Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[CH2:6]([SH:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[C:18]([Cl:31])=[C:19]([CH:24]=[CH:25][C:26]=1[S:27]([CH3:30])(=[O:29])=[O:28])[C:20]([O:22][CH3:23])=[O:21]>C(Cl)(Cl)Cl>[Cl:31][C:18]1[C:17]([CH2:16][S:8][CH2:6][CH3:7])=[C:26]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Reactant: CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCSCc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
To 100 ml of tetrahydrofuran, 1.3 g of ethanethiol and 1.5 g of potassium carbonate and then 4.4 g of methyl 3-bromomethyl-2-chloro-4-methanesulfonylbenzoate were added, and the mixture was stirred for 1 day at room temperature. Then, the mixture was stirred further for 1 hour at a temperature of from 50° to 60° C. After cooling, chloroform was added thereto, and the mixture was washed with a dilute potassium carbonate aqueous solution. The chloroform layer was separated and dried. Then, the solvent was distilled off to obtain 4.1 g of methyl 2-chloro-3-ethylthiomethyl-4-methanesulfonylbenzoate as an oily substance.
Reaction SMILES: [CH:1]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[C:10]1[CH2:15][CH2:14][CH2:13][S:12][CH:11]1[C:16](OC)=[O:17].C[O-].[Na+]>C(O)C>[CH:1]1([C:6]2[N:8]=[C:16]([OH:17])[C:11]3[S:12][CH2:13][CH2:14][CH2:15][C:10]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1SCCCC1=O
Reactant: N=C(N)C1CCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1nc(C2CCCC2)nc2c1SCCC2
Temperature: 85 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
To a solution of cyclopentanecarboximidamide (3.2 g, 28.0 mmol) in ethanol (150 mL) was added methyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate (4.95 g, 28.0 mmol) and sodium methoxide (1.5 g, 28.0 mmol). The mixture was stirred at 85° C. for 16 h. The ethanol was removed under vacuum and the residue was diluted with water and extracted with methylene chloride. The organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was diluted with hexanes and the solid was filtered to afford the title compound (2.9 g, 44%) as a white solid. MW=236.33. 1H NMR (CDCl3, 500 MHz) δ 11.41 (s, 1H), 3.13-2.99 (m, 1H), 2.99-2.94 (m, 2H), 2.81-2.70 (m, 2H), 2.21-2.14 (m, 2H), 2.14-2.04 (m, 2H), 1.92-1.79 (m, 4H), 1.73-1.64 (m, 2H); APCI MS m/z 237 [M+H]+.
Reaction SMILES: FC1C=CC(C([N:8]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]2[CH:15]=[C:16](C2C=C(F)C=CC=2C([O-])=O)[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)=CC=1.[OH2:36].[ClH:37]>>[ClH:37].[CH3:13][C:12]1[N:8]=[C:9]([CH2:15][C:16]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:36])[NH:10][C:11]=1[CH3:14]
Reactant: O
Reactant: Cc1nc(C=C(c2ccc(F)cc2)c2cc(F)ccc2C(=O)[O-])n(C(=O)c2ccc(F)cc2)c1C
Agent: Cl
Product: Cc1nc(CC(=O)c2ccc(F)cc2)[nH]c1C
Yield: 10 %

Procedure:
12.97 g crude compound of Example III are refluxed 1.5 h in 200 ml concentrated hydrochloric acid. The mixture is cooled to rT and 200 mL water are added. The solution is extracted twice with toluene and the aqueous phase is concentrated under vacuum. The residue is stirred with ethanol, filtered, washed once with ethyl acetate and once with petrol ether and dried to yield 0.74 g (10% of th.) 2-(4,5-Dimethyl-1H-imidazol-2-yl)-1-(4-fluorophenyl)ethanone hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:16]3[N:20](CCC#N)[N:19]=[N:18][N:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@H:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[C:16]3[NH:20][N:19]=[N:18][N:17]=3)=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)c1nnnn1CCC#N
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)c1nnn[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a suspension of (S)-tert-butyl 2-(3′-chlorobiphenyl-4-yl)-1-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)ethylcarbamate (300 mg, 0.662 mmol) in DCM (3 ml) at room temperature was added DBU (2 ml, 13.27 mmol), and the solution was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated reduced pressure. The obtained residue was purified by reverse phase HPLC [30 to 95% ACN-water (0.1% TFA) over 10 min by Sunfire C18 column] and gave the title compound: 250 mg (yield: 94%). LCMS (condition F): 400.1 (M+1); retention time=1.28 min.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[CH:19]1([CH2:22][CH2:23][CH2:24][CH2:25]O)[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][CH2:23][CH2:24][CH2:25][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)[CH2:21][CH2:20]1
Reactant: OCCCCC1CC1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCCCC2CC2)cc1
Yield: 88 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (251 mg, 1.00 mmol) prepared in Example 1 (1a) and 4-cyclopropylbutan-1-ol (which is the compound disclosed in J. Med. Chem., (1998), 41, 1112-1123, 137 mg, 1.20 mmol) to give 257 mg of the title compound (white powder, yield: 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].C([Mg]Cl)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([C:34](OC)=[O:35])[N:31]([CH3:38])[C:28]2=[CH:29][N:30]=1>O1CCCC1>[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([C:34]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([B:10]4[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]4)=[CH:9][C:3]=3[O:2][CH3:1])=[O:35])[N:31]([CH3:38])[C:28]2=[CH:29][N:30]=1
Reactant: COC(=O)c1cc2cc(OC)ncc2n1C
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3OC)n(C)c2cn1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.09 g, 8.37 mmol) in tetrahydrofuran (20 ml) under a nitrogen atmosphere was added ethylmagnesium chloride, 2.0 M in tetrahydrofuran (4.19 ml, 8.37 mmol) and the mixture was heated at reflux for one hour. To the warm reaction was added methyl 5-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (878 mg, 3.99 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was heated overnight. Then the reaction mixture was cooled to room temperature and concentrated. The residue was taken up in ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was coated on hydromatrix and purified by flash chromatography (gradient of heptane to heptane/ethyl acetate 1/1) to give 5-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (1.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])[NH2:5].[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:11]=[O:12])[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(Cl)c(Cl)c(Cl)c1

Procedure:
A mixture of 3,4,5-trichloroaniline (400 mg; 2 mmol) in toluene (15 ml) and phosgene (6 ml 20% in toluene; 12 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4,5-trichlorophenylisocyanate. To the crude product was added 3-[4-(4-chlorophenyl) -1-piperazinyl]propanol (510 mg; 2.0 mmol) in toluene (30 ml) and refluxed for 16 h. The solvent was evaporated rated and the residue resuspended in ethyl acetate, filtered and evaporated to dryness. The residue was submitted to flash chromatography on silica gel 60 eluting with toluene/ethyl acetate (1:1) graduated to toluene/ethyl acetate (1:3). The product was taken up in ethanol, which was treated with hydrogen chloride in ether to give 730 mg of the title compound. M.p. 211°-212° C. MS (70 eV): m/z 477 (4%, M+), 254 (56), 221 (59), 209 (100), 158 (35), 138 (25), 111 (20), 70 (45).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:17]([F:29])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[F:29][C:17]1[C:18]([C:20]2[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:31](=[O:32])[CH2:30][OH:33])[CH2:3]3)=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@@H](N)C4)cc3)ncc2F)n1C(C)C
Reactant: O=C(O)CO
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@@H](NC(=O)CO)C4)cc3)ncc2F)n1C(C)C

Procedure:
The title compounds was prepared (38 mg, 15%), was prepared using a procedure analogous to Example 155 starting from N-{4-[(3R)-3-aminopyrrolidin-1-yl]phenyl}-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 156; 220 mg, 0.556 mmol) and glycolic acid (51 mg, 0.667 mmol). NMR: 1.39 (d, 6H), 1.92-2.04 (m, 1H), 2.14-2.26 (m, 1H), 2.44 (s, 3H), 3.04-3.13 (m, 1H), 3.18-3.49 (m, 3H), 3.80 (d, 2H), 4.46-4.51 (m, 1H), 5.34 (t, 1H), 5.42-5.51 (m, 1H), 6.49 (d, 2H), 7.31 (d, 1H), 7.35 (d, 2H), 7.82 (d, 1H), 8.41 (d, 1H), 9.06 (s, 1H); m/z 454.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[CH3:31])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
10.0 g of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 10 ml of triethylamine were dissolved in 50 ml of dioxane, and the resulting mixture was cooled with ice. To the mixture was added 7.0 g of 2-methylbenzoyl chloride, and the resulting mixture was allowed to stand at room temperature for 30 minutes and then at 45° C. for 60 minutes. The crystals formed were filtered off, and the filtrate was concentrated under reduced pressure. The thus obtained oily residue was dissolved in 50 ml of ethanol by application of heat. After being cooled, the solution was inoculated, and there was obtained 2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(2-methylbenzoyl)-uridine) as crystals. Recrystallization of the product from ethanol afforded 11.3% (yield: 84.0%) of colorless prismatic crystals having a melting point of 108° to 109° C. The structure of the product was supported by the absorption spectra and elemental analysis.
Reaction SMILES: [CH2:1]([S:3][C:4]([O:6][Si](C)(C)C)=[CH2:5])[CH3:2].[CH2:11]([O:18][CH2:19][CH:20]=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.CO>C1(C)C=CC=CC=1>[CH2:11]([O:18][CH2:19][CH:20]([OH:21])[CH2:6][C:4](=[O:5])[S:3][CH2:1][CH3:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCOCc1ccccc1
Reactant: C=C(O[Si](C)(C)C)SCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCSC(=O)CC(O)COCc1ccccc1
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 21.5 mg (0.05 mmol) of (R)-1 in 3 ml of toluene were added 176 mg (1 mmol) of 1-ethylthio-1-(trimethylsilyl)oxyethene and 150 mg (1 mmol) of α-benzyloxyacetaldehyde at 0° C. After stirring for 2 hours at that temperature, the resultant mixture was poured into 10 ml of a buffer (pH 7) at 0° C. The solution was filtered through a pad of Celite, and the filtrate was extracted three times with a 5 ml portion of diethyl ether. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give a crude product in a silylated form. The crude product was poured into 10% hydrochloric acid-methanol, and the mixture was purified by silica gel chromatography (eluent: hexane/ethyl acetate=20/1 by volume) to obtain S-ethyl 4-benzyloxy-3-hydroxybutanethioate in a yield of 84%.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[CH2:15](O)[CH2:16][CH3:17]>C1C=CC=CC=1>[C:1]([O:14][CH2:15][CH2:16][CH3:17])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: CCCO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Solvent: c1ccccc1
Product: CCCOC(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 78 °C
Reaction time: 15 h
Yield: 64.3 %

Procedure:
In a three-necked flask, 19.4 g (0.1 mole) of ferulic acid, 6.01 g (0.1 mole) of n-propyl alcohol, and 1.0 g of paratoluenesulfonic acid were placed, and 200 ml of benzene was added. This reaction mixture was stirred at 78° C. for 15 hours. Thereafter, the same procedures were taken as in Example 1 to obtain 15.2 g (yield: 64%) of n-propyl ferulate.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][CH2:19]3)=[C:14]([O:28][CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.BrC1N=C(NC2C=CC(N3CCN(C4COC4)CC3)=CC=2)C2N(C=CN=2)C=1.BrC1N=C(N(C2C=CC(N3CCN(C4COC4)CC3)=CC=2)[C:76](=[O:82])[O:77][C:78]([CH3:81])([CH3:80])[CH3:79])C2N(C=CN=2)C=1>>[Br:1][C:2]1[N:3]=[C:4]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:22][CH2:23]3)=[C:14]([O:28][CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH:13]=2)[C:76](=[O:82])[O:77][C:78]([CH3:81])([CH3:80])[CH3:79])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCN(C3COC3)CC2)cc1)c1nc(Br)cn2ccnc12
Reactant: Brc1cn2ccnc2c(Nc2ccc(N3CCN(C4COC4)CC3)c(OCCOC3CCCCO3)c2)n1
Agent: Brc1cn2ccnc2c(Nc2ccc(N3CCN(C4COC4)CC3)cc2)n1
Product: CC(C)(C)OC(=O)N(c1ccc(N2CCN(C3COC3)CC2)c(OCCOC2CCCCO2)c1)c1nc(Br)cn2ccnc12

Procedure:
6-Bromo-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)imidazo[1,2-a]pyrazin-8-amine XXV (1.2 g, 2.4 mmol) was reacted according to the analogous method described in Intermediate Example 1.01 (conversion of III to IV) to provide tert-butyl (6-bromoimidazo[1,2-a]pyrazin-8-yl)(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)carbamate XXVI.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O.C([OH:42])C>C(OCC)(=O)C.O>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:42])[CH:7]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: CCO
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccnc(Cl)c3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1cc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc([N+](=O)[O-])cc3)cc2)cc[nH]1

Procedure:
2-Chloro-4-{4-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-phenyl}-pyridine (1.6 g, 3 mmol) was refluxed with 6M NaOH in 1/1 water/ethanol (10 mL, 60 mmol) for 2 to 4 hours, followed by regular ethyl acetate/water workup and silica gel column chromatography to give the intermediate 4-{4-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-phenyl}-1H-pyridin-2-one, which was then treated as described in general procedure L [using iodocyclohexane (0.78 mL, 6 mmol)] to give 1-cyclohexyl-4-{4-[4-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1H-imidazol-2-ylmethyl]-phenyl}-1H-pyridin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=2)[CH2:32][CH2:31]1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cc(CCCN3CCN(c4ccccc4F)CC3)nn2-c2ccccc2)cc1

Procedure:
57 mg (70%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (55 mg, 0.187 mmol), 1-(2-fluorophenyl)piperazine (0.027 mL, 0.170 mmol), DIPEA (0.030 mL, 0.170 mmol) and NaBH(OAc)3 (108 mg, 0.510 mmol).
Reaction SMILES: [CH:1]1(C2(C3C=CC(OC)=C(OC)C=3)CC(=O)C3C(=CC(O)=CC=3)O2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(OCC)(=[O:36])C>CO>[OH:36][C@@H:1]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCOC(C)=O
Reactant: COc1ccc(C2(C3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)CC(=O)c3ccc(O)cc3O2)cc1OC
Solvent: CO
Product: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
Compound (3), was obtained as a pale yellow crystalline mass from (ethyl acetate:methanol; 9:1) eluants. It responded to positive tests of flavonoid glycosides. Its IR spectrum showed characteristic absorption suggested that a flavanone was an aglycone moiety possessing one hydroxyl group in ring A and two methoxy groups in ring B. Further analysis indicated that (3) was an acyclic sesquiterpenic acid possessing three vinylic linkages at carbons C3″, C7″ (14″) and C-10″ was esterified with the sugar moiety. The 1H NMR spectrum of (3) exhibited the presence of aromatic carbons and sugar carbons. Acid hydrolysis of (3) yielded β-D-glucose as a glycone moiety (TLC comparable). On the basis spectral data analysis of (3), the structure has been established as 6″-(3′″,11′″-dimethyl-dodec-3′″,7′″(14′″) 10′″-trienyl glucopyranosyl-7-hydroxy-3′,4′-dimethoxyflavanone.
Reaction SMILES: [CH2:1]([NH:11][C:12]([NH:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[H-].[Na+].Br[CH2:26][CH2:27][CH2:28]Br.Cl>CN(C=O)C>[CH2:1]([N:11]1[CH2:28][CH2:27][CH2:26][N:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: BrCCCBr
Reactant: C=CCCCCCCCCNC(=O)NOCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCN1CCCN(OCc2ccccc2)C1=O
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of 9-decenyl isocyanate, prepared as in Example 18 above from 10.8 ml of 10-undecenoyl chloride in 1,2-dichloroethane (150 ml) at room temperature was added benzyloxyamine (7.2 g). After 20 minutes, the mixture was evaporated, hexane (50 ml) was added, and the mixture cooled to 0° C. The resulting solids were collected by filtration, to provide N-(9-decenyl)-N'-benzyloxyurea as a white solid (7.14 g, mp 53°-55° C.). To a stirred slurry of this urea (3.50 g, 11.65 mmol) in DMF (35 ml) at room temperature under nitrogen was added sodium hydride (490 mg of a 60% dispersion in oil). After one hour, 1,3-dibromopropane (1.45 ml) was added, and the reaction was stirred for two hours. The mixture was poured into 1% aqueous HCl (200 ml), and extracted twice with ether. The combined extracts were washed with water, dried (MgSO4), filtered and evaporated. Purification by chromatography on silica gave 3-decyl-1-benzyloxy-3,4,5,6-tetrahydro-lH-pyrimidin-2-one as a colorless oil (1.92 g, 48% yield). Hydrogenolysis as in Example 2 above provided the title compound as a light magenta solid, after recrystallization from carbon tetrachloride, mp 45°-46° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:33]([C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1)([O-:35])=[O:34]>ClCCl>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:44])=[CH:40][CH:41]=1)([O-:35])=[O:34]
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.2 g, 0.54 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (0.135 g, 1.34 mmol) (Aldrich), followed by the addition of 1-nitro-4-isocyanato-benzene (0.105 g, 0.64 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with wthyl acetate. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-nitro-phenyl)-amide as a yellow solid (Yield 0.19 g, 68%).
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](O)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:28])=O>CN(C)C=O>[C:1]([S:4][CH:5]1[N:8]([CH:9]([Cl:28])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1.15 h

Procedure:
To a mixture of acid 1 (10.0 g, 79 mmoles) in 100 ml of oxalyl chloride was added one drop of dimethylformamide. The mixture was stirred for 1.15 h at 23° and then the excess oxalyl chloride was distilled off at 23° and 10-20 torr to give acid chloride 2 as a brown oil, 11.4 g (100%). ##STR178##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[CH:18]([OH:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[O:21][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Oc1ccc(N)cc1Br
Temperature: 80 °C

Procedure:
3-Bromo-4-fluoronitrobenzene (1.0 eq) was added to a stirring solution of potassium carbonate (2.0 eq) in isopropanol. The solution was heated for 4 days at 80° C. The solution was cooled and filtered through Celite and the plug washed with EtOAc. The organic layer is then washed with brine and water, dried over MgSO4, filtered and concentrated to yield the desired product. Rt=8.72 min.