Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7](O)=[O:8].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH2:42])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:40][CH2:41][NH:42][C:7]([C:6]2[S:5][C:4]([NH:10][C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:3][C:2]=2[CH3:1])=[O:8])[CH:35]=[CH:36][C:37]=1[O:38][CH3:39]
Reactant: Cc1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C(=O)O
Reactant: COc1ccc(CCN)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)c2sc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc2C)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a mixture of 4-methyl-2-tritylamino-5-thiazolecarboxylic acid (7.2 g) and 2-(3,4-dimethoxyphenyl)ethylamine (3.26 g) in N,N-dimethylformamide (100 ml) were added 1-hydroxybenzotriazole (2.92 g) and dicyclohexylcarbodiimide (4.45 g) and the mixture was stirred at ambient temperature for 1 hour. After filteration, the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform-methanol (9:1 v/v, 20 ml), removed undissolved materials by filtration, and the filtrate was subjected to column chromatography on silica gel to give N-[2-(3,4-dimethoxyphenyl)ethyl]-4-methyl-2-tritylamino-5-thiazolecarboxamide (8.65 g).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[C:13]2[C:24]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:14]=[C:13]2[C:24]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25])([OH:7])=[O:5]
Reactant: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(OCC(=O)OC(C)(C)C)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCn1cc(C(=O)c2cccc3ccccc23)c2cc(OCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7 (3.0 g, 6.4 mmol) in dichloromethane (50 ml) was added TFA (25 ml) and the mixture was stirred at room temperature for 3 h. The mixture was evaporated to dryness and the crude obtained was purified by chromatography on silica-gel using 5% methanol in chloroform to give Hapten-B (2.1 g, 79%).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[CH:11][C:10]=2[CH:22]=1)=[O:5].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([Mg]Br)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:4]([C:6]2[CH:7]=[CH:8][C:9]3[O:13][C:12]([CH2:14][CH2:15][N:16]4[CH2:20][CH2:19][CH2:18][C@H:17]4[CH3:21])=[CH:11][C:10]=3[CH:22]=2)=[O:5])=[CH:28][CH:27]=1
Reactant: CON(C)C(=O)c1ccc2oc(CCN3CCC[C@H]3C)cc2c1
Reactant: COc1ccc([Mg]Br)cc1
Product: COc1ccc(C(=O)c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)cc1

Procedure:
The product from Example 71E and 4-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound. 1HNMR (CD3OD) δ 1.18 (d, 3H, J=6.1 Hz), 1.46 (m, 1H), 2.01-2.32 (m, 2H), 2.50 (m, 2H), 3.06 (m, 2H), 3.24 (m 2H), 3.88 (s, 3H), 6.67 (s, 1H), 7.05 (d, 2H, J=8.9 Hz), 7.54 (d, 2H, J=8.9 Hz), 7.68 (d, 2H, J=8.9 Hz), 7.80 (d, 2H, J=8.9 Hz), 7.92 (s, 1H); MS (ESI) m/z 364.1 (M++1).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH:17]([C:25]2[CH:36]=[CH:35][C:28]([CH:29]=[C:30]([CH3:34])[C:31]([OH:33])=[O:32])=[CH:27][CH:26]=2)[CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.[CH2:37](O)[CH3:38].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH:17]([C:25]2[CH:26]=[CH:27][C:28]([CH:29]=[C:30]([CH3:34])[C:31]([O:33][CH2:37][CH3:38])=[O:32])=[CH:35][CH:36]=2)[CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CC(=Cc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1)C(=O)O
Reactant: CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)=Cc1ccc(C(CNS(=O)(=O)c2ccc(Cl)cc2)Cc2cccnc2)cc1
Reaction time: 3 h

Procedure:
To 0.60 g of 4-[1-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)-2-propyl]-α-methylcinnamic acid thionyl chloride and stirred for one hour. To the mixture was added 5 ml of ethanol at 0° C., and stirred for three hours, followed by dropwise addition of saturated aqueous sodium hydrogencarbonate and extraction with ethyl acetate and then further washing in saturated aqueous sodium chloride solution, and dried over magnesium sulfate to distill off the solvent. The residue obtained was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 0.49 g of ethyl 4-[1-(4-chlorobenzenesulfonamido)-3-(3-pyridyl)-2-propyl]-α-methylcinnamate.
Reaction SMILES: [CH:1]1([CH:7]2[NH:12][C:11](=[O:13])[CH2:10][O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CN([CH:19]=[O:20])C>>[CH:1]1([CH:7]2[N:12]([CH2:7][C:1]3[CH:6]=[CH:5][C:4]([O:20][CH3:19])=[CH:3][CH:2]=3)[C:11](=[O:13])[CH2:10][O:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C=O
Reactant: O=C1COCC(C2CCCCC2)N1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN2C(=O)COCC2C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 5-Cyclohexyl-morpholin-3-one (1.0 g, 5.5 mmol, 1.0 equiv) in DMF (15.0 mL) at 0° C. was added NaH (0.26 g, 60% in oil, 6.5 mmol, 1.2 equiv) slowly. The mixture was stirred at room temperature for 30 minutes, then it was added PMBCI (0.94 g, 6.0 mmol, 1.1 equiv). After stirred at room temperature for 2 hours, the reaction mixture was quenched by added to sat. aq. NH4Cl solution. The mixtures were extracted with EtOAc. The organic layers were combined and washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel, acetone/heptane 30% to give 1.5 g (91%) of 5-Cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.C1C(=O)N([Cl:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:16][CH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1cnc(C)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cnc(CCl)cn1
Temperature: 80 °C
Yield: 20.2 %

Procedure:
To a solution of 2,5-dimethylpyrazine (500 mg, 4.62 mmol) in carbon tetrachloride (7 mL) was added NCS (679 mg, 5.09 mmol) followed by BPO (20 mg) and the mixture was heated to 80° C. for 6 hours. The mixture was diluted with DCM and extracted with saturated aqueous sodium sulfite solution and brine. The organic layer was dried and concentrated to give a crude product which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (1:0 to 15:1) to give 2-(chloromethyl)-5-methylpyrazine (133 mg, 20.19% yield) as yellow oil. LCMS retention time 0.557 min; LCMS MH+ 143.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18](OC4C=CC([N+]([O-])=O)=CC=4)=[O:19])[CH2:13]3)[C:9]2=[O:30])[CH2:4][CH2:3]1.O1CCCC1.C(N(CC)C(C)C)(C)C.[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]([N:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:19])[CH2:13]3)[C:9]2=[O:30])[CH2:4][CH2:3]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCC2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCCCC1)N1CCCC2(CCN([C@H]3CC[C@H](O)CC3)C2=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-nitrophenyl 2-(trans-4-hydroxycyclohexyl)-1-oxo-2,7-diazaspiro[4.5]decane-7-carboxylate (30 mg, 0.00007 mol) in tetrahydrofuran (0.5 mL, 0.006 mol) was added N,N-diisopropylethylamine (25.0 μL, 0.000144 mol) and piperidine (10 μL, 0.0001 mol). After stirring at rt for 16 h, the crude reaction mixture was purified by prep.-HPLC to afford the desired product. LC-MS: 364.3 (M+H)+.
Reaction SMILES: Cl.[CH2:2](N=C=NCCCN(C)C)[CH3:3].Cl.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[N:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.C(O)C>CN(C1C=CN=CC=1)C.ClCCl>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[N:24]1[CH2:25][CH2:26][CH:27]([C:30]([O:32][CH2:2][CH3:3])=[O:31])[CH2:28][CH2:29]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CCN(c2ccc3ccccc3n2)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1CCN(c2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.79 g, 9.34 mmol) was added to a solution of 1-(quinolin-2-yl)piperidine-4-carboxylic acid hydrochloride (1.14 g, 3.89 mmol), N,N-dimethyl-4-aminopyridine (1.42 g, 11.6 mmol), and ethanol (546 μL, 9.34 mmol) in dichloromethane (20 mL), and the mixture was stirred overnight at room temperature. Then, the solvent in the reaction solution was distilled off under reduced pressure. A solution of the obtained residue in ethyl acetate was washed with water twice and brine once and dried over anhydrous sodium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=95/5-60/40 (gradient)] to obtain the title compound (1.07 g, yield: 96%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[C:5]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:9])([CH3:6])[CH3:4]
Reactant: O=C(O)c1ccc(I)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(I)cc1
Temperature: 70 °C

Procedure:
4-Iodobenzoic acid (10 g, 40.3 mmol) was dissolved in dry toluene (100 ml, dried over mol. sieves). The solution was heated to 70° C. under a flow of nitrogen. A solution of N,N′-dimethylformamide di-tert-butyl acetal (24.6 g, 121 mmol) in toluene (25 mL) was added over ca. 30 min. The reaction was mixed for 16 h. At some point the heating unit failed, so the reaction cooled from 70° C. to rt. The solution was heated to 70° C. for and mixed for 5 h. The sample was concentrated under vacuum, and AcOEt (400 ml) was added. The solution was then washed with 1:1 sat. NaHCO3/water (150 ml), and sat. NaHCO3, water and sat. NaCl (75 mL each). The organic phase was dried (MgSO4) and concentrated under vacuum to yield light brown oil.
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[C:13]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=3[S:11][C:10]=2[CH2:21][CH3:22])=[O:8])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[C:13]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=3[S:11][C:10]=2[CH2:21][CH3:22])=[O:8])=[CH:5][CH:4]=1
Reactant: CCc1sc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1sc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 185 °C

Procedure:
A mixture of 7.7 g (0.0225 mole) of 3-(4-methoxy benzoyl) 2-ethyl 5-nitro benzothiophene and 35 g of pyridine hydrochloride are heated at 185° C. for 2.5 h. The mixture is cooled and taken up in 100 ml of water. The product is filtered off and washed on the filter with water and dried in a vacuum at a temperature of 50° C. After purification by chromatography on a column of silica (eluant: heptane/ethyl acetate 6/4), 5.6 g of 3-(4-hydroxy benzoyl) 2-ethyl 5-nitro benzothiophene are obtained.
Reaction SMILES: C([Li])CCC.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([CH3:23])[CH2:17]1>CCCCCC.C(OCC)C>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[C:19]1([OH:22])[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]1[CH3:23]
Reactant: c1ccc2occc2c1
Reactant: CC1CN(C)CCC1=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1CN(C)CCC1(O)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 ml of a bimolar solution of n-butyl lithium in hexane is added dropwise within 30 minutes, at a reaction temperature of -5°, to a solution of 11.8 g of benzofuran in 100 ml of diethyl ether. The solution is then stirred for a further hour at 0°. There is thereupon made within 15 minutes a dropwise addition of a solution of 1,3-dimethyl-4-piperidone in 50 ml of abs. diethyl ether. The reaction temperature is maintained at 0° by external cooling. The reaction solution is subsequently stirred for a further 15 hours at room temperature. It is then poured, with stirring, onto 200 g of ice, and the aqueous phase extracted three times with 500 ml of ethyl acetate each time. The combined organic extracts are dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 500 ml of 2 N hydrochloric acid and the acid solution washed with ether. The aqueous solution is thereupon adjusted by addition of 10% sodium hydroxide solution to pH 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered off under suction, and concentrated by evaporation to obtain 4-(2-benzofuranyl)-1,3-dimethyl-4-piperidinol, which melts at 128°-130° after recrystallisation from hexane.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([NH2:5])=[NH:4].[Cl:8][CH:9]([C:15]([CH3:17])=O)[C:10](OCC)=[O:11]>>[Cl:8][C:9]1[C:10]([OH:11])=[N:4][C:3]([C:2]([Cl:7])([Cl:6])[Cl:1])=[N:5][C:15]=1[CH3:17]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: N=C(N)C(Cl)(Cl)Cl
Product: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl

Procedure:
The carboxylic ester compounds of the present invention may be prepared by reacting trichloroacetamidine with a selected acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carboxylic acid chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with ethyl 2-chloroacetoacetate to form 5-chloro-4-hydroxy-6-methyl-2-trichloromethyl-pyrimidine. In equation (B), the 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with trichloroacetyl chloride to form 5-chloro-6-methyl-4-trichloroacetoxy-2-trichloromethylpyrimidine. ##STR3##
Reaction SMILES: Cl[C:2]([F:32])([F:31])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18]CC2C=CC=CC=2)[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C.Cl>C(O)C.[Pd]>[F:32][CH:2]([F:31])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH2:18])[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OCC)c1NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N
Reaction time: 18 h

Procedure:
A mixture of 340 g (0.722 mol) of product from Example 99, 87.67 g (0.866 mol) of triethylamine and 10.00 g of 5% Pd/C (50% water coated) in 700 ml of ethanol was hydrogenated at 50° C. under 446 kPa of H2 pressure for 18 hours. Then 150 ml of 18% HCl (0.722 mol) was added, and the mixture was hydrogenated at 50° C. under 446 of H2 pressure for 2 hours. The reaction mixture was filtered through celite, and concentrated in vacuo to remove the ethanol. The residue was taken up in H2O, and extracted with diethyl ether. The ether phase was dried (MgSO4) and concentrated in vacuo to 161.7 g (65%) of a brown oil, 90% pure by GC analysis. Then 5.0 g were purified by HPLC in 5% ethyl acetate/cyclohexane affording 3.9 g of product as a yellow solid; mp 29°-30° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:17][CH:18]=1)=[O:13])[CH3:10].C1(C)C=CC=CC=1>C(O)(=O)C>[CH2:9]([O:11][C:12]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:17][C:18]=1[Br:1])=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(-c2ccccc2)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(-c2ccccc2)sc1Br
Reaction time: 8 h
Yield: 56.5 %

Procedure:
N-Bromosuccinimide (1.22 g, 6.83 mmol) was added to a solution of ethyl-2-phenylthiophen-4-carboxylate (6.83 mmol) in acetic acid (10 mL) and stirred overnight. Toluene was added and the solvent was removed under vacuum. The product was purified by flash chromatography on silica, eluting with 0%-10% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (1.2 g). LCMS m/z 312.52 [M+H]+ R.T.=4.55 mins (Analytical Method 5).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][C:3]=1[O:18][CH3:19].Cl[CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:23]=1>>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:2]=1[O:1][CH2:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:23]=1
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1O
Reactant: ClCc1nc(-c2ccccc2)no1
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)no1

Procedure:
In substantially the same manner as in Working Example 9, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione was reacted with 5-chloromethyl-3-phenyl-1,2,4-oxadiazole to obtain 5-[3-[3-methoxy-4-(3-phenyl-1,2,4-oxadiazol-5-ylmethoxy)phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.110-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[O:2][CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: COc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 59.6 %

Procedure:
To a stirred solution of 0.362 g of 2-methoxybenzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0° C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, 1M NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered through hydrous magnesium silicate and evaporated in vacuo to give a solid which is purified by crystallization from ethyl acetate to give 0.430 g of the desired product as a crystalline solid, m.p. 185-188° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:12][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)cc2cccnc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc2cccnc21
Yield: 71.5 %

Procedure:
A solution of 103 mg of 2-hydroxymethyl-1-methyl-7-azaindole (prepared as described in Preparation 81), 346 mg of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 166 mg of diethyl azodicarboxylate and 250 mg of triphenylphosphine in 3 ml of tetrahydrofuran was stirred at room temperature for 15 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The resulting residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 5:1 to 4:1 by volume as the eluent, to give 277 mg of the title compound having Rf=0.41 (on silica gel thin layer chromatography using a 1:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1
Product: Cc1ccc(C(=O)Cl)cc1

Procedure:
4-methylbenzoic acid (0.408 g, 3 mmol) was dissolved in thionyl chloride (10 mL) and the mixture was stirred at reflux for 6 hr. The mixture was condensed under vacuum to yield 4-methylbenzoyl chloride. To a suspension of 3-hydroxyanthranilic acid (0.153 g, 1.0 mmol) in toluene (10 mL) was added 4-methylbenzoyl chloride (0.464 g, 3.0 mmol) followed by pyridine (0.275 g, 3.5 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes then heated to 80° C. for 1 hr. The mixture was cooled and poured into a mixture of ethyl acetate (50 mL) and 5% aqueous hydrochloric acid (20 mL). Subsequent separation of the layers, drying the organic over anhydrous magnesium sulfate and filtration afforded a solution. After removal of the solvent, the residue was dissolved in toluene (20 mL) and the solution treated with 4-methylbenzenesulfonic acid (0.4 g, 2.1 mmol). The reaction mixture was then heated to reflux overnight. After this time the reaction was cooled and poured into water (100 mL), the organic layer was separated then washed with water (100 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to get a solid. Re-crystallization of this solid from ethyl acetate gave 2 p-tolybenzo[d]oxazole-4-carboxylic acid as a white solid (0.15 g, 60% yield). LC-MS (ESI) m/z 254 [M+1]+.