Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=3)[CH:19]=[CH:20][C:21]=2OS(C(F)(F)F)(=O)=O)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH2:43]([Sn](CCCC)(CCCC)CCCC)[CH:44]=C.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=3)[CH:19]=[CH:20][C:21]=2[CH:43]=[CH2:44])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc(N(CC)CC)c(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 103.2 %

Procedure:
g of ethyl 3″-tert-butyl-4″-diethylamino-4′-trifluoromethanesulfonyloxy[1,1′;3′,1″]terphenyl-4-carboxylate (2 mmol) are dissolved at room temperature in 23 mL of dimethylformamide, and 250 mg of LiCl (6 mmol) and 0.74 mL of allyltributyltin (2.4 mmol) are then added. The reaction medium is heated and, at 40° C., 70 mg of dichlorobis(triphenylphosphine)palladium (0.1 mmol) are added and the reaction medium brought to 120° C. and stirred for 20 minutes. The reaction is stopped by adding 30 mL of water and then extracted with 30 mL of ethyl acetate. The organic phases are washed with 80 mL of water and then dried over magnesium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: heptane). 940 mg of ethyl 3″-tert-butyl-4″-diethylamino-4′-vinyl[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=100%).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[NH4+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5]([CH3:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(F)c2[nH]cnc12
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c([N+](=O)[O-])cc(F)c2nc[nH]c12
Temperature: 0 °C

Procedure:
To a cold (ice bath) solution of 4-fluoro-7-methylbenzimidazole (734 mg) in concentrated sulfuric acid (10 mL) is added dropwise concentrated nitric acid (0.22 mL) over 1 hour. The mixture is stirred an additional 15 minutes in the ice bath, then poured in a mixture of crushed ice (20 mL). and ammonium hydroxide (20 mL). The resulting mixture is extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered and rotary evaporated to afford 7-fluoro-4-methyl-5-nitrobenzimidazole as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:12])[NH:5][C:4](=[O:13])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH:22]=[CH2:23].C(Cl)(Cl)Cl>CN(C)C=O.O>[CH2:23]([O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([CH3:14])([CH3:1])[CH2:3][C:4](=[O:13])[NH:5]2)[CH:22]=[CH2:21]
Reactant: C=CCI
Reactant: CC1(C)CC(=O)Nc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cccc2c1C(C)(C)CC(=O)N2
Temperature: 100 °C
Reaction time: 24 h
Yield: 49.5 %

Procedure:
4,4-Dimethyl-5-hydroxy-3,4-dihydrocarbostyril (3.45 g, 18.0 mmol) was dissolved in dimethylformamide (100 ml). To the solution, potassium carbonate (2.99 g, 21.7 mmol) and allyl iodide (3.33 g, 19.9 mmol) were added, and the mixture was stirred at 100° C. for 24 hours. Subsequently, potassium carbonate (1.5 g, 10.9 mmol) and allyl iodide (1.65 g, 9.82 mmol) were added and stirring was continued for 24 hours. The reaction mixture was condensed under reduced pressure. Chloroform and water were added to the residue, and extracted. After the extract was dried and condensed, the residue was purified by silica gel column chromatography (developer=chloroform:methanol=50:1). Recrystallization from a solvent mixture of chloroform-hexane-ether yielded 2.06 g of the title compound as pale yellow needles (52.3%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[C:10]([O:16][OH:17])([CH2:13][CH2:14][CH3:15])([CH3:12])[CH3:11].C1(O)C=CC=CC=1>>[C:10]([O:16][O:17][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3])([CH2:13][CH2:14][CH3:15])([CH3:12])[CH3:11]
Reactant: CCCC(C)(C)OO
Reactant: C=C(C)c1ccccc1
Solvent: Oc1ccccc1
Product: CCCC(C)(C)OOC(C)(C)c1ccccc1
Yield: 87.8 %

Procedure:
Into the 200 ml jacketed reactor described in Example II were added 15.6 grams (0.13 m) alpha-methylstyrene, 15.0 grams (0.104 m) 82% t-hexyl hydroperoxide and 4.0 grams (0.043 m) phenol. The mixture was stirred to obtain a clear solution and the temperature was adjusted to 20° C. To this solution was added 1.5 grams (0.0095 m) of t-cumyl chloride from the addition funnel over 5 minutes while holding the temperature at 21°-22° C. The reaction self-exothermed to 25° C. over 10 minutes and then was stirred an additional 1/2 hour at 25° C. The reaction was then stirred 80 minutes at 35° C. and 90 minutes at 40° C. at which point the reaction was complete. The reaction was terminated by adding 25 mls of water, stirring 5 minutes, adding 5 mls of 50% NaOH, stirring another 5 minutes and separating the aqueous caustic layer. The organic layer was successively washed with 25 mls of 15% NaOH, saturated NaHCO3 solution, water, 15% NaHSO3 solution, saturated NaHCO3 solution and water. After drying with anhydrous sodium sulfate the crude product weighed 26.7 grams and contained 80.6% cumyl t-hexyl peroxide for a corrected yield of 21.5 grams and a 87.8% yield. The pure cumyl t-hexyl peroxide was isolated by fractional distillation under vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[N+](C1C=CC=CC=1)([O-])=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of 4-bromo-benzoyl chloride (3.3 g, 15 mmol) and AlCl3 (2.6 g, 20 mmol) in nitrobenzene (20 mL) was added a solution of methoxy-benzene (1.5 g, 14.5 mmol) in nitrobenzene (5 mL) slowly at 0° C. The resulting mixture was allowed to warm to rt and stir at rt for 16 h. The mixture was poured onto 150 mL ice-water solution and extracted with CH2Cl2 (5×100 mL). The combined organic layers were washed with water (2×100 mL) and brine (50 mL). and dried over anhy. Na2SO4. The solvent was removed in vacuo to obtain the crude product which was purified by recrystallization from cyclohexane to yield the title product (4.0 g, 91%) as a solid; 1H NMR (500 MHz, CDCl3); δ 3.90 (s, 3H), 6.97 (d, J=8.5, 2H), 7.63 (d, J=2.0, 4H), 7.79 (d, J=9.0, 2H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:15])[C:10](=[O:16])[C:9]12[CH2:18][CH2:17]1)=[O:4].[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C.O>[F:20][C:2]([F:1])([F:19])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[N+:21]([O-:23])=[O:22])[N:11]([CH3:15])[C:10](=[O:16])[C:9]12[CH2:17][CH2:18]1)=[O:4]
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)ccc21
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)C2(CC2)c2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(1′-methyl-2′-oxo-spiro[cyclopropane-1,3′-indole]-5′-yl)-acetamide (2 g) in acetic acid (20 ml) at 15° C. is added nitric acid (fuming, 0.8 ml) over a period of 3 min. The mixture is stirred at this temperature for 1 h and then diluted with water. The aqueous layer is extracted with EtOAc. The combined organic layer is washed with water, saturated K2CO3 solution and brine, dried over MgSO4 and evaporated. The compound (2.25 g) is obtained as a brown semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[CH:43]1([NH2:48])[CH2:47][CH2:46][CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:48][CH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: NC1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NC1CCCC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and cyclopentylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH3:13]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1ccccc1
Product: CC(=NNc1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
10.2 g of acetophenone -p-nitrophenylhydrazone (melting point: 186.5°-188.0° C.) obtained by equimolar reaction of p-nitrophenylhydrazine and acetophenone was subjected to Vilsmeir reaction with phosphorus oxychloride and dimethylformamide to obtain 11.8 g of 1-(p-nitrophenyl)-3-phenylpyrazole-4-carboxyaldehyde (melting point: 208.5°-211.0° C.) having the following structural formula. ##STR300##
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:52]([CH3:54])[CH3:53])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:49](=[CH:50][CH:51]=3)[C:31]3[NH:32][C:33]([C@@H:35]5[C@@H:40]6[CH2:41][C@@H:37]([CH2:38][CH2:39]6)[N:36]5C(OC(C)(C)C)=O)=[N:34][C:30]=3[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].Cl.[CH3:56][O:57][C@H:58]([CH3:68])[C@H:59]([NH:63][C:64]([O:66][CH3:67])=[O:65])[C:60]([OH:62])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:56][O:57][C@H:58]([CH3:68])[C@H:59]([NH:63][C:64](=[O:65])[O:66][CH3:67])[C:60]([N:36]1[C@H:35]([C:33]2[NH:32][C:31]3[C:49]4[C:27]([CH:28]=[CH:29][C:30]=3[N:34]=2)=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[NH:15][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:52]([CH3:54])[CH3:53])=[N:18][CH:17]=3)=[CH:24][CH:23]=2)=[CH:51][CH:50]=4)[C@@H:40]2[CH2:41][C@H:37]1[CH2:38][CH2:39]2)=[O:62]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)OC(C)(C)C)[nH]c54)c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(ccc5nc([C@@H]6[C@H]7CC[C@H](C7)N6C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)[nH]c54)c3)cc2)[nH]1)C(C)C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To (1R,3S,4S)-tert-butyl 3-(7-(4-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl) pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (280 mg, 0.38 mmol) in DCM (5 mL) was added HCl (4M in dioxane, 1 mL). The solution stirred for 2 h, and the solvent was removed. The intermediate (80 mg, 0.13 mmol) was dissolved in DMF (2 mL). (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (24 mg, 0.13 mmol), HATU (48 mg, 0.13 mmol), and DIPEA (0.11 mL, 0.64 mmol) were added sequentially. The solution stirred o/n and the mixture was purified by HPLC to yield product (54.6 mg). LCMS-ESI+: calc'd for C44H52N8O7: 804.93 (M+); Found: 806.23 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl.[CH2:8]([N:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([CH3:20])[CH:14]=1)[CH2:11][CH3:12])[CH3:9].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28]>CO.O.C(O)C>[Cl:21][C:22]1[C:23](=[O:28])[CH:24]=[CH:25][C:26](=[N:17][C:16]2[CH:18]=[CH:19][C:13]([N:10]([CH2:11][CH3:12])[CH2:8][CH3:9])=[CH:14][C:15]=2[CH3:20])[CH:27]=1
Reactant: CCN(CC)c1ccc(N)c(C)c1
Reactant: Oc1ccccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: CCN(CC)c1ccc(N=C2C=CC(=O)C(Cl)=C2)c(C)c1
Temperature: 55 °C
Yield: 90 %

Procedure:
1450 parts K3Fe(CN)6, 595 parts Na2CO3, and 4150 parts water were added to a 12-liter round bottom flask equipped with a mechanical stirrer, thermometer, and addition funnel. The mixture was heated to 55° C. with stirring. A solution of 227 parts 4-(N,N-diethylamino)-2-methylaniline monohydrochloride, 128 parts o-chlorophenol, 1960 parts ethanol, and 2500 parts water was charged to the addition funnel and added dropwise to the stirred, heated solution. After the addition was complete the reaction mixture was maintained at 55° C. with stirring for 20 minutes. The warm mixture was filtered with vacuum and the resulting filter cake was placed in a solution of 296 parts ethanol and 1125 parts water to form a slurry. The dye was isolated by vacuum filtration. This process was repeated two times, first with 296 parts ethanol and 1125 parts water, then with 608 parts methanol. After the final vacuum filtration the filter cake was dried at 40° C. under vacuum for 48 hours. Yield was ~90%. The final product can be recrystallized from ethyl acetate or ethanol.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=[CH:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.O>CN(C=O)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:6]([C:4]2[N:3]=[CH:2][S:1][CH:5]=2)[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1cscn1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cscn2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
To a solution of tert-butyl thiazol-4-ylcarbamate (13.0 g, 64.9 mmol) in DMF (150 mL) was added Cs2CO3 (42.3 g, 130 mmol) and 1-(chloromethyl)-4-methoxybenzene (12.1 g, 78.0 mmol, Spectrochem). The reaction mixture was stirred at 80° C. for 6 h. The reaction mixture was allowed to cool to room temperature and water (500 mL) was added. The aqueous layer was extracted with diethyl ether (2×500 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was further purified by column chromatography (silica gel 100-200 mesh and 0-20% ethyl acetate in hexanes) to obtain tert-butyl 4-methoxybenzyl(thiazol-4-yl)carbamate (15.0 g, 80%) as an off-white solid. MS (ESI, positive ion) m/z=321 (M+1)+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.ClCCl.[Cl-].[NH4+]>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][C:8]=3[OH:11])[O:1][CH2:2][CH2:3][CH2:4]4)[C:25]2=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Oc1ccc2c(c1)OCCC2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a cooled (0° C.) solution of chroman-7-ol (Cube, R. V., et al., Bioorg. Med. Chem. Lett. (2005), 15(9):2389-93) (0.55 g, 3.66 mmol) in tetrahydrofuran (11 mL) under nitrogen was added isopropylmagnesium chloride (2.4 mL, 2 M in tetrahydrofuran, 4.8 mmol). The resulting solution was stirred at 0° C. for 30 min. A suspension of 1-(diphenylmethyl)indoline-2,3-dione (1.16 g, 3.70 mmol) in dichloromethane (4 mL) was added. The reaction was stirred at 0° C. for 10 min, then warmed to ambient temperature and stirred for 15.5 h. The reaction was diluted with saturated ammonium chloride solution (10 mL) and the organic solvents were removed under reduced pressure. The residual mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organic solution was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (7:3) to afford 1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one (1.37 g, 81%) as a light yellow solid: mp 204-206° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.90 (s, 1H), 7.49 (dd, J=5.6, 3.2 Hz, 1H), 7.38-7.23 (m, 10H), 7.12-7.06 (m, 2H), 6.95 (s, 1H), 6.52-6.47 (m, 3H), 4.23 (s, 1H), 4.121 (dd, J=5.7, 4.5 Hz, 2H), 2.53 (t, J=6.3 Hz, 2H), 1.95-1.87 (m, 2H); MS (ES+) m/z 486.1 (M+23).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[Cl:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31](CO)[C:32]([CH3:37])=[C:33]2[OH:36])=[CH:28][CH:27]=1>O1CCCC1>[Cl:25][C:26]1[CH:35]=[C:34]2[C:29]([CH:30]=[C:31]([CH2:20][Cl:24])[C:32]([CH3:37])=[C:33]2[OH:36])=[CH:28][CH:27]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1c(CO)cc2ccc(Cl)cc2c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(CCl)cc2ccc(Cl)cc2c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To a solution of triphenylphosphine (20 g, 76 mmol) in anhydrous tetrahydrofuran (165 mL) was added carbon tetrachloride (50 mL). After the mixture was stirred at room temperature for 20 minutes, 7-chloro-3-hydroxymethyl-2-methyl-naphthalen-1-ol (8.4 g, 37.7 mmol) was added as a solid under a nitrogen atmosphere. After being stirred at reflux for 2 hours, the resulting mixture was cooled to room temperature, and concentrated in vacuo. The residue was purified by column chromatography (elution with 5% ethyl acetate in petroleum ether) to afford 7-chloro-3-chloromethyl-2-methyl-naphthalen-1-ol (8.7 g, 96%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[N:14]([CH3:15])[C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][C:11]=2[CH3:22])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(I)CC>>[CH2:16]([C:13]1[N:14]([CH3:15])[C:10]([C:8](=[O:9])[C:7]2[CH:23]=[CH:24][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[C:11]([CH3:22])[CH:12]=1)[CH3:17].[CH2:13]([CH2:16][C:17]([O-:19])=[O:18])[CH2:12][CH3:11]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc([N+](=O)[O-])cc2)n1C
Solvent: CCCI
Product: CCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccc([N+](=O)[O-])cc2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 85), using an equivalent quantity of n-propyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-propyl)-acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:39][NH:40][CH3:41]>C1COCC1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:40]([CH3:41])[CH3:39])=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 68.2 %

Procedure:
To a solution of 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (100 mg, 0.2 mmol) in THF (2 ml) was added potassium carbonate (109 mg, 0.79 mmol) and dimethylamine (2M solution in THF; 0.5 ml, 0.98 mmol) at 25° C. and the resulting reaction mixture was stirred at 70° C. for 3 h. The mixture was diluted with water (5 ml), and extracted with EtOAc (3×15 ml) and the organic phases were combined and washed with brine (15 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (3% EtOAc/hexane) to give 6-chloro-4-(2-chloro-benzyl)-2-dimethylamino-quinoline-3-carboxylic acid ethyl ester (55 mg, 69%) as pale yellow solid. LC-MS (ESI): 403 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([CH3:20])C=CC(S(O)(=O)=O)=CC=1.O.C([O-])([O-])=[O:23].[K+].[K+]>C1C=CC=CC=1.C(O)CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:23][CH2:10][CH2:20][O:7]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: c1ccccc1
Solvent: O
Product: Brc1ccc(C2OCCO2)cc1
Yield: 70 %

Procedure:
4-Bromobenzaldehyde (56 g, 0.3 mole) was dissolved in 500 mls of benzene containing 80 mls (excess) of ethylene glycol. This mixture was stirred rapidly via motor. p-Toluenesulfonic acid (5 g) was added and the mixture was refluxed with a water separator overnight (24 hours). The cooled mixture was poured into 1 liter of 5% K2CO3 and extracted with ethyl acetate. The organic phase was washed with H2O and then brine. The extract was dried over sodium sulfate and filtered. After solvent removal, the residue was chromatographed on silica gel using 10% ethyl acetate/hexane to give 50 g (70% yield.) of the title compound (m.p.=56°-57° C.).