperature. The reaction mixture is then poured into water, extracted with ether, the ether extracts dried over magsium sulfate and evaporated to dryness to afford 11.1 g of a black oil. This oil is purified by chromatography (silica gel; eluent: 1:1 mixture of methylene chloride:hexane), to afford 2 g of title product, a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=1[F:10])#[N:2].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH2:24][CH:23](B(O)O)[CH2:22][CH2:21][CH2:20]2)[C:12]1=[O:28].C([O-])(=O)C.[Na+].[OH-].[Na+]>COCCOC.O.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]([C:3]1[CH:8]=[CH:7][C:6]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][C:12](=[O:28])[C:13]23[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:5][C:4]=1[F:10])#[N:2]
Reactant: O=C1Nc2ccccc2C12CCCC(B(O)O)C2
Reactant: N#Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccc3c(c2)C2(CCCCC2)C(=O)N3)cc1F
Temperature: 25 °C
Yield: 37 %

Procedure:
A solution of 4-cyano-3-fluoro-bromobenzene (0.76 g, 3.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.3 g) in ethylene glycol dimethyl ether (15 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (1.4 g, 5.7 mmol) and sodium acetate (1.2 g, 11.4 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.45 g, 37%) as an off-white solid. mp: 258–260° C.; 1H NMR (DMSO-d6) δ 8.8 (s, 1H), 7.7–7.6 (m, 2H), 7.5 (td, 2H, J=0.9. 1.5, 5.7 Hz), 7.4 (dd, 1H, J=1.5, 8.8 Hz), 7.0 (d, 1H, J=8.1 Hz), 2.0–1.6 (m, 10H); MS (−)APCI [M−H]− @m/z 319.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:3]1=[O:7]
Reactant: O=C1NCC[C@@H]1O
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=C1[C@@H](O)CCN1c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a 1,4-dioxane (20 mL) solution of (3S)-3-hydroxypyrrolidin-2-one (372 mg, 3.68 mmol) and 1-bromo-4-(trifluoromethyl)benzene (508 μL, 3.68 mmol) at room temperature was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (64 mg, 0.11 mmol), palladium(II) acetate (17 mg, 0.070 mmol) and cesium carbonate (1.80 g, 5.52 mmol). After stirring at 80° C. for 16 hours, the reaction mixture was allowed to cool down to room temperature and partitioned between diethyl ether (100 mL) and brine (100 mL). The organic layer was washed with brine (2×100 mL), dried (magnesium sulfate) and concentrated in vacuo to afford the crude product. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 7.81 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.7 Hz, 2H), 4.52-4.48 (m, 1H), 3.89-3.77 (m, 2H), 3.05 (br s, 1H), 2.68-2.62 (m, 1H), 2.18-2.09 (m, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[N-:40]=[N+:41]=[N-:42].[Na+].O>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[N:40]([CH2:12][C@H:13]1[O:18][C@@:17]2([C:26]3[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=4)[CH:25]=3)[CH2:20][O:19]2)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]1[OH:39])=[N+:41]=[N-:42]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](CN=[N+]=[N-])[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 60 °C
Yield: 78.2 %

Procedure:
To a solution of ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (38 mg, 0.066 mmol) in 1 mL of DMF was added sodium azide (22 mg, 0.338 mmol) and a catalytic amount of TBAI. The solution was warmed to 60° C. and kept at the same temperature overnight. 5 mL of water was added and the solution was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 23 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.36 (s, 1H), 7.22 (s, 1H), 7.08 (s, 4H), 5.14 (d, J=12.4 Hz, 1H), 5.09 (d, J=12.4 Hz, 1H), 4.08 (s, 2H), 3.96-3.91 (m, 1H), 3.77-3.70 (m, 2H), 3.52-3.45 (m, 2H), 3.35-3.31 (m, 1H), 2.59 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H); MS ESI (m/z) 446 (M+1)+, calc. 445.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19](C4C=CC=CN=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:12][CH2:11]2)[N:6]=[CH:5]1.C([Sn](CCCC)(CCCC)[C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1)CCC>>[ClH:1].[ClH:1].[ClH:1].[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:12][CH2:11]2)[N:6]=[CH:5]1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccn3)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3cccnc3)cc2C1
Yield: 8 %

Procedure:
Example 67 was prepared as a yellow solid in 8% yield from Compound A of Example 37 and 3-(tributylstannyl)pyridine as described for Compound B of Example 37.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:37])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18](CC2C=CC=CC=2)[CH2:19][CH:20]([OH:29])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:12][CH:11]=1.Cl>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:37])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][CH:20]([OH:29])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:12][CH:11]=1
Reactant: COCCCNC(=O)COc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COCCCNC(=O)COc1ccc(CCNCC(O)COc2ccccc2)cc1
Reaction time: 4 h
Yield: 33.8 %

Procedure:
N-3- Methoxypropyl 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenoxyacetamide (2.7g) was dissolved in methanol (130 ml) and acidified to pH3 with an ethereal solution of hydrogen chloride. 10% Palladium on carbon (440 mg) was added and the mixture stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered through diatomaceous earth and the filtrate evaporated to give a crude product, which was purified by chromatography on K60 silica (55 g) using 10% methanol in dichloromethane as eluant. The product was dissolved in dichloromethane and ethereal hydrogen chloride added to give a pH of 3. The solvent was evaporated and the residue dissolved in dichloromethane which was also evaporated. The residue (1.4 g) was recrystallised from methyl acetate (50 ml) and methanol (15 ml). Thus was obtained N-3- methoxypropyl 4-[2-(2-hydroxy-3-phenoxypropyl-amino)ethyl]phenoxyacetamide (0.75 g), m.p. 167°9°, the NMR data were consistent with those of Example 11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH2:13][CH2:14][N:15]=[C:8]1[CH2:7][CH2:6]2.[CH:16]([O:19]C)(Cl)Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH:16]=[O:19])[N:9]1[CH2:13][CH2:14][N:15]=[C:8]1[CH2:7][CH2:6]2
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)CCC1=NCCN12
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)N1CCN=C1CC2
Reaction time: 0.17 h
Yield: 35 %

Procedure:
To a stirred solution of Compound 14 (63 mg, 0.31 mmol) in CH2Cl2 (5 ml) was added TiCl4 (0.17 ml, 1.6 mmol) at 0° C. After the reaction mixture was stirred for 10 minutes, Cl2CHOMe (0.14 ml, 1.6 mmol) was added at 0° C., and stirred for 3 h. The mixture was quenched by the addition of water, basified with NaOH aq., and extracted with CH2Cl2. The combined CH2Cl2 extracts were dried over MgSO4, filtered, and concentrated. The residue was purified by SiO2 chromatography to give Compound 15 (25 mg, 35%) as a slight yellow solid.
Reaction SMILES: [ClH:1].Cl.Cl.FC1C2C(=CC=CC=2)C=NC=1C1C(N)=NC=C(C2C=NN(C3CCNCC3)C=2)C=1.C(OC([N:40]1[CH2:45][CH2:44][CH:43]([N:46]2[CH:50]=[C:49]([C:51]3[CH:52]=[N:53][C:54]([NH2:69])=[C:55]([C:57]4[N:58]=[CH:59][C:60]5[C:65]([CH:66]=4)=[C:64]([Cl:67])[CH:63]=[CH:62][C:61]=5[F:68])[CH:56]=3)[CH:48]=[N:47]2)[CH2:42][CH2:41]1)=O)(C)(C)C>>[ClH:67].[ClH:1].[ClH:67].[Cl:67][C:64]1[CH:63]=[CH:62][C:61]([F:68])=[C:60]2[C:65]=1[CH:66]=[C:57]([C:55]1[C:54]([NH2:69])=[N:53][CH:52]=[C:51]([C:49]3[CH:48]=[N:47][N:46]([CH:43]4[CH2:42][CH2:41][NH:40][CH2:45][CH2:44]4)[CH:50]=3)[CH:56]=1)[N:58]=[CH:59]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5c(Cl)ccc(F)c5cn4)c3)cn2)CC1
Agent: Cl
Agent: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1ncc2ccccc2c1F
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(F)c2cn1

Procedure:
The procedure for the preparation of 3-(4-fluoroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using 4-{4-[6-amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester in place of 4-{4-[6-amino-5-(4-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.11-2.28 (m, 4H), 3.01-3.17 (m, 2H), 3.32-3.47 (m, 2H), 4.47-4.60 (m, 1H), 7.66 (dd, J=9.85, 8.59 Hz, 1H), 8.08-8.15 (m, 2H), 8.34-8.51 (m, 3H), 8.56 (s, 1H), 8.77 (d, J=2.02 Hz, 1H), 9.00 (br. s., 1H), 9.16 (br. s., 1H), 9.67 (s, 1H). 1H NMR (400 MHz, CD3OD): δ=2.29-2.44 (m, 4H), 3.20-3.30 (m, 2H), 3.60 (d, J=12.6 Hz, 2H), 4.54-4.66 (m, 1H), 7.39 (t, J=9.1 Hz, 1H), 7.91 (dd, J=8.3, 4.8 Hz, 1H), 7.94 (s, 1H), 8.14 (s, 1H), 8.18 (s, 1H), 8.29 (s, 1H), 8.43 (s, 1H), 9.61 (s, 1H). MS (ES+): m/z=339.76/341.64 [MH+]. HPLC: tR=2.27 min (ZQ2, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]3)[C:26]([Cl:28])=[CH:27][C:20]=2[N:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:29]3[CH2:30][CH2:31][CH:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]3)[C:26]([Cl:28])=[CH:27][C:20]=2[N:19]=1
Reactant: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl N-{4-chloro-3-[5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino]benzyl}-carbamate (790 mg, 1.38 mmol), TFA (1.54 mL, 20.7 mmol) and DCM (30 mL) was stirred at rt overnight. The mixture was cooled to 0° C., basicified to pH ˜10 and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated and the residue was washed with Et2O/PE.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH:33]=[CH2:34])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:8]2[CH2:34][CH2:33][C:32]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH2:27][CH2:28]2)=[O:35])=[CH:4][CH:3]=1
Reactant: C=CC(=O)N1CCN(c2ccccc2OC)CC1
Reactant: Fc1ccc(-c2cc3ccc(Cl)cc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(C(=O)CCn2c(-c3ccc(F)cc3)cc3ccc(Cl)cc32)CC1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of 6-chloro-2-(4-fluorophenyl)-1H-indole (Description 26, 348 mg, 1.4 mmol), 4-(2-methoxyphenyl)-1-(1-oxo-2-propenyl)piperazine (Description 25, 400 mg, 1.6 mmol) and potassium carbonate (1.5 g, 10.8 mmol) in dimethylformamide was stirred at 100° C. for 48 h. The mixture was cooled and aqueous ammonium chloride (saturated, 10 mL) and water (30 mL) were added. The mixture was extracted with ethyl acetate and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50), to give the title compound. 1H NMR (360 MHz, CDCl3) δ 7.51 (1H, d, J 8.4 Hz), 7.45 (3H, m), 7.18 (2H, t, J 8.7 Hz), 7.11 (1H, dd, J 8.4, 1.8 Hz), 7.01 (1H, m), 6.93-6.81 (3H, m), 6.48 (1H, s), 4.51 (2H, t, J 7.7 Hz), 3.85 (3H, s), 3.72 (2H, t, J 5.0 Hz), 3.30 (2H, t, J 5.0 Hz), 2.93 (2H, t, J 5.0 Hz), 2.79 (2H, t, J 5.0 Hz), and 2.56 (2H, t, J 7.7 Hz). m/z (ES+) 492, 494 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH2:21]([O:28][C:29]1[C:34]([C:35](=[O:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:21]([O:28][C:29]1[C:34]([C:35]([C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=2)([OH:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccccc1-c1cccc(Br)c1
Reactant: CC(=O)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1cccc(C(C)(O)c2cccc(-c3ccccc3)c2OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of 21 (0.7 g, 2.66 mmol) in anhydrous tetrahydrofuran (15 mL) was stirred under nitrogen at −78° C. and 2.5M n-butyllithium in hexanes (1.1 mL, 2.75 mmol) was added at such a rate that the temperature did not exceed −70° C. Stirring was continued at −78° C. for 1 hr when a solution of 20 (0.8 g, 2.66 mmol) in tetrahydrofuran (5 mL) was added at such a rate that the temperature did not exceed −65° C. Stirring was continued at −78° C. for 30 min., then for 2 hrs at room temperature. The reaction mixture was poured onto saturated ammonium chloride (120 mL) and extracted with ethyl acetate (150 mL). The organic extract was washed with water (2×80 mL), dried over sodium sulfate and stripped. The crude 22 was used as such in the next step.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH3:12].[C:27]([Si:31]([O:34][CH:35]([C:41]1[CH:46]=[CH:45][C:44]([CH2:47]I)=[CH:43][CH:42]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[CH2:11]([O:13][C:14](=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][CH2:47][C:44]1[CH:43]=[CH:42][C:41]([CH:35]([O:34][Si:31]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:32])[CH3:33])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:46][CH:45]=1)(=[O:23])=[O:24])[CH3:12]
Reactant: CCOC(=O)CCCCCCNS(C)(=O)=O
Reactant: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(CI)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(CCS(=O)(=O)NCCCCCCC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.0 mL of a 1.0 M solution in THF, 1.00 mmol) was added to a solution of the sulfonamide 4 (220 mg, 0.88 mmol) in THF (2.2 mL) at 0° C. The reaction was warmed to room temperature and a solution of the iodide 9 (432 mg, 1.00 mmol) in THF (3.0 mL) was added. The reaction was stirred at room temperature for 16 h, quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 4:1 hex/EtOAc) gave 159 mg (29%) of the silyl ether 10 as a light yellow viscous oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[CH:11]1([C:14]2[C:15]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[C:16]3[C:22]([I:23])=[N:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH:11]1([C:14]2[C:15]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[C:16]3[C:22]([I:23])=[N:21][N:20]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=4)[C:17]3=[N:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C3CC3)cnc3[nH]nc(I)c23)CC1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Reaction time: 2 h
Yield: 57.3 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (0.734 g, 4.69 mmol) was slowly added to a stirring mixture of tert-butyl 4-(5-cyclopropyl-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (2.00 g, 4.26 mmol) and potassium carbonate (0.883 g, 6.39 mmol) in DMF (30 mL) at room temperature, and the reaction was then stirred for 2 hours. EtOAc (200 mL) and water (100 mL) were added to the mixture, and the phases were separated. The organic suspension was washed with water (3×50 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide the crude as an oil. The residue was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 15% EtOAc/hexane to provide tert-butyl 4-(5-cyclopropyl-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.44 g, 57% yield) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]([F:16])([F:15])[C:12](O)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:12]([C:11]([Cl:10])([F:16])[F:15])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=C(O)C(F)(F)Cl
Solvent: O
Product: FC(F)(Cl)c1nc2cc(Br)ccc2[nH]1
Yield: 41.8 %

Procedure:
A mixture of 4-bromo-phenylene-diamine (1.00 g, 5.35 mmol), chlorodifluoroacetic acid (3.0 mL, 35.4 mmol), and a drop of water was heated to 80° C. for 14 hours. The crude product was purified by chromatography (silica, hexanes: EtOAc, 4:1) to afford the title compound as a colorless oil (0.63 g, 42%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[I:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[I:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(I)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(I)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
2-Chloro-5-nitro-pyridine (60 grams, 0.38 mol) and 4-iodo-phenol (83.5 grams, 0.38 mol), 50% aqueous sodium hydroxide (475 mL) and toluene (475 mL) were added to a flask and stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C. and concentrated hydrochloric acid was added to adjust the pH to two. The aqueous layer was separated from the toluene layer and extracted with diethyl ether (3×400 mL). The diethyl ether and toluene solution were combined and washed with 1M sodium hydroxide (2×300 mL). The organic layer was concentrated under vacuum to yield 96.5 grams of crude product. This material was recrystallized from hexanes and ethyl acetate to provide 85.3 grams (66%) of the title compound. MS m/z: ESI+ 343.0 (M+H)+.