Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH2:20]Br)[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:30]#[N:31].[K+]>O.C(O)C>[CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH2:20][C:30]#[N:31])[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CBr)nc12
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CC#N)nc12
Reaction time: 0.5 h
Yield: 74 %

Procedure:
0.46 g of 6-benzyl-2-bromomethyl-7-cyclopentyl-4-ethyl-imidazo[4.5-e]-s-triazolo[1.5-a]pyrimidin-5-one (for preparation see Synthesis example 1) are added to a solution of 0.72 g of KCN in 0.7 ml of water and 2.4 ml of ethanol heated to boiling. The mixture is boiled for a further 30 minutes until the reaction is complete. For working up the mixture is diluted with 10 ml of water and extracted with 15 ml of dichloromethane. The organic phase is separated off, washed with saturated sodium chloride solution and dried over magnesium sulphate. The solvent is distilled off and the residue remaining is purified by chromatography on silica gel (dichloromethane:methanol 99:1). 0.3 g of the title compound is obtained in the form of a colourless solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:14]([NH2:21])=[CH:15][C:16]=1[O:17][CH2:18][CH:19]=[CH2:20])[C:8]([O:10]CC=C)=[O:9])[CH:2]=[CH2:3].[OH-].[K+]>C(O)C.O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:14]([NH2:21])=[CH:15][C:16]=1[O:17][CH2:18][CH:19]=[CH2:20])[C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(OCC=C)c(OCC=C)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(N)c(C(=O)O)cc1OCC=C

Procedure:
To a suspension of allyl 3,4-diallyloxy-6-aminobenzoate * (16 mmol) in ethanol (50 ml) was added a solution of potassium hyroxide (48 mmol) in water (2ml). The mixture was heated at reflux for 40 minutes. The solution was partially evaporated at reduced pressure, acidified with acetic acid and extracted with ethylaceate. The organic layer was washed with water, a saturated solution of sodium chloride, dried (MgSO4) and decolourised with charcoal. Evaporation of the solvent gave 3,4-diallyloxy-6-aminobenzoic acid as a sandy solid. NMR (DMSO-d6): 4.5(m,4H); 5.33 ,4H); 6.60(s,1H); 7.3(s,1H): M/S +ve FAB (M+H)hu +=250.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:12](=O)[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B.CSC.Cl>C1COCC1.CO>[CH:1]1([C:7]2[C:8]3[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[N:13]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CC(=O)N(CCN(C)C)c2ccccc2-1
Agent: B
Agent: Cl
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(s1)c(C1CCCCC1)c1n2CCN(CCN(C)C)c2ccccc2-1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution (0.1 M) of methyl 12-cyclohexyl-5-[2-(dimethylamino)ethyl]-6-oxo-6,7-dihydro-5H-thieno[2′,3′:4,5]pyrrolo[1,2-d][1,4]benzodiazepine-10-carboxylate (from Example 7, Step 5) in THF was treated with borane-dimethylsulfide complex (2 M solution in THF, 20 eq.). The mixture was stirred at RT for 2 h then treated with HCl in methanol (1.25 M) and heated at 75° C. for 30 mins. The solvents were removed in vacuo and the residue taken into EtOAc and washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to give the title compound as a solid. 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 7.99 (s, 1H), 7.40-7.36 (t, J 8, 1H), 7.29-7.27 (d, J 8, 1H), 7.23-7.21 (d, J 8, 1H), 7.14-7.10 (t, J 8, 1H), 4.17 (m, 2H), 3.82 (s, 3H), 3.43-3.39 (m, 2H), 3.20-3.17 (m, 2H), 2.70-2.67 (m, 1H), 2.32-2.23 (m, 2H), 2.01 (s, 6H), 1.81-1.23 (m, 10H). MS (ES+) m/z: 452 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH3:10][S:11][Na]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][S:11][CH3:10])[CH:3]=1
Reactant: BrCc1cc(Br)ccn1
Reactant: CS[Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCc1cc(Br)ccn1
Reaction time: 0.17 h
Yield: 12.6 %

Procedure:
Crude 4-bromo-2-(bromomethyl)pyridine was dissolved in N,N-dimethylformamide (3.000 mL), and mixture was cooled on an ice bath followed by the portion wise addition of methylsulfanylsodium (2.037 g, 29.07 mmol). Reaction mixture was left to stir for 10 minutes. The mixture was diluted with ethyl acetate, organic layer was washed with water and brine. Organic layer was extracted, dried over MgSO4 and concentrated in vacuo to a solid. Residue was purification by silica gel column chromatography loaded with dichloromethane and eluted with 50% diethylether/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-titled product (0.8 g, 12.6%). 1H NMR (400.0 MHz, DMSO-d6) δ 2.25 (s, 3H), 3.80 (s, 2H), 7.4 (d, 1H), 7.6 (s, 1H), 8.4 (d, 1H); LC/MS m/z 220.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH2:35]([C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[CH2:45][OH:46])[CH:36]=[CH2:37].[H-].[Na+]>CN(C=O)C>[CH2:35]([C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[CH2:45][O:46][CH2:20][C:18]1[CH:19]=[C:15]2[N:14]=[C:13]([CH3:22])[C:12]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:11]([N:8]3[CH2:9][CH2:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])([CH3:34])[CH2:6][CH2:7]3)[N:16]2[N:17]=1)[CH:36]=[CH2:37]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CCc1cc(F)ccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(F)cc4CC=C)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (150 mg, 0.257 mmol) and (2-allyl-4-fluorophenyl)methanol (42.7 mg, 0.257 mmol) in DMF (5 mL) at 0° C. was added NaH (10.26 mg, 0.257 mmol). The reaction was stirred at 0° C. for 2 h. It was then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(2-(((2-allyl-4-fluorobenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (70 mg, 0.112 mmol, 43.8% yield) as an oil. LCMS (M+1)=623.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].O[C:10]1[CH:15]=[C:14](O)[C:13](O)=[CH:12][C:11]=1O>>[CH:4]1[C:3]2[NH:8][C:11]3[C:10](=[CH:15][C:14]4[NH:1][C:2]5[C:3]([NH:8][C:13]=4[CH:12]=3)=[CH:4][CH:5]=[CH:6][CH:7]=5)[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1N
Reactant: Oc1cc(O)c(O)cc1O
Product: c1ccc2[nH]c3cc4[nH]c5ccccc5[nH]c4cc3[nH]c2c1

Procedure:
Alternatively, the at least one 1,2-diaminobenzene compound and the 1,2,4,5-tetrahydroxybenzene compound are dissolved in a solvent to form a solution, and the solution is heated to form the 5,7,12,14-tetrahydro-5,7,12,14-tetraazapentacene compound. The solution can be heated at a temperature of from about 80° C. to about 180° C., and the solution can be heated for a time period of from about 30 minutes to about 12 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]SC1SCC(=O)N=1.[OH:24][C:25]1[C:34]2[C:29](=[N:30][C:31]([CH3:35])=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[C:36]([OH:38])=[O:37].[OH-].[Na+:40]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[C:25](=[O:24])[C:26]([C:36]([O-:38])=[O:37])=[CH:27]1.[Na+:40]
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Reactant: Cc1ccc2c(O)c(C(=O)O)cnc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCCCCn2cc(C(=O)[O-])c(=O)c3ccc(C)nc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir overnight at room temperature 1 gm. of the iodide prepared in Examples 2 or 3, 10 ml. DMF, 834 mg. 4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylic acid and 326 mg. sodium hydroxide in a reaction flask. Wash with water in methylene chloride. Elute on a coarse silica column with methylene chloride then 3% methanol/methylene chloride to isolate the title compound as the carboxylic acid.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.Cl[C:23]1[N:28]=[C:27]([NH:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[N:25][CH:24]=1>C1COCC1>[CH:30]([NH:29][C:27]1[CH:26]=[N:25][CH:24]=[C:23]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[N:28]=1)([CH3:32])[CH3:31]
Reactant: CC(C)Nc1cncc(Cl)n1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cncc(NC(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
To a solution of tributyl tin hydride (8.5 mL, 29.23 mmol, Aldrich) in THF (50 mL) was added LDA (2.0 M) (THF/heptane/ethyl benzene) (18.3 mL, 29.23 mmol, Aldrich) at 0° C. and the mixture was stirred for 10 min at RT. To the mixture at 0-5° C. was added 6-chloro-N-isopropylpyrazin-2-amine (2.5 g, 14.61 mmol) and the mixture was stirred for an additional 3 h at RT. The reaction was quenched with 10% aq KF (25 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was further purified with basic alumina column chromatography (eluent: 10% EtOAc in petroleum ether) to give N-isopropyl-6-(tributylstannyl)pyrazin-2-amine (2 g, 26.5%) as a colorless liquid. MS (ESI, pos. ion) m/z: 428.2 (M+1); 1H-NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 7.64 (s, 1H), 4.28-4.23 (m, 1H), 4.09-3.98 (m, 1H), 1.63-1.54 (m, 7H), 1.39-1.23 (m, 14H), 1.12-1.08 (m, 6H), 0.91-0.88 (q, 6H).
Reaction SMILES: [C:1]([O:5]O)([CH3:4])(C)C.[C:7]([O:30][CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]([CH3:40])([CH3:39])[CH2:32]1)(=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)=[O:17]>[Mo](=O)(=O)=O.CCCCCCCC>[C:7]([O:30][CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([O:5][CH2:1][CH2:4][CH2:27][CH2:21][CH2:20][CH2:19][CH2:24][CH3:23])[C:33]([CH3:40])([CH3:39])[CH2:32]1)(=[O:29])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]1[CH2:24][C:23]([CH3:25])([CH3:26])[N:22]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9])[C:21]([CH3:27])([CH3:28])[CH2:20]1)=[O:17]
Reactant: CC(C)(C)OO
Reactant: CC1(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: O=[Mo](=O)=O
Solvent: CCCCCCCC
Product: CCCCCCCCON1C(C)(C)CC(OC(=O)CCCCCCCCC(=O)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 160.5 %

Procedure:
70% Aqueous tert-butyl hydroperoxide (140 g, 1.09 mol) is added over a 6-hour period to a mixture of 75.4 g (0.157 mol) of bis(2,2,6,6-tetramethylpiperidin-4-yl) sebacate, 1.25 g (8.7 mmol) of molybdenum trioxide and 570 ml of n-octane, that is first heated to 115° C., under a nitrogen atmosphere. During the addition, the reaction mixture is maintained at reflux. Water is collected in a Dean-Stark trap. Upon completion of the addition, the red reaction mixture is heated at reflux (95°-97° C.) for seven hours to discharge the red color. The molybdenum trioxide is removed by filtration. The yellow filtrate is stirred at ambient temperature for 30 minutes with 15 g of activated charcoal (DARCO) to remove some of the yellow color before being concentrated under reduced pressure. The crude product is purified by flash chromatography on silica gel (100:3 heptane:ethyl acetate) to afford 92.9 g (80% yield) of the title compound as a colorless oil.
Reaction SMILES: ClCCCl.[N:5]([C:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[N:16][C:15]([Br:33])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[N+]=[N-]>C(Cl)Cl.CO.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[Br:33][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[NH:5][C:19]3[CH:20]=[C:21]([S:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)(=[O:26])=[O:25])[CH:22]=[CH:23][C:18]=3[C:17]=2[N:16]=1
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(S(=O)(=O)N3CCOCC3)cc2)c1N=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCCl
Solvent: CCCCCCCC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(S(=O)(=O)N3CCOCC3)ccc12
Temperature: 80 °C
Yield: 72.1 %

Procedure:
1,2-Dichloroethane (1.3 mL) was added to a mixture of methyl 3-azido-6-bromo-2-(4-(morpholinosulfonyl)phenyl)isonicotinate (918 mg, 1.90 mmol), rhodium octanoate dimer (74. mg, 0.095 mmol) and crushed 4A° molecular sieves (2.2 gm) and the reaction was heated at 80° C. overnight. It was then diluted with a mixture of DCM:MeOH (3:1) and filtered. The collected solid was washed with hot THF to extract any remaining product. The solvent was removed from the combined filtrates and the residue was suspended in MeOH. Filtration gave methyl 2-bromo-7-(morpholinosulfonyl)-5H-pyrido[3,2-b]indole-4-carboxylate (621 mg, 1.37 mmol, 72% yield) as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.15 (1H, s), 8.47 (1H, d, J=8.24 Hz), 8.19 (1H, s), 8.04 (1H, s), 7.65 (1H, dd, J=8.24, 1.53 Hz), 3.63-3.72 (4H, m), 2.87-3.02 (5H, m).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]1[CH:19]=[N:20][NH:21][CH:22]=1)=[CH:13][CH:12]=2.[CH:23]12[O:28][CH:27]1[CH2:26][CH2:25][CH2:24]2>CN(C=O)C>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]1[CH:22]=[N:21][N:20]([CH:26]3[CH2:25][CH2:24][CH2:23][CH:27]3[OH:28])[CH:19]=1)=[CH:13][CH:12]=2
Reactant: C1CC2OC2C1
Reactant: Clc1cc2cc(-c3cn[nH]c3)ccc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC1CCCC1n1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A mixture of Cs2CO3 (45.4 mg, 0.139 mmol), 3-chloro-6-(1H-pyrazol-4-yl)isoquinoline (16 mg, 0.070 mmol) and 6-oxabicyclo[3.1.0]hexane (Preparation 37, 23.4 mg, 0.279 mmol) in DMF (3 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction was cooled, concentrated in vacuo and purified using Biotage silica gel column chromatography eluting with 50-75% EtOAc/cyclohexane to give the title compound as white solid (11 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[CH:22][C:21]=2[C:34]#[N:35])[N:15]=[CH:14]3)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][C:21]=2[C:34]#[N:35])[N:15]=[CH:14]3)=[O:10])=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(-n2ncc3cc(C(=O)NCCc4ccc(Cl)cc4)ccc32)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(CC(=O)O)ccc1-n1ncc2cc(C(=O)NCCc3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 794 %

Procedure:
To a fitted solution of tert-butyl 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indazol-1-yl)-3-cyanophenyl)acetate (43.4 mg, 0.084 mmol) in DCM (2 mL) was added TFA (250 μL). The reaction was stirred at ambient temperature for 4 hours and then concentrated. The crude product was purified over silica gel on a Biotage Horizon high-performance FLASH chromatography system (12+M silica gel cartridge) eluting with a gradient of 0.5% MeOH/DCM containing 0.5% AcOH to 5% MeOH/DCM containing 0.5% AcOH to give 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indazol-1yl)-3-cyanophenyl)acetic acid (0.038 g, 0.667 mmol, 79%). 1H NMR (400 MHz, CDOD3) δ 8.68 (t, J=5.5 Hz, NH), 8.62 (s, 1H), 8.43 (s, 1H), 8.03 (s, 1H), 7.97 (d J=8.6 Hz, 1H), 7.84 (s, 2H), 7.65 (d, J=8.3 Hz, 1H), 7.35 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 3.82 (s, 2H), 3.53 (q. J=6.5 Hz, 2H), 2.88 (t, J=7.3 Hz, 2H). MS(APCI)=459.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[O:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])[CH:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10]CC1C=CC(OC)=CC=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[C:9](=[O:10])[NH:8][CH:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[O:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:38])([F:39])[F:37])[CH:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)no3)c(F)c2)cnc1OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)no3)c(F)c2)c[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
A mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (100 mg, 0.170 mmol) and TFA (10% in DCM, 100 mL) was stirred at 25° C. for 2 h. The mixture was then concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acid condition) to give a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (28.35 mg, 0.060 mmol, 36% yield): 1H NMR (400 MHz, CD3OD) δ 7.45-7.30 (m, 4H), 7.25 (d, J=1.6 Hz, 1H), 6.36 (s, 1H), 4.12 (q, J=6.8 Hz, 2H), 3.82 (s, 2H), 1.52 (s, 6H), 1.46 (t, J=6.8 Hz, 3H); ES-LCMS m/z 468 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CCN(CC)CC.[C:23]1([CH3:35])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[CH:4]1[C:3]2[C:8](=[N:9][C:10]3[C:15]([C:2]=2[NH:1][S:31]([C:24]2[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=2[CH3:35])(=[O:33])=[O:32])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Nc1c2ccccc2nc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(S(=O)(=O)Nc2c3ccccc3nc3ccccc23)c(C)c1
Yield: 5.9 %

Procedure:
To a suspension of 4.00 g (20.6 mmol) of 9-aminoacridine 40 in 350 mL of CHCl3 was added 2.9 mL (20.8 mmol) of Et3N and 4.50 g (20.6 mmmol) of mesitylenesulfonyl chloride. The reaction mixture was refluxed for 72 hr. Then the reaction mixture was filtered and the solvent was evaporated. The material was purified by column chromatography on silica gel by eluting first with 1% MeOH in CH2Cl2 and then with 5% MeOH in CH2Cl2 to yield 458.4 mg (6%) of sulfonamide 41 as an orange solid: 1H NMR (300 MHz, CDCl3, TMS) δ9.25 (s, 1H), 8.77 (d, J=8 Hz, 2H), 7.46 (t, J=8 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 7.15 (t, J=8 Hz, 2H), 7.02 (s, 2H), 2.78 (s, 6H), 2.36 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][OH:12])[C:4]=2[N:3]=1>[O-2].[Mn+4].[O-2].C(OCC)(=O)C>[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:4]=2[N:3]=1
Reactant: Cc1nc2c(CO)cccc2[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: Cc1nc2c(C=O)cccc2[nH]1
Temperature: 25 °C
Reaction time: 19 h
Yield: 35.2 %

Procedure:
(a-3) A mixture of 10 parts of 2-methyl-1H-benzimidazole-4-methanol, 10 parts of manganese(IV) oxide and 180 parts of ethyl acetate was stirred for 19 hours at room temperature. The reaction mixture was filtered over diatomaceous earth and washed with a mixture of ethyl acetate and methanol (80:20 by volume). The filtrate was evaporated and the residue was crystallized from 2-butanone. The product was filtered off and dried, yielding 3.5 parts (35.2%) of 2-methyl-1H-benzimidazole-4-carboxaldehyde (int. 67).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:12]1[O:20][CH:15](OC(=O)C)[C@H:14]([O:21][C:22](=[O:24])[CH3:23])[C@@H:13]1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:41]1[CH:49]=[C:47]([CH3:48])[C:45](=[O:46])[NH:44][C:42]1=[O:43].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[C:22]([O:21][C@@H:14]1[C@H:13]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:12]([C@@H:11]([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:20][C@H:15]1[N:41]1[CH:49]=[C:47]([CH3:48])[C:45](=[O:46])[NH:44][C:42]1=[O:43])(=[O:24])[CH3:23]
Reactant: CC(=O)OC1O[C@H]([C@@H](COC(=O)c2ccccc2)OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](OCc2ccccc2)[C@@H]([C@@H](COC(=O)c2ccccc2)OCc2ccccc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of the anomeric mixture 14 (4.50 g, 8.21 mmol) and thymine (1.55 g, 12.31 mmol) in anhydrous acetonitrile (50 cm3) was added N,O-bis(trimethylsilyl)-acetamide (12.2 cm3, 49.3 mmol). The reaction mixture was stirred at 60° C. for 1 h and then cooled to 0° C. Trimethylsilyl triflate (2.97 cm3, 16.4 mmol) was added dropwise during 10 min and the mixture was heated for 2 h under reflux. The reaction mixture was allowed to cool to room temperature and the volume was reduced by 50% under reduced pressure. After cooling to 0° C., a saturated aqueous solution of sodium hydrogen carbonate (100 cm3) was added and extraction was performed with dichloromethane (2×50 cm3). The combined organic phase was washed with brine (50 cm3), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99.5:0.5, v/v) as eluent to give nucleoside 15 as white solid material (4.06 g, 81%) after evaporation of the solvents under reduced pressure.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:14][C:15]([O:17]C)=O)[NH:9][C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].P([O-])([O-])([O-])=O>CO>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:14][C:15](=[O:17])[N:12]([CH3:13])[C:10](=[O:11])[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)NN(CC(=O)OC)c1cccc(I)c1
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)CN(c2cccc(I)c2)NC1=O
Reaction time: 1.5 h
Yield: 32.9 %

Procedure:
Methyl [1-(3-iodophenyl)-2-[(methylamino)carbonyl]hydrazino]acetate (2.0 g) was dissolved in methanol (60 ml) and sodium methoxide (0.64 g) was added. The solution was stirred under nitrogen for 1.5 h, added to pH 6.5 phosphate buffer solution (150 ml) and extracted with dichloromethane (100 ml). The organic phase was washed with water (100 ml) and brine (100 ml), dried and evaporated to give the title compound as a solid (0.6 g), m.p. 180°.