Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17](=[O:34])[CH:18](Br)[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][CH3:32].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([O:16][CH3:15])=[O:34])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cccc(O)c1
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCCCCCCCCCCCCOc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
3-Hydroxy-benzoic acid tert-butyl ester (1.79 g) was dissolved in MeCN 75 ml, then bromo-hexadecanoic acid methyl ester (3.22 g) was added followed by K2CO3 (2.5 g). The reaction was stirred for 3 d at 80° C. The reaction mixture was filtered. The filtrate was evaporated, and the residue was dissolved in EtOAc 100 ml, and the EtOAc layer was washed twice with 100 ml brine. The organic layer was dried over MgSO4 filtered and the solvent was removed by evaporation to give 4.165 g (98%).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:37])[N:13]2[C:16](=[C:33]([OH:36])[CH2:34]Cl)[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[OH:40]>O1CCCC1>[O:1]([CH2:8][C:9]([NH:10][CH:11]1[C:12](=[O:37])[N:13]2[C:16]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:33]([OH:36])[CH2:34][S:15][C@H:14]12)=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(=C(O)CCl)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: CO
Agent: Cl
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice cooled solution of diphenylmethyl α-[3-phenoxymethyl-7-oxo-2,6-diaza-4-thiabicyclo[3,2,0]hept-2-en-6-yl]-α-(2-chloro-1-hydroxyethylidene)acetate (36 mg) in a mixture of methanol and tetrahydrofuran (1:1) (1.1 ml) is added 1N-hydrochloric acid (0.39 ml), warmed to the room temperature, and the mixture is stirred for 1.5 hours. The reaction mixture is poured into ice water, and is extracted with methylene chloride. The extract solution is washed with 5% aqueous sodium hydrogen carbonate solution and water, dried over sodium sulfate, and evaporated. Purification of the obtained residue by thin-layer chromatography using a mixture of benzene and ethyl acetate (3:2) give diphenylmethyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate (6 mg). m.p. 125°-126° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:17][C:18]1[C:26]2[N:25]=[C:24](Cl)[NH:23][C:22]=2[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1>>[Br:17][C:18]1[C:26]2[N:25]=[C:24]([N:12]3[CH2:11][CH2:10][N:9]([C:4]4[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:14][CH2:13]3)[NH:23][C:22]=2[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Product: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The reaction of 1-(3-trifluoromethylpyridin-2-yl)piperazine (128 mg, 0.5 mmol, Fluorochem) and 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (210 mg, 0.7 mmol, Example 6b) under the conditions of Example 3c afforded the title compound as a white solid. M.p. 196° C. MS (ESI, pos. ion) m/z: 494 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:30])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][C:21]3[N:22]([CH2:26][CH3:27])[CH:23]=[CH:24][N:25]=3)=[C:14]([O:28][CH3:29])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:30])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][C:21]3[N:22]([CH2:26][CH3:27])[CH:23]=[CH:24][N:25]=3)=[C:14]([O:28][CH3:29])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CCn1ccnc1CCOc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC
Agent: [Pd]
Solvent: CO
Product: CCn1ccnc1CCOc1ccc(CCC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
Using 0.2 g of N-(trans-4-methylcyclohexyl)-4-{2-[1-(2-ethyl)imidazoly]ethoxy}-3-methoxycinnamamide (Example 162), 0.01 g of 10% palladium-carbon, and 25 ml of methanol, a reaction similar to that conducted in Example 147 was performed. As a result, 0.14 g of N-(trans-4-methylcyclohexyl)-3-{4-{2-[1-(2-ethyl)imidazolyl]ethoxy}-3-methoxyphenyl}propionamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [C:1]([CH:5]([OH:35])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[C:14]([C:15]([N:17]=[CH:18][N:19]=3)=[NH:16])=[N:13][C:12]2=[SiH2:21])[C@H:8]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@@H:7]1[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:4])([CH3:3])[CH3:2].[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([CH:5]([OH:35])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[C:14]([C:15]([N:17]=[CH:18][N:19]=3)=[N:16][C:36](=[O:43])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:13][C:12]2=[SiH2:21])[C@H:8]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C@@H:7]1[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](n2c(=[SiH2])nc3c2=NC=NC3=N)O[C@@H]1C(O)C(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)O[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](n2c(=[SiH2])nc3c2=NC=NC3=NC(=O)c2ccccc2)O[C@@H]1C(O)C(C)(C)C

Procedure:
introducing an acyl group at the N6 position of the product from step (2) with an acylating agent, for example, using benzoyl chloride under conditions suitable for obtaining 5′,3′-O-di-tert-butylsilanediyl-2′-O-tert-butyldimethylsilyl-N6-benzoyl adenosine,
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][NH:7][C:8]([N:10]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[C:26]([F:29])([F:28])[F:27])=[N:11]1)=[O:9]>C(O)(=O)C>[CH3:6][NH:7][C:8]([N:10]1[C:14]([CH3:15])=[C:13]([Cl:4])[C:12]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[C:26]([F:29])([F:28])[F:27])=[N:11]1)=[O:9]
Reactant: O=S(=O)(Cl)Cl
Reactant: CNC(=O)n1nc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)cc1C
Solvent: CC(=O)O
Product: CNC(=O)n1nc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c(Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
Sulfuryl chloride (0.16 g, 1.2 mmol) was added to a solution of N-methyl-5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.34 g, 1.0 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methyl-4-chloro-5-methyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.27 g, yield: 71.2%). mp: 157-158° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.66 (s, 3H), 2.96 (d, J=5.0 Hz, 3H), 6.70-6.95 (m, 1H), 7.31 (d, J=9.2 Hz, 1H), 8.41 (dd, J=2.7 and 9.2 Hz, 1H), 8.62 (d, J=2.7 Hz, 1H).
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[S:26])=[CH:23][CH:22]=1>C(O)C>[CH2:12]([O:11][C:9]([N:4]1[CH2:5][CH2:6][C:7]2[N:27]=[C:25]([C:24]3[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[S:26][C:2]=2[CH2:3]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1Br
Reactant: COc1ccc(C(N)=S)cc1
Solvent: CCO
Product: COc1ccc(-c2nc3c(s2)CN(C(=O)OCc2ccccc2)CC3)cc1
Yield: 49 %

Procedure:
Compound 502 (2.0 g, 6.5 mmol) was dissolved in ethanol (20 ml). To the solution was added 4-methoxythiobenzamide (503, 1.09 g, 6.5 mmol, 1 eq) and the yellow mixture was refluxed for 17 hrs after which time TLC analysis showed full conversion of 502. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc, washed with 5% Na2SO4 and the organic layer was dried (MgSO4) and subsequently concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography (diethyl ether, Rf 0.3) giving compound 504 in a yield of 49% as a colorless oil. Compounds having a Rb substitute can be prepared by choosing a properly substituted (Rb)-4-methoxythiobenzamide (503).
Reaction SMILES: O[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:4]#[N:5].CS(Cl)(=O)=O.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:26]1([CH:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:2][CH2:3][C:4]#[N:5])[CH:30]=[CH:29][N:28]=[CH:27]1
Reactant: CCCCCCCCCCCCCCCC(O)CC#N
Reactant: c1c[nH]cn1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCCCC(CCCCCCCCCCCC#N)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
To a stirred solution of β-hydroxyoctadecanenitrile (4.5 g, 15.99 mmol), TEA (2.9 ml, 20.78 mmol) and DMAP (0.19 g, 1.59 mmol) in dry DCM (70 ml) cooled to 0° C., was added methanesulfonyl chloride (1.3 ml, 16.78 mmol) under N2. After allowing the reaction mixture to warm to room temperature, stirring was continued for another 2 hours. The reaction mixture was diluted with DCM (100 ml), the organic layer was washed with 1N HCl, water and brine solution, dried over MgSO4 and concentrated under reduced pressure. This crude compound was mixed with imidazole (2.18 g, 31.97 mmol) and heated at 70° C. for 16 hours under N2. The crude product was purified by silica gel column (2% MeOH in DCM) to give 13-(1H-imidazol-1-yl)octadecanenitrile as a light yellow liquid (1.64 g, 32%).
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[ClH:17]>C(O)C.[Pd]>[ClH:17].[O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][NH2:11]
Reactant: N#Cc1ccccc1N1CCCCS1(=O)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccccc1N1CCCCS1(=O)=O
Reaction time: 24 h
Yield: 95 %

Procedure:
Intermediate 100, 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)benzonitrile, (2.63 g, 11.14 mmol) was dissolved in ethanol (150 mL) and 1N HCl (13 mL). Added to this was 10% Pd—C (0.5 g) and the mixture shaken under H2 at 55 psi for 24 h. Filtration through Celite followed by concentration gave the title compound as a white solid (2.93 g, 95% yield). 1H-NMR (300 MHz, CD3OD) δ ppm: 7.61–7.47 (4H, m), 4.30 (2H, q, J=13.7 Hz), 3.96–3.87 (1H, m), 3.49–3.36 (3H, m), 2.40–2.31 (2H, m), 2.05–1.96 (2H, m). LCMS [M+H]+ calcd for C11H17N2SO2: 241.10. found: 241.10.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[N:14]=[C:15]=[O:16]>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:15]([NH:14][C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:16]
Reactant: CN1CC(=O)N=C1N
Reactant: O=C=Nc1cccs1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CC(=O)NC1=NC(=O)Nc1cccs1
Temperature: 55 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To 9.4 g (83 mM) of creatinine in 100 ml of anhydrous DMF was added with stirring of solution of 9.2 g (75 mM) 2-thienyl isocyanate in 60 ml of toluene. After the addition was completed, the mixture was stirred at 55° C. for 1 hr., cooled, and the solvents removed in vacuo. The residue was recrystallized first from ethanol and then ethyl acetate (treated with charcoal) to give 5.3 g of the above urea as an off-white solid, m.p. 191°-192° C. (dec.).
Reaction SMILES: Cl.[C:2]1([O-:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[K+]>>[C:2]1([OH:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: [O-]c1cccc2ccccc12
Agent: Cl
Agent: [K+]
Product: Oc1cccc2ccccc12

Procedure:
An alcoholic solution of potassium α-naphtholate produced as in Example 4 hereinabove is acidified with gaseous hydrochloric acid taken in the equimolar amount relative to potassium α-naphtholate at a temperature ranging from 20° to 30° C. After separation of precipitated pure potassium chloride, the solution of α-naphthol in ethanol is separated following the procedure described in the foregoing Example 4 to give 116 g of α-naphthol with a purity of 97.5%. The total yield of α-naphthol is 140 g (98% of theory) as calculated for the employed naphthalene.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:25])[CH2:23][CH3:24])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:25])[CH2:23][CH3:24])=[O:19]
Reactant: CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 16 h
Yield: 105.2 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-7-oxo-N′-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 203 (0.31 g, 0.89 mmol) and Pd/C (0.12 g) in methanol (20 mL) was hydrogenated at 1 atm at room temperature for 16 h. The mixture was filtered through Celite and concentrated to provide 204 (0.24 g, quant. yield) as a white foam.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5]1.Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22].Cl>C1COCC1>[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]3)=[O:22])[C:7]=2[CH2:6][CH2:5]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC1CCN(C(=O)CCl)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCC(C)CC2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium hydride (46 mg, 1.16 mmol) in THF (5 ml), 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.1 g, 0.46 mmol) was added at 0° C. and stirred at RT for 30 min. 2-Chloro-1-(4-methylpiperidin-1-yl)ethanone (98 mg, 0.55 mmol) was added slowly dropwise at RT and stirred for 2 h at RT. After completion of the reaction (monitored by TLC & LCMS), the reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to afford free base, which was converted to HCl salt using ethanolic HCl. 1H NMR (DMSO-d6, HCl salt) δ (ppm): 11.22 (bs, 1H), 7.20 (m, 2H), 5.0-5.20 (m, 2H), 4.23 (d, 1H), 4.0 (d, 1H), 3.5-3.6 (m, 2H), 3.0-3.23 (m, 4H), 2.8-2.95 (m, 2H), 2.26-2.42 (m, 2H), 1.5-1.8 (m, 3H), 1.09-1.2 (m, 1H), 0.96 (d, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:45])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27]([C:28]5[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=5[O:35][CH3:36])=[N:26][N:25](COCC[Si](C)(C)C)[C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1.[OH-].[Na+]>Cl(O)(=O)(=O)=O.CO>[CH3:1][N:2]([CH3:45])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]4[C:27]([C:28]5[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=5[O:35][CH3:36])=[N:26][NH:25][C:22]4=[N:23][CH:24]=3)[CH:14]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: COc1ccc(F)cc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1-c1n[nH]c2ncc(-c3cccc(C(=O)N4CCN(CCN(C)C)CC4)c3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
A solution of (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-(5-fluoro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone from Step 5 in 5% of perchloric acid in methanol (1 mL) was stirred for 45 minutes at room temperature. Sodium hydroxide solution (2M) was then added to the solution slowly until pH ˜8. Ethyl acetate was then used for extraction and the organic layers were combined and concentrated to dryness, which was then redissolved in methanol (1 mL) and sodium carbonate (2M, 1 mL). The mixture was stirred at room temperature for 15 hours before being diluted with water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Mass triggered reverse phase HPLC purification afforded (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-(5-fluoro-2-methoxyphenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (25.6 mg, 64% yield from 12) as white solids. 1H NMR (500 MHz, CD3OD) δ 2.42 (s, 6H), 2.49 (br, 2H), 2.59 (m, 4H), 2.69 (m, 2H), 3.54 (br, 2H), 3.81 (br, 2H), 3.85 (s, 3H), 7.17 (m, 2H), 7.40 (dd, J=3.0, 9.5 Hz, 1H), 7.44 (d, br, J=7.5 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.72 (br, 1H), 7.77 (d, J=8.5 Hz, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.80 (d, J=2.5 Hz, 1H). MS: m/z 503.2 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][OH:19])[C:13]=1[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[Br:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH:18]=[O:19])[C:13]=1[CH3:20]
Reactant: Cc1c(Br)ccnc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(Br)ccnc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a stirred and cooled (−78° C.) solution of oxalyl chloride (2.82 mL, 33.37 mmol) in DCM (70 mL) under nitrogen was added dropwise a solution of dimethyl sulfoxide (5.17 mL, 72.81 mmol) in DCM (10 mL). Stirring was continued for 10 minutes. A solution of (4-bromo-3-methyl-2-pyridyl)methanol (which may be prepared as described in Description 6) (6130 mg, 30.34 mmol) in DCM (35 mL) was then added dropwise over 20 minutes. The reaction was then allowed to stir for 1 hour. Triethylamine (18.98 mL, 136.53 mmol) was then added dropwise and the reaction was allowed to warm to room temperature over 1.5 hours. The reaction was then quenched by addition of water (approximately 100 mL). The organics were separated and washed with additional water (150 mL). The organics were dried using a hydrophobic frit and concentrated in vacuo to give 4-bromo-3-methyl-pyridine-2-carbaldehyde (D7) (5.709 g, 28.541 mmol, 94.1% yield) as a brown oil which crystallised on standing.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:13]([O-])([OH:15])=[O:14]>CC(O)=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(OC(C)=O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1ccc(OC(C)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 270 g. (1.62 m.) of p-methoxyphenyl acetate (part A) and 772 ml. of HOAc was added dropwise 77.5 ml. of fuming HNO3 maintaining a temperature of 5° to 10°C. Stirring was continued for 60 minutes at 5° to 10°C following the addition, then the solution was poured into 6 liters of ice. The orange semi-solid was collected by filtration and washed with cold water. The crude product was recrystallized from 1000 ml. of ethanol to give 61 g., m.p. 93°-97°C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[CH:8]=1)=O>O=P(Cl)(Cl)Cl>[C:2]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:7]=2[CH:8]=1)#[N:1]
Reactant: NC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2cc([N+](=O)[O-])ccc2o1
Temperature: 0 °C

Procedure:
A heterogeneous solution of 2-aminocarbonyl-5-nitrobenzofuran (0.206 g, 1 mmol) in POCl3 (5 mL) was heated at 100° C. for 24 to give a clear solution. The resulting clear solution was carefully poured over ice-water to give a solid mass which was isolated by filtration followed by washing with water to give 2-cyano-5-nitrobenzofuran. 1H NMR (DMSO-d6): δ 8.80 (d, 1H; J=2.4 Hz), 8.42 (dd, 1H, J=2.7 and 9.0 Hz), 8.27 (s, 1H), 7.99 (d, 1H, J=8.7 Hz); LCMS: purity: 98%, MS (m/e): 189 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:9]2=[N:8][C:7]=1[C:26]([F:29])([F:28])[F:27])=O)C.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.CO>C(Cl)Cl>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[N:17]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]2[C:6]([CH2:4][OH:3])=[C:7]([C:26]([F:29])([F:28])[F:27])[N:8]=[C:9]12
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2n(-c3ccc(Cl)cc3Cl)c3ccccc3n12
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: OCc1c(C(F)(F)F)nc2n(-c3ccc(Cl)cc3Cl)c3ccccc3n12
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a solution of 8-(2,4-Dichloro-phenyl)-2-trifluoromethyl-8H-1,3a,8-triaza-cyclopenta[α]indene-3-carboxylic acid ethyl ester (490 mg, 1.11 mmol) in methylene chloride (20 mL), was added at 0° C. a toluene solution of DIBAL-H (5.55 mL, 5.55 mmol). After stirring at 0° C. for 75 min, the reaction mixture was cooled down to −78° C. and methanol (2.2 mL) was added dropwise, followed by additions of ground Na2SO4-10H2O (15.2 g) and celite (2.6 mL). The resulting mixture was warmed up to room temperature in 4 h. After filtration, the solvents were removed in vacuo to afford the title compound as an off white solid (443 mg, 100% yield). 1H NMR (CDCl3, 500 MHz) δ 8.00–7.93 (m, 1H), 7.65 (d, J=2.2 Hz, 1H0, 7.57 (d, J=7.4 Hz, 1H), 7.46 (dd, J=8.6, 2.3 Hz, 1H), 7.37–7.33 (m, 2H), 7.08–7.05 (m, 1H); Mass spec.: 400.02 (MH+).