Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][OH:17])=[N:8]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([OH:24])=[O:23].[H-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][O:17][CH2:21][C:22]([OH:24])=[O:23])=[N:8]2)=[CH:18][CH:19]=1
Reactant: OCc1nn(Cc2ccc(F)cc2)c2ccccc12
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COCc1nn(Cc2ccc(F)cc2)c2ccccc12
Temperature: 0 °C
Yield: 57.8 %

Procedure:
A suspension containing [1-(4-fluorobenzyl)-1H-indazol-3-yl]methanol (6 g; 0.022 mol), bromoacetic acid (4 g; 0.03 mol) and 50% NaH (3 g; 0.066 mol) in THF (170 ml) was stirred at reflux for 72 hours. The reaction was then stopped by diluting with a suspension with water and ice (300 ml) and washing the aqueous phase with diethyl ether (3×150 ml). The aqueous phase was acidified with concentrated HCl. The solid thus formed was filtered off and purified by crystallization from isopropanol. 4 g of {[1-(4-fluorobenzyl)-1H-indazol-3-yl]methoxy}acetic acid were thus obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[CH:3]1.C1C=CC(CC(Cl)=[O:21])=CC=1>>[CH:3]([N:2]([CH3:1])[C:11](=[O:12])[CH2:10][C:9]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:21]
Reactant: Cn1cc2ccccc2cc1=O
Reactant: O=C(Cl)Cc1ccccc1
Product: CN(C=O)C(=O)Cc1ccccc1

Procedure:
In this case, the yield of N-methyl-2H-3-isoquinolone, with a melting point of 235°-236°C., calculated upon the amount of phenacetyl chloride used, reaches 40- 45%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH2:7][C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17])=[O:9]>CN(C)C=O>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([OH:17])=[C:10]([C:8](=[O:9])[CH2:7][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:15]=1
Reactant: O=C(CBr)c1cc(Cl)ccc1O
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C(Cn1ccnc1)c1cc(Cl)ccc1O
Temperature: 0 °C
Yield: 82.4 %

Procedure:
Imidazole (17.9 g, 0.26 mol) was added to a solution of 2-bromo-1-(5-chloro-2-hydroxyphenyl)-1-ethanone [compound (4-1)] (21.8 g, 87.7 mmol) in N,N-dimethylformamide (50 mL), and the resultant mixture was stirred for 17 hours at room temperature. The reaction mixture was added to ice-water, followed by extraction with ethyl acetate. The organic layer was washed with water, and dried over magnesium sulfate. Subsequently, the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography, followed by drying under reduced pressure, to thereby yield 1-(5-chloro-2-hydroxyphenyl)-2-(1H-1-imidazolyl)-1-ethanone as colorless crystals (17.1 g, yield: 82.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:7]([N+:17]([O-:19])=[O:18])=[CH:6][C:4]=1[NH2:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:33]1[N:38]=[C:37]([C:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)[C:36]([CH3:48])=[CH:35][N:34]=1>CC(O)CCC>[NH:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([C:37]2[C:36]([CH3:48])=[CH:35][N:34]=[C:33]([NH:5][C:4]3[CH:6]=[C:7]([N+:17]([O-:19])=[O:18])[C:8]([N:10]4[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]4)=[CH:9][C:3]=3[O:2][CH3:1])[N:38]=2)=[CH:40]1
Reactant: Cc1cnc(Cl)nc1-c1c[nH]c2ccccc12
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1
Yield: 43.1 %

Procedure:
A mixture of 2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitroaniline (Intermediate 14, 204 mg, 0.77 mmol), p-toluene sulphonic acid monohydrate (291 mg, 1.53 mmol) and 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (Intermediate 17, 192 mg, 0.77 mmol) were heated at 120° C. in 2-pentanol (15 mL) for 24 h, resulting in a dark brown suspension. The mixture was then concentrated in vacuo and the resulting residue was dissolved in a mixture of CH2Cl2 and CH3OH (50 mL and 5 mL) and this solution was concentrated onto silica in vacuo. Purification by FCC, eluting with 1-5% methanolic ammonia in CH2Cl2 gave the title compound (157 mg, 43%) as an orange gum; m/z: ES+ MH+ 474.24.
Reaction SMILES: [OH-].[Na+:2].C([O:5][C:6]([C:8]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][O:9]1)=[O:7])C.CC(C)=O>O1CCCC1>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:8]2([C:6]([O-:7])=[O:5])[CH2:10][O:9]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1.[Na+:2]
Reactant: CCOC(=O)C1(CCCCCc2ccccc2)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C([O-])C1(CCCCCc2ccccc2)CO1
Reaction time: 0.75 h

Procedure:
A mixture of 166 ml of 1 N sodium hydroxide solution and 90 ml of tetrahydrofuran is added dropwise to a solution of 43.6 g of 2-(5-phenylpentyl)oxirane 2-carboxylic acid ethyl ester in 90 ml of tetrahydrofuran. When the addition has ended, the mixture is stirred for about 45 minutes, until a clear solution has formed. 1.6 l of acetone are now added dropwise in the course of 3 hours, a crystalline precipitate, which is filtered off and washed with acetone, separating out. The product is recrystallized from water to give 42.9 g of the title compound as the dihydrate of m.p. 82° to 86° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[NH:10][C@H:9]2[CH3:14])[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C:37]1[CH:38]=[C:39]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][C:46]=2[CH3:55])[CH:40]=[CH:41][C:42]=1[O:43][CH3:44]>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=[CH:29][C:28]=3[C:37]3[CH:38]=[C:39]([C:45]4[CH:50]=[CH:49][C:48]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][C:46]=4[CH3:55])[CH:40]=[CH:41][C:42]=3[O:43][CH3:44])[C@H:9]2[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cccc(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cccc(F)c4)[C@@H]3C)c2)c(C)c1
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of (4S,5R)-5-(3-fluorophenyl)-4-methyl-1,3-oxazolidin-2-one (16.2 mg, 0.0830 mmol) in DMA (1 mL) was added NaHMDS (83 μL, 0.083 mmol). Next, a solution of methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (49 mg, 0.0996 mmol) in DMA (1 mL) was added via cannula. After 5 minutes, the reaction was quenched with saturated NH4Cl solution (10 mL) and diluted with EtOAc (20 ml). The aqueous layer was extracted with EtOAc (20 mL), and the combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 25% EtOAc/hexanes) afforded methyl 2″-{[(4S,5R)-5-(3-fluorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS=608.2 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.94 (d, J=5.9 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.71-7.61 (m, 2H), 7.41-7.36 (m, 2H), 7.33-7.24 (m, 2H), 7.14-7.12 (m, 1H), 7.07-7.05 (m, 1H), 7.02-6.90 (m, 3H), 5.46 (d, J=8.2 Hz), 5.24 (d, J=8.2 Hz), 4.90 (d, J=15.8 Hz), 4.82 (d, J=15.8 Hz), 4.20 (d, J=15.8 Hz), 3.97 (d, J=15.8 Hz), 3.92 (s, 3H), 3.95 (s, 3H), 3.75-3.69 (m, 1H), 2.36 (s), 2.31 (s), 0.53 (d, J=6.6 Hz), 0.43 (d, J=6.6 Hz).
Reaction SMILES: [CH2:1]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:16][NH2:17]>C(O)C>[CH3:16][NH:17][CH2:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C(CCc1ccccc1)C(=O)OCC
Reactant: CN
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)CNC

Procedure:
26.3 g of ethyl 2-methylene-4-phenylbutyrate (1.4) and 4 g of methylamine in 150 ml of ethanol in an autoclave were heated at 80° C. for 10 hours. After cooling down, the ethanol was removed, the residue was taken up in 1N HCl, this was extracted with ether, made alkaline with sodium carbonate and again extracted, dried and evaporated.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[N:19]([C:22]1[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=1)=[C:20]=[O:21].C(N(C(C)C)CC)(C)C>>[NH2:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:20]([NH:19][C:22]3[C:23](=[O:28])[NH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])[CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: O=C=Nc1ccc[nH]c1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)Nc3ccc[nH]c3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, 3-isocyanato-2(1H)-pyridinone, and diisopropylethyl amine, are reacted to give the title product as a white solid. LC-MS: 399 (M++1). 1H NMR (DMSO-d6) δ 7.95 (m, 2H), 7.76 (d, 1H), 7.40 (s, 1H), 7.12 (m, 1H), 7.0 (d, 1H), 6.45 (m, 2H), 6.25 (s, 1H), 6.22 (m, 1H), 3.75 (m, 4H), 3.10 (m, 4H).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:8]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:24]=1>>[CH3:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][CH2:26][CH2:27][N:28]2[C:9](=[O:11])[C:8]3[CH:7]=[C:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[S:5][C:4]=3[NH:1][C:2]2=[S:3])[CH:24]=1
Reactant: COC(=O)c1cc(-c2ccccc2)sc1N=C=S
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc(-c4ccccc4)cc3c2=O)cn1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanato-5-phenylthiophene-3-carboxylate (0.107 g. 0.39 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.054 g, 0.39 mmol) as described above.
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:16](=[O:25])[CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[OH:24])[CH2:14]3)[C:10](=[O:26])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:40]CCCl)[C:34]1C=CC=CC=1>>[C:27]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][N:13]([C:16](=[O:25])[CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH2:34][CH2:33][OH:40])[CH2:14]3)[C:10](=[O:26])[CH2:9][CH2:8]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3O)CC12
Reactant: ClCCOCc1ccccc1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3OCCO)CC12

Procedure:
Following the procedure of Example 102 and using (3aRS,7aRS)-7,7-diphenyl-2-(2-hydroxyphenylacetyl)-4-perhydroisoindolone and 1-benzyloxy-2-chloroethane as starting materials, (3aRS,7aRS)-7,7-diphenyl-2-{2-[2-(2-hydroxyethoxy)phenyl]acetyl}-4-perhydroisoindolone (0.5 g) is obtained in the form of white crystals melting at 150° C.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][S:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(SCc2c(C)cccc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1CSc1ccc(C(=O)CCC(=O)O)cc1
Reaction time: 3 h

Procedure:
A solution of Ethyl 4-(4-[(2,6-dimethylbenzyl)-thio]-phenyl)-4-oxobutyrate (Step D, 0.680 g, 2 mmol) in abs ethanol (20 ml) was treated with 1N NaOH (3 ml) at room temperature. The reaction mixture was stirred for 3 hours, acidified with 1M HCl and concentrated. The residue was taken in chloroform and washed with 0.1 M HCl, brine, dried over Na2SO4, filtered and concentrated. The purification was done by flash chromatography on a silica gel column (chloroform:methanol (95:5) spiked with acetic acid) to provide the title compound as off white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8](=[O:14])[NH:9]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:21](OC(=O)C)(=[O:23])[CH3:22]>O1CCCC1>[C:21]([N:9]1[C:10]2[C:6](=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH2:7][C:8]1=[O:14])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Oc1cccc2c1CC(=O)N2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc2c1CC(=O)N2C(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.4 %

Procedure:
To a mixture of 4-(acetyloxy)-1,3-dihydro-2H-indol-2-one (J. Med. Chem., 38:2802-2808, 1995; 1.44 g, 7.5 mmol) and sodium carbonate (5.3 g, 50 mmol) in tetrahydrofuran (50 mL) is added acetic anhydride (4.3 mL, 45 mmol). The mixture is stirred at ambient temperature for 18 hours, and partitioned between ethyl acetate and water. After drying (magnesium sulfate), the solvent is removed in vacuo. The crude material is preadsorbed on silica gel (10 g), and purified by flash chromtography (90 g SiO2, 10% ethyl acetate:hexane to 70% ethyl acetate:hexane, linear gradient over 30 minutes) to provide 480 mg (27%) of acetic acid 1-acetyl-2-oxo-2,3-dihydro-1H-indol-4-yl ester as a white solid.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(C1C=CC=C(O)C=1O)(C)(C)C>COCCOCCOC>[C:15]1([CH:14]2[CH2:13][CH:2]([C:1]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4][CH:5]2[C:6]([O:8][CH3:9])=[O:7])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)/C=C/C=C/C(=O)OC
Reactant: C=Cc1ccccc1
Agent: CC(C)(C)c1cccc(O)c1O
Solvent: COCCOCCOC
Product: COC(=O)C1CCC(C(=O)OC)C(c2ccccc2)C1
Temperature: 150 °C

Procedure:
In a 75 ml sealed tube, a stirred suspension of trans,trans dimethyl muconate (10.0 g, 58.8 mmol), two equivalents of styrene (13.5 ml, 117.6 mmol), neutral Al2O3 (300 mg of Aldrich 199974, 3 mass percent), and tert-butyl catechol (25 mg, 0.2 mol percent) in diglyme (20 ml, 2.9 M) is heated to 150° C. for 24 hours. After cooling to room temperature, the reaction mixture is filtered, transferred to a flask, and concentrated. The residue is redissolved in triglyme (0.5 M). Pd/Al2O3 catalyst is added (636 mg (0.5 mol percent) of Johnson-Matthey 5 percent Pd/Al2O3 #12) at room temperature. The flask is equipped with a reflux condenser, fritted gas dispersion tube, and internal Temperature probe. Under N2 flow (190 ml/min) and stirring (190 rpm) the mixture is heated to reflux for 63 hours whereby dimethyl phenyl-terephthalate is formed. Some dimethyl 2-phenyl-cyclohexane-1,4-dicarboxylate is also produced.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11].N(OS(=O)(=O)O)=O.S(=O)(=O)(O)O.F[B-](F)(F)F.[I-:36].[K+]>O.C(OCC)(=O)C>[Br:8][C:7]1[C:2]([I:36])=[C:3]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[O:11])[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1c(Br)cc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: [I-]
Agent: F[B-](F)(F)F
Agent: O=NOS(=O)(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccccc1Cl)c1cc(Cl)cc(Br)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 11.4 g sample of the product of Example 1 (33 mmol) was added portionwise with stirring to a mixture of 36.5 mmol of 40% nitrosylsulfuric acid and 9 mL of concentrated sulfuric acid. The rate of addition was such that the internal temperature was maintained below 45° C. After the addition was completed, stirring was maintained at room temperature for 1.5 hours when the mixture was poured into 75 mL of ice water and filtered. To the filtrate, a solution of 2.2 g of sodium tetrafluoroborate in 15 mL of water was slowly added. The resulting mixture was refrigerated overnight, filtered and the precipitate washed with 12 mL of ice water. The precipitated tetrafluoroborate salt was then stirred in a mixture of 70 mL of water and 25 mL of ethyl acetate while a solution of 11 g (66 mmol) of potassium iodide in 40 mL of water was added over a 20 minute period. The resulting mixture was extracted with three 50 mL portions of methylene chloride which were combined and in turn extracted with 25 mL of 5% sodium thiosulfate solution. The organic extract was concentrated in vacuo to a residual solid which was dissolved in ether and refrigerated overnight. Impurities (mainly bromo-dichlorofluorenone, m.p. 183°-184° C.) were removed by filtration and the filtrate crystallized by concentration to the product which was then recrystallized from ether to produce (3-bromo-5-chloro-2-iodopheny)(2-chlorophenyl)-methanone having a m.p. of 86°-87° C.
Reaction SMILES: P(Br)(Br)[Br:2].[O:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>O1CCOCC1>[O:5]([C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][Br:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccccc1Oc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: BrCc1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 89.4 %

Procedure:
Phosphorus tribromide (5.5 ml, 57.1 mmol) was added dropwise over a period of 10 min to a solution of 2-phenoxybenzylalcohol (4.08 g, 20.4 mmol) in dioxane (165 ml). The reaction mixture was stirred for 40 min. Another portion of phosphorus tribromide (5.5 ml, 57.1 mmol) was added. The reaction mixture was stirred for 56 hours at room temperature. It was cooled to 0° C. Water (45 ml) was added carefully. The reaction mixture was stirred for 30 min at room temperature. The mixture was extracted with ethyl acetate (100 ml). The ethyl acetate phase was washed with 1 N hydrochloric acid. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous soludtion of sodium hydrogen carbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane (1:3) as eluent, to give 4.80 g of 2-phenoxybenzyl bromide.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]([CH3:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]3[NH:19][C:20](=[O:22])[NH:21][C:13]3=[CH:12][C:11]=2[CH:10]=1>CO.CN(C)C=O>[OH:3][CH:4]([CH3:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]3[NH:19][C:20](=[O:22])[NH:21][C:13]3=[CH:12][C:11]=2[CH:10]=1
Reactant: CC(=O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
Sodium borohydride (1.00 g, 26 mmol) was added portionwise to a stirred suspension of 1,3-dihydro-7-(4-oxopentoxy)-2H-imidazo[4,5-b]quinolin-2-one (3.70 g, 13 mmol) in methanol (85 mL) and dimethylformamide (85 mL). The mixture was stirred at room temperature for 3 hours and then the solvent removed in vacuo. The residual oil was triturated with water (50 mL) and the solid material filtered off, washed with water and dried in air. Crystallization from aqueous dimethylformamide followed by trituration with methanol afforded 1,3-dihydro-7-(4-hydroxypentoxy)-2H-imidazo[4,5-b]-quinolin-2-one (3.20 g, 86%), m.p. 301°-303° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[CH3:5].[OH-].[Na+]>CO>[C:12]([C:8]1[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:20])=[O:2])[CH:11]=[CH:10][CH:9]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The solution of (5) (2.4 g, 0.009 mol) in methyl alcohol (25 ml) was added with 1N NaOH (13.5 ml) and the mixture was left under stirring for 8 hours at room temperature. After evaporating the solvent, the residue was diluted with water and 5% monobasic sodium phosphate was added drop by drop to the mixture to adjust pH to 5. The aqueous layer was then extracted with methyl acetate (2×100 ml). The collected organic extracts were dried over Na2SO4 and evaporated under vacuum, then crystallized from a benzene/petroleum ether 6:20 mixture to obtain 2.05 g of (6) (0.0081 mol; yield 90%) as a white solid (melting point 92-92° C.) following crystallization.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH:18]=O.CC(OC)(C)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH:4]=1
Reactant: CN(C)CCOc1cc(N)ccc1Cl
Reactant: COC(C=O)OC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(CNc1ccc(Cl)c(OCCN(C)C)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 4-chloro-3-(2-dimethylaminoethoxy)aniline (1.22 g, 0.006 mol) in MeOH (30 ml) containing dimethoxyethanal in MTBE (1.76 g, 0.17 mol) and glacial acetic acid (1.71 g) was added sodium cyanoborohydride (1.78 g, 0.03 mol ) portionwise at 0° C. The reaction was left to stir at room temperature for 1 hour, and then 10% aq. NaOH was added and the mixture was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), and concentrated in vacuo to give a brown oil. Purification by FCC, eluting with CH2Cl2 gave the title compound (1.49 g, 87%)
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[O:14][Si](C(C)(C)C)(C)C)[CH:2]=[CH2:3].[C-:22]#[N:23].[K+].C(O)C>O>[OH:14][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:1][CH2:2][CH2:3][C:22]#[N:23]
Reactant: [C-]#N
Reactant: C=CCc1ccc2ccccc2c1O[Si](C)(C)C(C)(C)C
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCCCc1ccc2ccccc2c1O
Yield: 35 %

Procedure:
A mixture of the product of Example 122 Part C (3.79 g, 0.010 mole), potassium cyanide (0.72 g, 0.011 mole), ethanol (15 mL) and water (2 mL) was heated at reflux for 20 hours. The cooled mixture was poured into water and extracted with ethyl acetate. The crude product was chromatographed with 1:1 ether/hexane and recrystallized (cyclohexane/toluene) to provide the title compound (0.73 g, 35%) as a white solid, mp 76°-78°.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.[CH:19]1N=C[N:21](C(N2C=NC=C2)=O)[CH:20]=1.C(N)C.CO>>[CH2:20]([NH:21][C:14]([C:7]1([CH3:17])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[O:8]1)=[O:16])[CH3:19]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: CCN
Solvent: CO
Product: CCNC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 356 mg CDI (2.20 mmol) and 1.1 mL of a 2.0 solution of ethylamine in methanol (2.2 mmol) produced 334 mg of as N-ethyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a white solid.