Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)=O.[Cl-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][PH3+]>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:1][C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Fc1cccc(C[PH3+])c1
Agent: [Cl-]
Product: Fc1cccc(C=Cc2c[nH]c3ccccc23)c1
Yield: 36.6 %

Procedure:
3-Formylindole (1.0 g) and 3-fluorobenzylphosphonium chloride (2.8 g) were treated as in the above Production Example 41-1 to give the title compound (0.598 g) as colorless crystals (yield: 73.1%).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:3]=2[CH2:2]1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>CO.O>[N:8]1[C:3]2[CH2:2][CH2:1][CH2:11][C:9](=[N:13][OH:14])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C1CCCc2ncccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1CCCc2ncccc21
Temperature: 25 °C

Procedure:
A mixture of 1.0 eq of 5,6,7,8-tetrahydroquinolinone-5 (93) (Tyger Scientific, T11850), 3.0 eq of hydroxylamine hydrochloride (Aldrich, 37,992-1), and 3.0 eq of sodium acetate in 50 mL of MeOH and 15 mL of H2O was refluxed for 4 hrs. The mixture was allowed to cool to rt. After rotary evaporation of the MeOH, 100 mL of H2O was added. The solid formed was collected by vacuum filtration. The solid collected was triturated with hexanes and dried under vacuum to give 94.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=[CH:4][C:3]=1[C:29]#[N:30].[CH3:31][O:32][CH2:33][C:34]#[C:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[C:38]2[O:43][CH2:44][O:45][C:37]=12.[ClH:46].CN(C)C(=N)N(C)C>C(O)CC.C(OCC)C>[ClH:1].[ClH:46].[C:29]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:40][C:39]1[CH:41]=[CH:42][C:36]([C:35]#[C:34][CH2:33][O:32][CH3:31])=[C:37]3[O:45][CH2:44][O:43][C:38]=13)=[C:10]([O:12][CH:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[CH:9]=[C:8]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[CH:7]=2)#[N:30]
Reactant: COCC#Cc1ccc(N)c2c1OCO2
Reactant: N#Cc1cnc2cc(OCCCN3CCOCC3)cc(OC3CCOCC3)c2c1Cl
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCCO
Solvent: CCOCC
Product: COCC#Cc1ccc(Nc2c(C#N)cnc3cc(OCCCN4CCOCC4)cc(OC4CCOCC4)c23)c2c1OCO2

Procedure:
A mixture of 4-chloro-3-cyano-7-(3-morpholin-4-ylpropoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinoline (125 mg) and 4-(3-methoxyprop-1-ynyl)-2,3-methylendioxyaniline (179 mg) in 1-propanol (8 ml) was treated with a 11.0M solution of hydrogen chloride in diethyl ether (0.30 ml) then stirred and heated at reflux for 1 hour. The mixture was allowed to cool and neutralised by the addition of tetramethylguanidine (0.10 ml). The resulting solution was evaporated to dryness and the residue was purified by chromatography on a Biotage silica cartridge (20 g) eluting with a gradient of methanol in dichloromethane (1–10%). The fractions containing the product were combined and evaporated. The residue was dissolved in ethanol (8 ml) and treated with 2 equivalents of hydrogen chloride (1.0M in diethyl ether). The title compound was thus obtained as a white solid (130 mg); NMR Spectrum: (DMSOd6, 300K) 1.87 (m, 2H), 2.10 (m, 2H), 2.31 (m, 2H), 3.11 (m, 2H), 3.30 (m, 2H), 3.36 (s, 3H), 3.50 (m, 4H), 3.87 (m, 4H), 3.97 (m, 2H), 4.32 (m, 2H), 4.37 (s, 2H), 5.10 (m, 1H), 6.18 (s, 2H), 1.05 (m, 3H), 7.13 (s, 1H), 8.87 (s, 1H), 10.43 (s, 1H), 11.34 (s, 1H); Mass Spectrum: M+H+ 601.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:22])[N:5]([CH2:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:6]2=[O:12].[N:23]1[S:27][N:26]=[C:25]2[C:28]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:24]=12>CCOC(C)=O>[Br:11][C:9]1[CH:8]=[C:7]2[C:3]([C:4](=[O:22])[N:5]([CH2:13][C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:6]2=[O:12])=[C:2]([NH:1][S:32]([C:28]2[C:25]3=[N:26][S:27][N:23]=[C:24]3[CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH:10]=1
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Reactant: C[C@H](CN1C(=O)c2cc(Br)cc(N)c2C1=O)c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](CN1C(=O)c2cc(Br)cc(NS(=O)(=O)c3cccc4nsnc34)c2C1=O)c1ccccc1
Temperature: 170 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
A mixture of (S)-4-amino-6-bromo-2-(2-phenyl-propyl)-isoindole-1,3-dione (30 mg, 0.08 mmol) and benzo[1,2,5]thiadiazole-4-sulfonyl chloride (150 mg, 0.64 mmol) was heated to 170° C. forming a melt and stirred for 2 h. The mixture was allowed to cool, and the solidified residue was dissolved in EtOAc, and the solution was washed with satd. aq. NaHCO3, dried (Na2SO4), and concentrated. Purification by flash chromatography (EtOAc/hexanes) gave the desired sulfonamide as a tan solid (30 mg, 64%). HPLC: RT=11.01 min. MS (ESI−): mass calcd. for C23H17BrN4O4S2, 555.99; m/z found, 555/557 [M−H]−. 1H NMR (400 MHz, CDCl3): 9.59 (br s, 1H), 8.39 (dd, J=7.0, 1.0, 1H), 8.27 (dd, J=8.8, 1.0, 1H), 8.08 (d, J=1.4, 1H), 7.75 (dd, J=8.8, 7.1, 1H), 7.47 (d, J=1.3, 1H), 7.27-7.22 (m, 2H), 7.21-7.17 (m, 3H), 3.78 (dd, J=13.6, 8.1, 1H), 3.68 (dd, J=13.6, 7.81, 1H), 3.26 (sextet, J=7.4, 1H), 1.26 (d, J=7.0, 3H).
Reaction SMILES: [S:1]1[C:5]([C:6]([O:8]C)=O)=[CH:4][N:3]=[CH:2]1.[C:10](#[N:12])[CH3:11].[H-].[Na+:14].C(OC)(C)(C)C>C1COCC1>[C:10]([CH:11]=[C:6]([C:5]1[S:1][CH:2]=[N:3][CH:4]=1)[O-:8])#[N:12].[Na+:14]
Reactant: CC#N
Reactant: COC(=O)c1cncs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: N#CC=C([O-])c1cncs1
Reaction time: 0.5 h

Procedure:
A solution of 1.5 g (10.5 mmol) of methyl 1,3-thiazole-5-carboxylate and 430 mg (10.8 mmol) of acetonitrile in 15 ml of THF was added dropwise to a suspension of 419 mg of sodium hydride (60% strength suspension in mineral oil) in 16 ml of THF which was heated under reflux. The reaction mixture was heated under reflux for 20 h. After cooling, 50 ml of methyl tert-butyl ether were added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered off with suction through a frit and dried under oil pump vacuum. This gave 1.71 g (94% of theory) of the title compound which was combined with the product (3.48 g, 95% of theory) from a second batch starting with 3.0 g (21 mmol) of methyl 1,3-thiazole-5-carboxylate. This material was used without further characterization for the next step.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:38][CH2:39][OH:40]>CN(C=O)C.O>[OH:40][CH2:39][CH2:38][NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: OCCBr
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CN)cc(C(F)(F)F)c2)CC3)ccn1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CNCCO)cc(C(F)(F)F)c2)CC3)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[7-({[3-(aminomethyl)-5-(trifluoromethyl)phenyl]amino}-carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide (0.459 g, 0.921 mmol) in DMF (10 mL) was added 2-bromoethanol (0.100 mL, 1.41 mmol) and TEA (0.300 mL, 2.15 mmol). The reaction mixture was allowed to stir at rt overnight, and then diluted with water. The mixture was extracted with EtOAc and the combined organic solutions were washed with 10% aqueous LiCl, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 4-{[7-({[3-{[(2-hydroxyethyl)amino]methyl}-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide I-276 (0.352 g, 71%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 10.65 (s, 1H), 9.19-9.09 (br s, 1H), 8.85-8.77 (m, 1H), 8.50 (d, 1H), 8.17-8.02 (m, 2H), 7.66 (s, 1H), 7.41-7.36 (m, 1H), 7.28-7.21 (m, 1H), 7.19-7.14 (m, 1H), 7.04-6.94 (m, 2H), 4.22 (t, 2H), 3.83-3.76 (m, 2H), 3.67 (t, 2H), 3.03-2.81 (m, 5H), 2.77 (d, 3H), 2.17-2.08 (m, 1H), and 1.89-1.75 (m, 1H). LCMS: (FA) ES+543.2, ES−541.2.
Reaction SMILES: [CH3:1][C:2]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[I:18])=[N:7][N:6]=1)([CH3:4])[CH3:3].[Cl:20][S:21](O)(=[O:23])=[O:22]>>[CH3:4][C:2]([C:5]1[S:9][C:8]([NH:10][C:11]([C:12]2[CH:17]=[C:16]([S:21]([Cl:20])(=[O:23])=[O:22])[CH:15]=[CH:14][C:13]=2[I:18])=[O:19])=[N:7][N:6]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1nnc(NC(=O)c2ccccc2I)s1
Reactant: O=S(=O)(O)Cl
Product: CC(C)(C)c1nnc(NC(=O)c2cc(S(=O)(=O)Cl)ccc2I)s1
Temperature: 25 °C

Procedure:
N-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]-2-iodobenzamide (600 mg) was added to 2 ml chlorosulfonic acid and heated at 180 C in a microwave for 1 min. The reaction was cooled to rt and added dropwise to ice water. A solid resulted, was filtered off, and was vacuum dried to give 450 mg of crude 3-({[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]amino}carbonyl)-4-iodobenzenesulfonyl chloride which was add to 5 ml of a 2M ethyl amine solution in THF. The reaction was stirred at it for 15 min and then washed with water and evaporated to give 280 mg crude product. 50 mg of this solid was purified by HPLC to give 36 mg N-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]-5-[(ethylamino)sulfonyl]-2-iodobenzamide which was pure by LCMS.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][Si:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]3)=[C:13]([F:25])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].O.O1CCO[CH2:29][CH2:28]1>>[N:1]1([CH2:4][C@@H:5]2[O:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][Si:20]([CH3:23])([CH3:24])[CH2:19][CH2:18]4)=[C:13]([F:25])[CH:12]=3)[CH2:6]2)[CH:29]=[CH:28][N:3]=[N:2]1
Reactant: C[Si]1(C)CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Reactant: C1COCCO1
Solvent: O
Product: C[Si]1(C)CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1

Procedure:
A solution of azide 19 (0.60 mmol) and bicyclodiene 20 (0.31 mL, 3.03 mmol) in dioxane (4.0 mL) is refluxed for 5 h. Water (5 mL) is added and extracted with DCM (2×5 mL), dried and concentrated. The product is further purified by column chromatography on silica using hexane-EtOAc mixtures to obtain the product as a brown solid (60 mg) in 26% over 3 steps.
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[S:17]([CH3:20])(=[O:19])=[O:18].[H-].[Na+].[Cl:23][C:24]1[CH:37]=[CH:36][C:27]2[S:28][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:30]([CH3:31])[C:26]=2[CH:25]=1>CN(C=O)C>[Cl:23][C:24]1[CH:37]=[CH:36][C:27]2[S:28][C:29]([S:32]([NH:6][C:7]3[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=3[S:17]([CH3:20])(=[O:19])=[O:18])(=[O:33])=[O:34])=[C:30]([CH3:31])[C:26]=2[CH:25]=1
Reactant: COC(=O)c1ccc(N)c(S(C)(=O)=O)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Into a mixed solvent of 20 mL of THF and 3 mL of DMF was dissolved 985 mg of methyl 4-amino-3-methanesulfonylbenzoate, followed by addition of 170 mg of sodium hydride (oily, 60%) at 0° C. After 20 minutes of stirring at the same temperature, 1.28 g of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at 0° C., followed by 1 hour of stirring at room temperature. Further, 150 mg of sodium hydride (oily, 60%) was added at room temperature and the mixture was stirred for 2 hours at the same temperature. After confirmation of disappearance of the starting material, the reaction was terminated by adding saturated aqueous ammonium chloride solution at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1) to obtain 911 mg of the title compound as colorless powder.
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: CN(CCNc1ccc([N+](=O)[O-])cn1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methylamine and 2-chloro-5-nitro-pyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]-methyl{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].[CH3:57][Li]>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1([OH:56])[CH3:57])[CH3:2]
Reactant: [Li]C
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: C1CCOC1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1(C)O)C(C)CC2OC
Temperature: -78 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
A solution of 0.101 g (0.1 mmole) of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetrone in 5 mL of dry THF was cooled to 0° C. under nitrogen. Then 1 mL of a 0.5M solution of methyllithium was added dropwise and the solution was stirred at -78° C. for 24 h. The solution was quenched at -78° C. by addition of 0.2 mL of glacial acetic acid and then diluted with 20 mL of ether and partitioned between ether and 1M KHCO3 solution. The ether layer was washed with 1M KHCO3 and brine, dried over MgSO4, and concentrated. The residue was dissolved in 2 mL of 1:9 48% aqueous HF-acetonitrile was stirred at room temperature for 8 h. The reaction was quenched by addition of 2 mL of ethoxytrimethylsilane and the solution was concentrated to dryness under vacuum. The residue was purified by flash chromatography (2×20 cm silica gel) using 25% acetone-hexane to afford 0.053 g (68%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[CH2:21][C:20](=[O:22])[N:19](COCC[Si](C)(C)C)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:38][CH2:39][CH2:40][CH2:41]I>CN(C=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[CH:14]=[C:15]3[C:21]4([CH2:41][CH2:40][CH2:39][CH2:38]4)[C:20](=[O:22])[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: ICCCCI
Reactant: COc1cc(-c2cnc3c(c2)CC(=O)N3COCC[Si](C)(C)C)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnc3c(c2)C2(CCCC2)C(=O)N3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.8 %

Procedure:
To a solution of 5-(3,4,5-trimethoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (Compound BN, 43 mg, 0.10 mmol) in DMF (2 mL) was added cesium carbonate (0.17 g, 0.50 mmol) and 1,4-diiodobutane (13 μL, 0.10 mmol). The resulting solution was stirred for 4 hr at room temperature, after which it was partitioned between EtOAc and H2O. The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 6 N HCl (10 mL) and MeOH (5 mL), and the resulting mixture was stirred at room temperature overnight, after which it was partitioned between EtOAc and H2O. The organic layer was concentrated in vacuo, and the residue was dissolved in EtOH (2 mL). Potassium acetate (100 mg) was then added, and the reaction was stirred for 2 hr. The resulting solution was purified via preparatory HPLC to give the title compound (18 mg, 51%). 1H NMR (CDCl3, 300 MHz): δ 9.53 (s, 1H), 8.32 (d, J=2.1 Hz, 1H), 7.56 (s, 1H), 6.69 (s, 2H), 3.95 (s, 6H), 3.90 (s, 3H), 2.28 (m, 2H), 2.24 (m, 2H), 1.97 (m, 4H). HPLC retention time: 2.00 minutes; MS ESI (m/z): 355.4 (M+1)+, calc. 354.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])[CH3:2].S(=O)(=O)(O)O.[Cl:18][C:19]([Cl:23])([Cl:22])[CH:20]=O>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10]([CH:20]([C:19]([Cl:23])([Cl:22])[Cl:18])[O:8][C:7]2=[O:9])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOc1cccc(C(=O)O)c1
Reactant: O=CC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOc1ccc2c(c1)C(=O)OC2C(Cl)(Cl)Cl
Temperature: 25 °C
Yield: 9.3 %

Procedure:
To a stirred solution of 6.6 g (40 mmoles) of 3-ethoxybenzoic acid in 50 ml. of concentrated sulfuric acid were added dropwise over fifteen minutes 8.0 g (55 mmoles) of trichloroacetaldehyde (chloral). The reaction mixture was stirred for twelve hours at 25° C., and then an additional 8.0 g of chloral were added in one portion and the mixture was stirred for an additional three hours. The reaction mixture was next added to 50 g of ice and 50 ml of water, and the aqueous mixture was extracted several times with diethyl ether. The ethereal extracts were combined, washed with aqueous sodium bicarbonate and then with fresh water, and dried. The solvent was removed by evaporation under reduced pressure to provide an oil. The oil solidified and then was crystallized from ethanol to afford 1.1 g of 6-ethoxy-3-(trichloromethyl)phthalide. m.p. 112°-114° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[F:21][C:19]1[CH:18]=[CH:17][C:15]2=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[N:13]=[C:14]2[CH:20]=1
Reactant: Brc1ccccn1
Reactant: C#CCCn1nc2ccc(F)cc2n1
Product: Fc1ccc2nn(CCC#Cc3ccccn3)nc2c1
Yield: 20000 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (20 mg, 0.13 mmol) and 2-(but-3-ynyl)-5-fluoro-2H-benzo[d][1,2,3]triazole (24 mg, 0.13 mmol). Reaction time: 1 day. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM, DCM/MeOH 98:2 to DCM/MeOH/NH4OH 95:4:1) to yield 7.6 mg (26 mmol, 21%) of 5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:12]1([CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCC2CCCCC2)cc1
Temperature: 100 °C
Yield: 82.5 %

Procedure:
A solution of 4-hydroxybenzaldehyde (0.244 g, 2.00 mmol) in CH3CN (4.0 mL) was treated with bromomethylcyclohexane (0.279 g, 2.00 mmol) and K2CO3 (0.332 g, 2.40 mmol). The reaction mixture was heated to 100° C. for 1 h in a Biotage Initiator microwave synthesizer. Additional bromomethylcyclohexane (0.279 g, 2.00 mmol) and K2CO3 (0.332 g, 2.40 mmol) were added and the reaction mixture was again heated to 100° C. for 1 h in a Biotage Initiator microwave synthesizer. Additional bromomethylcyclohexane (0.279 g, 2.00 mmol) and K2CO3 (0.332 g, 2.40 mmol) were added and the reaction mixture was again heated to 100° C. for 1 h in a Biotage Initiator microwave synthesizer. Following cooling, the reaction mixture was filtered and concentrated in vacuo. Purification via flash column chromatography (10% EtOAc/hexanes) gave the title compound as a white solid (0.360 g; 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.86 (s, 1 H) 7.85 (d, J=8.8 Hz, 2 H) 7.11 (d, J=8.8 Hz, 2 H) 3.89 (d, J=6.3 Hz, 2 H) 1.80 (d, J=12.6 Hz, 2 H) 1.61-1.79 (m, 4 H) 1.13-1.32 (m, 3 H) 1.07 (dd, J=12.6, 2.6 Hz, 1 H) 1.01 (dd, J=11.9, 2.5 Hz, 1 H). MS(ES+) m/e 219 [M+H]+.
Reaction SMILES: [CH:1]12[O:7][C:6]1([C:8]1[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:19][C:18]=4[CH:28]=3)=[CH:10][N:9]=1)[CH2:5][CH2:4][O:3][CH2:2]2.S(=O)(=O)(O)[OH:36].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.O>[OH:7][CH:1]1[C:6]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[C:17]4[S:21][C:20]([NH:22][C:23]([NH:25][CH2:26][CH3:27])=[O:24])=[N:19][C:18]=4[CH:28]=3)=[CH:10][N:9]=2)([OH:36])[CH2:5][CH2:4][O:3][CH2:2]1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C45CCOCC4O5)nc3)cc(-c3ccccn3)c2s1
Reactant: O=S(=O)(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C4(O)CCOCC4O)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Yield: 42 %

Procedure:
Compound iii (20 mg; 0.042 mmol) was dissolved in THF-H2O (10:1, 11 mL). Conc. sulfuric acid (20 μL) and p-toluenesulphonic acid (0.7 mg, 4 mmol) were added and the mixture stirred at RT. The mixture was concentrated in vacuo and purified over silica (0-100% 0.1% FA (aq)-MeCN) yielding Compound 8 (8.8 mg, 42%).