Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[NH:19][CH:18]=2)=[CH:13][CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2]>N.CO.[Pd]>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:14]1[CH2:13][CH2:12][CH:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[CH2:16][CH2:15]1
Reactant: CCN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Pd]
Agent: N
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)C1CCC(c2c[nH]c3ccc(N)cc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
A solution of compound 118 (0.55 g, 1.427 mmol) in 2 M NH3 in methanol (10 mL) was treated with Pd—C (0.05 g) and flushed with hydrogen gas. The reaction was stirred at room temperature overnight (16 h) under hydrogen atmosphere (balloon pressure). The solution was filtered through a celite bed using methanol washes (2×10 mL). The solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 2.5:97.5) to obtain compound 119 (0.43 g, 84%) as a solid in 2:3 ratio of diastereomers. 1H NMR (DMSO-d6) δ: 0.99, 1.07 (2t, 3H, J=7.2, 6.6 Hz), 1.37-1.51 (m, 11H), 1.63-1.78 (m, 4H), 2.01-2.18 (m, 2H), 2.98-3.04 (m, 1H), 3.11-3.17 (m, 2H), 3.68-3.80 (m, 1H), 4.52 (brs, 2H), 6.44-6.47 (m, 1H), 6.66-6.70 (m, 1H), 6.86-6.88, 6.99-7.06 (2m, 2H), 10.23, 10.27 (2s, 1H); ESI-MS m/z (%): 380 (M+Na, 6), 358 (MH+, 5), 302 (100), 258 (54); ESI-HRMS calculated for C21H32N3O2 (MH+). Calculated: 358.2507: Observed: 358.2489.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=O)[C:5]([CH:9]=O)=[CH:6][C:7]=1[Cl:8].[C:13]1(=[O:20])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[C:4](=[CH:11][C:18]3[C:13](=[O:20])[C:14]4[C:15]([C:16](=[O:19])[C:17]=3[CH:9]=2)=[CH:11][C:4]2[C:5](=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:9]=4)[CH:3]=1
Reactant: O=C1CCC(=O)CC1
Reactant: O=Cc1cc(Cl)c(Cl)cc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2cc3cc(Cl)c(Cl)cc3cc2C(=O)c2cc3cc(Cl)c(Cl)cc3cc21
Temperature: 25 °C

Procedure:
4,5-Dichlorobenzene-1,2-dicarbaldehyde (2.0 g, 9.90 mmol) and 1,4-cyclohexanedione (0.62 g, 5.53 mmol) were stirred in 60 mL ethanol. To this was added dropwise with stirring, 10 mL of 5% aq potassium hydroxide. Upon addition of first drop, solution became black, brown, and then solids precipitate. Reaction mixture was stirred at RT for 1 h and refluxed for 2 h. Reaction mixture was cooled to RT, solids filtered, washed with water, dried to give 2,3,9,10-tetrachloro-6,13-pentacenequinone as brown solids in good yields (1.73 g, 70%). LDI-MS m/z: 446 [M+].
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.[NH2:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][OH:56]>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:31]=[CH:32][C:33]([C:34]([NH:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][OH:56])=[O:35])=[CH:37][CH:38]=4)[C:17]=3[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=2)=[CH:11][N:10]=1
Reactant: NCCOCCO
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(C(=O)NCCOCCO)cc2)cn1
Yield: 10 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (38 mg) obtained in Step A in Example 1-D-19 and 2-(2-aminoethoxy)ethanol (6 μl) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-N-[2-(2-hydroxy-ethoxy)-ethyl]-benzamide was obtained, and further PMB group was removed according to the above Deprotection method 3, to obtain the desired compound (D-179) as a colorless powder (3 mg, 10%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10])[CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[S:16][C:17]([C:23]2[C:28]([F:29])=[CH:27][C:26]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:25][C:24]=2[F:34])=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21]>>[F:34][C:24]1[CH:25]=[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])[CH:27]=[C:28]([F:29])[C:23]=1[C:17]1[S:16][C:15]([NH:14][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10])[N:7]=2)=[C:19]([C:20]([NH2:22])=[O:21])[CH:18]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: CNC(=O)C(O)c1cccc(Br)n1
Product: CNC(=O)C(O)c1cccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-(6-bromopyridin-2-yl)-2-hydroxy-N-methylacetamide (94 mg, 0.38 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (126 mg, 0.40 mmol) as starting materials.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[F:15][CH2:16][CH2:17]I.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[F:15][CH2:16][CH2:17][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCF)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.2 mmol), 1-fluoro-2-iodoethane (0.049 g, 0.28 mmol, SynQuest Labs, Cat. No. 1100-k-18), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1.0 mL) in a sealed reaction vial was heated at 90° C. with stirring overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 19 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[O:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][N:7]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:24]1([CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:23][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([NH:1][CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][CH2:33][CH2:32][CH2:31][CH2:30][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:36][CH:37]=3)[C:11]=2[O:10][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1
Reactant: O=Cc1ccc(OCCCCc2ccccc2)cc1
Reactant: CCOC(=O)C1CN(CCCC(=O)OC)c2cccc(N)c2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)C1CN(CCCC(=O)OC)c2cccc(NCc3ccc(OCCCCc4ccccc4)cc3)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 8-amino-4-(4-methoxy-4-oxobutyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (80 mg; prepared by subjecting the compound prepared in Example 3 to the same procedure as described in Example 29) and 4-(4-phenylbutoxy)benzaldehyde (60 mg) were dissolved in 1,2-dichloroethane (4 mL), and to this solution was added sodium triacetoxyborohydride (96 mg) with ice cooling, and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The extract was washed sequentially with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=8:2) to give the title compound (121 mg) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH3:25].[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][CH:36]=[C:37]([CH:39]=O)[N:38]=2)[CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([CH2:39][C:37]3[N:38]=[C:34]([N:31]4[CH2:30][CH2:29][CH:28]([OH:27])[CH2:33][CH2:32]4)[S:35][CH:36]=3)[CH2:20][CH2:19]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH3:25]
Reactant: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCNCC1
Reactant: O=Cc1csc(N2CCC(O)CC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCN(Cc2csc(N3CCC(O)CC3)n2)CC1
Reaction time: 1 h

Procedure:
The product from step 2 (3.63 mmol) was dissolved in 1,2-dichloroethane (7.26 mL), and 2-(4-Hydroxy-piperidin-1-yl)-thiazole-4-carbaldehyde (771 mg, 3.63 mmol) was then added. This solution was stirred for 1 h, then NaBH(OAc)3 (1.54 g, 7.26 mmol) was added. The solution was stirred for 2 h, then diluted with CH2Cl2. The solution was washed with sat. aq. NaHCO3, then brine. The organic was dried over MgSO4, filtered, and concentrated to give the crude product. This was carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl>[OH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:19]([CH:16]2[CH2:18][CH2:17]2)=[O:20])[CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(O)ccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(O)ccn1)C1CC1
Yield: 32.1 %

Procedure:
Dissolve 2-amino-pyridin-4-ol (5 g, 45.4 mmol) in DCM (30 mL), add Et3N (13.8 g, 136 mmol) and then cyclopropanecarbonyl chloride (14.2 g, 136 mmol) dropwise while keeping the temperature below 10° C. After addition, stir the reaction at room temperature for 16 hrs. Remove the solvent under reduced pressure, dissolve the residue in THF (40 mL), adjust pH=12 with 1N NaOH solution. Stir the mixture for 3 hrs. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:MeOH=9:1) affords the title compound (2.6 g, 32%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11](=[CH2:22])[CH2:12][O:13]C(=O)C1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OCC(=C)CCOC(=O)C1C=CC=CC=1)(C(C)(C)C)(C)C.[OH-].[Na+]>CO.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[Si:1]([O:8][CH2:9][CH2:10][C:11](=[CH2:22])[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=C(CCO[Si](C)(C)C(C)(C)C)COC(=O)c1ccccc1
Agent: C=C(CCOC(=O)c1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=C(CO)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To an ˜7:1 mixture of benzoic acid 4-(tert-butyldimethylsilyloxy)-2-methylene-butyl ester and benzoic acid 3-(tert-butyldimethylsilyloxymethyl)-but-3-enyl ester (1.00 g, 3.13 mmol) in methanol (31 mL) was added NaOH (0.306 g, 7.64 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (75 mL) and saturated aqueous NaHCO3 (20 mL). The phases were separated and the organic phase was washed with brine (2×10 mL), dried (MgSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (9:1 hexanes-ethyl acetate) provided 0.58 g (58%) of 4-(tert-butyldimethylsilyloxy)-2-methylene-butan-1-ol as a colorless oil. 1H NMR (CDCl3) δ 0.06 (s, 6H), 0.90 (s, 9H), 2.34 (t, 2H, J=6.0 Hz); 2.78 (br s, 1H), 3.75 (t, 2H, J=6.0 Hz), 4.07-4.11 (m, 2H), 4.90 (s,111), 5.04 (s, 1H);
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([NH2:10])=[O:9].CN(C)[CH:13]=[CH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl>[C:17]1([C:15]2[N:4]3[CH:5]=[N:6][C:7]([C:8]([NH2:10])=[O:9])=[C:3]3[N:2]=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CN(C)C=CC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1ncn2c(-c3ccccc3)ccnc12
Yield: 43.9 %

Procedure:
A stirred mixture of 11.0 g of 4-amino-5-imidazolecarboxamide hydrochloride and 15.0 g of 3-dimethylaminoacrylophenone (prepared as described in Example 1) in 120 ml of glacial acetic acid was heated at reflux for 4 hours. The solvent was evaporated in vacuo to give a dark oil which was dissolved in dichloromethane, then treated by stirring with saturated sodium bicarbonate. The organic solvent was evaporated and the remaining mixture was filtered and the solid was washed with water, dried, and then was recrystallized from ethanol to give 7.08 g of the desired product as a yellow solid, mp 226°-228° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([OH:37])[CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=5)[O:24][N:23]=4)[CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH3:40]I.O>C1(C)C=CC=CC=1>[CH3:40][O:37][CH:13]([CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[O:24][N:23]=2)[CH2:19][CH2:20]1)[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: CI
Reactant: Cc1nc2cc(OCC(O)CN3CCN(Cc4noc(-c5ccc(C(F)(F)F)cc5)n4)CC3)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(COc1ccc2sc(C)nc2c1)CN1CCN(Cc2noc(-c3ccc(C(F)(F)F)cc3)n2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 3-(2-methylbenzothiazol-5-yloxy)-1-[4-({5-[4-(trifluoromethyl)phenyl]-(1,2,4-oxadiazol-3-yl)}methyl)piperazinyl]propan-2-ol (0.10 g) in toluene (6 ml) was added to a suspension of sodium hydride (0.09 g) in toluene (2 ml) at 0° C. The mixture was stirred at 100° C. for 2 hours, then cooled to 0° C. Methyl iodide (0.14 ml) was then added, and the mixture stirred overnight at room temperature. After slow addition of water the mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and the solvent removed under reduced pressure. The residue was purified by flash chromatography (3% methanol in methylene chloride), to provide 5-{2-methoxy-3-[4-({5-[4-(trifluoromethyl)phenyl](1,2,4-oxadiazol-3-yl)}methyl)piperazinyl]propoxy}-2-methylbenzothiazole (0.0075 g).
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:14][CH2:15][CH3:16])[NH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:3].[C:17]([N:36]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=2)=[N:39][N:38]=[N:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>>[OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:14][CH2:15][CH3:16])[N:7]([CH2:51][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40]3[N:36]([C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:37]=[N:38][N:39]=3)=[CH:54][CH:53]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:3]
Reactant: CCCc1nc(C(C)O)c(C(=O)OCC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 72.6 %

Procedure:
Following a procedure similar to that described in Example 35(a), but using 113 mg of ethyl 4-(1-hydroxyethyl)-2-propylimidazole-5-carboxylate [prepared as described in Preparation 23(iii)], 280 mg of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 60 mg of potassium t-butoxide, 255 mg of the title compound were obtained as a viscous oil. The Nuclear Magnetic Resonance Spectrum of this compound was identical with that of the compound obtained as described in Example 40(b).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=1>C(OC(=O)C)(=O)C>[CH3:32][N:31]([CH3:33])[C:27]1[CH:26]=[C:25]([N:24]([CH3:34])[CH3:23])[CH:30]=[CH:29][C:28]=1[C:12]1([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=[CH:10][CH:9]=2)[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:17])[O:18]1
Reactant: O=C(O)c1ccccc1C(=O)c1cccn1-c1ccccc1
Reactant: CN(C)c1cccc(N(C)C)c1
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ccc(C2(c3cccn3-c3ccccc3)OC(=O)c3ccccc32)c(N(C)C)c1
Yield: 59.7 %

Procedure:
A mixture of 2.91 g (0.01 mole) of 2-[(1-phenyl-2-pyrrolyl)carbonyl]benzoic acid prepared in part A above, 2.34 g (0.017 mole) of 84.6 percent active N,N,N',N'-tetramethyl-m-phenylenediamine in 4.0 ml of acetic anhydride was interacted in a manner similar to that described in Example 1, part C to obtain 2.61 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-phenyl-2-pyrrolyl)phthalide (Formula IV: Ro =R1 =R2 =R3 =H; R=CH3 ; R4 =N(CH3)2 ; R7 =C6H5), a peach-colored powder melting at 193°-194° C. The infrared spectrum showed a maximum at 1760 cm-1 (C=O; s). A toluene solution of this product spotted on silica gel developed an immediate orange-red-colored image.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:48][C:49]1[CH:73]=[C:72](O)[CH:71]=[CH:70][C:50]=1[C:51]([NH:53][C:54]1[CH:63]=[C:62]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:61]=[CH:60][C:55]=1[C:56]([O:58][CH3:59])=[O:57])=[O:52]>O1CCCC1>[OH:48][C:49]1[CH:73]=[C:72]([CH:71]=[CH:70][C:50]=1[C:51](=[O:52])[NH:53][C:54]1[CH:63]=[C:62]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[CH:61]=[CH:60][C:55]=1[C:56]([O:58][CH3:59])=[O:57])[O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(O)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
1-(tert-Butoxycarbonyl)-4-hydroxypiperidine (0.15 g), triphenylphosphine (0.21 g), and diisopropyl azodicarboxylate (0.16 mL) were added to a tetrahydrofuran (3.6 mL) suspension of methyl 2-(2,4-dihydroxybenzamido)-4-phenylbenzoate (0.24 g), followed by stirring at room temperature for 1 hour. 1-(tert-Butoxycarbonyl)-4-hydroxypiperidine (0.066 g), triphenylphosphine (0.086 g), and diisopropyl azodicarboxylate (0.064 mL) were added to the reaction mixture, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: 100-75% hexane/ethyl acetate] to obtain 0.050 g of tert-butyl 4-(3-hydroxy-4-(2-(methoxycarbonyl)-5-phenylphenylcarbamoyl)phenoxy)piperidine-1-carboxylate as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)=[O:4].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C>[Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:3](=[O:4])[CH3:2])=[C:7]([O:12][C:8](=[O:11])[CH3:7])[CH:6]=1)=[O:4]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(C(=O)CCl)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A suspension of α-chloro-3',4'-dihydroxyacetophenone (9.33 g, 0.05 mole) in 78 ml of acetic anhydride was treated with 0.1 ml of concentrated sulfuric acid and stirred for 1.5 hours under an argon atmosphere. Initially, the reaction temperature rose to 40° C. and the starting material completely dissolved yielding a clear, colorless solution which was poured onto approximately 300 g of crushed ice. After standing for one hour, the crystallized product was filtered, washed with cold water (200 ml) and dried in vacuo overnight at room temperature; yield: 11.5 g.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[C:22]([O:24][CH:25]1[CH:32]2[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:34][CH:26]1[CH2:27]3)[CH2:31]2)=[O:23].Cl>C(Cl)Cl>[C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:22]([O:24][CH:25]2[CH:26]3[CH2:34][CH:30]4[CH2:29][CH:28]([CH2:33][CH:32]2[CH2:31]4)[CH2:27]3)=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: c1ccc(C2CCCN2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OC1C2CC3CC(C2)CC1C3)N1CCCC1c1ccccc1
Yield: 61.5 %

Procedure:
A vial equipped with a flea stir bar was charged with 2-phenylpyrrolidine (17 mg, 0.12 mmol), i-Pr2NEt (0.031 mL, 0.17 mmol). A solution of 2-adamantyl chloroformate (25 mg, 0.12 mmol) in CH2Cl2 (1.5 mL) was added. The mixture was stirred over the weekend and applied to a 10-mL ChemElut cartridge prewetted with 5% aq HCl (5 mL). The cartridge was eluted with ether (20 mL). The eluate was concentrated and the residue was purified by prep HPLC to afford the title compound (24 mg, 63%). LC-MS Method 2 tR=11.81 min, m/z=326, 1H NMR (CDCl3) 0.92 (m, 1H), 1.03 (m, 1H), 1.30-2.20 (14H), 2.32 (m, 1H), 2.50 (br s, 1H), 3.64 (m, 2H), 4.70-5.10 (2H), 7.18 (m, 3H), 7.28 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[CH3:21][NH2:22].O>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][C:10](=[O:20])[CH2:11][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[N:22]1[CH3:21]
Reactant: Cc1ccccc1C=CC(=O)C=Cc1ccccc1C
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1C1CC(=O)CC(c2ccccc2C)N1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
1,5-Bis(2-methylphenyl)-1,4-pentadien-3-one (20ac, 0.50 g, 1.9 mmol) was dissolved in dimethyl formamide (10 ml). Methylamine (51, 1.0 ml, 11.6 mmol, 40% in water) was added and the mixture stirred for 24 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 2 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized from ethanol to give 0.29 g (52%) of a white solid: mp 155-157° C.; 1H NMR δ 1.82, (s, 3H), 2.40, (s, 6H), 2.44 (d, 2H, J=11.9 Hz), 2.77 (t, 2H, J=13.3 Hz), 3.74 (d, 2H, J=11.9 Hz), 7.16 (m, 6H), 7.67, (d, 2H, J=7.0 Hz); 13C NMR: δ 19.5, 39.9, 49.3, 65.8, 126.7, 126.9, 130.6, 134.8, 140.9, 207.2; Exact mass calcd for C20H23NO: 293.1779, observed (M+H) 294.1856.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1>>[CH3:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:2])[NH2:24])[CH:18]=1
Reactant: Cn1c([N+](=O)[O-])cnc1C=Cc1cccc(C#N)c1
Reactant: O=S(=O)(O)O
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1cccc(C(N)=O)c1
Temperature: 0 °C

Procedure:
To 5 ml. of cold 90% sulfuric acid was added 1 g. (0.004 mole) of 1-methyl-5-nitro-2-[2-(3-cyanophenyl)vinyl]imidazole, and the resulting solution was warmed on a steam bath for five minutes and then poured into ice water. The solid which separated was collected by filtration, washed with water, dried and recrystallized from ethanol to give 1-methyl-5-nitro-2-[2-(3-carbamylphenyl)vinyl]imidazole, m.p. 254°-256° C.