Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][CH:12]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Oc1ccccc1-c1ccc[nH]1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1c[nH]c(-c2ccccc2OCC2CO2)c1
Yield: 48.6 %

Procedure:
7.0 g of 2-(o-hydroxyphenyl)-pyrrole, 7.3 g of epibromohydrin and 11.4 g of dry potassium carbonate in 50 ml of acetone are refluxed for 7 hours. After the mixture has cooled, it is filtered and the filter residue is washed with acetone. The combined filtrates are freed from the solvent by distillation. The residue is chromatographed twice on silica gel, using methylene chloride as the eluant, and gives 4.6 g (48% of theory) of 2-[2-(2,3-epoxypropoxy)-phenyl]-pyrrole as a colorless oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:19]=1[CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:6][CH2:7][N:2]([C:26]([C:23]3[CH:22]=[C:21]([CH2:20][C:19]4[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:18]=4[F:17])[O:25][N:24]=3)=[O:27])[CH2:3][CH2:4]2)=[CH:9]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2cc(F)ccc2F)on1)N1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
The mixture of 3-(piperidin-4-yl)-1H-indole hydrochloride (0.060 g; 0.253 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.061 g; 0.253 mmol), HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.096 g: 0.253 mmol) and N,N-diisopropylethylamine (0.110 mL; 0.634 mmol) in DMF (3 mL) was stirred for 72 hours at room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) to give 0.069 g (65%) of (4-(1H-indol-3-yl)piperidin-1-yl)(5-(2,5-difluorobenzyl)isoxazol-3-yl)methanone as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18].[CH3:20][C:21]([CH3:23])=O>O>[N+:14]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:21]([CH3:23])([CH3:20])[O:19][CH:17]([CH3:18])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(O)c1cc(-c2cccc([N+](=O)[O-])c2)ccc1N
Reactant: CC(C)=O
Solvent: O
Product: CC1OC(C)(C)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 1-(4-amino-3′-nitro-biphenyl-3-yl)-ethanol and acetone in the same fashion as that of Example 4. Yellow solid: mp 188-189° C.; Anal. Calc. For C17H18N2O30.35 H2O: C, 67.02; H, 6.19; N, 9.20. Found: C, 66.7; H, 5.89; N, 9.03.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH:20]([F:22])[F:21])=[CH:17][CH:16]=[C:15]([F:23])[C:14]=3[Cl:24])[CH3:12])=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][C:33]1[N:37]([CH:38]2[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]2)[N:36]=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.[F-].[K+].O.Cl>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.O1CCOCC1>[Cl:24][C:14]1[C:15]([F:23])=[CH:16][CH:17]=[C:18]([O:19][CH:20]([F:21])[F:22])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:34]3[CH:35]=[N:36][N:37]([CH:38]4[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]4)[C:33]=3[CH3:32])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[C@H](c1c(OC(F)F)ccc(F)c1Cl)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cnc3[nH]cc([C@H](C)c4c(OC(F)F)ccc(F)c4Cl)c3c2)cnn1C1CCNCC1
Temperature: 30 °C

Procedure:
A mixture of tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (60.0 mg, 0.115 mmol), tert-butyl 4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (58.73 mg, 0.1501 mmol), Pd(PPh3)4 (6.670 mg, 0.005772 mmol), potassium fluoride (20.12 mg, 0.3463 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated in a microwave reactor at 100° C. for 30 min. 12 M of HCl in H2O (0.19 mL, 2.3 mmol) was added, and the solution was heated to 30° C. overnight. The organic solvent was removed in vacuo, and the material was extracted with DCM and sat. NaHCO3. The organic layer was concentrated in vacuo and purified via column chromatography, eluting with 3-8% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as white solid. 1H NMR (400 MHz, CD3OD): δ=1.84 (d, J=7.3 Hz, 3H), 1.87-1.96 (m, 2H), 2.00-2.12 (m, 2H), 2.23 (s, 3H), 2.72-2.82 (m, 2H), 3.15-3.23 (m, 2H), 4.31 (tt, J=11.6, 3.9 Hz, 1H), 5.11 (q, J=7.3 Hz, 1H), 6.43 (br. s., 1H), 7.12 (dd, J=9.0, 4.7 Hz, 1H), 7.18 (t, J=8.7 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.48 (s, 1H), 8.13 (d, J=2.0 Hz, 1H). MS (ES+): m/z=504.15/506.16 (100/50) [MH+]. HPLC: tR=1.15 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: C(NC1C=C(Cl)C2N(C)C(=O)C(C)(C)N=C(C3C=CC=CC=3F)C=2C=1)CCC.[Cl:29][C:30]1[C:40]2[N:39]([CH3:41])[C:38](=[O:42])[C:37]([CH3:44])([CH3:43])[N:36]=[C:35]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[F:51])[C:34]=2[CH:33]=[C:32]([N:52](CC)[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[O:54])[CH:31]=1>CCCCCC>[Cl:29][C:30]1[C:40]2[N:39]([CH3:41])[C:38](=[O:42])[C:37]([CH3:44])([CH3:43])[N:36]=[C:35]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[F:51])[C:34]=2[CH:33]=[C:32]([NH:52][C:53]([O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)=[O:54])[CH:31]=1
Reactant: CCN(C(=O)OCc1ccccc1)c1cc(Cl)c2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C
Agent: CCCCNc1cc(Cl)c2c(c1)C(c1ccccc1F)=NC(C)(C)C(=O)N2C
Solvent: CCCCCC
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(NC(=O)OCc3ccccc3)cc(Cl)c21

Procedure:
From 9.6 g (0.02 mol) of benzyl 9-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepine-7-carbamate there is obtained, in analogy to the details in paragraph (b) of Example 39, benzyl 9-chloro-N-ethyl-5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepine-7-carbamate of melting point 125°-127° (hexane).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([NH:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=3)[CH:8]=2)[NH:3]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]=3)=[CH:6][CH:5]=2)[C@H:10]([NH:12][C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])[CH2:11][C@@H:2]1[CH3:1])(=[O:35])[CH3:34]
Reactant: CC1CC(NC(=O)OC(C)C)c2cc(-c3cn(CCC(=O)OC(C)(C)C)cn3)ccc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1c2ccc(-c3cn(CCC(=O)OC(C)(C)C)cn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 16 h
Yield: 66 %

Procedure:
A solution of 1,1-dimethylethyl 3-{-4-[2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}propanoate (for a preparation see Intermediate 93) (1.46 g, 3.3 mmol) in acetic anhydride (3 mL) was allowed to stand at room temperature for 16 h then most of the solvent was removed in vacuo. The residue was co-evaporated twice with toluene. Its purification by flash chromatography on silica gel (gradient: 0 to 2% MeOH in DCM) gave 1,1-dimethylethyl 3-{(cis)-4-[1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-imidazol-1-yl}propanoate (1.055 g, 2.177 mmol, 66%) as a colourless solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:8]=[C:9]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH2:26])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[C:10]([F:14])=[CH:11][C:12]=1[Cl:13]>C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:26][C:1](=[O:4])[CH:2]=[CH2:3])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[C:10]([F:14])=[CH:11][C:12]=1[Cl:13]
Reactant: Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1

Procedure:
Acryloyl chloride was reacted with 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline in THF, at 0° C. The final product was obtained in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([F:7])=[C:4]([F:6])[F:5].[C:10]1([CH3:17])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1>>[F:5][C:4]([F:6])([CH:3]([F:7])[C:2]([F:9])([F:8])[F:1])[CH2:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: Cc1cccc(C)c1
Product: Cc1cccc(CC(F)(F)C(F)C(F)(F)F)c1
Yield: 70 %

Procedure:
Meta-xylene and hexafluoropropene (3:1 molar ratio), heated at 290° for 3 days, gave 3-(2,2,3,4,4,4-hexafluorobutyl)toluene: ##STR14## in 70% yield based on hexafluoropropene consumed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29](/[CH:31]=[CH:32]/[C:33]([O:35]C)=[O:34])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C(O)C.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)/C=C/c1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a suspension of methyl (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino) [1]benzothieno[2,3-d]pyrimidin-7-yl]acrylate (100 mg, 0.19 mmol) in THF (3 vmL) were added ethanol (1 mL) and lithium hydroxide (2 N, 0.5 mL, 1 mmol, 5 equiv). The contents were stirred at rt for 16 h. The mixture was concentrated to dryness and the residue was triturated with ether and ethyl acetate to remove organic impurities. To the solid was added some water and 1N HCl to adjust the pH to ˜6. The solid was filtered and dried to obtain (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]acrylic acid (50 mg, 51%). 1H-NMR (DMSO-d6) δ 9.10 (s, 1H), 8.56 (d, 1H), 8.52 (s, 1H), 8.39 (d, 1H), 7.87 (dd, 1H), 7.74 (d, 1H), 7.42-7.59 (m, 3H), 7.30 (m, 2H), 7.23 (d, 1H), 7.17 (m, 1H), 6.69 (d, 1H), 5.26 (s, 2H); LCMS RT=3.77 min, [M+H]+=506.0.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]([O:9]CC)=[O:8])=[N:2]1.[OH-].[Na+].O.CO>C1COCC1>[NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]([OH:9])=[O:8])=[N:2]1
Reactant: CCOC(=O)Cc1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)Cc1nc[nH]n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of ethyl 1H-1,2,4-triazol-3-ylacetate obtained in Reference Example 14 (900 mg, 5.80 mmol), 4N aqueous sodium hydroxide solution (7.25 mL, 29.0 mmol), water (10 mL), methanol (10 mL) and THF (10 mL) was stirred at 100° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was acidified with 1N hydrochloric acid, and the mixture was concentrated under reduced pressure. Ethanol was added to the residue, and the insoluble material was filtered off, and the filtrate was concentrated. The residue was crystallized from toluene to give the title compound as a white powder (369 mg, 50%).
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[O:18][C@@H:17]([CH2:19][O:20]C(=O)C3C=CC=CC=3)[C@:15](C(=O)C3C=CC=CC=3)([OH:16])[C@:13]2(C(=O)C2C=CC=CC=2)[OH:14])[N:3]=1.[NH3:45]>CO.[Cu]>[NH2:45][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[O:18][C@@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@@H:13]2[OH:14])[N:3]=1
Reactant: N
Reactant: O=C(OC[C@@H]1O[C@H](n2nc(Br)c3c(=O)[nH]cnc32)[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1)c1ccccc1
Agent: [Cu]
Solvent: CO
Product: Nc1nn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c2nc[nH]c(=O)c12
Yield: 36 %

Procedure:
3-Bromo-1-(2′,3′,5′-O-tribenzoyl-β-L-ribofdranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one 24 (714 mg, 1.08 mmoles) was dissolved in MeOH saturated with NH3 at 0 C (30 mL). Thin copper wire (21 mg, 0.33 mmole) and cuprous chloride.(33 mg, 0.33 mmole) were added. The mixture in a sealed, stainless steel bomb was heated at 100 C for 16 h. After cooling, silica gel (2 g) was added to the reaction mixture and, the solvent evaporated. The silica gel absorbed with the crude product was loaded onto a silica column and eluted with 5% Et3N, 17% MeOH in CH2Cl2). The product was further purified by recrystallization (95% EtOH) to afford 3-amino-1-β-L-ribofuranosylpyrazolo[3,4-d]pyrirnidin-4(5H)-one 26 as a white needles (110 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]1[CH2:19][O:18]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.NCC1CCN([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=2[S:36]([NH2:39])(=[O:38])=[O:37])CC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][NH:6][CH2:5][CH:13]1[CH2:14][CH2:2][N:39]([S:36]([C:29]2[CH:28]=[CH:33][C:32]([O:34][CH3:35])=[CH:31][CH:30]=2)(=[O:37])=[O:38])[CH2:11][CH2:12]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Clc1ccc2[nH]c3ccccc3c2c1OC[C@@H]1CO1
Reactant: COc1ccc(S(N)(=O)=O)c(N2CCC(CN)CC2)c1
Product: COc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3c(Cl)ccc4[nH]c5ccccc5c34)CC2)cc1
Yield: 122.2 %

Procedure:
Prepared from 3-chloro-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.060 g, 0.22 mmol) and (4-aminomethyl-1-piperidinyl) 4-methoxybenzenesulfonamide (0.125 g, 0.5 mmol) according to procedure used for Example 2 to give 0.075 g of the title compound as a white solid.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH3:13][O:14][NH2:15]>C(O)C>[CH3:13][O:14][N:15]=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CON
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CC(C)=O)=NOC
Temperature: 25 °C
Yield: 45.3 %

Procedure:
A mixture of 2.5 g of ethyl 2,4-dioxovalerate, 1.45 g of O-methylhydroxylamine hydrochloride and 10 ml of ethanol was heated to reflux for 2 hours. The reaction mixture was allowed to cool to room temperature, and partitioned between water and ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.34 g of ethyl 2-methoxyimino-4-oxopentanoate of the formula:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH2:62].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:62][CH:61]=[CH2:60])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CC1OC
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (510 mg) in 6.6 ml 33% methylene chloride in cyclohexane, was added allyl trichloroacetimidate (266 mg neat) and the reaction mixture was allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (12 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 24 hours the reaction mixture was diluted with ethyl acetate and washed with saturated sodium carbonate, water and brine. The organic layer was dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:9))+1% methanol) gave the title compound (434 mg). 1H NMR consistent with the desired structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:9]#[N:10].FC1C=CC=CC=1[CH:27]([CH2:30][CH2:31][N:32]([CH:36]([CH3:38])C)[CH:33]([CH3:35])C)C#N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])([CH2:38][CH2:36][N:32]1[CH2:31][CH2:30][CH2:27][CH2:35][CH2:33]1)[C:9]#[N:10]
Reactant: CC(C)N(CCC(C#N)c1ccccc1Cl)C(C)C
Reactant: CC(C)N(CCC(C#N)c1ccccc1F)C(C)C
Product: CC(C)N(CCC(C#N)(CCN1CCCCC1)c1ccccc1Cl)C(C)C

Procedure:
When an equivalent quantity of α-(o-chlorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile prepared according to the first paragraph of Example 19, is substituted for α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile called for in Example 20 and the procedure detailed in the second paragraph of that example is substantially repeated, there is obtained α-(o-chlorophenyl)-α-[2-(diisopropylamino)ethyl]-α-(2-piperidinoethyl)acetonitrile, as an oil boiling at about 190°-195° C. at 0.3 mm. pressure.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12](O)[CH2:13][C:14]#[CH:15].C(OC(C#CCCN)=O)C>>[CH2:15]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH2:14][C:13]#[CH:12]
Reactant: C#CCCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)C#CCCN
Product: C#CCCN1C(=O)c2ccccc2C1=O
Yield: 84 %

Procedure:
The title compound was prepared according to the procedure of lyer and Liebeskind (J. Amer. Chem. Soc, 1987, 109, 2759-2770) via a Mitsunobu reaction between phthalimide and 3-butyn-1-ol in 84% yield. The product was isolated as white crystals. mp=137-139° C. (lit. mp=136-137° C.). N-(Ethoxycarbonyl)but-3-ynylamine
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:12]=1[C:13]([NH2:15])=[O:14].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:15][C:13](=[O:14])[C:12]2[C:11](=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=2[O:22][CH3:23])[N:10]=1
Reactant: O=Cc1ccccc1Cl
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccccc3Cl)nc2c1
Temperature: 140 °C
Yield: 38.9 %

Procedure:
A mixture of 2-chlorobenzaldehyde (0.0430 g, 306 mmol), 2-amino-4,6-dimethoxybenzamide (0.0600 g, 0.306 mmol), NaHSO3 (94%, 0.0474 g, 0.428 mmol), and p-TsOH.H2O (0.0175 g, 0.0918 mmol) in DMA (3.06 mL) was heated at 140° C. for 16 h. The mixture was cooled and chromatographed on silica gel, fractions containing the product were combined, concentrated under vacuum, diluted with EtOAc (300 mL), washed with water (3×75 mL), brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum to provide 2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0377 g, 39%) as a yellow solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 912.14 (s, 1H), 7.65-7.40 (m, 4H), 6.72 (d, J=2.29 Hz, 1H), 6.59 (d, J=2.30 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H); MS (APCI) m/z 317 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[NH:6][CH2:5][CH2:4][CH:3]1C(OCC)=O.Cl>O>[NH:6]1[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:2](=[O:1])[CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C1CCNC2(CCCCC2)C1=O
Agent: Cl
Solvent: O
Product: O=C1CCCNC12CCCCC2

Procedure:
A mixture of ethyl 5-oxo-1-azaspiro[5.5]undecane-4-carboxylate (13.9 g, prepared in a similar manner to that described above), concentrated hydrochloric acid (50 ml) and water (50 ml) was heated at 90°-95° C. for 5 hours. The solvent was removed in vacuo, and the residue diluted with ice-water (50 ml) and basified by the addition of an excess of 5M aqueous sodium hydroxide solution. The product was extracted into ethyl acetate and the extracts were washed with brine, dried over magnesium sulphate, and the solvent removed in vacuo to give 1-azaspiro[5.5]undecan-5-one as a pale brown solid. Yield 5.9 g, mp 55° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:11]=[CH:10]2
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1ccc2cc(O)ccc2c1
Product: O=C(Cc1ccccc1)Nc1ccc2cc(O)ccc2c1

Procedure:
The 6-aminonaphthalen-2-ol from Step (a) above (320 mg, 2.0 mmol) reacted with phenylacetyl chloride (683 mg, 4.4 mmol, Aldrich) under the conditions of Example 1d to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 278.3 (M+1). Mass Calc'd for C18H15NO2: 277.11.
Reaction SMILES: O[C:2]1([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:29])[CH3:28]>C(O)C>[CH3:28][C:3]1([CH3:29])[CH:2]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc5ccccc5c3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc5ccccc5c3)C(C)(C)O4)CC2)cc1
Yield: 88 %

Procedure:
Using 1-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(2-naphthyl)-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine obtained in Example 34, the title compound was synthesized in the same manner as in Example 46. Yield 88%. mp. 170–171° C. (ethanol).