Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:36][C:6]1[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10](=[O:29])[N:11]2[C@@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@H](c1ccccc1)n1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)nc(-c3cccnc3)c21
Temperature: 25 °C
Yield: 22 %

Procedure:
A mixture of (R)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.063 mmol), β-alanine (560 mg, 6.3 mmol) and NaOMe solution (9.5 mL, 4.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 7.4 mg of the title compound. MS: (+) m/z 535.33 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](=[CH:16]N(C)C)[C:11](OCC)=[O:12].[NH2:20][C:21]([NH2:23])=[O:22].[Na+].[I-].C[Si](Cl)(C)C.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[C:11](=[O:12])[NH:20][C:21](=[O:22])[NH:23][CH:16]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C(=CN(C)C)c1cccc(OC)c1Cl
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc(-c2c[nH]c(=O)[nH]c2=O)c1Cl
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To a mixture of ethyl 2-(2-chloro-3-methoxyphenyl)-3-(dimethylamino)acrylate 7d (1.7 g, 6 mmol), urea (1.08 g, 18 mmol) and NaI (2.7 g, 18 mmol) in acetonitrile (20 mL) was added TMSCl (2.3 mL, 18 mmol). The resulting mixture was refluxed for 16 hours, cooled to room temperature, and 1.0 M NaOH (30 mL) was added. The resultant solution was stirred for 20 hours, and acetonitrile was removed in vacuo. The aqueous solution was washed with ether, cooled in ice bath, and neutralized with 1 N HCl (30 mL). The precipitate was filtered, washed with additional H2O, and dried to give 5-(2-chloro-3-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione 7e (1.24 g, 82%) as a pale yellow solid. MS (CI) m/z 253.1, 255.1 (MH+).
Reaction SMILES: O1CC[C@H]([O:6][C:7](=[O:34])[NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)C1.[ClH:35].[CH3:36][CH2:37][O:38][CH2:39][CH3:40]>C(Cl)Cl>[ClH:35].[O:38]1[CH2:39][CH2:40][C@H:36]([N:8]([CH2:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=4)[N:19]=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[OH:33])[N:17]=3)[CH2:11]2)[C:7](=[O:34])[OH:6])[CH2:37]1
Reactant: Cc1ccc2c(N3CCC[C@H](CNC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(N3CCC[C@@H](CN(C(=O)O)[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 0.04 h

Procedure:
To a solution of (S)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate in 12 mL CH2Cl2 was added dropwise 2.0 M HCl solution in ether (0.13 mL, 0.25 mmol). To the solution was then added 20 mL ether leading to the precipitation of ((S)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride which was filtered and dried (116 mg, 92%). LC/MS: m/z 463.5 (M+H)+ at 2.33 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([OH:21])=O)[CH:16]=[CH:17][CH:18]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC2N(O)N=[N:28]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:19]([NH2:28])=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cccc2oc(-c3ccc([N+](=O)[O-])cc3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1cccc2oc(-c3ccc([N+](=O)[O-])cc3)nc12
Temperature: 30 °C
Reaction time: 18 h
Yield: 56.5 %

Procedure:
To a solution of 2-(4-nitrophenyl)benzo[d]oxazole-4-carboxylic acid (1.42 g, 5 mmol) in DMF (70 mL) was added HOBt (0.75 g, 5.5 mmol), NH4Cl (0.27 g, 5.0 mmol), DIPEA (1.94 g, 15.0 mmol) and EDCI (1.15 g, 6.0 mmol). The mixture was stirred at 30° C. for 18 hr. The resulting mixture was purged in water (10 mL) and aqueous hydrochloric acid (1 N) to pH=3, then filtered, and the filtrate was washed with saturated sodium bicarbonate solution (100 mL×2) and brine (100 mL×2), and dried in vacuum to obtain the crude product. Re-crystallization in THF obtained 2-(4-nitrophenyl)benzo[d]oxazole-4-carboxamide as a yellow solid (800 mg, yield 56%). LC-MS (ESI) m/e 284 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:8]=[C:7]([NH:19][CH3:20])[N:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:29])[N:12]=3)=[CH:9][N:8]=[C:7]([NH:19][CH3:20])[N:6]=2)[CH2:2][CH2:3]1
Reactant: CNc1ncc(-c2ccnc(SC)n2)c(CC2CC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CNc1ncc(-c2ccnc(S(C)=O)n2)c(CC2CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-(cyclopropylmethyl)-N-methyl-2-(methylsulfanyl)-4,5′-bipyrimidin-2′-amine (4-1) (770 mg, 2.68 mmol), m-CPBA (925 mg, 5.36 mmol) was added and the reaction mixture was stirred at rt for 2 hours. The reaction was partitioned between water and DCM. The organic layer was separated, and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [50 g SNAP column, 100% DCM to 10% MeOH/DCM] to obtain a mixture of the desired product and the corresponding sulfone (645 mg, 79% yield). MS (ES+): m/z=304.2/305.2 (100/20) [MH+]. HPLC: tR=0.85 minute over 3 minutes. Purity: 73.2% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [Si]([SiH2][O:9][CH2:10][CH2:11][N:12]([CH3:37])[C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]4[CH:36]=3)=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+]>CN(C=O)C>[OH:9][CH2:10][CH2:11][N:12]([CH3:37])[C:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]4[CH:36]=3)=[CH:23][CH:22]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc2nc(-c3ccc(/C=C/c4ccc(N(C)CCO[SiH2][Si](C)(C)C(C)(C)C)cc4)cc3)cn2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccc(N(C)CCO)cc4)cc3)cn2c1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
To a stirred suspension of 4-[N-(2-tert-butyldimethylsilylsilanyloxyethyl)-N-methyl-4-{(E)-2-[4-(6-methylimidazo[1,2-a]pyridin-2-yl)phenyl]ethenyl}aniline (0.18 g, 0.362 mmol) in a mixture of dry THF (5 ml) and dry DMF (3 ml) at 0-5° C. was added a solution of TBAF in THF (1 M, 800 μl, 0.800 mmol). The reaction mixture was stirred at 0-5° C. for 5 min and then left to rise to room temperature and stirred for a further 50 min. A solution of saturated ammonium chloride (25 ml) was added to the reaction mixture and this was extracted with DCM/MeOH (1:1, 5×30 ml). The combined organics were washed with brine (40 ml), dried (Na2SO4) and the solvent removed under reduced pressure to give a yellow oil that slowly solidified at room temperature. The solid was purified by flash chromatography (10:1 DCM/MeOH) to give the title compound (0.136 g, 98%) as a yellow solid.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:18]1[C@H:20]2[C:21](=[O:42])[CH:22]=[C:23]3[C@:39]([CH3:40])([C@@H:19]12)[C@@H:38]1[C@H:26]([C@H:27]2[C@:35]([CH3:41])([CH2:36][CH2:37]1)[C@@H:30]([C@H:31]([CH3:34])[CH2:32][OH:33])[CH2:29][CH2:28]2)[CH:25]=[CH:24]3.C1C=CC=CC=1>CCOCC>[O:18]1[C@H:20]2[C:21](=[O:42])[CH:22]=[C:23]3[C@:39]([CH3:40])([C@@H:19]12)[C@@H:38]1[C@H:26]([C@H:27]2[C@:35]([CH3:41])([CH2:36][CH2:37]1)[C@@H:30]([C@H:31]([CH3:34])[CH2:32][O:33][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:29][CH2:28]2)[CH:25]=[CH:24]3
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: C[C@H](COC1CCCCO1)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 65 %

Procedure:
1.8 ml. of 3,4-dihydro-2H-pyran and 20 mg of anhydrous p-toluenesulphonic acid were added to a solution of 2.45 g of (20S)-1α,2α-epoxy-21-hydroxy-20-methyl-pregna-4,6-dien-3-one in 125 ml. of absolute benzene. After standing at room temperature for 1 hour, the solution was diluted with ether, washed with saturated sodium bicarbonate solution and water, dried over sodium sulphate and concentrated in a water-jet vacuum. The residue was chromatographed on 30 g of silica gel using hexane/ether (4:1) for the elution, there being obtained 2.0 g (65%) of (20S)-1α,2α-epoxy-20-methyl-21-tetrahydropyranyloxy-pregna-4,6-dien-3-one. After recrystallisation from hexane, the product melted at 101°-102° C. and was shown by thin-layer chromatography, mixed melting point and IR spectrum to be identical with the compound prepared as described in Example 7.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH2:17][NH:18][O:19][CH3:20]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:18]([CH2:17][C:16]2[CH:21]=[CH:22][CH:23]=[C:14]([F:13])[CH:15]=2)[O:19][CH3:20])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1cccc(F)c1
Product: CON(Cc1cccc(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 94 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(3-fluorobenzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as a white solid (94% yield): mp 110-111° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.70 (3H, s, OCH3), 4.82 (2H, s, NCH2). 6.40 (1H, s, CH), 6.96-7.32 (4H, m, aromatics). Anal. calcd. for C15H16FNO5: C, 58.25; H, 5.21; N, 4.52. Found: C, 58.00; H, 5.30; N, 4.49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.[F:24][CH:25]([F:34])[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:24][CH:25]([F:34])[O:26][C:27]1[CH:28]=[CH:29][C:30]([NH:31][C:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:32][CH:33]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: COc1cc2ncnc(C3CCN(C(=O)Cl)CC3)c2cc1OC
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(OC(F)F)cc4)CC3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a solution of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (46.9 mg, 0.14 mmol), as prepared in Example 3a, in DMSO (1 mL) was added 4-(difluoromethoxy)aniline (26.6 mg, 0.17 mmol), followed by DIEA (35.9 mg, 0.28 mmol). The mixture was heated at 100° C. with stirring. After 2 h, it was cooled to room temperature and partitioned between EtOAc and water. The combined EtOAc extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc→5% MeOH/EtOAc as eluent) to afford the title compound as a white solid (20.4 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.40 (s, 1H), 7.38 (d, J=8.99 Hz, 2H), 7.27 (s, 1H), 7.07 (d, J=8.93 Hz, 2H), 6.48 (s, 1H), 6.45 (t, J=74.22 Hz, 1H), 4.28 (m, 2H), 4.08 (s, 3H), 4.07 (s, 3H), 3.62 (m, 1H), 3.20 (td, J=13.02 and 2.64 Hz, 2H), 2.14 (m, 2H), 2.01 (m, 2H). LC-MS (ESI) calcd mass 458.2, found 459.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[CH:10]([C:11](O)=[O:12])[S:9][CH2:8][C:7](=[O:14])[C:6]=2[CH:15]=1.C(Cl)(=O)C(Cl)=O.[NH3:23].C(OCC)(=O)C>C1COCC1.CN(C=O)C>[CH3:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]2[CH:10]([C:11]([NH2:23])=[O:12])[S:9][CH2:8][C:7](=[O:14])[C:6]=2[CH:15]=1
Reactant: N
Reactant: Cc1cc2c(cc1C)C(C(=O)O)SCC2=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)C(C(N)=O)SCC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
In THF (10 ml) was dissolved 6,7-dimethyl3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (0.473 g) followed by addition of oxalyl chloride (0.305 g) and, then, DMF (1 drop). The mixture was stirred at room temperature for 2 hours. This reaction mixture was added to aqueous ammonia (20 ml)--ethyl acetate (40 ml) and the whole mixture was stirred at room temperature for 30 minutes. The ethyl acetate layer was then separated, washed with water, dried (MgSO4) and the solvent was distilled off to give 6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxamide (0.38 g, 81%). Recrystallization from ethyl acetate gave colorless plates melting at 197°-198° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]([OH:16])=[O:15].[F:17][C:18]([F:28])([F:27])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>C1COCC1.O>[OH:20][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:18]([F:17])([F:27])[F:28])[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: CC(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(O)(c1ccccc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a cooled (0° C.) solution of n-butyl lithium (1.6M in hexanes, 40 mL) in dry THF (90 mL), was added dropwise diisopropylamine (9.45 mL) and the mixture was stirred for 5 min. Keeping the temperature at 0° C., AcOH (1.92 mL, 0.0336 mol) was added dropwise and the reaction mixture was stirred for 10 min and then heated at 50° C. for 30 min. The resulting solution was allowed to cool, a solution of 2,2,2-trifluoroacetophenone (4.76 mL (0.0336 mol) in dry THF (15 mL) was added at 0° C. and the resulting mixture was stirred at room temperature overnight. Finally, Et20 (150 mL) and H2O (50 mL) were added, the aqueous phase was separated, acidified with HCl and extracted with EtOAc (3×). The organic phase was dried and concentrated to afford the title compound as an orange solid (3.88 g, 49%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[CH2:12])[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:12]=[C:9]1[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8]1
Reactant: C=C1CCC(C(=O)OCC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=C1CCC(CO)CC1

Procedure:
The reduction reaction of 4-methylene-cyclohexanecarboxylic acid ethyl ester with LAH is as described in the above reference. The product was purified by distillation to provide (4-methylene-cyclohexyl)-methanol as clear oil (3.67 g, 29.09 mmol, 50% over Step A and B).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[C:17]([NH2:19])=[O:18])[CH3:12].C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([C:17]2[O:18][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:19]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:12]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOc1ccc(C(N)=O)cc1OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3ccccc3)co2)cc1OCC
Temperature: 170 °C
Yield: 16.9 %

Procedure:
In a microwave vial were dissolved 2-bromo-1-phenylethanone (95 mg, 0.478 mmol) and 3,4-diethoxybenzamide (100 mg, 0.478 mmol) in DMF (5 ml) and the reaction was heated at 170° C. for 40 min. The reaction mixture was poured in a saturated solution of NaHCO3 and extracted with EtOAc (50 ml×3). The combined organic phases were washed with a saturated solution of NaCl (30 ml×2) and concentrated under reduced pressure. The product was purified by column chromatography using CH2Cl2:MeOH (95:5) to yield 25 mg (17%) of the product. MS (EI) m/z: 310 (M+)
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]([OH:27])[CH3:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:1]([N:20]1[CH:24]=[C:23]([C:25](=[O:27])[CH3:26])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To 1-(1-trityl-1H-imidazol-4-yl)ethanol (8.06 g, 22.7 mmol) in dioxane (400 mL) is added manganese dioxide (9.9 g, 113.8 mmol). The reaction mixture is heated to 90° C. and stirred for 18 h. The reaction is allowed to cool to room temperature and filtered through diatomaceous earth. The filtered solvent is removed in vacuo to yield the product. MS (ESI) m/z 353 (M+H) (prepared similarly in Bioorg. Med. Chem. 2004, 12(9), 2251.)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]#[N:14])[C:6]#[CH:7].Cl[CH:16]([O:18]C(Cl)Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O.[N+](C)([O-])=O>[CH:16]([C:11]1[CH:10]=[C:9]([C:13]#[N:14])[N:8]([CH2:5][C:6]#[CH:7])[CH:12]=1)=[O:18]
Reactant: ClC(Cl)OC(Cl)Cl
Reactant: C#CCn1cccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: ClCCl
Product: C#CCn1cc(C=O)cc1C#N
Temperature: -78 °C
Reaction time: 1 h
Yield: 117 %

Procedure:
A mixture of 2.36 g of aluminium chloride in 6 ml of anhydrous methylene chloride was cooled to -78° C. and 1.3 g of the product of Step A in solution in 8 ml of methylene chloride and 0.5 ml of nitromethane were added. 1.49 g of dichloromethyl ether in solution in 15 ml of methylene chloride were added at -55° C. and the reaction mixture was kept for 1 hour at -60° C., then allowed to return to 20° C., at which temperature it was held for 18 hours. It was poured into water, stirred, and neutralized to pH 7 by addition of 33 ml of 2N sodium hydroxide. Extraction was with methylene chloride and the extracts were washed with a 1M potassium bicarbonate solution, dried and concentrated to dryness to obtain 1.5 g of 4-formyl-[(2-propynyl)]-1H-pyrrole-2-carbonitrile which was washed with dupentane and dried to obtain 1.1 g of the said product melting at 97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:16])=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:17](OCC)(=[O:21])[C:18]([CH3:20])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[N:16]=[C:18]([CH3:20])[C:17]2=[O:21])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Nc2ccc(Cl)cc2)c(N)c1
Reactant: CCOC(=O)C(C)=O
Product: Cc1ccc2c(c1)nc(C)c(=O)n2-c1ccc(Cl)cc1

Procedure:
Preparation as in Example 1 but using N-(4-chlorophenyl)-4-methylbenzene-1,2-diamine and ethyl pyruvate gave the title compound mp 223°-225° C.
Reaction SMILES: [CH3:1][C:2]1([OH:29])[CH2:7][CH2:6][CH:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[CH:20]4)[CH:10]=2)[CH2:3]1.[CH3:30]I>>[CH3:1][C:2]1([O:29][CH3:30])[CH2:7][CH2:6][CH:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[CH:20]4)[CH:10]=2)[CH2:3]1
Reactant: CC1CCC(C)(O)CC1c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Reactant: CI
Product: COC1(C)CCC(C)C(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)C1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 2, (1SR,3RS,4SR)-1,4-dimethyl-1-hydroxy-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]cyclohexane was reacted with methyl iodide to give (1SR,3RS,4SR)-1,4-dimethyl-1-methoxy-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]cyclohexane as an oil in 58% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15]O)[N:14]=2)[CH:9]=[CH:10][CH:11]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH3:17])=[C:13]([CH2:15][Cl:25])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CO)nc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cccc(C)c1CNc1cccn2c(C)c(CCl)nc12
Temperature: 5 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of 8-(2,6-dimethylbenzylamino)-2-hydroxymethyl-3-methylimidazo[1,2-a]pyridine (1.0 g, 3.4 mmol) in methylene chloride (50 ml) was added dropwise thionyl chloride (0.5 g, 3.4 mmol) solved in methylene chloride (10 ml) at 5° C. The reaction mixture was stirred 2 h. at 5° C. To the mixture was washed with a saturated bicarbonate solution, the organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure to give 1.0 g (93%) of the title compound.
Reaction SMILES: [CH3:1][C:2](=[O:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH3:6][C:5]1([CH2:4][CH2:3][C:2](=[O:8])[CH3:1])[O:11][CH2:10][CH2:9][O:7]1
Reactant: CC(=O)CCC(C)=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)CCC1(C)OCCO1

Procedure:
A commercially available hexan-2,5-dion (137 g) was dissolved in benzene (300 ml). Thereafter, ethylene glycol (100 ml) and p-toluenesulfonic acid (11.4 g) were added to the solution, and the mixture was then dehydrated by heating to reflux for 5 hours. The reaction product was diluted with ethyl acetate, and then washed with an aqueous saturated sodium bicarbonate solution and a saturated saline solution. The organic layer was then dried over anhydrous sodium sulfate. The solvent was-distilled off under a reduced pressure, and the residue was subjected to vacuum distillation (80° C. to 82° C./3 mmHg) to obtain 4-(2-methyl[1,3]dioxolan-2-yl)butan-2-one (56.83 g).