Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:37])=[C:24]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[O:29])[CH:25]=2)[NH:20][C:19](=[O:38])[C:18]=1[C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:37][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:19](=[O:38])[NH:20]2)=[CH:25][C:24]=1[NH:27][C:28]([NH:30][C:31]1[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccs2)c(=O)[nH]c2cc(Cl)c(NC(=O)Nc3ccncc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Nc1cc2c(OCCC3CCCCN3)c(-c3cccs3)c(=O)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-{2-[7-chloro-2-oxo-6-(3-pyridin-4-yl-ureido)-3-thiophen-2-yl-1,2-dihydroquinolin-4-yloxy]-ethyl }-piperidine-1-carboxylic acid tert-butyl ester in methylene chloride is added trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes, the mixture is concentrated in vacuo, resolvated in 10% ammonium hydroxide in methanol and concentrated once again. Purification by flash chromatography on silica gel gives the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O(C)[Na].[NH2:20][OH:21].Cl>CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([C:15](=[N:20][OH:21])[NH2:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C#N)o2)cc1
Reactant: NO
Agent: CO[Na]
Agent: Cl
Solvent: CO
Product: CC(=O)c1ccc(-c2ccc(C(N)=NO)o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 17.0 g (0.080) mole of 5-(4-acetylphenyl)-2-furonitrile, 4.24 g (0.080 mole) of NaOCH3 and 300 ml of anhydrous CH3OH was refluxed for 1 hour and then cooled to room temperature. After adding 5.16 g (0.080 mole) of NH2OH.HCl, the reaction was stirred at room temperature for 2 hours at near reflux for 15 minutes and then cooled in an ice bath. The resulting solid was filtered, air dried, and recrystallized from ethyl acetate/Darco to yield 4.5 g (23%). An analytical sample was prepared by drying a sample in the vacuum pistol at the temperature of refluxing CHCl3, m.p. 197°-199°.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27].C([N-]C(C)C)(C)C.[Li+]>>[CH3:28][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39]([CH:15]1[CH2:16][CH2:17][CH2:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]1=[O:19])=[O:40])[CH3:27]
Reactant: O=C1CCCCC1(CCCCCOc1ccccc1)c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1CCCC(CCCCCOc2ccccc2)(c2ccccc2)C1=O

Procedure:
The title compound, mp 150°-153° C., was prepared from 2-(5-phenoxypentyl)-2-phenylcyclohexanone (2.50 g, 0.007 mol), 2,6 diisopropylphenyl isocyanate (1.42 g, 0.007 mol), and lithium diisopropylamide (0.007 mol) using the procedure described in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1.[Cl-].[Li+].[CH:18](NC(C)C)([CH3:20])[CH3:19].C([Li])CCC.O=C1N([Li])C2C=CC=CC=2C(=O)C([Li])=C1OC.C(Br)C=C.Cl>O1CCCC1.O>[CH2:20]([C:4]1[C:5](=[O:15])[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[NH:8][C:9](=[O:10])[C:3]=1[O:2][CH3:1])[CH:18]=[CH2:19]
Reactant: CC(C)NC(C)C
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1c(OC)c(=O)[nH]c2ccccc2c1=O
Temperature: 20 °C
Yield: 34 %

Procedure:
A solution of 3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (10 g), lithium chloride (12.5 g) and diisopropylamine (7.5 mL) in tetrahydrofuran (200 mL) was cooled to -70° C.; and butyllithium (2.5M in hexanes, 43 mL) was added, maintaining the temperature below -60° C. The mixture was warmed to 20° C. for 1 hour, and cooled to -70° C. A portion of the resulting 2,5-dihydro-2,5-dioxo-1,4-dilithio-3-methoxy-1H-benz[b]azepine solution (0.188M in tetrahydrofuran, 26 mL) was added to a solution of allyl bromide (0.85 mL) in tetrahydrofuran (15 mL) at -70° C. The mixture was warmed to room temperature, diluted with water, acidified (2N hydrochloric acid) and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The solid was purified by chromatography, with ethyl acetate:toluene (1:3) as the eluent, to give the title compound (0.189 g, 34%); NMR: 5.77 (m,1); 4.99 (d,1) 4.94 (s,1) 3.29 (d,2); MS: m/z=244(M+1).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[CH:20]=[N:19][CH:18]=[N:17][CH:16]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cncnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cncnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 43.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyrimidin-5-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.075 mmol), β-alanine (672 mg, 7.54 mmol) and NaOMe solution (11 mL, 5.66 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 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 4, and the resulting precipitate was isolated by filtration to give 17 mg of the title compound as a yellow solid. MS: (+) m/z 522.23 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([CH2:8][C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7].Cl.[N:21]([O-])=[O:22].[Na+]>CO>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:4]=[C:5]([C:6](=[O:7])[C:8](=[N:21][OH:22])[C:9](=[O:14])[C:10]([O:12][CH3:13])=[O:11])[CH:15]=[CH:16][CH:17]=1
Reactant: O=N[O-]
Reactant: COC(=O)C(=O)CC(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)C(=NO)C(=O)c1cccc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
A solution was prepared by dissolving 40 g. of methyl 3-trifluoromethylbenzoylpyruvate in 300 ml. of methanol. N2O3Gas was slowly passed into the solution over a period of four hours (until all of the ester had dissolved plus one additional hour). N2O3 gas was generated by the dropwise addition of 12N aqueous hydrochloric acid into an aqueous slurry of sodium nitrite. Next, the solvent was removed from the reaction mixture and 200 ml. of water added to the residue. The aqueous mixture was extracted with three 300 ml. portions of ether. The ether extracts were separated, combined and the combined extracts dried. The ether was removed in vacuo leaving as a residue methyl 4-(3-trifluoromethylphenyl)-2,4-dioxo-3-oximinobutanoate formed in the above reaction.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][CH:13]([C:49]1[CH:54]=[CH:53][C:52]2[O:55][CH2:56][O:57][C:51]=2[CH:50]=1)[CH:14]([N:16]([CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[C:17]([CH2:19][CH:20]([C:33]([O:35]CC)=[O:34])[CH:21]([C:28]([O:30]CC)=[O:29])[CH2:22][C:23]([O:25]CC)=[O:24])=[O:18])[CH3:15].[OH-].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][CH:13]([C:49]1[CH:54]=[CH:53][C:52]2[O:55][CH2:56][O:57][C:51]=2[CH:50]=1)[CH:14]([N:16]([CH2:38][C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[C:17]([CH2:19][CH:20]([C:33]([OH:35])=[O:34])[CH:21]([C:28]([OH:30])=[O:29])[CH2:22][C:23]([OH:25])=[O:24])=[O:18])[CH3:15]
Reactant: CCOC(=O)CC(C(=O)OCC)C(CC(=O)N(Cc1ccc2ccccc2c1)C(C)C(C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C(C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)CC(C(=O)O)C(CC(=O)O)C(=O)O
Reaction time: 8 h
Yield: 52 %

Procedure:
The N-acylated compound obtained in the above step (1) was treated in the same manner as in Example 27 to obtain triethyl 4-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-1,2,3-butanetricarboxylate. The obtained ester was dissolved in 1 ml of tetrahydrofuran, and then 0.5 ml of a 3N sodium hydroxide aqueous solution was added thereto. The mixture was left to stand at room temperature overnight. The reaction solution was diluted with ethyl acetate and then acidified by an addition of 1N hydrochloric acid, and it was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography (Lobar column™, size A, RP-8, manufactured by Merck Co.; acetonitrile/0.1% trifluoroacetic acid aqueous solution=1/1) to obtain 14 mg (yield: 52%) of the above-identified compound as white powder.
Reaction SMILES: [C:1]([O:4][CH:5]([CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][C:13]=1[Cl:19])[CH2:6][C:7](=[O:9])[CH3:8])(=[O:3])[CH3:2].BrCC(OCC)=O.[Cl-:27].C([Al+]CC)C>C1COCC1.[Zn]>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:27])[C:12]=1/[CH:11]=[CH:10]/[CH:5]1[O:4][C:1](=[O:3])[CH2:2][C:7]([OH:9])([CH3:8])[CH2:6]1
Reactant: [Cl-]
Reactant: CC(=O)CC(C=Cc1ccc(Cl)cc1Cl)OC(C)=O
Agent: CCOC(=O)CBr
Agent: CC[Al+]CC
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(/C=C/c2c(Cl)cccc2Cl)C1
Reaction time: 5 h
Yield: 92.7 %

Procedure:
A solution of 6-(2,4-dichlorophenyl)-2-oxo-5-hexene-4-yl acetate (1.3 g, 4.3 mmole) and ethyl bromoacetate (0.47 ml, 4.2 mmole) in dry THF (10 ml) was added dropwise to a vigorously stirred slurry of activated zinc dust (490 mg, 7.5 mmole), cuprous bromide (29 mg, 0.2 mmole), diethylaluminum chloride (25% solution in toluene; 1.72 ml, 4.3 mmole) and dry THF (5 ml) under N2 at 20° C. Stirring was continued for 5 hours before quenching with pyridine (3.5 ml). After the addition of water (50 ml) the mixture was extracted with ether (3×80 ml). The combined ether extracts were washed with 1N HCl (2×25 ml), H2O (2×50 ml) and brine, then dried (MgSO4), filtered and evaporated leaving the crude title compound as a pale yellow oil (1.2 g); pmr (CDCl3) δ1.28 (3H, t), 1.33 (3H, t), 2.10 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[N:18]\[OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: O/N=C\c1ccc(OCc2ccccc2)cc1

Procedure:
To 4-(benzyloxy)benzaldehyde (12.9 g) in MeOH (129 ml), Hydroxylamine hydrochloride (6.34 g) was added and the reaction mixture was refluxed for 3 hours and then cooled. The reaction mixture was concentrated to obtain pale brown residue. To this residue, water was added and it was extracted with EtOAc. Organic layer was collected, dried over Na2SO4 and concentrated to obtain off white solid, which was crystallized from DCM-Petroleum ether to obtain the title compound as white solid. Yield: 11.5 g (83%); 1HNMR (DMSO-d6; 300 MHz): δ 10.98 (s, 1H), 8.06 (s, 1H), 7.53 (d, 2H), 7.33-7.46 (m, 5H), 7.05 (d, 2H), 5.13 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1)([O-])=O>[Fe].CC(O)=O>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]1
Reactant: COC(=O)N1CCN(C2CCc3c2cccc3[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)N1CCN(C2CCc3c(N)cccc32)CC1
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a room temperature solution of methyl 4-(4-nitro-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate (216 mg, 0.71 mmol, 1.0 equiv) in MeOHH (2.8 mL) and glacial HOAc (2.8 mL) was added iron powder (198 mg, 3.54 mmol, 5.0 equiv) as a solid in one portion. After stirring overnight, the reaction mixture was concentrated in vacuo and then diluted with EtOAc and 3 N NaOH. The organic layer was washed with brine and concentrated in vacuo to provide the title compound as a brown oil (180 mg, 92%).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:12][O:13][C:14]1[C:19]2[O:20][C:21]([CH2:23][CH2:24]O)=[CH:22][C:18]=2[CH:17]=[CH:16][CH:15]=1.[NH3:26]>O1CCCC1>[CH3:12][O:13][C:14]1[C:19]2[O:20][C:21]([CH2:23][CH2:24][NH2:26])=[CH:22][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: N
Reactant: COc1cccc2cc(CCO)oc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Product: COc1cccc2cc(CCN)oc12
Yield: 76 %

Procedure:
A mixture of 26.7 g of the tosylate of 7-methoxy-3-benzofuranethanol (Example 2a), prepared as described in Example 1b, 300 ml of tetrahydrofuran and 100 g of ammonia was heated in a pressure vessel to 100° for 4 hours. The crude product was partitioned into basic and neutral fractions, and the basic fraction short-path distilled (to 170° bath temperature, 1 micron pressure) to give 11.2 g (76%) of 7-methoxy-3-benzofuranethylamine; nmr spectrum (in CDCl3): τ2.6 (s, 1); 2.9-3.4 (m, 3); 6.1 (s, 3); 6.9-7.5 (m, 4) and 8.9 (s, 2).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:18]#[N:19].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C.C[O-].[Na+]>C(O)C>[NH2:19][C:18]1[C:3]2[C:4]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[C:5]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]3=[N:7][C:2]=2[S:1][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: N#Cc1c(S)nc2c(c1-c1cccs1)CCCCC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CCCCC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-mercapto-4-thien-2-yl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carbonitrile (143 mg, 0.5 mmol), tert-butyl bromoacetate (97 mg, 0.5 mmol) and triethyl amine (51 mg, 0.5 mmol) in ethanol (20 mL) was stirred at room temperature overnight, followed by the addition of NaOMe (30 mg, 0.56 mmol). The mixture was then refluxed for 30 min., and poured onto ice. The precipitate is filtered and washed with water to furnish pure t-butyl 3-amino-4-thiophen-2-yl-6,7,8,9-tetrahydro-5H-1-thia-10-aza-cyclohepta[f]indene-2-carboxylate.
Reaction SMILES: C[Mg]Br.[CH2:4]([C:8]1[N:9]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]([C:17]#[N:18])=[C:11]([C:13](=[O:16])[CH2:14][CH3:15])[N:12]=1)[CH2:5][CH2:6][CH3:7].[Cl-].[NH4+].[C:40](OCC)(=O)C>O1CCCC1>[CH2:4]([C:8]1[N:9]([C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:10]([C:17]#[N:18])=[C:11]([C:13]([OH:16])([CH3:40])[CH2:14][CH3:15])[N:12]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCOC(C)=O
Reactant: CCCCc1nc(C(=O)CC)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCc1nc(C(C)(O)CC)c(C#N)n1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
5 ml of a 1M solution of methylmagnesium bromide in tetrahydrofuran were added dropwise at 10° C. under an atmosphere of nitrogen to a solution of 2 g of 2-butyl-5-cyano-4-propionyl-1-tritylimidazole (prepared as described in Preparation 15) in 36 ml of tetrahydrofuran, and the resulting mixture was stirred at 20° C. for 1 hour and subsequently at 30° C. for a further 1 hour. At the end of this time, a mixture of a saturated aqueous solution of ammonium chloride and ethyl acetate was added to the reaction mixture, which was then well shaken. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. After the drying agent had been removed by filtration, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.29 g of the title compound as crystals, melting at 90°-93° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([O:11][CH2:12][CH:13]=C)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:16]=[O+][O-].CSC>ClCCl>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:11][CH2:12][CH:13]=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=[O+][O-]
Reactant: C=CCOC(C(=O)OC)c1ccccc1
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)C(OCC=O)c1ccccc1
Temperature: -75 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Allyloxy-phenyl-acetic acid methyl ester (described in EJOC 2000, 3145-3163; 3 g, 14.5 mmol) was dissolved in dichloromethane (300 mL) and cooled to −75° C. O3 was blubbled through the solution for 6 hours until the solution turned blue. Argon was blubbled through the solution for 1 hour, then dimethyl sulfide (9.04 g, 10.8 mL, 145 mmol) was added to the reaction mixture and kept at room temperature for 12 hours. The reaction mixture was evaporated and the residue purified by flash chromatography over 50 g SiO2-flash pack using gradient 10-100% EtOAc in heptane over 60 minutes to give the title compound as light yellow oil (2.72 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[S:14]([N:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)(=[O:16])=[O:15].Cl.CCOC(C)=O>C(Cl)Cl.O1CCOCC1>[Cl:1][C:2]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc([N+](=O)[O-])ccc2Oc2cc(Cl)ccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ccc2Cl)c(S(=O)(=O)N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.4 %

Procedure:
To a solution of compound 39 (0.100 g, 0.19 mmol) in DCM (6.00 mL) was added 1N HCl in 1,4-dioxane (0.570 mL). The reaction was monitored with TLC (25% EtOAc in hexanes, Rt=0.0). The reaction was complete after stirring at room temperature for 16 hrs, as indicated by the absence of the starting material). The reaction mixture was concentrated and the residual was redissolved in MeOH (2.00 mL). Et2O (4.00 mL) was then added and the mixture was stirred until precipitate formed (10 min). The solid was collected by filtration to yield compound 40 as a white solid (0.080 g, 100% HPLC purity, 83% yield). 1H NMR (500 MHz, DMSO-d6): δ 9.39 (s, 2H), 8.61 (d, J=2 Hz, 1H), 8.45 (dd, J1=3 Hz, J2=9 Hz, 1H), 7.78 (d, J=9 Hz, 1H), 7.73 (d, J=2 Hz, 1H), 7.53 (dd, J1=2 Hz, J2=8 Hz, 1H), 7.12 (d, J=8 Hz, 1H), 3.57 (m, 4H), 3.16 (m, 4H).
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(OCC)=O)C.[Li+].CC([N-]C(C)C)C.[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:46](=[O:56])[CH2:45]1)=O>C1COCC1>[C:22]1([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:13]2[CH:14]=[C:10]([CH:9]=[CH:42][CH:44]3[CH2:49][CH2:48][N:47]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:46](=[O:56])[CH2:45]3)[N:11]=[CH:12]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CC1CCN(c2ccccc2)C(=O)C1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CC(C=Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCN1c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
The product from Step H is dissolved in THF and cooled to -78° C. under nitrogen. A solution of LDA in THF is added dropwise. The reaction is stirred at -78° C. for 1 h, then a solution of 4-formyl-1-phenyl-2-piperidinone from Step E is added, and the reaction warmed to room temperature overnight. The reaction is quenched with ammonium chloride solution, and extracted with ethyl acetate. The title compound is obtained after chromatography on silica gel
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:39])=[C:7]([CH:38]=1)[CH2:8][N:9]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C@H:16]([CH3:30])[CH2:17][CH2:18][NH:19][C:20]([C:22]2[C:23]([CH3:29])=[N:24][CH:25]=[N:26][C:27]=2[CH3:28])=[O:21])[CH2:12][CH2:11]1)#[N:2].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:45]([O:44][C:42](=[O:43])[CH2:41][O:37][C:34]1[CH:33]=[CH:32][C:31]([N:9]([CH2:8][C:7]2[CH:38]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[F:39])[CH:10]2[CH2:11][CH2:12][N:13]([C@H:16]([CH3:30])[CH2:17][CH2:18][NH:19][C:20]([C:22]3[C:27]([CH3:28])=[N:26][CH:25]=[N:24][C:23]=3[CH3:29])=[O:21])[CH2:14][CH2:15]2)=[CH:36][CH:35]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(O)cc2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc(OCC(=O)OC(C)(C)C)cc2)CC1
Temperature: 80 °C
Yield: 72.6 %

Procedure:
A mixture of COMPOUND 233 (100 mg, 0.188 mmol), t-butyl bromoacetate (37 mg, 0.19 mmol) and K2CO3 (39 mg, 0.28 mmol) in DMF (1.9 mL) were heated at 80° C. for 18 h to give COMPOUND 235 as a yellow foam (88 mg, 72%) following work-up and purification. 1H NMR (CDCl3) δ 0.92-1.03 (m, 1H), 1.01 (d, 3H, J=6.6 Hz), 1.08-1.20 (m, 1H), 1.46 (s, 9H), 1.52-1.63 (m, 1H), 1.76 (m, 3H), 2.16 (m, 1H), 2.50 (s, 6H), 2.54 (m, 1H), 2.68-2.95 (m, 3H), 3.31-3.46 (m, 2H), 3.82 (m, 1H), 3.92 (s, 2H), 4.41 (s, 2H), 6.58 (m, 2H), 6.73 (m, 2H), 7.16 (m, 1H), 7.51 (m, 2H), 8.30 (m, 1H), 8.83 (s, 1H). ES-MS m/z 645 (M+H).