Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:11]=3[CH:10]=2)=[CH:3][CH:2]=1.[CH3:21][C:22]([CH3:24])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:21][C:22]1([CH3:24])[C:16]2[NH:15][C:12]3[C:11]([C:17]=2[CH2:18][CH2:19][O:20]1)=[CH:10][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[CH:14][CH:13]=3
Reactant: OCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21
Temperature: 25 °C

Procedure:
A mixture consisting of 5-benzyloxytryptophol (3.2 g, 0.012 mol), acetone (7 mL), benzene (300 mL) and p-toluene sulfonic acid (500 mg) is refluxed for 3.5 hours using a Dean-Stark trap to remove the water. The reaction mixture is cooled to room temperature and washed with 5% sodium bicarbonate (1×200 mL), water (200 mL) and brine (200 mL). It is dried (MgSO4), filtered and concentrated to give 5.0 g product as thick oil. The crude product is flash chromatographed with 15% ethyl acetate/hexane as an eluent to afford 2.5 g product, m.p. 128°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1.B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[Cl-].[Na+]>C1(C)C=CC=CC=1.CCCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccc(F)cc1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: O=C(CCC[C@H](O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Reaction time: 15 h
Yield: 96 %

Procedure:
3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone (100 gm) is dissolved in toluene (750 ml), the mixture of (−)-β-chlorodiisopinocampheylborane ((−)-DIP chloride) in heptane (545 ml, 1.5M) and toluene (750 ml) is added at 0° C. to 5° C. for 1 hour. The reaction mixture is stirred for 15 hours at 25° C. to 30° C. and 340 ml of 10% sodium chloride is then added at the same temperature. The layers are separated and the organic layer is washed with 5% sodium bicarbonate (300 ml), 1N sulfuric acid (300 ml), and 10% sodium chloride (300 ml). Then the organic layer is dried on sodium sulfate to give 3-[(5S)-5-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone in 96% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].[C-:11]#[N:12].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:11]#[N:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Product: N#CC(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 70 g of 3,4-dichlorobenzaldehyde and 90 g of Na2S2O5 in 300 ml of water is stirred overnight at RT. The reaction mixture is cooled to 0° C., a solution of 52 g of KCN in 100 ml of water is added dropwise and the reaction mixture is stirred while the temperature is allowed to rise to RT. It is extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum to give 76 g of the expected product, which is used as such.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:16]3[C:23]([C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[C:16]3[C:23]([C:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:31])=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)c1
Temperature: 50 °C

Procedure:
To a mixture of tert-butyl(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)phenyl)carbamate (5.8 g, 13.5 mmol) in DCM (50 mL) was added 25 mL of TFA. The mixture was heated at 50° C. for 1 hour. Solvent was removed under reduced pressure. The residue was washed with DCM and dried on high vacuum to give an off-white solid. M.p.=280-282° C.; 400 MHz 1HNMR (DMSO-d6) δ 13.11 (s, 1H), 11.56 (s, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.86 (d, J=7.6 Hz, 2H), 7.70 (t, J=10 Hz, 2H), 7.60 (t, J=7.2 Hz, 2H), 7.46 (t, J=8.0 Hz, 1H), 6.95 (d, J=7.2 Hz, 1H); LCMS [M+H] 330.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[C:6](Cl)(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>O.CCOCC>[C:6]([NH:1][CH2:2][C:3]([OH:5])=[O:4])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCC(=O)Cl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCCCCC(=O)NCC(=O)O
Yield: 27.6 %

Procedure:
Glycine (20 mmol) was reacted with octanoyl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of water and ether using the method described in Example 1 Part A. The crude crystalline product (3.06 g, 76%) was recrystallized from EtOAc (15 ml) to give the title compound (1.11 g, 28%), m.p. 105-107° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:18][CH3:19])[C:13]=2[Cl:17])[C:8]=1[Cl:20])(=O)=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:17][C:13]1[C:14]2[C:9](=[C:8]([Cl:20])[C:7]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]=1[O:18][CH3:19]
Reactant: COc1ccc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc2c1Cl
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc3c(Cl)c(OC)ccc3c2Cl)cc1

Procedure:
The title compound was prepared by 1,5-dichloro-6-methoxy-2-naphthyl trifluoromethanesulfonate (0.32 g, 0.85 mmol) with 4-methoxyphenyl boronic acid (0.18 g, 1.2 mmol) according to method A to yield 0.27 g (95%) of a white solid mp 146-149° C.;1H NMR (CDCl3): δ 3.88 (3H, s), 4.07 (3H, s), 7.02 (2H, d, J=8.73 Hz), 7.41 (1H, d, J=9.52 Hz), 7.46 (2H, d, J=8.83 Hz), 7.53 (1H, d, J=8.73 Hz), 8.19 (1H, d, J=8.73 Hz), 8.36 (1H, d, J=9.12 Hz);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:13]3[NH:12][CH2:11][C@@H:10]4[CH2:16][C@H:17]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH2:18][C:8]=2[C:9]=34)[CH:2]=1.N1C2C(=CC=CC=2)C=C1.C1([Se](O[Se](C2C=CC=CC=2)=O)=O)C=CC=CC=1>C1COCC1.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[CH2:16][C@H:17]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH2:18][C:8]=2[C:9]=34)[CH:2]=1
Reactant: CCCN(CCC)[C@@H]1Cc2c(-c3cccnc3)ccc3c2[C@H](CN3)C1
Agent: O=[Se](O[Se](=O)c1ccccc1)c1ccccc1
Agent: c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)[C@H]1Cc2c[nH]c3ccc(-c4cccnc4)c(c23)C1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
A solution of 1.0 g (2.99 mmol) of (2aR,4S)-6-(3-pyridyl)-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole and 1.0 g (9 mmol) of indole in 50 ml of THF was treated at 0° C. with 0.61 g (1.70 mmol) of benzeneseleninic anhydride. The resulting solution was allowed to warm to room temperature. After 2 hours the reaction solution was diluted with water and the product was extracted into methylene chloride. The methylene chloride was evaporated and the resulting residue was taken up in aqueous tartaric acid. This acidic solution was washed with methylene chloride, then basified with 5M sodium hydroxide solution. The product was extracted into methylene chloride. After evaporating the methylene chloride the product was chromatographed over 25 g of silica gel using 10% ethyl acetate in toluene followed by 1:1 ethyl acetate/toluene as eluent. The material from the column was crystallized from toluene/hexane to afford 0.53 g of title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:24]([C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:18]4[S:17][CH:21]=[CH:20][CH:19]=4)=[O:25])[CH2:15]3)[CH2:10]2)[N:5]=1
Reactant: O=C(O)c1ccccc1-c1cccs1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4ccccc4-c4cccs4)C[C@@H]32)n1
Yield: 58.9 %

Procedure:
A mixture of (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 4, 28 mg, 0.13 mmol), 2-thiophen-2-yl-benzoic acid (29 mg, 0.14 mmol), HATU (73.2 mg, 0.19 mmol), diisopropylethylamine (50 mg, 0.38 mmol) was stirred in DMF (4 mL) at room temperature for 2 h. Then the reaction mixture was partitioned between water and ethyl acetate mixture. The organic phase was separated and washed with 1N aq. NaOH (10 mL) and then with water (2×15 mL). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified on HPLC (basic system) to yield the title compound (31.0 mg, 59.8%). MS (ESI) mass calcd. for C23H24N4OS, 404.53; m/z found, 405.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.60-6.75 (m, 7H), 6.43-6.10 (m, 1H), 4.10-1.78 (m, 16H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[NH2:14][OH:15]>C(O)C>[Br:1][C:2]1[C:11]2[CH:10]=[N:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[N:14][OH:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)c2cnccc12
Reactant: NO
Solvent: CCO
Product: ON=Cc1ccc(Br)c2cnccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 8-bromo-5-isoquinolinecarboxaldehyde (i.e. a product from Step A) (75 mg, 0.3 mmol) in ethanol (7 mL) was added an aqueous solution of hydroxylamine (0.5 mL, 50% in water). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure to provide the title compound as a yellow solid (70 mg).
Reaction SMILES: COC(OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1[CH:11]=[CH:12][N:13]=C2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:16](=O)[C:15]=12.[Cl-].[NH4+].C(O)(=O)C>CN(C)C=O>[CH:20]1[CH:21]=[CH:22][C:23]2[C:24](=[O:25])[C:5]3[C:15]4[C:10]([CH:9]=[CH:6][N:4]=3)=[CH:11][CH:12]=[N:13][C:16]=4[C:18]=2[CH:19]=1
Reactant: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Reactant: COC(OC)N(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2nccc3ccnc1c23
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Dimethylformamide dimethyl acetal (1.50 mL, 11.34 mmol, Aldrich) was added to a solution of cleistopholine, (1.95 g, 8.73 mmol) in dimethylformamide (5 mL). The mixture was then heated for 30 minutes by submerging the reaction vessel into an oil bath preheated to 120° C. At this point, ammonium chloride (4.5 g) and glacial acetic acid (15 mL) were added to the reaction and the heating (120° C.) continued for an additional 30 minutes. After allowing to cool, the reaction was poured onto water (200 mL) and partitioned with methylene chloride (5×100 mL). The combined organic phases were washed with saturated sodium bicarbonate solution (3×100 mL), water (3×100 mL), dried over potassium carbonate, and concentrated to dryness. The residual dark brown solids were chromatographed on silica gel (4×70 cm column, Merck 230-400 mesh) while eluting with ethyl acetate. Concentration of the appropriate column fractions provided pure sampangine (1.60 g, 79%), mp 220-222 (lit. mp 216°-218° C.). IR 1670, 1615, 1590, 1400, 1380, 1320, 1275, 1225, 760, 725 cm−1; 1H and 13C NMR (see Tables I and II).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH:41][NH2:42])(=O)[CH:37]([CH3:39])[CH3:38]>CC1C=CC(C)=CC=1>[CH:37]([C:36]1[N:26]2[C:21]3[CH:20]=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:28][C:22]=3[O:23][CH2:24][C:25]2=[N:42][N:41]=1)([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: CC(C)C(=O)NN
Solvent: Cc1ccc(C)cc1
Product: CC(C)c1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Temperature: 150 °C
Yield: 16.9 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (150 mg, 0.308 mmol) and isobutyrohydrazide (28 mg, 0.308 mmol) in p-xylene (1.5 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (28 mg, 17%). LCMS (Method D): RT=1.497 min, M+1=538. 1H NMR (500 MHz, CDCl3) δ 7.85 (1H, s), 7.36-7.31 (5H, m), 7.28 (2H, m), 7.24-7.19 (2H, m), 5.56 (2H, s), 3.46-3.36 (1H, m), 2.57-2.39 (4H, m), 2.13-2.02 (1H, m), 1.88-1.76 (1H, m), 1.57-1.53 (6H, d), 1.44-1.29 (9H, bs).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49][CH2:50][CH2:51][OH:52])[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49][CH2:50][CH2:51][OH:52])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(SCCO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(SCCO)c4)c4ccccc43)cn12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of Intermediate 5c (109 mg, 0.3 mmol) and Intermediate 35c (140 mg, 0.3 mmol) in 1,4-dioxane (3 mL) and DIPEA (78 μL, 0.45 mmol) was stirred at 90° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (115 mg, 56%). LCMS (Method 5): Rt 3.47 min, m/z 681 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.83-2.26 (11H, m), 2.31-2.39 (1H, m), 3.04 (2H, t, J 6.8), 3.09 (1H, m), 3.59 (2H, q, J 6.0), 3.99 (1H, t, J 8.2), 4.78-4.86 (1H, m), 4.95 (1H, t, J 5.6), 5.36-5.41 (1H, m), 6.33 (1H, s), 7.08 (1H, d, J 8.4), 7.24-7.46 (9H, m), 7.75 (1H, d, J 9.6), 8.12 (1H, s), 8.25 (1H, br d).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][OH:10])[CH:6]=[CH:7][CH:8]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O>>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([N+:9]([O-:10])=[CH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccc(NO)c1
Reactant: O=Cc1ccccn1
Product: [O-][N+](=Cc1ccccn1)c1cccc(CO)c1
Yield: 65 %

Procedure:
The reaction of hydroxylamine 91 (1.36 g, 10 mmol) with 2-pyridinecarboxaldehyde (63) (1.07 g, 10 mmol) afforded, after workup, a yellow oil. The crude product was purified by passing through a short column of silica gel with 20:1 ethyl acetate/methanol as the eluant then recrystallized from acetone/petroleum ether to obtain 1.48 g (6.5 mmol, 65%) of 95 as a yellow crystalline solid: mp 117°-119° C.; IR (CH2Cl2) 3610, 3340, 1580, 1550, 1390, 1090 cm-1 ; 1H NMR (CDCl3) δ 4.53 (t, J=5.8, 1H), 4.65 (d, J=5.6 Hz, 2H), 7.28-9.27 (m, 9H); 13C NMR (CDCl3) δ 63.86, 119.70, 120.37, 124.33, 124.91, 128.59, 129.31, 135.80, 137.25, 143.61, 148.62, 149.50, 149.84. Anal. Calcd for C13H12N2O2 : C, 68.42; H, 5.26. Found: C, 68.52; H, 5.30.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH2:20]([NH:23][CH:24]([CH3:26])[CH3:25])[CH2:21][CH3:22]>>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([NH:10][C:8]([C:4]3[CH:3]=[C:2]([N:23]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:21][CH3:22])[N:7]=[CH:6][N:5]=3)=[O:9])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: CCCNC(C)C
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Product: CCCN(c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1)C(C)C

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1H-indazol-5-yl)-amide (Intermediate 16) and propyl-isopropylamine (Matrix), the title compound was obtained as a white solid.
Reaction SMILES: [N+:1]([CH:4]([CH2:9][CH2:10][CH:11]=O)[CH2:5][CH2:6][CH:7]=[O:8])([O-:3])=[O:2].N1CCCC1.C(O)(=O)C1C=CC=CC=1>C(Cl)Cl>[N+:1]([CH:4]1[CH2:5][C:6]([CH:7]=[O:8])=[CH:11][CH2:10][CH2:9]1)([O-:3])=[O:2]
Reactant: O=CCCC(CCC=O)[N+](=O)[O-]
Agent: O=C(O)c1ccccc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=CC1=CCCC([N+](=O)[O-])C1
Temperature: 25 °C

Procedure:
To a solution of 4-Nitro-heptanedial (35.2 g, 0.2 mol) in methylene chloride (0.7 L) were added pyrrolidine (2 ml, 0.024 mol) and benzoic acid (1.46 g, 0.012 mol), and the resulting mixture was refluxed for 10 to 15 hours. The reaction mixture was cooled to room temperature, washed with 1N HCl (170 ml), saturated with NaHCO3 (170 ml) and water (170 ml) and concentrated to give brownish oil with a purity of about 80%. The product was carried to the next step without further purification. Yield: 32.2 g, 75%. 1H NMR (400 MHz, CDCl3) δ 2.29-2.34 (m, 2H), 2.46-2.64 (m, 2H), 2.85-2.88 (m, 2H), 4.74 (m, 1H), 6.86 (m, 1H), 9.50 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([Cl:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:13][C:6]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[N:3]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:27]4[C:26](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[N:5]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Reactant: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N1CCCC1
Temperature: 80 °C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
A mixture of methyl {4,6-dichloro-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.100 g, 0.21 mmol), pyrrolidine (0.019 mL, 0.23 mmol), and N,N-diisopropylethylamine (0.109 mL, 0.62 mmol) in anhydrous DMF (2 mL) was stirred at 80° C. for 5 hours. After cooling to room temperature, the solvent was evaporated and the remaining residue dissolved in EtOAc. This organic solution was sequentially washed with 1N HCl, water, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by preparative TLC then afforded methyl {4-chloro-2-[4-(2-naphthoylamino)benzyl]-6-pyrrolidin-1-ylpyrimidin-5-yl}-acetate (0.100 g, 95% yield) as a white powder.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:35])([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)[CH:23]([F:25])[F:24]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:31][C:30]2[CH:29]=[CH:28][C:27]([O:26][C:22]([F:21])([F:35])[CH:23]([F:24])[F:25])=[CH:34][CH:33]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)C(F)F)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)C(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-(1,1,2,2-tetrafluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 441.83 g/mol.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].N1C=CN=C1.[C:14]([Si:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)Cl)([CH3:17])([CH3:16])[CH3:15]>N1C=CC=CC=1>[Si:18]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Yield: 55.1 %

Procedure:
To a solution of 8.26 g of hydroquinone and 6.3 g of imidazole in 80 mL of pyridine was added 20.6 g of t-butyldiphenylchlorosilane in 20 mL of pyridine. After 1.5 h the mixture was partitioned between water and ethyl acetate. The organic layer was washed twice with phosphate buffer (pH 2) and once each with phosphate buffer (pH 8) and brine before being filtered through N/N/S and concentrated in vacuo. Preparative liquid chromatography [silica; hexane/ethyl acetate (85:15)] afforded 14.4 g of 4-(t-butyldiphenylsilyloxy)phenol. The structure was confirmed by its NMR spectrum. To a solution of 46 mg of 1,1'-carbonyldiimidazole in 0.5 mL nitromethane was added 65 μL of methyl triflate followed by 100 mg of 4-(t-butyldiphenylsilyloxy)phenol in 1.4 mL of nitromethane. A total of 1.9 mL of this solution was added to a mixture of 100 mg of phorbol 12,13-bis[(2',4'-difluorophenyl)acetate] and approximately 10 mg of 4-dimethylaminopyridine in 500 μL of anhydrous tetrahydrofuran. After 4.5 h this mixture was partitioned between ethyl acetate and water. The organic layer was filtered through N/N/S, concentrated in vacuo and subjected to preparative liquid chromatography [silica; hexane/ethyl acetate (80:20)] to afford 142 mg of 20-O-[4'-(t-butyldiphenylsilyloxy)phenoxy]carbonylphorbol 12,13-bis[(2',4'-difluorophenyl)acetate]. A solution of this material in 1 mL tetrahydrofuran was treated with 160 μL of 1.0M tetrabutylammonium fluoride in tetrahydrofuran. After 14 min the mixture was partitioned between ethyl acetate and phosphate buffer (pH 8). The organic layer was filtered through N/N/S and concentrated in vacuo. After preparative liquid chromatography [silica, hexane/ethyl acetate (65:35)] 108 mg of 20-O-(4'-hydroxyphenoxy)carbonylphorbol 12,13-bis[(2',4'-difluorophenyl)acetate] was obtained. The structure was confirmed by NMR and mass spectral analysis.