Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:10][CH2:11][CH3:12])[C:8]=1[OH:9])[NH2:5].[C:13](Cl)(Cl)=[O:14]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:5]=[C:13]=[O:14])[CH:6]=[C:7]([CH2:10][CH2:11][CH3:12])[C:8]=1[OH:9]
Reactant: O=C(Cl)Cl
Reactant: CCCc1cc(N)cc(C)c1O
Solvent: CCOC(C)=O
Product: CCCc1cc(N=C=O)cc(C)c1O
Temperature: 25 °C

Procedure:
A mixture of 3-methyl-4-hydroxy-5-n-propylaniline (1.65 g) and ethyl acetate (20 ml) was added to an ethyl acetate solution containing 10 g of phosgene at 0° to 5° C. The resulting mixture was gradually heated and, after the solution became clear, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-methyl-4-hydroxy-5-n-propylphenyl isocyanate. the thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and isopropanol (1.0 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-methyl-4-hydroxy-5-n-propylphenyl)carbamate (1.70 g). Sodium hydride (0.28 g, 60% dispersion in mineral oil) was added to dimethylformamide (50 ml). To the resulting mixture was added isopropyl N-(3-methyl-4-hydroxy-5-n-propylphenyl)carbamate (1.70 g) under 5° C. The resulting solution was stirred at a temperature of 20° C. for 30 minutes, and (chloromethyl)methylsulfide (0.67 g) was added thereto in 5 minutes. The mixture was heated at 90° C. for 10 minutes, poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution and water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-methyl-4-methylthiomethyloxy-5-n-propylphenyl)carbamate (Compound No. 14) (1.90 g) in a yield of 61.0%. nD21.4
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14](C=O)=[CH:13][N:12]=[C:11]([NH:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:10]=1.[C:28]([BH3-])#[N:29].[Na+].C(O)(=O)C.O.[CH2:37]1[CH2:41][O:40][CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([CH2:28][N:29]2[CH2:37][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:13][N:12]=[C:11]([NH:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[N:10]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NCCNc1ncc(C=O)c(-c2ccc(Cl)cc2Cl)n1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCNc1ncc(CN2CCOCC2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 70 °C

Procedure:
N-(2-{[4-(2,4-dichlorophenyl)-5-formylpyrimidin-2-yl]amino}ethyl)(tert-butoxy)-carboxamide (50 mg, 0.121 mmol) was dissolved in 5 mL of THF, 242 μL of sodium cyanoborohydride (1 M in THF) and 5 μL of glacial acetic acid added and the mixture was heated to 70° C. for 18 h. Following slow addition of 1 mL of water to decompose excess reagent, the mixture was partitioned between ethyl acetate and saturated citric acid solution. The organic layer was discarded, and aqueous layer was carefully basified with sodium hydoxide to PH 9, then extracted with ethyl acetate twice. The combined organic layers was dried (sodium sulfate), concentrated, and purified by chromatography (selica gel, 10% methanol/methylene chloride) to afford N-(2-{[4-(2,4-dichlorophenyl)-5-(morpholin-4-ylmethyl)pyrimidin-2-yl]amino}ethyl)(tert-butoxy)carboxamide, 30 mg (52%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][C@H:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:31])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(N(CC)CC)C>[ClH:31].[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C@@H:20]1[C:19]2[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=2[C:17]2[N:16]=[C:15]([NH:14][C:11]3[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:13][CH:12]=3)[N:24]=[CH:23][C:22]=2[CH2:21]1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2[C@@H](c2ccccc2Cl)C3)cc1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Product: Cl
Product: Clc1ccccc1[C@H]1Cc2cnc(Nc3ccc(CCN4CCCCC4)cc3)nc2-c2ccccc21

Procedure:
This was synthesized by using (S)-4-(6-(2-chlorophenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, piperidine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=164-167° C. 1H NMR (DMSO) 400 MHz δ 10.10 (bs, 1H), 9.64 (s, 1H), 8.36-8.32 (m, 1H), 8.30 (s, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.53-7.43 (m, 3H), 7.26-7.20 (m, 3H), 7.18-7.13 (m, 1H), 7.00 (d, J=7.2 Hz, 1H), 6.79-6.75 (m, 1H), 4.77 (t, J=6.8 Hz, 1H), 3.51-3.46 (m, 2H), 3.25-3.09 (m, 4H), 3.01-2.96 (m, 2H), 2.93-2.83 (m, 2H), 1.80-1.67 (m, 5H), 1.41-1.31 (m, 1H). LCMS 495 [M+H]. Calc. for C31H31ClN4.2.07 Hydrochloric acid.0.08 Ethyl Acetate: C, 65.13; H, 5.88; N, 9.70. Found C, 65.13; H, 5.84; N, 9.69.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][CH:12]1[C:36](=[O:37])[N:14]2[CH:15]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:16]([OH:19])[CH2:17][S:18][C@H:13]12.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([NH:11][CH:12]1[C:36](=[O:37])[N:14]2[CH:15]([C:20]([O:22][CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:16]([OH:19])[CH2:17][S:18][C@H:13]12)=[O:2]
Reactant: O=CO
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CNC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
Formic acid (0.4 ml) and acetic anhydride (1 ml) were stirred at 40° C. for 30 minutes. The reaction mixture was cooled in an ice-water bath and added dropwise to a mixture of benzhydryl 7-amino-3-hydroxycepham-4-carboxylate (1.0 g) in methylene chloride (30 ml) at 3° C.. The mixture was stirred at 3° C. for 10 minutes and adjusted to pH 7.0 with 5% aqueous solution of sodium bicarbonate, washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give benzhydryl 7-formamido-3-hydroxycepham-4-carboxylate (1.05 g) as powder.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[NH4+:22].O>CO>[N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([NH2:22])=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Temperature: 25 °C

Procedure:
Methyl 4-((1H-indol-1-yl)methyl)benzoate 1 was dissolved in MeOH (10 mL) and to it was added a 30% solution of ammonium hydroxide (5 mL). The reaction was heated to reflux for 16 h after which it was cooled to RT and H2O (30 mL) was added. The organic products were extracted with EtOAc (3×15 mL), washed with brine (15 mL), dried with Na2SO4 and concentrated in vacuo. The crude product was dissolved in DMF and purified by preparatory HPLC method 1. The title compound was isolated as a white solid (37 mg, 13%). 1H NMR (400 MHz, MeOD): δ 7.79 (d, J=7.9 Hz, 2H), 7.58 (d, J=7.8 Hz, 1H), 7.29 (m, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.11 (t, J=7.2 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H), 5.47 (s, 2H). 13C NMR (100 MHz, MeOD): δ 170.59, 142.41, 136.24, 132.64, 128.93, 128.14, 127.57, 126.36, 121.13, 120.32, 118.99, 109.29, 101.14, 48.93. ESI-LRMS: [M+H]+=251.1 m/z. ESI-HRMS: calc. for C16H14N2O: [M+H]+=251.1179 m/z, found: [M+H]+=251.1179 m/z.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][N:8]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+].C>O.C(#N)C>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][N:8]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][CH2:15]3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)N(C1CCN(Cc3ccccc3)CC1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: O=C1Nc2cc(O)ccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
A mixture of 18.0 g (0.0512 mol) of 3,4-dihydro-7-methoxy-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone and 100 g of pyridine hydrochloride was heated to 160° C. with stirring for 3 hours. After cooling, the product was dissolved in 500 mL of water, the solution obtained was carefully treated with excess solid sodium hydrogen carbonate, whereupon a highly viscous oil was precipitated. This oil was taken up in 150 mL of methanol, the methanolic solution formed was clarified over activated charcoal, then freed from solvent in vacuo once more. The residue was stirred with 50 mL of acetonitrile and then brought to the boil. It was left to cool and the precipitate formed was suction filtered and dried in vacuo at ambient temperature. Yield: 10.8 g (63% of theoretical). Rf=0.32 (MP F). IR (KBr): 1649 (C═O) cm−1; MS: M+=337.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.O1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16]CC1.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1.C1(PC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:12][C:5]1[CH:4]=[CH:3][C:2]([N:20]2[CH2:21][CH2:22][C:17](=[O:16])[CH2:18][CH2:19]2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: C1CC2(CCN1)OCCO2
Reactant: Fc1ccc(Br)c2ncccc12
Agent: c1ccc(Pc2ccccc2)cc1
Agent: c1ccc2c(-c3cccc4ccccc34)cccc2c1
Solvent: Cc1ccccc1
Product: O=C1CCN(c2ccc(F)c3cccnc23)CC1
Temperature: 55 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a 5-L jacketed cylindrical reactor equipped with an impeller-style agitator, condenser, thermocouple, and vacuum/nitrogen inlet was charged 2-L, 15% toluene solution of 8-bromo-5-fluoroquinoline, 209 g of 1,4-Dioxa-8-azaspiro[4.5]decane. Meanwhile in a 500-mL Erlenmeyer flask, a suspension of 16.5 g (26.5 mmol)±-[1,1′-binaphthalene]-2,2′-diylbis[diphenyl-Phosphine, and 6.08 g (6.64 mmol) tris[μ-[(1,2-η:4,5-η)-(1E,4E)-1,5-diphenyl -1,4-pentadien-3-one]]dipalladium in 260 g of toluene was prepared. This freshly made suspension was charged into the 5-L reactor followed by a rinse of 170 g of toluene. 166 g sodium tert-butoxide was then charged into the reactor followed by a rinse with 430 g of toluene. The reactor was degassed by vacuum to less than 125 mmHg and then filled with nitrogen to atmosphere three times. The mixture was then heated to 50-60° C. and stirred for 1 h and then heat to 65-75° and stirred at this temperature for about 10 hours. The mixture was cooled to 40-50° C. and then quenched with 800 g of water. The lower aqueous layer was split off and the volume of the organic layer was reduced to about 1.5 L by vacuum distillation. To this residual was charged 2.28 kg of 20% sulfuric acid at 25-30° C. The mixture was stirred for an hour and was clarified by filtration and a bi-phase filtrate was obtained. The aqueous phase was split and retained. Toluene 870 g was added to the aqueous solution and the mixture was neutralized by slowly adding 770 g 50% sodium hydroxide solution. The lower aqueous layer was split off and extracted with 600 g of toluene. The organic layers were combined and the volume of the reaction was reduced to about 1 L by vacuum distillation. The residue was cooled to room temperature and 480 g of toluene was charged. The mixture was heated to 45-55° C. to form a clear solution, which was filtered through a celite/charcoal pad to remove palladium. The filtrate was concentrated by vacuum distillation to about 0.7 L and diluted with 620 g heptane, cooled to −15 to −5° C. to form a slurry. The solid was collected by filtration. The product was dried by air flow at room temperature. Typical yield is about 70%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:13].C(=O)([O-])[O-].[K+].[K+].F[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29].O>CN(C=O)C>[Cl:27][C:25]1[CH:26]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([S:13][C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:7][C:2]=2[Cl:1])[CH:24]=1
Reactant: CCS(=O)(=O)c1ccc(S)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2[N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from step (i) (1.60 g), potassium carbonate (0.934 g) and 2-fluoro-4-chloro-nitrobenzene (1.18 g) in DMF (20 ml) was stirred at RT overnight. Water (200 ml) was added and the mixture extracted with ethyl acetate. The organics were dried, evaporated under reduced and the residue purified by chromatography on silica eluting with isohexane/diethylether 4:1, yield 0.80 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:6]([CH3:11])([CH3:7])[CH3:4])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][C:6]([CH3:11])([CH3:7])[CH3:4])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](O)CC1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](OC(C)(C)C)CC1
Product: CCOC(=O)[C@H]1CC[C@H](OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of cis/trans-4-hydroxycyclohexane carboxylic acid ethyl ester (2:1) (1.0 g, 5.8 mmol) and di-tort-butyl dicarbonate (2.9 g, 13.4 mmol) in dichloromethane (6 ml) was added anhydrous magnesium perchlorate (0.13 g, 0.58 mmol) which was previously activated in high vacuo (ca. 1 mbar) at 150° C. for 1 h. Stirring for 16 h at 40° C. was followed by partitioning between dichloromethane (50 ml) and water (30 ml). The layers were separated. The aqueous layer was extracted with one 50-ml portion of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash-chromatography with n-heptane/tert-butyl methyl ether as eluent gave pure trans-4-tert-butoxy-cyclohexanecarboxylic acid ethyl ester and cis-4-tert-butoxy-cyclohexanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=O.[OH-].[Na+]>O>[F:9][C:10]1[CH:11]=[C:12]([C:13]2[NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:1]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccncc1N
Reactant: O=C(O)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(-c2nc3cnccc3[nH]2)c1
Temperature: 200 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
A mixture of 3,4-diaminopyridine (1.09 g., 10 mmoles), 3-fluorobenzoic acid (1.40 g., 10 mmoles), and polyphosphoric acid (PPA, 40 g.) was heated to about 200° C. with stirring for 3.5 hours. The solution was then slowly added to water. The solution was then neutralized by the addition of 50% aqueous sodium hydroxide and the resulting precipitate was collected by filtration. Crystallization from isopropanol/water gave 1.72 g. (81% yield) of 2-(3-fluorophenyl)imidazo[4,5-c]pyridine (base), m.p. about 290°-291° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].Br[CH2:19][CH2:20][O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][CH2:20][CH2:19][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: COCCBr
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(N)c([N+](=O)[O-])c1
Yield: 23.6 %

Procedure:
Powdered and dried Potassium carbonate (3.58 g, 0.025 mol) was added to a solution of 4-amino-3-nitrophenol (2 g, 0.012 mol) in DMF (20 mL) at 0° C. under nitrogen atmosphere. To this, 1-bromo-2-methoxyethane (1.34 mL, 0.014 mol) was added dropwise and the resultant reaction mixture was refluxed for overnight. Then, the reaction mixture was filtered through celite. The filterate was concentrated and diluted with ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The organic phase was washed with brine, dried on Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the title compound (0.6 g, yield: 24%) as a solid. MS (ESI): 213.15 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.ClCC(Cl)=O.C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[Cl:1][CH2:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Agent: CC[SiH](CC)CC
Agent: O=C(Cl)CCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1Cc2cc(CCCl)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
5-Chloroacetyl-2-oxindole (prepared by the same procedure used for the preparation of O-53, except starting from chloroacetyl chloride) (4.18 g) in 30 mL of trifluoroacetic acid in an ice bath was treated with 4.65 g of triethylsilane and stirred at room temperature for 3 hours. The mixture was poured into 150 mL of water and the precipitate collected by vacuum filtration, washed with 50 mL of water and dried to give 2.53 g (65% yield) of 5-(2-chloroethyl)-2-oxindole as a reddish-brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].C(N(CC)CC)C.[C:17]1([CH3:29])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>O1CCCC1.O>[CH3:29][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])(=[O:26])=[O:27]
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
L-Asparagine (20.0 g, 0.15M) was suspended in a mixture of tetrahydrofuran (l30 mL) and water (250 mL). Triethylamine (49 g, 0.48M) was added followed by mesitylenesulfonyl chloride (49.7 g, 0.227M), The reaction mixture became slightly exothermic and the solids dissolved over a period of 0.5 h. to yield a yellow solution. The reaction mixture was stirred for 3 h at room temperature, then washed with ether, and methylene chloride. The aqueous layer was separated, and acidified to ca. pH=1.5 with conc. HCl, during which time a thick precipitate formed. After 0.5 h. the product was filtered,washed with water and dried to yield a white solid (34 g, 72%). m.p.=193.5 - 1950C 1H NMR (DMSO) δ 2.24 (s, 3H), 2.28 (dd, 1H), 2.45 (dd, 1H), 2.55 (s, 6H, 3.98 (m, 1H), 6.88 (br s, 1H), 6.99 (s, 2H), 7.32 (br s, 1H), 7.82 (d, 2H), 12.58 (br s, 1H). Mass spectrum ESI m/z 315.2, (M+H base peak).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10]/[C:11](/[C:14]([CH3:16])=O)=[N:12]\[OH:13].O.[NH3:18]>CCO>[CH3:16][C:14]1[N:18]=[C:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=2)[N:12]([OH:13])[C:11]=1[CH3:10]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(=O)/C(C)=N/O
Reactant: N
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n(O)c1C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Chlorobenzaldehyde (160 mmol) was added to a suspended solution of 2,3-butanedione monoxime (240 mmol) in EtOH. After stirring for 30 minutes, 2,3-butanedione monoxime (240 mmol) and 112 mL of 28% ammonia water were added. The reaction mixture was stirred for 12 hours at room temperature. The mixture was concentrated under reduced pressure and the residue was diluted with methylene chloride. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. Purification by column chromatography on silica gel with an eluent of 5% MeOH in CH2Cl2 gave 19.3 g (64%) of 4,5-dimethyl-2-phenyl-1H-imidazol-1-ol as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13]O>>[CH3:13][O:11][C:10](=[O:12])[CH2:9][NH:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C(O)CNc1ccc(O)cc1
Reactant: CO
Product: COC(=O)CNc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
The p-hydroxy phenyl glycine (74.0 g, 442 mmol) was suspended in methanol (500 mL), cooled in an ice bath and HCl (gas) was bubbled through the reaction mixture for 20 minutes, to give a clear solution. The reaction was stirred at rt for 48 h, concentrated in vacuo to give an oil which was triturated with ethyl ether to give the p-hydroxy phenyl glycine methyl ester (95.8 g, 99%) as a white powder. MS found: (M+H)+ =182.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].N1C=CC=CC=1.Cl[C:20](OCC)=[O:21]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]1[NH:5][C:20](=[O:21])[O:7][N:6]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(C(N)=NO)c(C)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2noc(=O)[nH]2)c(C)c1

Procedure:
Under an inert atmosphere, 10.5 g of 2,4-dimethyl benzamidoxime are dissolved in 40 ml of anhydrous toluene; 6.5 ml of pyridine and 7.6 g of ethyl chloroformate are added.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]#[C:11][C:12]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:20]=3)[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:9]=1)([O:3]C)=[O:2].[OH-].[K+].O.Cl>O1CCCC1.CO>[C:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]#[C:11][C:12]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:20]=3)[CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17]2)[CH:9]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1cc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCC(=O)CC2)cs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(C2(C#Cc3csc(C(=O)O)c3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 95.5 %

Procedure:
A solution of 4-(2-carbomethoxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.19 g, 0.43 mmol) and coarsely ground potassium hydroxide (0.036 g, 0.64 mmol) in tetrahydrofuran (2 mL), methanol (2 mL), and water (0.4 mL) was stirred at room temperature under an argon atmosphere for 24 h. The reaction was acidified (10% HCl), was extracted three times with 5:95 methanol:dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 0.1:3:97 acetic acid:methanol:dichloromethane, provided 4-(2-carboxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as an off-white solid (0.18 g, 95%), mp 80°-82° C. Anal. (C25H26O5S.0.25 H2O) calcd: C, 67.78; H, 6.03; found: C, 67.72; H, 6.02.