Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41](O)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=2[Cl:1])=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(Cl)cc3Cl)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.6 %

Procedure:
2,4-Dichloroaniline (0.383 g, 2.366 mmol), triethylamine (0.239 g, 2.366 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.400 g, 2.366 mmol) were added to a methylene chloride solution (100 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.295 g, 0.789 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.150 g, 0.289 mmol, 37%).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[N:6]=1)C.[ClH:21]>>[OH2:3].[OH2:3].[ClH:21].[F:17][C:13]1[CH:12]=[C:11]([C:7]2[N:6]=[C:5]([CH:4]=[O:3])[N:9]([CH3:10])[N:8]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(OCC)c1nc(-c2cccc(F)c2)nn1C
Agent: Cl
Product: Cn1nc(-c2cccc(F)c2)nc1C=O
Product: O
Yield: 47 %

Procedure:
A solution of 5-(diethoxymethyl)-3-(3-fluorophenyl)-1-methyl-1H-1,2,4-triazole (24.0 g, 86 mmol) in 4M HCl (86 mL) was stirred at 60° C. for 2 h. The mixture was concentrated in vacuo, and the residue was recrystallized from MeOH/Et2O mixture (1:1). The resulting solvate was dissolved in water/THF (1:2) and concentrated in vacuo to dryness to afford 11.33 g (47%) of the title product. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, D2O+TFA): δ 4.16 (s, 3H), 6.47 (s, 1H), 7.42 (m, 1H), 7.62 (m, 1H), 7.70 (m, 1H), 7.77 (m, 1 H). LC/MS (API-ES) calcd for C10H8FN3O: 205.07, found (M+H+): 206.0; (M+18+H+): 224.0 m/z.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: Cc1cc(O)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)cc1C

Procedure:
2-Methyl-4-hydroxybenzoic acid was heated in methanol under the influence of sulfuric acid catalyst to convert it into its methyl ester. One mole of the methyl 2-methyl-4-hydroxybenzoate thus obtained was reacted with two moles of hydrogen in the presence of palladium-carbon catalyst. This reaction was carried out in isopropyl alcohol at a temperature of 150°-170° C. and a hydrogen pressure of 20-40 kg/cm2. After the reaction mixture was filtered to recover the catalyst therefrom, the filtrate was distilled to obtain 3-methylcyclohexanone-4-carboxylic acid methyl ester as the distillate at 112°-120° C./5 mmHg.
Reaction SMILES: [P:1](Cl)([Cl:6])([O:3][CH2:4][CH3:5])=[S:2].[O-:8][CH2:9][CH2:10][CH3:11].[Na+].C(O)CC>O1CCCC1>[P:1]([Cl:6])([O:8][CH2:9][CH2:10][CH3:11])([O:3][CH2:4][CH3:5])=[S:2]
Reactant: CCC[O-]
Reactant: CCOP(=S)(Cl)Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCO
Product: CCCOP(=S)(Cl)OCC
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To 30 g (167 mmole) of O-ethyl dichlorothiophosphate in 100 ml of tetrahydrofuran (THF) and cooled to -70° C. was added a solution of sodium propoxide (from 7.4 g of 60% NaH (184 mmole) and 11 g (176 mmole) of 1-propanol) in 50 ml of THF. After warming to room temperature over 2 hours, the THF was removed in vacuo and the residue was partitioned between 50 ml diethyl ether, 50 ml hexanes, and 25 ml cold water. The organic layer was dried over magnesium sulfate, concentrated in vacuo, and distilled (bp 45°-50° C. 1 torr) yielding 20 g of the title compound, an oil. nmr 1.0 t 3H, 1.4 t 3H, 1.8 sextet 2H, 4.4M 4H.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])([O-])=O.C1(C)C=CC=CC=1>CN(C)C=O.[Pd].[H][H]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: CCOC(=O)C(=CNc1ncnc2ccc([N+](=O)[O-])cc12)C(=O)OCC
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2ccc(N)cc12)C(=O)OCC
Yield: 97.4 %

Procedure:
A suspension of diethyl [(6-nitro-4-quinazolinylamino)methylene]propanedioate (2.8 g) in N,N-dimethylformamide (152 ml) was shaken with 10% palladium on carbon (0.93 g) in hydrogen atmosphere at ambient temperature for an hour. After the reaction was completed, the catalyst was removed by filtration and washed with chloroform. The combined filtrate and washing was concentrated under reduced pressure to give a residue, to which was added toluene and concentrated under reduced pressure. This operation was repeated to give crystalline diethyl [(6-amino-4-quinazolinylamino)methylene]propanedioate (2.50 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13]Br.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of compound 4 (3.5 g, crude material), morpholine (0.99 g), potassium carbonate (2.89 g), and potassium iodide (1.66 g) in DMF (22 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, and concentrated to a residue. The crude material was purified by flash chromatography (silica gel, 30-50% ethyl acetate/hexanes) to yield compound 5 as a yellow solid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[C:15]([OH:30])[CH:14]=1.[CH:31](O)([CH3:33])[CH3:32].O>CN(C=O)C>[F:25][C:24]1[CH:23]=[C:22]([F:26])[CH:21]=[CH:20][C:19]=1[C:18]1[CH:13]=[CH:14][C:15]([OH:30])=[C:16]([C:27]([O:29][CH:31]([CH3:33])[CH3:32])=[O:28])[CH:17]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CC(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
CDI (972 mg, 5.99 mmol) was added to a solution of diflunisal (1.50 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 50° C. for 2 h and isopropyl alcohol (1.15 mL, 14.97 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 3 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×60 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (15% EtOAc/hexanes) to furnish 720 mg of isopropyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 41%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH2:14][CH2:15][CH2:16][C:17]2[C:21]=1[O:20][C:19](=[O:22])[C:18]=2[CH3:23])=[O:12].[K+].C([O-])(=O)C.C1(C)C=CC=CC=1.Cl>O>[CH3:23][CH:18]([C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])[CH:21]=1)[C:19]([OH:22])=[O:20]
Reactant: CC1=C2CCCC(C(=O)c3ccc4ccccc4c3)=C2OC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccc3ccccc3c2)c1
Temperature: 220 °C
Reaction time: 1 h

Procedure:
A mixture of 7-(2-naphthoyl)-3-methyl-5,6-dihydro-2(4H)-benzofuranone (10 g) and acetic acid potassium salt (0.3 g) was added to a reactor and stirred for 1 hr at 220° C. The reaction mixture was cooled down to room temperature. Toluene and water were added to the reaction mixture and acidified to pH 2 with 5% hydrochloric acid. Toluene layer separated was dried over anhydrous MgSO4, filtered and evaporated to give crude product. The crude product was purified by column chromatograph on silica gel by eluting with a mixture of ethylacetate and n-hexane (1:5) to give the desired product (9:42 g, 94 % .
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:13]=1.C(O)C.CCOC(/N=N/C(OCC)=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:12]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[C:3]([Cl:11])=[N:4][CH:5]=1)[CH3:13]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 103.6 %

Procedure:
To a solution of 5,6-dichloronicotinic acid (10.0 g, 50.0 mmol) in THF (600 mL), triphenylphosphine (19.67 g, 75.0 mmol) and ethanol (5.55 g, 75.0 mmol) is added. The mixture is cooled to 0° C. before DEAD (32.65 g, 75.0 mmol) is added. The mixture is stirred and warmed to rt. Stirring is continued for 16 h before sat. aq. NaHCO3 solution is added. The mixture is repeatedly extracted with EA. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC (heptane:EA 7:3) to give 5,6-dichloronicotinic acid ethyl ester (11.4 g) as a white solid; LC-MS: tR=0.96 min, [M+1]+=220.02.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6]S([O-])(=O)=O)[CH3:3].[Na+].[CH3:12][N:13]([CH:15]([CH3:17])[O-])[CH3:14].[Na+]>>[CH3:1][N:2]([CH2:4][CH2:5][O:6][CH2:17][CH2:15][N:13]([CH3:14])[CH3:12])[CH3:3]
Reactant: CN(C)CCOS(=O)(=O)[O-]
Reactant: CC([O-])N(C)C
Agent: [Na+]
Product: CN(C)CCOCCN(C)C

Procedure:
subsequently, heating the resulting sodium dimethylaminoethylsulfate in the presence of sodium dimethylaminoethoxide to produce bis(N,N-dimethylaminoethyl)ether.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:14])(=[O:25])=[O:24]
Reactant: COc1cccc(CCO)c1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CCOS(C)(=O)=O)c1CCOS(C)(=O)=O
Yield: 96.1 %

Procedure:
To a slurry of 2,3-bis-(2-hydroxyethyl)-1-methoxybenzene (50.6 g, 0.258 mol, 1 equiv.) and triethylamine (78.3 g, 0.774 mol, 3 equiv.) in DCM (500 mL) at 0° C., add dropwise a solution of methanesulfonyl chloride (65.0 g, 0.567 mol, 2.2 equiv.) in DCM (100 mL) over 45 min. The addition is exothermic and the methanesulfonyl chloride is added at a rate to keep the temperature below 10° C. After the addition is complete, warm the reaction to ambient temperature. Wash the solution with water (2×500 mL), and then brine (750 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a dark yellow oil (87.4 g, 96.2%), which is used in the next reaction without further purification. An analytical sample is obtained by flash column chromatography eluting with 100% diethyl ether. 1H NMR (300 MHz, CDCl3), δ 7.20 (t, 1H, J=7.9), 6.82 (s, 1H, J=7.2), 6.80 (s, 1H, J=8.2), 4.41-4.34 (m, 4H), 3.83 (s, 3H), 3.16-3.09 (m, 4H), 2.91 (s, 3H), 2.87 (s, 3H); 13C NMR (300 MHz, CDCl3), δ 158.07, 136.55, 128.26, 123.34, 122.39, 109.24, 69.88, 69.08, 55.55, 37.35, 37.14, 32.57, 26.47; 13C NMR (300 MHz, DMSO-d6), δ 157.58, 136.79, 127.81, 122.91, 122.00, 109.33, 70.19, 68.88, 55.55, 36.49, 36.47, 31.56, 25.72; IR (KBr): 1586.8, 1469.4, 1358.51, 1267.3, 1173.9, 1105.4, 972.4, 954.6, 914.3 cm−1; MS (ES+) m/z 257 (M+H)+; Anal. Calc'd. for C13H20O7S2: C, 44.31; H, 5.72; N, 0. Found: C, 44.22, H, 5.68; N, 0.13; Rf=0.72 eluting with 95:5 DCM/methanol.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1.[C:19]1(C)[C:20](S(O)(=O)=O)=CC=C[CH:24]=1>C(O)CC>[CH3:1][S:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH2:24][CH2:19][CH3:20])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH3:17])[C:9]2=[O:18])=[N:5][N:4]=1
Reactant: CCCN1CCC(O)N(c2nnc(SC)s2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CCCO
Product: CCCOC1CCN(CCC)C(=O)N1c1nnc(SC)s1

Procedure:
Tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), propyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methylthio-1,3,4-thiadiazol-2-yl)-3-propyl-6-propoxy-2(1H)-pyrimidinone.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][CH3:14])[CH:3]=1.[C:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:11][C:4]1[CH:3]=[C:2]([N:21]2[CH2:22][CH2:23][N:18]([C:15](=[O:17])[CH3:16])[CH2:19][CH2:20]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH2:13][CH3:14]
Reactant: CC(=O)N1CCNCC1
Reactant: CCCOc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]

Procedure:
The compound obtained in Step 1 above (300 mg), N-acetylpiperazine (300 mg), and potassium carbonate (500 mg) were dissolved in dimethylformamide (3 mL) and reacted at 80° C. overnight. The dimethylformamide of the reaction mixture was removed under reduced pressure, and added with water to form a solid. The solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]([CH:31]=O)[CH:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][C:24](=[O:26])[CH3:25])[O:10][C:9]1([CH3:34])[CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][C:24](=[O:26])[CH:25]=[CH:31]2)[O:10][C:9]1([CH3:34])[CH3:33])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(CC(C)=O)C(C=O)CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CC(=O)C=CC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A solution of 4-benzyl-5-(2-formyl-3-methoxycarbonyl-5-oxo-hexyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (13.5 g, 27 mmol) and para-toluenesulfonic acid monohydrate (660 mg, 2.7 mmol) in dry toluene (250 ml), was refluxed for 24 hours using a Dean-Stark apparatus to remove water formed during the reaction. The mixture was then cooled to room temperature and treated with and saturated aqueous sodium hydrogen carbonate solution (20 ml). After dilution with ethyl acetate and brine, the layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed with brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography on silica gel provided 4-benzyl-5-(6-methoxycarbonyl-4-oxo-cyclohex-2-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (5.64 g, 43%). Mass spectrum 458 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=C(C#N)[CH:3]=1.[OH-:16].[Na+].[O:18]1[CH2:23][CH2:22]OCC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[N:11]([CH3:13])[CH3:12])=[C:22]([CH:3]=1)[C:23]([OH:18])=[O:16]
Reactant: C1COCCO1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1C#N
Reactant: [OH-]
Agent: [Na+]
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1C(=O)O
Yield: 34 %

Procedure:
A mixture of 4-bromo-2-cyano-N,N-dimethylbenzenesulfonamide (110 mg, 0.38 mmol) and 1N aqueous NaOH (2.0 mL, 2.0 mmol) in 1,4-dioxane (2 mL) was heated at reflux. The cooled reaction mixture was washed with dichloromethane (5 mL). The aqueous layer was acidified by the addition of 1N aqueous HCl. The acidified aqueous layer was extracted with dichloromethane (2×5 mL). The combined organics were dried over Na2SO4 and evaporated to dryness to yield 5-bromo-2-(N,N-dimethylsulfamoyl)benzoic acid in 34% yield (40 mg, 0.13 mmol). ESI-MS m/z calc. 307.0, found 308.1 (M+1)+; retention time 1.13 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]1[NH:30][CH:31]=[C:32]([Br:34])[CH:33]=1)=[O:28])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27]([C:29]3[NH:30][CH:31]=[C:32]([Br:34])[CH:33]=3)=[O:28])[CH:13]=2)[N:6]=1
Reactant: [N-]=[N+]=NCCNC(=O)c1cc(Br)c[nH]1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2cn(CCNC(=O)c3cc(Br)c[nH]3)nn2)nc1N

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.104 g, 0.375 mmol) was reacted with N-(2-azidoethyl)-4-bromo-1H-pyrrole-2-carboxamide (0.131 g, 0.375 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-bromo-1H-pyrrole-2-carboxamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 11.44 (s, 1H), δ 7.84 (s, 1H), δ 7.28 (s, 1H), δ 6.84 (s, 1H), δ 6.74 (s, 1H), δ 6.46 (s, 1H), δ 4.89 (s, 2H), δ 3.82 (s, 2H), δ 2.57 (s, 2H), δ 2.28 (s, 2H), δ 1.55 (m, 13H), δ 1.29 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 186.8, 161.4, 150.7, 149.3, 148.2, 137.6, 126.3, 122.5, 122.1, 113.1, 100.4, 96.9, 85.4, 49.6, 29.1, 28.7, 28.2, 27.7, 25.5 ppm; HRMS (ESI) calcd for C22H31BrN8O3(M+) 534.1703. found 534.1705, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-bromo-1H-pyrrole-2-carboxamide hydrochloride (0.129 g, 73% yield). 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), δ 6.93 (s, 1H), δ 6.82 (s, 1H), δ 6.47 (s, 1H), δ 4.76 (s, 2H), δ 3.87 (s, 2H), δ 2.79 (s, δ 2.45 (s, 2H), δ 1.69 (s, δ 1.60 (s, 2H), δ 1.37 (s, 2H) ppm; 13C NMR (100 MHz, CD3OD) δ 161.4, 159.5, 159.1, 147.3, 147.2, 127.6, 125.8, 122.3, 122.1, 112.8, 108.6, 108.5, 96.4, 51.9, 38.9, 28.0, 27.9, 27.6, 24.1, 23.6 ppm; HRMS (ESI) calcd for C17H23BrN8O (M+) 434.1178. found 434.1171.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[S:3][C:4]=2[CH:10]=1
Reactant: C1CNCCN1
Reactant: COc1ccc2nc(Cl)sc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 160 °C

Procedure:
A mixture of 1.50 mmol 2-chloro-6-methoxybenzothiazole (CA=[2605-14-3]), 4.51 mmol of piperazine and 4.51 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 5 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:40][C:41](O)=[O:42])[CH:26]=[CH:27][C:28]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:31].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:41](=[O:42])[CH2:40][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:31])=[C:23]([O:22][CH3:21])[CH:24]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)c1ccc(OC[C@@H]2CCCN2)c(OC)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a stirred solution of ethyl (S)-3-methoxy-4-(2-pyrrolidinylmethoxy)benzoate (424 mg, 1.52 mmol) in DMF (8 mL) was added pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (728 mg, 1.52 mmol) and Et3N (0.26 mL, 1.87 mmol). And the resulting mixture was stirred at room temp overnight. The mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated off in vacuo and the residue was purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give 830 mg (95%) ethyl (S)-3-methoxy-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenyl acetyl]-2-pyrrolidinyl methoxy]benzoate as an amorphous solid. 1H-NMR (CDCl3) δ1.38 (t, 3 H, J=7.3 Hz), 1.88-2.20 (m, 4 H, m), 2.24 (m, 3 H), 3.44-3.50 (m, 1 H), 3.53-3.58 (m, 7 H), 3.82 (s, 3 H); 4.09-4.17 (m, 1 H), 4.22-4.25 (m, 1 H), 4.35 (q, 2 H, J=7.3 Hz), 4.38-4.49 (m, 1 H), 6.71-4.78 (m, 1 H), 6.99 (d, 1 H, J=8.3 Hz), 7.04-7.07 (m, 1H), 7.16-7.19 (m, 2 H), 7.49-7.66 (m, 3 H), 8.06 (d, 1 H, J=8.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1.O>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH2:10][O:11][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(CO)cc1Br
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.8 %

Procedure:
To a solution of 98.8 g of the compound obtained in Step 204-1 in DMF (455 ml) was added 72.0 g of TBSCl and 62.0 g of imidazole under ice cooling, and the reaction mixture was stirred for 10 minutes. The solution was warmed to room temperature then stirred for two hours, water and Et2O were added and liquid separation was performed. The organic layer was washed with saturated brine and dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. n-hexane was used on the obtained solid residue for a recovery by filtration to obtain 152 g of the title compound.