Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH2:17][CH:16]=[CH:15][CH2:14][N:13]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:5][C:4]=2[CH:3]=1>CCCCCC.C(O)C>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:5][C:4]=2[CH:3]=1.[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=CC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1

Procedure:
tert-Butyl(2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.86 g, 51.1% ee) was fractionated by high performance liquid chromatography (column: CHIRALPAK IC (50 mm i.d.×500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 80 mL/min, column temperature: 30° C.). tert-Butyl(2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (0.54 g, 99.8% ee, retention time 10.16 min) and tert-butyl(2R)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)piperidine-1-carboxylate (0.20 g, >99.9% ee, retention time 7.31 min) were obtained under the above-mentioned high performance liquid chromatography conditions. The analysis was performed by high performance liquid chromatography (column: CHIRALPAK IC (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1 mL/min, column temperature: 30° C., detection 220 nm).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]([O-:14])([O-])=O.[Cs+].[Cs+].Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>CC(C)=O.O>[CH:8]([C:7]1[CH:6]=[C:5]2[C:10](=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:11]([O:14][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH:2]=3)[CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)([CH3:9])[CH3:7]
Reactant: c1ccc2ncccc2c1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1cc(-c2cccc(OCc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of Quinoline 2 (1.0 eq) in acetone (0.2M) was added Cs2CO3 (1.5 eq) and 1-chloromethyl-4-methanesulfonyl-benzene (1.5 eq). The resulting mixture was stirred 2 days at room temperature, poured in water and extracted with Et2O (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 in 15 min) afforded the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:25](Cl)(=[O:27])[CH3:26].O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:25](=[O:27])[CH3:26])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccccc3)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(-c3ccc(C(C)=O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.4 %

Procedure:
To 1-(biphenyl-4-yl)cyclopropanecarboxylic acid ethyl ester (9 g, 33.8 mmol) in CH2Cl2 (100 mL) was added aluminum chloride (9.4 g, 71 mmol) followed by acetyl chloride (5.5 g, 71 mmol). The solution was stirred at room temperature for 1.5 hours then slowly poured into water. The organic layer was separated and extracted 2 times with water. The organic layer was dried and evaporated to yield 11.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:59]=[CH:60][CH:61]=1)[O:54][CH2:55][CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:56][CH2:55][O:54][C:53]2[CH:59]=[CH:60][CH:61]=[C:51]([O:50][CH3:49])[CH:52]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1cccc(OCCCO)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cccc(OCCCOC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (75 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (112 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(3-methoxyphenoxy)-1-propanol (69 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 69%).
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:6]=[N:7][NH:8][CH:9]=1)([O-:3])=[O:2].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[N+:1]([CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])Cc1cn[nH]c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])Cc1cnn(C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 430 mg of 4-(nitromethyl)-1H-pyrazole in 4.3 ml of ethyl acetate were added 0.62 ml of 3,4-dihydro-2H-pyran and 129 mg of 4-methylbenzenesulfonic acid monohydrate, followed by stirring at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 213 mg of 4-(nitromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[S:10][C:3]=12.[CH:18]1([NH:21][C:22]([C:24]2[C:25]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:26]=3[S:27][C:28]=2[CH3:29])=[O:23])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:18]1([NH:21][C:22]([C:24]2[C:25]3[CH:33]=[CH:32][C:31]([O:34][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]6[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=6)[S:10][C:3]=45)=[CH:30][C:26]=3[S:27][C:28]=2[CH3:29])=[O:23])[CH2:20][CH2:19]1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NC1CC1
Reactant: OCc1csc(-c2cc3nccc(Cl)c3s2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nc(CO)cs5)sc34)ccc2c1C(=O)NC1CC1
Yield: 43.6 %

Procedure:
This material was prepared by reacting [2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]methanol (124 mg, 0.5 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid cyclopropylamide 8c (113 mg, 0.4 mmole) and Cs2CO3 (391 mg, 1.2 mmole) in a manner similar to that previously described for example 1 to give a yellow solid (86 mg, 44%). 1H NMR (DMSO-d6, 300 MHz) δ 8.56 (1H, d, J=5.4 Hz), 8.46 (1H, d, J=4.3 Hz), 8.17 (1H, s), 7.96 (1H, d, J=2.2 Hz), 7.81 (1H, d, J=8.8 Hz), 7.63 (1H, s), 7.34 (1H, dd, J=2.2, 8.8 Hz), 6.75 (1H, d, J=5.4 Hz), 4.60 (2H, d, J=4.9 Hz), 2.96–2.85 (1H, m), 2.57 (3H, s), 0.78–0.67 (2H, m), 0.62–0.53 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3](B(O)O)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Br[C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]([F:23])[F:22]>>[Cl:1][C:2]1[C:3]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[CH:21]([F:23])[F:22])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1cc(B(O)O)c(Cl)cn1
Reactant: FC(F)c1ccc(Cl)cc1Br
Product: COc1cc(-c2cc(Cl)ccc2C(F)F)c(Cl)cn1

Procedure:
463 mg (purity 93%, 2.3 mmol) of (5-chloro-2-methoxypyridin-4-yl)boronic acid and 515 mg (2.1 mmol) of 2-bromo-4-chloro-1-(difluoromethyl)benzene in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 305 mg (purity 77%, 34% of theory)
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([CH:11]=[O:12])[CH:3]=1.C(Cl)Cl.[CH3:16][CH2:17][O:18]C(C)=O>>[O:12]1[CH2:16][CH2:17][O:18][CH:11]1[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: Cc1cc(C=O)ncc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C2OCCO2)ncc1[N+](=O)[O-]

Procedure:
2-(1,3-Dioxolanyl)-4-methyl-5-nitropyridine was synthesized by the method of Example XLIX except that the starting material was 4-methyl-5-nitropyridine-2-carboxaldehyde. Yield: 2.3 g (91%); mp 77°-79° C.; (lit mp 77° C.); TLC, Rf 0.74 (CH2Cl2 /EtOAc, 3:2, v/v); 1H NMR (90 MHz, CDCl3) δ 2.65 (s, 3H, 4-CH3), 4.10 (s, 4H, CH2CH2), 5.85 (s, 1H, 2-CH), 7.50 (s, 1H, 3-H), 9.12 (s, 1H, 6-H). Anal. (C9H10N2O4) C, H, N.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[CH:20]=[C:19]2[C:9]([NH:10][CH:11]=[C:12]2[CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:8][CH:7]=1.[CH3:21]O>>[ClH:3].[CH3:21][O:17][C:16](=[O:18])[C@H:14]([CH2:13][C:12]1[C:19]2[C:9](=[CH:8][CH:7]=[C:6]([OH:5])[CH:20]=2)[NH:10][CH:11]=1)[NH2:15]
Reactant: O=S(Cl)Cl
Reactant: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Reactant: CO
Product: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Methanol (5 ml) was maintained at 0° C., and thionyl chloride (2.4 ml) was added dropwise under an argon atmosphere. To this solution was added 5-hydroxy-L-tryptophan (2.0 g), and the mixture was gradually warmed from 0° C. to room temperature, and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from a mixed solvent of ethanol and ether to give 5-hydroxy-L-tryptophan methyl ester hydrochloride (1.8 g, yield 74%) as crystals.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:7]=1.[CH:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=1)[CH:19]=[O:20])=[O:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:8]([C:6]1[N:7]=[C:3]([CH2:2][O:22][C:17]2[CH:16]=[CH:15][C:14]([CH:12]=[O:13])=[CH:21][C:18]=2[CH:19]=[O:20])[S:4][CH:5]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1csc(CBr)n1
Reactant: O=Cc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(COc2ccc(C=O)cc2C=O)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 73.5 %

Procedure:
A mixture of 2-bromomethyl-4-tert-butylthiazole (1.05 g), 5-formyl-2-hydroxybenzaldehyde (0.74 g), potassium carbonate (0.89 g) and potassium iodide (small mass) in N,N-dimethylformamide was stirred at 50° C. for 5 hours. After being cooled, the resulting solution was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-(2,4-diformylphenoxymethyl)thiazole (1.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:29].C(N(CC)C(C)C)(C)C.[Cl:39][C:40]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>C(Cl)Cl>[Cl:39][C:40]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:41]=1[C:42]([NH:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:29])=[O:43]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(N)c(C)c1)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)c(C)c1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 0.30 g of ethyl 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine-3-carboxylate in 20 ml of methylene chloride is added 0.15 g of N,N-diisopropylethylamine and 0.24 g of 2,4-dichlorobenzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated NaHCO3 and dried with Na2SO4. The organic layer is passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.24 g of solid, m.p. 174-184° C.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1O.[C:18](#[N:21])[CH:19]=[CH2:20]>CO.[Pd]>[NH2:21][CH2:18][CH2:19][CH2:20][C:16]1[C:14](=[O:15])[NH:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:2]1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: C=CC#N
Agent: [Pd]
Solvent: CO
Product: NCCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
Uridine is reacted with mercuric chloride (5 mmol) at pH 5.0. The 5-mercurichloride-dU so produced is reacted with acrylonitrile and lithium tetrachloro-palladiate in methanol yielding 5-(2-cyanoethenyl) dU which is reduced by hydrogenation at 3 atmospheres in the presence of 10% palladium on charcoal in methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[OH:31][CH:32]([CH:36]([OH:40])[C:37]([OH:39])=[O:38])[C:33]([OH:35])=[O:34]>C(O)C>[CH2:32]([O-:31])[CH3:33].[OH:31][CH:32]([CH:36]([OH:40])[C:37]([O-:39])=[O:38])[C:33]([O-:35])=[O:34].[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: O=c1[nH]c2ccccc2n1CCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Solvent: CCO
Product: CC[O-]
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
To a stirred solution of 1 part of 5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one in 32 parts of ethanol is added a solution of 0.35 parts of (±)-2,3-dihydroxy-1,4-butanedioic acid in 8 parts of ethanol. Upon stirring, the product is allowed to crystallize. It is filtered off and dried, yielding 1 part of (±)-5-chloro-1-{1-[3-(1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one 2,3-dihydroxybutanedioate ethanolate; mp. 153.5° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[Cl:7][C:8]1[C:13]([NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:12][CH:11]=[CH:10][N:9]=1>ClCCl>[Cl:7][C:8]1[C:13]([N:14]([S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[C:2]([C:1]([N:14]([C:13]2[C:8]([Cl:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[S:15]([C:18]([F:19])([F:20])[F:21])(=[O:16])=[O:17])=[O:5])=[O:3])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=S(=O)(Nc1cccnc1Cl)C(F)(F)F
Solvent: ClCCl
Product: O=C(C(=O)N(c1cccnc1Cl)S(=O)(=O)C(F)(F)F)N(c1cccnc1Cl)S(=O)(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Oxalyl chloride (0.762 gram; 0.006 mole) is added dropwise to a suspension of N-(2-chloro-3-pyridyl)-trifluoromethanesulfonamide (2.61 grams; 0.01 mole) and powdered Type 3A molecular sieves (5.0 grams) in dichloromethane (75 mls) at 0° C. under a nitrogen atmosphere. The mixture is then heated to 60° C., held thereat for 3 hours, and then stirred at room temperature for 60 hours. The reaction mixture is filtered and the filtrate is evaporated to dryness. The resulting residue is extracted with diethyl ether, and the combined ethereal extracts are dried over anhydrous sodium sulfate. The dried ethereal extract is then separated and evaporated to obtain 2.33 grams (81% of theoretical) of crude product.
Reaction SMILES: [CH2:1]([S:8](Cl)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:14](=[O:26])[N:15]([CH2:23][CH:24]=[CH2:25])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1>N1C=CC=CC=1>[CH2:1]([S:8]([NH:12][C:13]1[C:14](=[O:26])[N:15]([CH2:23][CH:24]=[CH2:25])[C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCn1c(C(F)(F)F)ccc(N)c1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: C=CCn1c(C(F)(F)F)ccc(NS(=O)(=O)Cc2ccccc2)c1=O
Yield: 96.7 %

Procedure:
Benzylsulfonyl chloride (103 mg, 0.542 mmol) was added to a stirred solution of 3-amino-6-trifluoromethyl-1-allyl-2-pyridinone (106.5 mg, 0.488 mmol) in pyridine (1 ml) at 0° C. After 1 h the reaction was evaporated in vacuo and the residue was partitioned between methylene chloride and 10% potassium hydrogen surfate solution, dried (Na2SO4), and evaporated in vacuo to give the title compound (175.8 mg): 1H NMR (CDCl3) selected signals at δ 4.42 (s, 2H), 4.74 (d, J=5.5 Hz, 2H), 5.16-5.31 (m, 2H), 5.86-5.96 (m, 1H), 6.55 (d, J=7.7 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.27-7.33 (m, 5H), 7.70 (br s, 1H, NH).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:17]([CH3:21])[C:18]([OH:20])=[O:19].[N+](=[CH2:24])=[N-]>O1CCOCC1>[CH3:24][O:19][C:18](=[O:20])[CH:17]([C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]=2[CH:1]=1)[CH3:21]
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: C=[N+]=[N-]
Solvent: C1COCCO1
Product: COC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
5.0 G. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid (preparation described infra) is suspended in 50 ml. of dioxane, added to excess ethereal diazomethane and stirred until dissolution is complete and evaporated to dryness. Purification as in part A on silica gel affords a nearly quantitative yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid methyl ester as in part A.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH:10]=[CH:11][CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4].[OH-:22].[Na+].OO>C1COCC1.C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([NH:5][C:6]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]2[C:9]([CH2:10][CH:11]([OH:22])[CH2:12][O:13]2)=[CH:8][CH:7]=1)=[O:4]
Reactant: [OH-]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC=C2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1OCC(O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of borane dimethyl sulphide complex (7.38 mL) was added to an ice cooled, stirred solution of methyl 7-(2,2-dimethylpropionylamino)-2H-chromene-8-carboxylate (Intermediate 12, 7.49 g) in anhydrous THF (100 mL) and the mixture was stirred at room temperature for two hours. The resulting mixture was cooled in an ice bath and water (2.6 mL) was added carefully followed successively by 3M sodium hydroxide (31 mL) and 50% hydrogen peroxide (16 mL). After stirring vigorously at room temperature for 45 minutes, the mixture was diluted with ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 10-60% to give methyl 7-(2,2-dimethylpropionylamino)-3-hydroxychroman-8-carboxylate (3.46 g) as a white foam.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][NH:10][CH2:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:25](=[O:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]2[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=2[C:39]([O:41][CH3:42])=[O:40])=[CH:30][CH:29]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:11][CH3:12])[C:25](=[O:47])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=3[C:39]([O:41][CH3:42])=[O:40])=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)Cl)cc1
Reactant: CCNCc1ccc(C(C)(C)C)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
N-(4-tert-butylbenzyl)-N-ethylamine (0.143 g, 0.746 mmol) was dissolved in dry acetonitrile under N2 and N-ethyl-N,N-diisopropylamine (0.371 g, 2.867 mmol) was added. The mixture was stirred for 30 min and methyl 2-{2-[4-(2-chloro-2-oxoethoxy)phenyl]ethoxy}benzoate (0.200 g, 0.573 mmol) was added. The solution was stirred overnight at room temperature. The crude was purified by flash cromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.229 g of methyl 2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoate (yield 79.3%).