Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C(O)(=O)C>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CSc1ccc(CN)cc1
Solvent: CC(=O)O
Product: CSc1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
A mixture of 4-(methylthio)benzylamine (2.00 mL, 2.20 g, 14.38 mmol) and phthalic anhydride (2.39 g, 15.79 mmol) in acetic acid (40 mL, 42 g, 700 mmol) is heated at reflux for 3 h. The mixture is concentrated under reduced pressure, and the residue is partitioned between water and dichloromethane. The phases are separated, and the aqueous phase is extracted twice with dichloromethane. The combined organic layers are concentrated under reduced pressure and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 9:1 to 7:3). Yield: 3.60 g (88% of theory); ESI mass spectrum: [M+H]+=284; r.t. HPLC: 0.75 min (X001_004).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12]O[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:14].ClCCl.C[OH:19]>C(O)C>[CH2:1]([C@@:8]([OH:19])([CH2:13][CH3:12])[C:9]([NH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCC[C@@H]1Cc1ccccc1
Reactant: CO
Reactant: N
Solvent: CCO
Solvent: ClCCl
Product: CC[C@](O)(Cc1ccccc1)C(N)=O

Procedure:
(S)-2-benzylbutyrolactone (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography (eluent dichloromethane/methanol 20:1). After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (S)-2-benzylhydroxybutyramide.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[CH2:27]1[O:42][C:41]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:30][C:29]=2[O:28]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:27]1[O:42][C:41]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([C:19]6[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=6)[CH:14]=5)=[CH:5][CH:4]=4)[CH2:35][CH2:34]3)=[CH:30][C:29]=2[O:28]1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CN4CCN(Cc5ccc6c(c5)OCO6)CC4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)-phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added 1-(3,4-methylenedioxybenzyl)piperazine (158 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 16 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[1-(3,4-methylenedioxybenzyl)-4-piperazinylmethyl]phenyl]-3-(4-methylphenyl)cinnamamide (Compound 57) (266 mg) as colorless crystals.
Reaction SMILES: C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:41][CH:42]2[S:46][C:45](=[O:47])[NH:44][C:43]2=[O:48])=[C:24]2[C:29]=1[N:28]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](O)=[O:38])=[CH:33][CH:32]=1)[C:27](=[O:40])[CH2:26][CH2:25]2.[CH:49]([C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1)([CH3:51])[CH3:50]>O.CN(C=O)C>[CH:49]([C:52]1[CH:58]=[CH:57][C:55]([NH:56][C:37]([C:34]2[CH:33]=[CH:32][C:31]([CH2:30][N:28]3[C:29]4[C:24](=[C:23]([CH2:41][CH:42]5[S:46][C:45](=[O:47])[NH:44][C:43]5=[O:48])[CH:22]=[CH:21][C:20]=4[O:19][CH3:18])[CH2:25][CH2:26][C:27]3=[O:40])=[CH:36][CH:35]=2)=[O:38])=[CH:54][CH:53]=1)([CH3:51])[CH3:50]
Reactant: CC(C)c1ccc(N)cc1
Reactant: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(C(=O)O)cc1)C(=O)CC2
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(Cc1ccc(C(=O)Nc3ccc(C(C)C)cc3)cc1)C(=O)CC2
Reaction time: 0.5 h
Yield: 90 %

Procedure:
0.34 g of triethylamine and 0.28 g of diethyl phosphorocyanidate (DEPC) were added with ice cooling to a DMF solution (10 ml) of 0.5 g of 5-[8-methoxy-1-(4-carboxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione and 0.23 g of 4-isopropylaniline, followed by stirring for 0.5 hours. Water was added to the reaction liquid and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1→20:1), and recrystallized from a mixed solvent of ethyl acetate and n-hexane, giving 0.57 g (64% yield) of 5-{1-[4-(4-isopropylphenylaminocarbonyl)benzyl]-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl}thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:13][CH:12]=2)[CH:2]=1.[CH2:35]([I:37])[CH3:36]>CN(C=O)C>[I-:37].[CH2:35]([N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:13][CH:12]=2)[CH:2]=1)[CH3:36]
Reactant: O=C(NCCc1cccnc1)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reactant: CCI
Solvent: CN(C)C=O
Product: CC[n+]1cccc(CCNCc2ccc(CCCc3ccccc3OCc3ccccc3)cc2)c1
Product: [I-]
Yield: 35.2 %

Procedure:
A mixture of N-(2-(3-pyridyl)ethyl)-4-[3-(2-benzyloxyphenyl) propyl]benzamide(1 g) and ethyl iodide (0.54 g) was stirred in DMF (5 ml) at 100° C. for 4 hours. The solvent was evaporated and the residue crystallised from ethyl acetate to give 1-ethyl-3-[2-(4-[3-(2-benzyloxyphenyl)propyl]benzylamino)ethyl]pyridinium iodide (463 mg); mpt 89° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([NH:21][CH:22]=[O:23])[N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].Cl.Cl[CH2:28][C:29]1[N:30]=[CH:31][NH:32][C:33]=1C.[CH3:35]N(C)C=O>>[CH3:28][C:29]1[NH:30][CH:31]=[N:32][C:33]=1[C:22]([N:21]([CH3:35])[C:13]1[N:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[N:14]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NC=O)n2)cc1
Reactant: Cc1[nH]cnc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1[nH]cnc1C(=O)N(C)c1nc(-c2ccc(S(C)(=O)=O)cc2)cc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-ylformamide (0.5 g, 1.54 mmol) in dry dimethylformamide (10 ml) under N2 was added sodium hydride (60% dispersion in oil, 0.16 g). The mixture was stirred for 30 mins, 4-(chloromethyl)-5-methyl-1H-imidazole, hydrochloride (0.283 g) was added and stirring was then continued at room temp for 18 h. The mixture was then partitioned between water and ethyl acetate. The extracts were dried (Na2SO4) and evaporated. The residue was then triturated with diethyl ether giving the crude title compound as a pale yellow solid (0.27 g).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:18]12CC(C=C1)C=[CH:19]2>O1CCOCC1>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:19]=[CH:18][N:3]=[N:2]3)[O:9][C:8]2=[O:10])=[N:12][CH:13]=1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(Br)cn1
Reaction time: 16 h
Yield: 71.6 %

Procedure:
(5R)-5-(Azidomethyl)-3-(5-bromopyrid-2-yl)-1,3-oxazolidin-2-one (5.60 g, 18.7 mM) was dissolved in 1,4-dioxane (12 ml). Bicyclo[2.2.1]hepta-2,5-diene (10.3 g, 112 mM) was added and the yellow solution was stirred at 100° for 16 hours. The brown solution was concentrated and the residue was purified by flash chromatography eluting with ethyl acetate. Relevant fractions were combined to give the desired product (4.36 g) as a beige solid.
Reaction SMILES: O[N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH3:22].P(Cl)(Cl)Cl.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:22][O:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:3]1[NH:2][C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]=1
Reactant: COc1cc(C)ccc1-c1nc(C)c(-c2cccnc2)n1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(C)ccc1-c1nc(C)c(-c2cccnc2)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of 1-hydroxy-2-(2-methoxy-4-methylphenyl)-4-methyl-5-(3-pyridyl)imidazole (1.40 g) in N,N-dimethylformamide (28 ml), was added phosphorus trichloride (0.83 ml), and the mixture was stirred for 2 hours at ambient temperature. Then, the solution was poured into water (150 ml), and stirred for an hour at ambient temperature. After neutrallized with aqueous sodium bicarbonate, resulting precipitates were collected by filtration. The precipitates were dried, dissolved in chloroform, and chromatographed on silica gel eluting with a mixture of chloroform and methanol. The fractions were collected, evaporated and triturated in diisopropyl ether to give 2-(2-methoxy-4-methylphenyl)-4-methyl-5-(3-pyridyl)imidazole (0.82 g)
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]2[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([CH2:22]O)[O:21][C:17]=2[CH:16]=1.S(Cl)([Cl:34])=O.C(=O)([O-])O.[Na+]>>[Cl:34][CH2:22][C:20]1[O:21][C:17]2[CH:16]=[C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[O:6][C:2]=3[CH3:1])[CH:31]=[CH:30][C:18]=2[C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(CO)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(CCl)oc2c1
Reaction time: 1 h
Yield: 92 %

Procedure:
{6-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methanol (1.50 g) was added to thionyl chloride (5 mL) at 0° C., and the mixture was stirred for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-{[(2-chloromethyl-3-phenyl-1-benzofuran-6-yl)oxy]methyl}-5-methyl-2-phenyl-1,3-oxazole as colorless crystals (1.43 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:27])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1.[CH3:28][S:29]([Cl:32])(=[O:31])=[O:30]>C(OC(=O)C)C.C(OCC)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:11]([NH2:10])=[O:27])[CH2:18][CH2:17]2)=[CH:21][CH:22]=1.[ClH:32].[CH3:28][S:29]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:27])[CH3:12])[CH:7]=[CH:8][CH:9]=1)(=[O:31])=[O:30]
Reactant: Nc1cccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)Nc1cccc(NS(C)(=O)=O)c1
Product: NC(=O)CN1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from N-(3-amino-phenyl)-2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-acetamide dihydrochloride (Example 183) and methanesulfonyl chloride according to the method described in Example 176. Melting Point: 85-90° C. (dec.) (diethylether- ethyl acetate)
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH2:21][CH3:22])[C:18]([OH:23])=[C:17]([CH2:24][CH3:25])[CH:16]=4)[C:4]=2[C:3]=1[CH3:26])[CH:12]=[CH:11][CH:10]=[CH:9]3.[H-].[Na+].[CH3:29][O:30][C:31]1[C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][S:33][C:32]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH3:39][O:38][C:36]([C:35]1[C:31]([O:30][CH3:29])=[C:32]([S:40]([O:23][C:18]2[C:19]([CH2:21][CH3:22])=[CH:20][C:15]([C:14]3[C:4]4[C:3]([CH3:26])=[C:2]([CH3:1])[S:6][C:5]=4[CH:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[CH:16][C:17]=2[CH2:24][CH3:25])(=[O:41])=[O:42])[S:33][CH:34]=1)=[O:37]
Reactant: CCc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(CC)c1O
Reactant: COC(=O)c1csc(S(=O)(=O)Cl)c1OC
Agent: [H-]
Agent: [Na+]
Product: CCc1cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc(CC)c1OS(=O)(=O)c1scc(C(=O)OC)c1OC
Yield: 63.3 %

Procedure:
The title compound was prepared according to the procedure in Example 10, step 1, using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenol (0.604 g, 1.67 mmol), 60% sodium hydride/mineral oil (0.0669 g, 1.67 mmol) and 3-methoxy-4-(methoxycarbonyl)thiophene-2-sulphonylchloride (0.499 g, 1.84 mmol) to give 0.629 g (63%) of the title compound. 1H NMR (DMSO-d6) δ 1.10 (t, 6 H), 1.59 (s, 3 H), 2.42 (s, 3 H), 2.57-2.68 (m, 4 H), 3.86 (s, 3 H), 4.02 (s, 3 H), 7.20 (s, 2 H), 7.38-7.50 (m, 3 H), 7.98 (d, 1 H), 8.50 (s, 1 H), 8.81 (s, 1 H).
Reaction SMILES: Cl.CN.[CH3:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[CH:17][CH3:18])[C:14](Cl)=[O:15].[N:19]1C=CC=C[CH:20]=1>ClCCl>[CH3:20][NH:19][C:14](=[O:15])[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][O:5][CH3:4])=[CH:17][CH3:18]
Reactant: CC=C(C(=O)Cl)c1ccccc1COC
Reactant: c1ccncc1
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CC=C(C(=O)NC)c1ccccc1COC
Temperature: 20 °C
Reaction time: 15 h
Yield: 29.7 %

Procedure:
1.7 g of methylamine hydrochloride was added to 5.2 g (23 mmol) of α-(2-methoxymethylphenyl)-β-methylacrylic chloride in 30 ml of dichloromethane, and 4 g of pyridine was dripped in at 0° to 5° C. The mixture was stirred for a further 15 hours at about 20° C. The reaction mixture was diluted with 20 ml of dichloromethane and washed with water. The organic phase was dried over sodium sulfate and evaporated down. The crude product was chromatographed on silica gel with methyl tert-butyl ether/cyclohexane (5/1). Removal of the solvent gave 1.5 g (30%) of the title compound in the form of colorless crystals (m.p.: 58° C.).
Reaction SMILES: [O:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N([CH2:24][CH3:25])CC)C.[C:26](Cl)(=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1C=CC=CC=1>[C:26]([N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:26](=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:24][CH3:25])[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:1][CH2:2][CH2:3]1)(=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: C1COCCOCCNCCOCCOCCN1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCC(=O)N1CCOCCOCCN(C(=O)CCCCCCCCC)CCOCCOCC1

Procedure:
In a manner similar to that described in Example 5, treat the cyclic diamine obtained in Example 4 and triethylamine in anhydrous benzene with a solution of n-decanoyl chloride (capryl chloride) in anhydrous benzene. Isolate and purify the resultant product in a manner similar to that described to obtain 4,13-di-(n-decanoyl)-1,7,10,16-tetraoxa-4,13-diazacyclooctadecane.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21]Cl>ClCCl.C(OCC)(=O)C.C(N(C(C)C)C(C)C)C>[C:12]1([CH2:11][CH2:10][CH:9]([O:18][CH2:19][O:20][CH3:21])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OC(CCc1ccccc1)CCc1ccccc1
Reactant: COCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC(CCc1ccccc1)CCc1ccccc1
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A solution of 101 mg (0.42 mmol) of 1,5-diphenyl-3-pentanol, 0.18 ml (1 0 mmol) of ethyldiisopropylamine, and 0.063 ml (0.84 mmol) of chloromethyl methyl ether in 1 ml of dichloromethane was allowed to stand for 16 h. The resulting solution was taken up in ethyl acetate, washed sequentially with 10% aqueous citric acid, water, and saturated sodium bicarbonate, dried over Na2SO4, and concentrated in vacuo. Flash chromatography using 10% ethyl acetate in hexane gave 109 mg (92%) of the desired compound (Rf 0.51, 25% ethyl acetate in hexane) as an oil. 1H NMR (CDCl3) δ 1.88 (m, 4H), 2.70 (m, 4H), 3.44 (s, 3H), 3 64 (pentet, J=6 Hz, 1H), 4.70 (s, 2H), 7.15-7.3 (m, 10H). Mass spectrum (M+NH4)+ =302.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:15][CH:14]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
To a solution of 4-(pyridin-2-yl)benzoic acid (100 mg, 0.5 mmol) in DCM (5 mL) was added EDCI (144 mg, 0.75 mmol), HOBt (101 mg, 0.75 mmol), Et3N (152 mg, 1.5 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (103 mg, 0.5 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (30 mg, Yield 15.5%). 1H NMR (CD3OD, 400 MHz): δ 8.70-8.60 (m, 1H), 8.01-7.84 (m, 6H), 7.45-7.36 (m, 1H), 7.16-6.99 (m, 4H), 4.20-4.10 (m, 1H), 3.79 (s, 2H), 3.62-3.46 (m, 2H), 2.92 (s, 4H), 2.78-2.65 (m, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9]([NH:12][C:13]1[S:14][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:16][N:17]=1)(=[O:11])[CH3:10].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][S:18]([C:15]1[S:14][C:13]([NH:12][C:9](=[O:11])[CH3:10])=[N:17][CH:16]=1)(=[O:19])=[O:20])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CNS(=O)(=O)c1cnc(NC(C)=O)s1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of glycine ethylester hydrochloride (15 mmol), 2-acetylamino-thiazole-5-sulfonyl chloride (12 mmol) (prepared as described in J. Am. Chem. Soc 69, 2063, 1947), DIPEA (35 mmol) in DCM (50 mL) was stirred at room temperature over night. Addition of water and 1N HCl to pH 2 resulted in precipitation. The precipitate was isolated by filtration, washed with water and dried to give (2-acetylamino-thiazole-5-sulfonylamino)-acetic acid ethyl ester (64%) as crystals. This was suspended in EtOH (15 mL) and added 4N HCl in dioxane (15 mL) and heated for 4 h at 80° C. and then cooled to room temperature. Addition of aqueous NaHCO3 to neutral pH. The organic phase was isolated and the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried and concentrated in vacuo to give (2-amino-thiazole-5-sulfonylamino)-acetic acid ethyl ester (80%) as colourless crystals.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:10]([C:9]2[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccc(Oc2ccc(C(=O)O)c(Oc3ccc(C#N)cc3)n2)cc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Oc3ccc(C#N)cc3)nc2Oc2ccc(C#N)cc2)CC1
Yield: 65.2 %

Procedure:
Following the procedure of Example 5(c) 2,6-bis(4-cyano phenoxy)-nicotinic acid 1.25 g (3.5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.65 g, 3.5 mmol) were used to afford 1.2 g of the required product. Percentage purity (LCMS): 95.6%, (M+1)=525.2 (with BOC). 1H NMR (DMSO-d6): δ 1.40 (9H, s), 3.30 (2H, m), 3.42 (4H, m), 3.61 (2H, m), 6.98 (1H, d), 7.35 (4H, m), 7.82 (4H, dd), 8.02 (2H, d).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6](N)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[ClH:13].N([O-])=O.[Na+].[S:18](=[O:20])=[O:19]>C(O)(=O)C.O>[Cl:13][S:18]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=[O:20])=[O:19]
Reactant: O=S=O
Reactant: Cl
Reactant: COC(=O)c1c(C)cccc1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1c(C)cccc1S(=O)(=O)Cl
Temperature: 0 °C

Procedure:
The methyl 6-methylanthranilate so prepared (4.23 g, 0.026 mol) was dissolved in 25 ml of acetic acid and the solution cooled to 0° C. Concentrated hydrochloric acid (45 ml) was added to produce a tan slurry. A solution of 1.89 g (0.027 mol) of sodium nitrite in 8 ml water was added dropwise with stirring, the resulting orange solution was stirred at 0° C. for 1 hour and then added in 6 portions to a mixture of 2.18 g (0.013 mol) of cupric chloride dihydrate and sulfur dioxide (6.3 g) in 33 ml of acetic acid and 6 ml of water at 0° C. The dark green solution was stirred at room temperature overnight, poured into 300 ml of ice-water, and the solid which separated was collected and dried by suction to provide 1.11 g of methyl 2-chlorosulfonyl-6-methylbenzoate which was immediately added to 100 ml of ice cold ammonium hydroxide and stirred at room temperature overnight. The solution was acidified to pH 1 with concentrated hydrochloric acid, and the resulting precipitate was collected and air-dried to provide 729 mg (12%) of 4-methylsaccharin, mp 224°-226° C.