Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH2:10][C:11]1([O:42][C@H:41]([CH2:43][O:44][C:45](=[O:52])[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:31]([O:32]C(=O)C2C=CC=CC=2)[C@@H:21]1[O:22]C(=O)C1C=CC=CC=1)OC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:53]([Si](C)(C)C)[C:54]#[CH:55].B(F)(F)F.CCOCC>C(#N)C>[C:45]([O:44][CH2:43][C@@:41]1([O:42][C@H:11]([CH2:10][OH:9])[C@@H:21]([OH:22])[C@@H:31]1[OH:32])[CH:53]=[C:54]=[CH2:55])(=[O:52])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: C#CC[Si](C)(C)C
Reactant: O=C(OC[C@H]1OC(COC(=O)c2ccccc2)(OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: C=C=C[C@@]1(COC(=O)c2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
In accordance with Flowchart G, D-fructofuranose pentabenzoate 57 and propargyltrimethylsilane in acetonitrile at 0° C. are reacted with boron trifluoride etherate, giving 4,7-anhydro-4-C-[(benzoyloxy)methyl]-1,2,3-trideoxy-D-manno-octa-1,2-dienitol, tribenzoate 58, which is treated with sodium methoxide in methanol, giving 4,7-anhydro-1,2,3-trideoxy-4-C-(hydroxymethyl)-D-oluco (or D-manno)-octa-1,2-dienitol 59. Compound 59 is treated with cupric sulfate and sulfuric acid in acetone followed by sodium carbonate in pyridine, giving 4,7:41,5-dianhydro-1,2,3-trideoxy-4-C-[(1-hydroxy-1-methylethoxy)methyl]-D-manno-octa-1,2-dienitol 60 which is reacted with sodium hydride in dimethylformamide at 0° C. and then with 15 benzyl bromide and methanol, giving 4,7:41,5-dianhydro-1,2,3-trideoxy-4-C-[(1-hydroxy-1-methylethoxy)methyl]-6,8-bis-O-(phenylmethyl)-D-manno-octa-1,2-dienitol 61. Compound 61 is ozonized at -78° C. in dichloromethane containing pyridine, then treated with zinc dust and acetic acid, giving 2,5:21,3-dianhydro--2-C-[(1-hydroxy-1-methylethoxy)methyl]-4,6-bis-O-(phenylmethyl)-D-mannose 62, which is dissolved in diethyl phosphite and reacted with sodium ethoxide in ethanol, followed by sodium dihydrogen phosphate in dichloromethane, giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)hydroxymethyl]-1,3-0-(1-m®thylethylidene)-4,6--bis-O-(phenylmethyl)-D-glucitol 63. Compound 63 is treated with diisopropylethylamine and 2-(trimethylsilyl)ethoxymethyl chloride in dichloromethane, giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1,3-O-(1-methylethylidene)--4,6-bis-O-(phenylmethyl)-D-glucitol 64, which is hydrogenated in methanol over palladium hydroxide on carbon, giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)-[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1,3-O-(1-methylethylidene)-D-glucitol 65. Compound 65 is reacted with diphenyl phosphorochloridate in pyridine at 0° C., giving 2,5-anhydro-2-C-[(diethoxyphosphinyl)-[[2-(trimethylsilyl)ethoxy]methoxy]methyl]-1,3-O-(1-methylethylidene)-D-glucitol, 6-(diphenyl phosphate) 66, which is reacted with bromotrimethylsilane in dichloromethane, then hydrogenated in ethanol over platinum oxide, giving 2,5-anhydro-2-C-(hydroxyphosphonomethyl)-D-glucitol, 6-(dihydrogen phosphate) 67. ##STR16##
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.O=O.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(N(CC)CC)C.CN(C=O)C.[Cu]I>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Agent: [Cu]I
Agent: O=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1c[nH]c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-iodouracil (8 g, 30 mmol) in redistilled triethylamine (500 mL) and dry DMF (10 mL) was degassed with oxygen-free nitrogen for 15 minutes. Bis(triphenylophosphine)palladium (II) chloride (0.5 g), copper (I) iodide (0.5 g) and trimethylsilylacetylene (10 g, 102 mmol) were then added and the mixture was heated with stirring at 50° C. for 24 hours. The cooled reaction mixture was filtered, the filtrate evaporated to dryness and the residue dissolved in dichloromethane (500 mL). The organic solution was washed with a 2% aqueous solution of disodium EDTA (3×250 mL), water (3×200 mL), dried (Na2SO4) and evaporated to dryness. The residue was triturated with ethanol to give the first crop of the title compound. The solid filtered from the reaction mixture was also found to contain the required product but in a more impure form and so was worked up as above in a separate batch to give a second crop.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[CH:13]1)[CH2:9][CH2:10][CH3:11].C[O-:21].[K+:22]>CO>[OH2:18].[OH2:21].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[C:16]([C:17]([O-:19])=[O:18])=[CH:15][N:14]=[CH:13]1)[CH2:9][CH2:10][CH3:11].[K+:22]
Reactant: C[O-]
Reactant: CCCC(c1ccccc1Cl)n1cncc1C(=O)O
Agent: [K+]
Solvent: CO
Product: CCCC(c1ccccc1Cl)n1cncc1C(=O)[O-]
Product: O
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A mixture of 1 part of 1-[1-(2-chlorophenyl)butyl]-1H-imidazole-5-carboxylic acid, 80 parts of methanol and 35.9 parts of a potassium methoxide solution 0.1N was stirred for 1 hour at reflux temperature. The reaction mixture was evaporated and the residue was dried in a dry pistol at 70° C., yielding 0.34 parts (26.7%) of potassium 1-[1-(2-chlorophenyl)butyl]-1H-imidazole-5 -carboxylate dihydrate; mp. 70.7° C. (compound 2.14).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[CH2:21][CH2:20][C:19]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:12][C:11]=3[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:9]2)=[O:7])=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:37])C=1Cl>C1COCC1.O>[CH2:25]([O:24][C:22]([C:10]1[C:11]2[NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[C:20](=[O:37])[CH2:21][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=2)[CH:9]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(=O)c2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 3-(4-fluorobenzoyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (190 mg, 0.5 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (139 mg, 0.6 mmol) was added a mixture of THF-H2O (9:1, 8 mL) at ambient temperature. The reaction mixture was allowed to stir at ambient temperature for 2 hours. Additional DDQ (139 mg, 0.6 mmol) was added, and the mixture was stirred at ambient temperature for another 2 hours. The solvent was removed in vacuo, and the residue was taken up in EtOAc and washed thoroughly with saturated sodium bicarbonate solution and then with brine. The organic phase was dried with sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with hexane-EtOAc (85:15) to give the title compound as a yellow solid (180 mg, 92%); 1H-NMR (CDCl3): δ 11.4 (1H, s), 8.52-8.48 (2H, m), 7.66-7.62 (2H, m), 7.48-7.46 (1H, m), 7.37-7.31 (2H, m), 7.22-7.17 (2H, m), 4.53 (2H, s), 4.38 (2H, q), 1.35 (3H, t); MS (ES): 393 (MH+).
Reaction SMILES: C(O[C:5](=[O:14])[CH:6]=[C:7]([NH:12][CH3:13])[C:8]([F:11])([F:10])[F:9])(C)C.[CH2:15]([O:18][C:19]([C:21]([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[CH:29]=[CH:28][C:27]=1[Cl:35])([CH3:23])[CH3:22])=[O:20])[CH:16]=[CH2:17].Cl>C(#N)C>[CH2:15]([O:18][C:19]([C:21]([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([N:32]2[C:5](=[O:14])[CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[N:12]([CH3:13])[C:33]2=[O:34])[CH:29]=[CH:28][C:27]=1[Cl:35])([CH3:23])[CH3:22])=[O:20])[CH:16]=[CH2:17]
Reactant: CNC(=CC(=O)OC(C)C)C(F)(F)F
Reactant: C=CCOC(=O)C(C)(C)OC(=O)c1cc(N=C=O)ccc1Cl
Agent: Cl
Solvent: CC#N
Product: C=CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Temperature: 2.5 °C
Yield: 91.2 %

Procedure:
2.9 g of potassium tert.butylate (content 97%, 0.025 mols) are suspended in 169 g of dry acetonitrile (water content <0.01%) and cooled to 0-5° C. Subsequently, at 0-5° C., 36.2 g of 3-methylamino-4,4,4-trifluorobut-2-enoic acid isopropylester (content 98.3%, 0.17 mols) are added and maintained at this temperature for 30 minutes, whereby a red-brown solution is produced. Then, over the course of 15 minutes, at 0-5° C., 27.3 g of 5-isocyanato-2-chloro-benzoic acid 1-allyloxycarbonyl-1-methyl-ethyl-ester (content 99%, 0.084 mols) are dispensed in, whereby a dark brown solution is obtained. The latter is adjusted to pH 7 with 3.0 g of 1 N hydrochloric acid [content of desired product in the solution is 15.5%, which corresponds to a yield of 91.2%]. The solvent is subsequently distilled off in a vacuum, and the residue (68 g) is recrystallised in 200 g of isopropyl alcohol, whereby the inorganic salts are removed by hot filtration. After drying in a vacuum drying chamber at 60° C. for 12 hours, 32.8 g (82% of theory) of the desired product are isolated in a content of 98.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]3[N:9]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=3)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]3[N:9]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c(ccc3ccc(Cl)cc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cn2c(ccc3ccc(Cl)cc32)n1

Procedure:
200 mg of ethyl 8-chloroimidazo-[1,2-a]-quinoline-2-carboxylate in 8 ml of ethanol and 2 ml of water were hydrolyzed with 1 ml of N sodium hydroxide solution. The mixture was acidified with 1.1 ml of N HCl as in Example 36 to obtain colorless needles of 8-chloroimidazo-[1,2-a]-quinoline-2-carboxylic acid melting at 288°-289° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[C:4]([CH3:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]4[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]4)=[C:4]([CH3:18])[CH:3]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Cc1cc(I)ccc1NCCN1CCC(C)CC1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1NCCN1CCC(C)CC1

Procedure:
The product was prepared analogously to Example 7.1e starting from (4-iodo-2-methylphenyl)-[2-(4-methylpiperidin-1-yl)ethyl]amine and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 60 mg (20% of theoretical); C28H30ClN3 (M=444.011); calc.: molpeak (M+H)+444/446 (Cl); found molpeak (M+H)+: 444/446 (Cl); HPLC-MS: 5.53 minutes (method B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-])=O)=[CH:19][C:18]=3[CH3:27])[CH:13]=[CH:12][C:11]=2[OH:28])=[O:9])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pt]>[NH2:24][C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([O:16][C:14]2[CH:13]=[CH:12][C:11]([OH:28])=[C:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])[CH:15]=2)=[C:18]([CH3:27])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(=O)c2ccc(F)cc2)c1

Procedure:
(4-Fluorophenyl) [2-hydroxy-5-(2,6-dimethyl-4-nitrophenoxy)phenyl]methanone (62.8g, 0.16 mol) is dissolved in ethyl acetate (4L) and hydrogenated at atmospheric pressure over 5% platinum on carbon (13.2g). When the theoretical amount of hydrogen is consumed, the hydrogenation is stopped, the catalyst is filtered off, and the ethyl acetate solution is concentrated to dryness at 50°/3mm Hg. The residue is triturated hot with isopropanol (1L) and collected to yield [5-(4-amino-2,6-dimethylphenoxy)-2-hydroxyphenyl](4-fluorophenyl)-methanone, m.p. 198°-202°.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Product: CC(=O)c1ccccc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.153 mmol) and 2-acetyl-phenylboronic acid (28 mg, 0.17 mmol) as an off -white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.92 (dd, 1H), 8.21 (d, 1H), 8.20 (s, 1H), 8.14 (d, 1H), 8.10 (dd, 1H), 7.86 (d, 1H), 7.63 (dd, 1H), 7.57 (td, 1H), 7.48 (m, 3H), 7.40 (dd, 1H), 7.35 (dd, 1H), 3.85 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(F)c(N)c1
Yield: 88.7 %

Procedure:
Stir mixture of 4-fluoro-3-nitro-benzoic acid methyl ester (5.30 g, 26.6 mmol) and palladium (5% on carbon, 5.66 g, 2.66 mmol, Aldrich Chemical Co.) in ethanol (0.2 M). Carefully introduce hydrogen (balloon) and stir the reaction for 24 h. Filter the reaction mixture through a glass-fiber filter and wash the filter cake with ethanol. Concentrate the filtrate to afford the title compound (4.00 g, 23.6 mmol, 89%): MS (m/z): 170 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11]O.C1(C)C=CC=CC=1.O>CC(CC(C)=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)#[N:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)CC(C)C
Product: N#Cc1ccc(O)cc1
Yield: 91 %

Procedure:
503 Milligrams of p-hydroxybenzaldehyde, 323 mg of hydroxylamine hydrochloride and 10 ml of toluene were introduced to a flask of 50 ml, equipped with a Dean-Stark dehydrating apparatus. The reaction mixture was stirred under reflux for 4 hrs. After the reaction finished, water and MIBK were added to the reaction mixture and mixed, followed by separation into two layers. Aqueous layer was extracted again by MIBK and the extract was combined with toluene layer first separated and subjected to the analysis of the products by gaschromatography [5% PEG 20M, 0.5 m, 190° C. (4 minutes retention)→220° C. (5 minutes retention), 2° C./min]. From the results, it was found that the conversion of p-hydroxybenzaldehyde was 100% and 449 mg (91% yield) of p-cyanophenol and 6.1 mg (1.1% yield) of p-hydroxybenzaldoxime were produced.
Reaction SMILES: [CH3:1][OH:2].[CH3:3][C:4]1([CH3:25])[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[C:10]2[CH:9]=[C:8]([CH:16]3[C:21]4[CH:22]=[CH:23][O:24][C:20]=4[CH2:19][CH2:18][CH2:17]3)[CH:7]=[CH:6][C:5]1=2.[OH-:26].[Na+]>O>[CH3:3][C:4]1([CH3:25])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[C:10]2[CH:9]=[C:8]([CH:16]3[C:21]4[CH:22]=[C:23]([C:1]([OH:26])=[O:2])[O:24][C:20]=4[CH2:19][CH2:18][CH2:17]3)[CH:7]=[CH:6][C:5]1=2
Reactant: CO
Reactant: [OH-]
Reactant: CC1(C)CCC(C)(C)c2cc(C3CCCc4occc43)ccc21
Agent: [Na+]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C3CCCc4oc(C(=O)O)cc43)ccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A methanol solution (20 mL) was mixed with 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-4,5,6,7-tetrahydro-1-benzofuran]-2-carboxaldehyde (100 mg, 0.30 mmol, see example 1 part C for preparation), 5.0 N NaOH (10 mL) and Ag2O (138 mg, 0.59 mmol. The resulting black heterogeneous reaction mixture was allowed to stir at room temperature for a period of 17 hours. The reaction mixture was diluted with water and washed with ethyl ether. The ether washes were discarded and the aqueous mixture was made acidic (pH 3.0) using concentrated HCl. The resulting mixture was extracted with ether and dried over MgSO4. The solvent was evaporated in vacuo to yield 73 mg of pure solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[C:10]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34].C(N(CC)CC)C.O>ClCCl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[CH2:30][CH2:31][CH2:32][C:33]3=[O:34])[CH2:23][CH2:22]2)[C:10]=1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCBr
Reactant: Cc1c(CO[C@H]2CC[C@H](N)CC2)nc2ccccc2c1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(CO[C@H]2CC[C@H](N3CCCC3=O)CC2)nc2ccccc2c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexaneamine (300 mg) in dichloromethane (5 mL) were added 4-bromo butanoic acid chloride (0.11 mL) and triethylamine (0.15 mL) under ice-cooling, followed by stirring at the same temperature for 45 minutes. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was dissolved in THF, and 60% sodium hydride (50 mg) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, followed by stirring for another 15 hours while heating it in an oil bath at 60° C. 60% sodium hydride (50 mg) was added to the reaction mixture, followed by stirring for 4 hours while heating it in an oil bath at 60° C. The reaction mixture was cooled to room temperature, and water was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=100/0˜95/5). The solvent was evaporated under reduced pressure, and the residue was then dried under vacuum at room temperature to obtain 161 mg of 1-(trans-4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}cyclohexyl)pyrrolidin-2-one as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C1(C)C=CC=CC=1>[Br:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([NH:1][C:20](=[O:21])[CH2:19][Cl:18])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1cccc(Br)c1C(=O)O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CCl)Nc1cccc(Br)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a stirred solution of 2-amino-6-bromo-benzoic acid (3.06 g, 14.2 mmol) in toluene (75 mL) cooled to 0° C. in an ice-bath was added pyridine (0.60 mL, 7.10 mmol) followed by a solution of chloroacetyl chloride (2.26 mL, 28.4 mmol) in toluene (75 mL) drop-wise over 1 hr. The reaction mixture was allowed to warm to RT, and was heated at 115° C. for 3 hr and then allowed to cool to RT. The solvent volume was reduced by half by evaporation in vacuo. Upon standing overnight, the product precipitated and was collected by filtration to afford 2-bromo-6-(2-chloroacetamido)benzoic acid (1a, X═Cl) (1.44 g) as a white solid: m/z 290/292 (M+H)+ (ES+). The filtrate was concentrated in vacuo and the residue triturated with ethanol/heptane to afford 2-bromo-6-(2-hydroxyacetamido) benzoic acid (1b X═OH) (1.02 g, combined yield, 59%): m/z 274/276 (M+H)+ (ES+). Both 1a and 1b can be used without further purification in the next step.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([Cl:30])[CH:6]=1.C(O)C.[OH-].[Na+]>C(O)(=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([Cl:30])[CH:6]=1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3Cl)ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)c(Cl)c1

Procedure:
0.3 g (0.66 mmol) of the ester from Example 75 were stirred overnight at room temperature with a mixture of 5 ml ethanol and 0.5 ml 2 N aqueous sodium hydroxide solution. It was brought to pH 5 with 2 N acetic acid. The precipitate of the title compound was filtered with suction, washed successively with water and with acetone, and dried in vacuo. Yield: 0.19 g (74%) of a white powder, m.p. 269-270° C.(dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[CH2:13].O.O.O.[N+]([O-])([O-])=[O:18].[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(Cl)(Cl)Cl>CO>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][C:13](=[O:18])[CH2:8][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: C=C1CCCc2c(OC)cccc21
Reactant: O=[N+]([O-])[O-]
Agent: [Tl+3]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cccc2c1CCCC(=O)C2
Reaction time: 0.02 h

Procedure:
5-Methoxy-1-methylene-1,2,3,4-tetrahydro-naphthalene (23.8 g, 0.137 mol) in 150 mL MeOH added in one portion to freshly prepared solution of thallium(III)nitrate trihydrate (1.0 eq) in 300 mL MeOH. Stirred one minute and 400 mL chloroform added. The solution was filtered and the organics partitioned between dichloromethane and water. The organics were dried (MgSO4) and concentrated. Purification by chromatography (ISCO, 330 g silica cartridge; stepwise elution hexane (5 min) then 7 minute gradient to 100% dicloromethane (20 min) affords the title compound as the most polar of the products as a pale yellow oil (26 g, 97%). 1H-NMR (400 MHz, CDCl3) 7.16 (t, J=7.9 Hz, 1H), 7.84 (d, J=8.3 Hz, 1H), 6.79 (d, J=7.5 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 2H), 3.05-3.01 (m, 2H), 2.55 (t, J=7.0 Hz, 2H), 2.01-1.96 (m, 2H). LC/MS (ESI+) m/z=191 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH2:21]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:20][NH:21][C:10]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=1)=[O:12]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1cccc(-c2ccccc2)c1

Procedure:
Using preparation method 1, 3-phenylbenzoic acid (125 mg, 0.63 mmol) was reacted with 3,4-dichlorobenzylamine (123 mg, 0.7 mmol). The product was purified by flash chromatography on SiO2 using CH2Cl2/hexanes 50:50 then CH2Cl2 100%. White crystals were obtained (111 mg, 50%). NMR 1H (ppm, CDCl3): 8.00 (s, 1H), 7.73 (dd, J3=7.7 Hz, J4=1.6 Hz, 2H), 7.59 (d, J3=7.3 Hz, 2H), 7.50 (t, J3=7.7 Hz, 1H), 7.46-7.34 (m, 6H), 7.19 (dd, J3=8.2 Hz, J4=1.8 Hz, 1H), 6.54 (br. s, 1H), 4.61 (d, J3=5.9 Hz, 2H).