Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(O)(O)=O>CC#N.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>[Cl:14][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([F:27])([F:26])[F:15])=[N:3]2
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=Cc1cc2c(Cl)cccc2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)O
Solvent: O
Solvent: CC#N
Product: O=Cc1cc2c(Cl)cccc2nc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2,5-dichloroquinoline-3-carbaldehyde (1.9948 g, 8.8243 mmol), 2-(trifluoromethyl)phenylboronic acid (1.8436 g, 9.7067 mmol), tetrakis(triphenylphosphine)palladium (0.50985 g, 0.44121 mmol), and sodium carbonate anhydrous (4.6763 g, 44.121 mmol) in 88 mL of CH3CN—H2O (3:1) was stirred at 100° C. After 5 hr, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×2), dried over MgSO4, filtered, and concentrated under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 30 min as eluent to give 5-chloro-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.01 (1 H, s), 9.19 (1H, d, J=1.0 Hz), 8.08-8.14 (1 H, m), 7.97-8.03 (2 H, m), 7.89-7.95 (1 H, m), 7.73-7.84 (2 H, m), 7.55-7.61 (1 H, m); LC-MS (ESI) m/z 336.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:23][CH:24]([O:29][Si](C(C)(C)C)(C)C)[C:25]([F:28])([F:27])[F:26])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([OH:50])=[CH:46][C:45]=1[CH2:51][CH3:52].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1>CC(N(C)C)=O.C1(C)C=CC=CC=1>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][C:2]2[CH:3]=[C:4]([N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:22])([F:21])[CH:18]([F:19])[F:20])[CH:11]=3)[CH2:23][CH:24]([OH:29])[C:25]([F:27])([F:26])[F:28])[CH:5]=[CH:6][CH:7]=2)=[CH:46][C:45]=1[CH2:51][CH3:52]
Reactant: CC(C)(C)[Si](C)(C)OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Br)c1)C(F)(F)F
Reactant: CCc1cc(O)ccc1Cl
Agent: O=C(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CCc1cc(Oc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)ccc1Cl
Yield: 23.1 %

Procedure:
A solution of N-(3-bromophenyl)-N-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3,3,3-trifluoropropyl]-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine (75 mg, 0.124 mmol), cesium carbonate (81 mg, 0.248mmol), 4-chloro-3-ethylphenol (44 mg, 0.358 mmol), copper triflate benzene complex (6.24 mg, 10 mol %), 1-naphthoic acid (43 mg, 0.248 mmol) in 2:1 toluene:dimethylacetamide (3.0 mL) was heated at 105° C. for 96 hours. The reaction mixture was filtered through celite, and the solvent was evaporated. The residue was purified by reverse phase chromatography eluting with 50-90% acetonitrile in water to afford 16.2 mg (23%) of the desired 3-[[3-(4-chloro-3-ethylphenoxy)phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl] methyl]amino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd. for C26H23ClF7NO3: 566.1332 [M+H]+, found: 566.1332. 1H NMR (CDCl3) δ1.18 (t, 3H), 2.69 (q, 2H), 3.50-3.61 (m, 1H), 3.87 (dd, 1H), 4.284.39 (m, 1H), 4.63 (s, 2H), 5.88 (tt, 1H), 6.32-6.40 (m, 2H), 6.48 (dd, 1H), 6.69 (dd, 1H), 6.87 (d, 1H), 7.0-7.34 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19](=O)[C:20]([F:23])([F:22])[F:21])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:25][NH2:26].O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[N:25][NH:26][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CSc1ccc(C(=O)C(C(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CSc1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 89 %

Procedure:
Crude 2-(4-fluorophenyl)-1-[4-(methylthio)phenyl]-4,4,4-trifluoro-1,3-butanedione (Example 3, Step 2) (1.0 g) was reacted with anhydrous hydrazine (0.13 g) in glacial acetic acid. The mixture was held at 80°-110° C. for 18 hours and poured into water. The resulting solid precipitate was filtered, purified by HPLC and recrystallized from methylene chloride-hexane to give 4-(4-fluorophenyl)-3-[4-(methylthio)phenyl]-5-(trifluoromethyl)-1H-pyrazole as a solid (0.88 g, 89%): mp 189°-190° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:13]C([N-]C(C)C)C.CI>O1CCCC1>[CH3:13][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCOCC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCOCC1
Reaction time: 3 h
Yield: 91.8 %

Procedure:
Into a 500-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl tetrahydro-2H-pyran-4-carboxylate (8 g, 50.6 mmol) in tetrahydrofuran (100 mL). This was followed by the addition of LDA (50 mL, 101.1 mmol, 2M in THF) dropwise at −78° C. and stirred for 3 h. To this was added a solution of CH3I (9.5 mL, 151.9 mmol) in tetrahydrofuran (50 mL) dropwise at −78° C. The reaction mixture was stirred for 3 h at −78° C., then carefully quenched with 400 mL of NH4Cl (sat.). The aqueous phase was extracted with 300 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 8 g (92%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1[F:25])=[CH:5]/[O:6][CH3:7].[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:26])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:25])=[CH:5]/[O:6][CH3:7]
Reactant: [H][H]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1ccc(N)cc1F
Reaction time: 18 h
Yield: 93.9 %

Procedure:
1.0 g (2.7 mmol) of the compound obtained in Step 1 was dissolved in a mixture of 5 ml of methanol and 5 ml of ethyl acetate, and 200 mg of 10% palladium/carbon was added thereto. The resulting mixture was placed in a hydrogenation reactor, and hydrogen gas was introduced therein with stirring the mixture for 18 hours. The reaction mixture was filtered through Cellite, and concentrated under a reduced pressure. The residue was subjected to column chromatography using 40% ethyl acetate/hexane as an eluent to obtain 0.84 g (yield 92%) of (E)-methyl-2-[2-((2-fluoro-4-aminophenoxy)methyl)phenyl]-3-methoxyacrylate.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](O)=[O:29])=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C[O:33][C:34](=[O:37])[CH2:35][NH2:36].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](=[O:29])[NH:36][CH2:35][C:34]([OH:33])=[O:37])=[CH:23][C:22]=3[F:31])[CH2:19][CH2:20]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)CN
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)O)cc3F)CC2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)NCC(=O)O)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-1 (32 mg, 0.073 mmol), amino-acetic acid methyl ester (0.11 mmol) and HOBT (15 mg, 0.11 mmol) were combined in DCM (1 mL) and stirred at room temperature for 10 minutes. EDC(19 mg, 0.1 mmol) was added and the mixture was stirred for 18 h. The solution was washed with 2 mL of aqueous NaHCO3, concentrated and taken up with 0.5 mL of dioxane. 0.5 mL of 1N NaOH was added and the mixture was stirred at 60° C. for 1 h. It was then cooled to room temperature, acidified with 0.5 mL of 2N HCl and extracted with ethyl acetate (1.5 mL). The organic layer was concentrated under a stream of nitrogen and purified on preparative HPLC to give 30-1: LC-MS 497.4 (MH).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[N:6]=[CH:5][N:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([CH2:29][C@H:30]([OH:35])[C:31]([F:34])([F:33])[F:32])[C:25](=[O:28])[NH:26][N:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]([CH2:29][C@H:30]([OH:35])[C:31]([F:33])([F:34])[F:32])[C:25](=[O:28])[N:26]([CH2:2][C:3]3[CH:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[Cl:15])[N:6]=[CH:5][N:4]=3)[N:27]=2)=[CH:19][CH:18]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-c1cc(CBr)ncn1
Product: O=c1n(Cc2cc(-c3ccccc3Cl)ncn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
Analogously to the preparation of the compound in Example 94, 27 mg (0.10 mmol) of the compound from Example 83A and 32 mg (0.11 mmol) of the compound from Example 5A were reacted with one another. This gave 29 mg (54% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=CC=CC=4)[CH:20]=[N:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][CH:3]=1.BrC1C=[CH:30][C:31]([O:34]CC)=NC=1.C1(C)C=CC(P(C2C=CC(C)=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1>>[CH2:31]([O:34][C:20]1[CH:21]=[CH:26][C:17]([N:14]2[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:16][CH2:15]2)=[CH:18][N:19]=1)[CH3:30]
Reactant: CCOc1ccc(Br)cn1
Reactant: Cc1cccc(C#CC=C2CCN(c3cncc4ccccc34)CC2)n1
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Product: CCOc1ccc(N2CCC(=CC#Cc3cccc(C)n3)CC2)cn1
Yield: 10 %

Procedure:
Following the procedure reported for the compound of Example 234 and using 5-bromo-2-ethoxypyridine instead of 4-bromoisoquinoline and tol-BINAP (2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl) instead of BINAP the title compound was prepared. After the work-up, the residue was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with PE-EtOAc 8:2. affording the title product as a yellow oil. Yield: 10%.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Cl[CH2:14][C:15]1[N:16]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]3[N:25]=[N:26][N:27]=[C:19]3[C:18]=2[N:28]=1.C(N(CC)CC)C>CN(C=O)C>[O:7]=[C:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:12])[N:2]1[O:1][CH2:14][C:15]1[N:16]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:17]2[C:22]([CH3:23])=[C:21]([CH3:24])[N:20]3[N:25]=[N:26][N:27]=[C:19]3[C:18]=2[N:28]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCNS(C)(=O)=O)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNS(C)(=O)=O)c12
Reaction time: 3 h

Procedure:
N-Hydroxyphthalimide (64 mg, 0.39 mmol) was added to a stirred solution of N-{4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}methanesulfonamide (100 mg, 0.26 mmol) in DMF (2.6 mL). Triethylamine (0.109 mL, 0.78 mmol) was added dropwise, causing the solution to turn red. After 3 hours, more N-hydroxyphthalimide and triethylamine (3 equivalents each) were added and stirring was continued overnight. The solvent was removed under reduced pressure. To the resulting oil was added ethyl acetate and water, which caused a yellow solid to form. The solid was isolated by filtration, washed with chloroform, and then was triturated with ethyl acetate and isolated by filtration to afford N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]methanesulfonamide as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH3:11][OH:12]>>[Br:1][C:2]1[C:3]([O:12][CH3:11])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CO
Agent: Cl
Product: COc1ncc(Br)nc1Br
Temperature: 60 °C
Yield: 47 %

Procedure:
A 100 mL round bottom flask was charged with 3,5-dibromopyrazin-2-amine (1.0 g, 4.0 mmol), methanol (10 mL), methanolic HCl (2.5 M, 0.32 mL, 0.80 mmol) and isoamylnitrile (1.6 mL, 12 mmol). The resulting mixture was heated at 60° C. for 2 h. TLC indicated a complete conversion. Work-up: the solvent was evaporated. The residue was re-dissolved in dichloromethane, washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with a 1:20 EtOAc/petroleum ether, to afford 0.50 g (47%) of the product as a white crystal. MS m/z: 267 (M+H+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][C:13]=2[CH3:22])[N:3]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.FC(F)(F)C(O)=O>FC(F)(F)CO>[CH:19]1([C:15]2[CH:16]=[C:17]([CH3:18])[C:12]([O:11][C:4]3[N:3]=[C:2]([NH:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[N:10]=[C:9]4[C:5]=3[N:6]=[CH:7][NH:8]4)=[C:13]([CH3:22])[CH:14]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2[nH]cnc12
Reactant: N#Cc1ccc(N)cc1
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2[nH]cnc12
Temperature: 90 °C
Yield: 20.1 %

Procedure:
To a suspension of 2-chloro-6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purine (28 mg, 0.088 mmol) and 4-aminobenzonitrile (42 mg, 0.35 mmol) in 2,2,2-trifluoroethanol (3 mL) in a sealed tube was added trifluoroacetic acid (0.056 mL, 0.70 mmol). The resulting solution was heated at 90° C. for 3 days. The reaction was cooled to room temperature and concentrated to dryness. Silica gel chromatography (CH2Cl2:Acetone=80:20) yielded 7 mg (20%) of 4-(6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purin-2-ylamino)benzonitrile as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][CH2:28][C@@:29]1([OH:58])[C:34](=[O:35])[O:33][CH2:32][C:31]2[C:36]([N:38]3[C:50](=[CH:51][C:30]1=2)[C:49]1N=C2C(C(CC[Si](C)(C)C)=CC=C2)=C[C:40]=1[CH2:39]3)=[O:37]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:27][CH2:28][C@@:29]1([OH:58])[C:34](=[O:35])[O:33][CH2:32][C:31]2[C:36]([N:38]3[C:50](=[CH:51][C:30]1=2)[C:49]1[C:40](=[C:8]([CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:39]3)=[O:37]
Reactant: C[Si](C)(C)CCC(=O)c1ccccc1N
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c(CC[Si](C)(C)C)cccc3nc2-1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 20 h
Yield: 98 %

Procedure:
To a solution of 1-(2-amino-phenyl)-3-trimethylsilanyl-propan-1-one (3) (34 mg) and CDE ring moiety (4) (24 mg) in acetic acid (0.5 mL) and toluene (1 mL) was added p-toluenesulfonic acid (1 mg). The reaction solution was stirred for 20 hours at 100° C. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and the residue was washed with hexane (10 mL), water (10 mL), and a mixture of acetone (5 mL) and hexane (5 mL). The yellow solid was evaporated to dryness in vacuo to yield 39 mg (98% Yield) of BNP1350 (Karenitecin; Cositecan; 7-(2′-trimethylsilyl)ethyl camptothecin; IUPAC Nomenclature: (4S)-4-ethyl-4-hydroxy-11-[2-(trimethylsilyl)ethyl]-1H-pyrano[3′:4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][S:24]([NH2:27])(=[O:25])=[O:26])=[CH:19][CH:18]=2)[N:7]=1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: COc1ccccc1-c1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccnc(Nc2ccc(CS(N)(=O)=O)cc2)n1

Procedure:
A solution of 2-chloro-4-(2-methoxy-phenyl)-pyrimidine (0.883 g, 0.004 mol), and (4-amino-phenyl)-methanesulfonamide (0.745 g, 0.004 mol) (Bosch, J.; Roca, T. et al., Tetrahedron (2001), 57(6), 1041-1048. Owa, Takashi et al., Journal of Med. Chem. (1999), 42(19), 3789-3799) in DMF (12 ml) was stirred for 2 hours at 80° C. (TLC control). The solvent was removed under reduced pressure to afford {4-[4-(2-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanesulfonamide.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.COC1C=CC(C[C:22]2([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[C:28](OCC)=[S:29])=CC=1.[C:42]([O:45]C(=O)C)(=[O:44])[CH3:43]>O1CCCC1>[C:42]([O:45][C:22]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:28]=2[S:29][C:33]=1[C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)(=[O:44])[CH3:43]
Reactant: CCOC(=S)C1CCCCC1(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3c(c2OC(C)=O)CCCC3)cc1
Reaction time: 0.25 h
Yield: 43.4 %

Procedure:
A solution of 1.5 mL (10.7 mmol) of diisopropylamine in 10 mL of dry tetrahydrofuran was cooled to -78° under nitrogen. To this was added 4 mL of 2.5M n-butyllithium (in hexane) and after 15 minutes, a solution of 1.36 g (3 mmol) of ethyl 2,2-bis-(4-methoxyphenyl)methylthiocyclohexanecarboxylate in 5 mL of dry tetrahydrofuran was added and the solution was stirred under N2 for 2 hours. Then 1.5 mL (15 mmol) of acetic anhydride was added and the solution was stirred at room temperature for 1 hour. The solution was partitioned between ether and NaHCO3 and the ether layer was washed with NaHCO3, then brine, and dried over MgSO4. The solution was concentrated and the residue chromatographed on silica gel (20% ethyl acetate-hexane) to afford a colorless oil. This was crystallized from ethyl acetate-hexane to afford 0.394 g (47%) of title compound as a white crystalline solid, m.p. 81° C. NMR (CDCl3, (CH3)4Si) δ1.81 (4H, m), 2.25 (3H, s, CH3CO), 2.35 (2H, t, J=6Hz), 2.71 (2H, t J=6Hz), 3.80 (3H, s, OCH3), 6.90 (2H, AB), 7.39 (2H, AB).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH:13]=[CH:12][C:9]=1[CH:10]=O)[CH3:2].[CH2:28]([NH:32][C:33]1[CH:39]=[C:38]([O:40][CH2:41][CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[CH:37]=[CH:36][C:34]=1[NH2:35])[CH2:29][CH2:30][CH3:31]>C(O)C>[CH2:28]([N:32]1[C:33]2[CH:39]=[C:38]([O:40][CH2:41][CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[CH:37]=[CH:36][C:34]=2[N:35]=[C:10]1[C:9]1[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:15][C:8]=1[O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:26][CH3:27])[CH2:1][CH3:2])[CH2:29][CH2:30][CH3:31]
Reactant: CCN(CC)CCCOc1cc(OCCc2ccc(Cl)cc2)ccc1C=O
Reactant: CCCCNc1cc(OCCCN(CC)CC)ccc1N
Solvent: CCO
Product: CCCCn1c(-c2ccc(OCCc3ccc(Cl)cc3)cc2OCCCN(CC)CC)nc2ccc(OCCCN(CC)CC)cc21
Yield: 64.8 %

Procedure:
A solution of 2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde (synthesized via General Procedures D1 and D2) (429 mg; 1.1 mmol) and 2-(n-butylamino)-4-(3-diethylaminopropoxy)aniline (synthesized via General Procedures G1 and G2 and I) (293 mg; 1 mmol) in ethanol (5 mL) was heated to reflux following General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford of (3-{2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethylamine (430 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[OH:59][C:52]1[C:51]([CH2:50][NH:49][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:2])[CH3:3])=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=2)=[C:56]([CH3:57])[CH:55]=[C:54]([CH3:58])[N:53]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(C)c1ccc(C(=O)O)cc1Oc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)C)c(Oc3ccccc3)c2)c(O)n1
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
To a solution of 4-isopropyl-3-phenoxybenzoic acid (100 mg, 0.39 mmol) in dichloromethane (20 mL) were added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol), N-hydroxy benzotriazole (68 mg, 0.50 mmol) and triethylamine (175 mg, 1.73 mmol). The resultant reaction mixture was stirred for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (61 mg, 0.40 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified through pre-HPLC and the obtained solution was freeze-dried to afford N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropyl-3-phenoxy benzamide (50 mg, 32.8%) as a white solid. LRMS (M+H+) m/z: calcd 391.19. found 391 HPLC purity (214 nm): 90.4%. 1H NMR (300 MHz, DMSO) δ 7.58 (m, 1H), 7.55 (m, 1H), 7.33 (m, 3H), 7.07 (m, 1H), 6.89 (m, 2H), 6.07 (s, 1H), 4.44 (s, 2H), 3.31 (m, 1H), 2.32 (s, 3H), 2.22 (s, 3H), 1.24 (d, J=9 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.N([O-])=O.[Na+].[N-:13]=[N+:14]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(Cl)nc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=Nc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
5-Amino-2-chloropyridine (2.28 g; 17.7 mmol; 1.0 eq.) was dissolved in TFA (7 mL). Sodium nitrite (1.35 g; 19.5 mmol; 1.1 eq.) was then added portion wise to this solution maintained at 0° C. Reaction mixture was stirred at 0° C. for 30 min before the addition of and ice-cold solution of sodium azide (1.15 g; 17.7 mmol; 1.0 eq.) in water (8 mL). It was stirred at 0° C. for 1 h. TFA was then removed and the residue was dissolved in EtOAc. Organic phase was washed with an aqueous saturated solution of NaHCO3, brine, dried over magnesium sulfate, filtered and concentrated. The crude obtained was purified by flash chromatography on silica (heptane:EtOAc, gradient from 95:5 to 80:20) to afford the title compound as a brown oil (1.89 g, 69%). 1H NMR (300 Mz, DMSO-d6) δ 8.23 (dd, J=0.6, 2.9 Hz, 1H), 7.68 (dd, J=2.9, 8.6 Hz, 1H), 7.54 (dd, J=0.6, 8.6 Hz, 1H).