Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.S(=O)(=O)(O)O.[CH2:7]([N:14]1[CH2:21][CH:20](O)[CH2:19][N:18](S(C2C=CC=CC=2)(=O)=O)[CH2:17][CH:16]([OH:32])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:7]([N:14]1[CH2:15][CH:16]2[O:32][CH:20]([CH2:19][NH:18][CH2:17]2)[CH2:21]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(=O)(c1ccccc1)N1CC(O)CN(Cc2ccccc2)CC(O)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3CNCC(C2)O3)cc1
Temperature: 95 °C

Procedure:
Water (11.2 mL) and concentrated sulfuric acid (24.5 mL) were added to 5-benzyl-3,7-dihydroxy-1-phenylsulfonyl-1,5-diazacyclooctane (2.92 g, 7.76 mmol; see step (ii) above). The reaction mixture was heated for 24 hours at 95° C. The temperature was adjusted to 60° C., and toluene (40 mL) was added. Sodium hydroxide solution was then added (150 mL of 5 M), causing the internal temperature to rise to 85° C. The pH of the reaction mixture was then checked, and was found to be 2. A few pellets of solid sodium hydroxide were then added. The pH was measured again, and was found to be 13. The layers were separated, and the aqueous phase extracted with toluene (50 mL). The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo to provide 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane as an orange-brown oil. This can be converted to the title compound (dihydrochloride salt) by reaction with hydrochloric acid under standard conditions.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:14][C:15]([NH:17][C:18]1[C:19]([I:29])=[C:20]([C:24]([I:28])=[CH:25][C:26]=1[I:27])[C:21]([OH:23])=[O:22])=[O:16]>CC#N>[C:21]([C:20]1[C:19]([I:29])=[C:18]([NH:17][C:15](=[O:16])[CH2:14][N:1]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:26]([I:27])=[CH:25][C:24]=1[I:28])([OH:23])=[O:22]
Reactant: O=C(CCl)Nc1c(I)cc(I)c(C(=O)O)c1I
Reactant: C1CNCCNCCNCCN1
Solvent: CC#N
Product: O=C(CN1CCNCCNCCNCC1)Nc1c(I)cc(I)c(C(=O)O)c1I
Yield: 90.5 %

Procedure:
To a solution of 143.9 g of 1,4,7,10-tetraazacyclododecane (product commercially available) (0.84 mol) in 1000 ml of CH3CN under reflux, a suspension of 50 g of compound (A) 3-[(2-chloro-1-oxoethyl)amino]-2,4,6-triiodobenzoic acid (0.084 mol) in 500 ml of CH3CN is added during 1 h. The mixture is kept under reflux for 24 h, yielding a solid precipitation. The reaction mixture is filtered and the solid is purified by chromatography on silica gel. 55 g of N-(3-carboxy-2,4,6-triiodophenyl)-1,4,7,10-tetraazacyclododecane-1-acetamide (0.076 mol) are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[I:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[C:21]=1[CH:28]=O>CO>[I:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:26][CH3:27])[C:21]=1[C:28]1[NH:1][C:2]2[CH:3]=[C:4]([N:10]3[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]3)[CH:5]=[C:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: COc1nccc(I)c1C=O
Reactant: CC(=O)N1CCN(c2cc(C)c(N)c(N)c2)CC1
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)cc(N3CCN(C(C)=O)CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66 %

Procedure:
To a solution of 1-[4-(3,4-diamino-5-methyl-phenyl)-piperazin-1-yl]-ethanone (4.00 g, 16.18 mmol) in methanol (100 mL) was added 4-iodo-2-methoxy-pyridine-3-carbaldehyde (4.25 g, 16.18 mmol). The reaction mixture was stirred at room temperature for 14 h. After concentration, the residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to yield the title compound (5.25 g, 66%). 1H NMR (400 MHz, CD3OD) δ 7.81 (1H, d, J=5.4 Hz), 7.48 (1H, d, J=5.4 Hz), 7.26 (1H, s), 6.85 (1H, s), 3.85 (3H, s), 3.78 (2H, t, J=5.0 Hz), 3.64 (2H, t, J=5.0 Hz), 3.16 (2H, t, J=5.2 Hz), 3.11 (2H, t, J=5.2 Hz), 2.62 (3H, s), 2.13 (3H, s). LCMS (M+H)+ m/z 492 (t=1.71 min.).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([C:15]1([N+:21]([O-:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:13]=[CH2:14]>C(Cl)Cl>[N+:21]([C:15]1([CH2:12][CH:13]2[CH2:14][O:9]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([O-:23])=[O:22]
Reactant: C=CCC1([N+](=O)[O-])CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=[N+]([O-])C1(CC2CO2)CCCCC1
Reaction time: 0.3 h

Procedure:
A 1 neck 500 mL round bottom flask equipped with dropping funnel, temperature controller, nitrogen outlet, stir bar and condenser is charged with approximately 37 g of mCPBA (72% pure, 0.15 mols) and 100 mL of CH2Cl2. The reaction slurry is warmed to dissolve all the solids in CH2Cl2. Once a clear solution is obtained, 20 g (0.12 mols) of 1-allyl-1-nitrocyclohexane (11) is added slowly. After complete addition, the reaction is refluxed for 2 hrs and stirred for 48 h at room temperature. The progress of the reaction is monitored by GC. After the duration of almost 50 h, the composition of the epoxide in the reaction mixture is approximately 38.5%. Solid mCPBA that crashes out of solution is removed by gravity filtration. The organic layer is washed with 10% Na2CO3 (3×30 mL) followed by brine (3×30 mL). The organic layer is dried under MgSO4 and excess solvent stripped off under rotary evaporator. This affords 11.8 g of crude material. The retention time of the epoxide on the GC is 18.3 minutes. The presence of epoxide is confirmed by GC-MS CI. The parent ion is not detected due to the labile nature of NO2 groups. However, the fragment minus the NO2 is observed. CI GC/MS, [C9H15O]+=139.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][N:17]([CH3:22])[S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH:1]1([C:4]2[N:5]([S:18]([N:17]([CH3:22])[CH3:16])(=[O:20])=[O:19])[CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: c1c[nH]c(C2CC2)n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1ccnc1C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 2-cyclopropyl-1H-imidazole (compound 238.1, 12 g, 110.9 mmol) in dichloromethane (60 mL). Triethylamine (31.4 mL, 225.3 mmol), N,N-dimethylsulfamoyl chloride (13.2 mL, 121.87 mmol, 1.10 equiv) were added to the reaction. The reaction mixture was stirred for 4 h at room temperature, then quenched with 20 mL of water. The aqueous phase was extracted with 3×100 mL of dichloromethane. The combined organic layers were washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:4) as eluent to furnish 16 g (67%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH3:21])[C:12]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:37](=[O:39])[CH3:38])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH3:21])[C:12]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2.49 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 15 ml of acetic anhydride and 5 ml of pyridine is stirred at 100° C. for 2 hours. The mixture is evaporated under reduced pressure to remove acetic anhydride and pyridine. Toluene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent (This operation is repeated again). 3.08 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]2[C@@H:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([O:24][CH3:25])[CH:23]=3)[C:14](=[O:15])[O:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9].[C:27]([O:46]C(=O)CCCCCCCCCCCCCCCCC)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]2[C@@H:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([O:24][CH3:25])[CH:23]=3)[C:14](=[O:15])[O:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9].[C:27]([O-:46])(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCC
Agent: COc1cc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(O)c(OC)c2)ccc1O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Temperature: 65 °C
Reaction time: 24 h

Procedure:
Matairesinol (500 mg, 1.4 mmol) was dissolved in 25 ml pyridine. To the solution stearic acid anhydride (3.1 g, 5.6 mmol) was added in small portions. The temperature was raised to 65° C. and the mixture was stirred for 24 h. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane. Unreacted stearic anhydride and stearic acid precipitated from the dichloromethane solution and were filtered off. The solvent was then removed and the residue was washed with n-hexane to afford matairesinol stearate as a white solid. Yield 514 mg, 41%. Purity approximately 90%, consisting of some free stearic acid and acid anhydride (NMR).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)[C:5]=1[NH2:15])([O-:3])=[O:2].[H-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[C:5]2[NH:15][CH:12]([CH2:14][OH:13])[CH2:11][O:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1c(OCC2CO2)cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1NC(CO)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 2-nitro-6-oxiranylmethoxy-phenylamine (14.7 g, 0.070 mol) in DMF (200 mL) was added sodium hydride (3.5 g, 60 wt. %, 0.087 mol). The resulting reaction mixture was stirred at room temperature overnight. The mixture was evaporated in vacuum, the residue diluted with water (200 mL) and extracted with methylene chloride (2×200 mL). The combined organic layers were washed with water (300 mL) and saturated sodium chloride solution (300 mL), dried (Na2SO4) and concentrated to provide the title compound as a dark red crystal (11.0 g). 1H NMR (DMSO-d6): δ 8.30 (d, 1H); 7.60 (dd, 1H); 7.00 (dd, 1H); 6.65 (dd, 1H); 5.15 (t, 1H); 4.10 (m, 2H); 3.70 (m, 1H); 3.50 (m, 2H).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.[Cl:13][C:14]1[S:15][C:16]([CH2:19]Cl)=[CH:17][CH:18]=1>>[Cl:13][C:14]1[S:15][C:16]([CH2:19][O:1][NH2:2])=[CH:17][CH:18]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: NOCc1ccc(Cl)s1

Procedure:
Prepared by a similar procedure as described for preparation 15. Starting materials: N-hydroxyphthalimide and 2-chloro-5-(chloromethyl)thiophene (Aldrich). 13C-NMR (DMSO-d6) δ 140.2, 127.9, 126.3, 126.0, 71.1.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:41]=[CH:40][CH:39]=[CH:38][C:7]=1[CH2:8][N:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29](C2C=CC=CC=2)[CH2:28][CH2:27]1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2].BrCCCCCCN([CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1OC(C)(C)C)CCNC(=O)OC(C)(C)C.C(C1CCNCC1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][N:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:27][CH2:28][CH:29]([CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:30][CH2:31]1)[CH2:8][C:7]1[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=1[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCN(CCCCCCBr)Cc1ccccc1OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCN(CCCCCCN1CCC(c2ccccc2)CC1)Cc1ccccc1OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(CC2CCNCC2)cc1
Product: CC(C)(C)OC(=O)NCCN(CCCCCCN1CCC(Cc2ccccc2)CC1)Cc1ccccc1OC(C)(C)C
Yield: 58 %

Procedure:
The same procedure as described for compound 16 was applied to starting material 15 (2.4 g, 5.89 mmol), 4-benzylpiperidine (2.06 g, 11.78 mmol) and K2CO3 (0.814 g, 5.89 mmol). Purification was carried out on a silica gel TLC plate that was developed in with a 3% methanolic NH3 (7 M NH3 in methanol/97% CH2Cl2. The product was isolated as pale yellow oil (58%). 1H NMR (CDCl3) δ 7.328 (dd, 1H, Ar), 7.211 (t, 2H, Ar), 7.132 (t, 1H, Ar), 7.077 (m, 3H, Ar), 6.951 (m, 2H, Ar), 3.576 (s, 2H, —CH2—), 3.302 (d, 2H, —CH2—), 3.112 (m, 2H, —CH2—), 2.729 (m, 2H, —CH2—), 2.525 (m, 6H), 2.395 (m, 2H, —CH2—), 1.819 (m, 2H, —CH2—), 1.724 (m, 5H), 1.424 (m, 2H, —CH2—), 1.356 (s, 9H, —C(CH3)3), 1.325 (s, 9H, —C(CH3)3), 1.224 (s(br), 4H, —CH2—CH2—). Mass Spec.=579.86 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl[CH:9]([C:15](=O)[CH3:16])[C:10]([O:12]CC)=[O:11]>C(O)C>[CH3:16][C:15]1[N:7]=[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]2[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1ccccn1
Solvent: CCO
Product: Cc1nc2ccccn2c1C(=O)O
Temperature: 80 °C
Reaction time: 48 h
Yield: 44.5 %

Procedure:
A mixture of pyridin-2-amine (10 g, 106 mmol), ethyl 2-chloro-3-oxobutanoate (16 g, 97 mmol) and ethanol (200 mL) was stirred at 80° C. for 2 days. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (25 mL), water (75 mL) and ethanol (200 mL) were added to the obtained residue, and the mixture was stirred at 70° C. for 1 hr. 6N Hydrochloric acid (34 mL) was added dropwise to the reaction mixture under ice-cooling. The resulting precipitate was collected by filtration, washed with water, ethanol and diethyl ether and dried to give the title compound (7.6 g, 44%) as a pale-pink solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:21].C([OH:24])C>O>[CH3:20][C:16]1[CH:17]=[CH:18][C:19]([NH:11][C:3]2[C:4]([F:10])=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])=[C:14]([CH2:13][C:12]([OH:21])=[O:24])[CH:15]=1
Reactant: Cc1ccc2c(c1)CC(=O)N2c1c(F)cc(F)c(F)c1F
Reactant: CCO
Solvent: O
Product: Cc1ccc(Nc2c(F)cc(F)c(F)c2F)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The suspension of 350 mg of N-(2′,3′,4′,6′-tetrafluorophenyl)-5-methyloxindole in 20 ml of ethanol and 5 ml of water is degassed by passing through nitrogen for 1.5 h. Then 260 mg of 30% aqueous sodium hydroxide is added and the mixture is heated to reflux for 6.5 hours. Most of the ethanol is then removed by distillation the mixture is cooled to room temperature followed by the slow addition of 1N hydrochloric acid (1.05 g) to reach a pH of about 3. The precipitate is then filtered, washed with ethanol/water (1:1) and dried in vacuo at room temperature affording the title product.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:26][C:27]1[CH:36]=[CH:35][C:30]2[NH:31][C:32](=[O:34])[O:33][C:29]=2[CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:1](=[C:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:26][C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(=Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(=Cc2ccccc2)CC1

Procedure:
A mixture of 49 mg (0.2 mmol) of (4-benzylidene-piperidine-1-yl)-oxo-acetic acid, 33 μl (0.24 mmol) of triethylamine, 30 mg (0.2 mmol) of 6-amino-3H-benzoxazol-2-one [J. Chem. Soc., 321. (1938)] 79.6 mg (0.21 mmol) of HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)]and 1 ml of dimethylformamide is stirred at room temperature for 24 h. The reaction mixture is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. The quality and the quantity of the product are determined by HPLC-MS method as described above. k′=9.66.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](O)=[O:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:39][NH:40][CH3:41].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]([N:40]([CH3:41])[CH3:39])=[O:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:6][CH:7]=1
Reactant: CNC
Reactant: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)O)n(C)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(S(N)(=O)=O)cc2)c(C(=O)N(C)C)n(C)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a stirred solution of 5-(4-chlorophenyl)-1,4-dimethyl-3-(4-sulfamoylphenyl)-1H-pyrrole-2-carboxylic acid (49ε, 1.00 g, 2.47 mmol) in DMF (15 ml) was added HOBT (0.41 g, 2.72 mmol) at room temperature, which was then followed by the addition of dimethylamine hydrochloride (0.40 g, 4.94 mmol). the reaction mixture was cooled to 0° C. and to the cooled reaction mixture was then added EDC (0.71 g, 3.70 mmol) and triethylamine (1.00 g, 1.37 ml, 9.88 mmol). The reaction mixture was then stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. Ethyl acetate (100 ml) was added to the residue so obtained. The mixture so obtained was then washed with saturated sodium bicarbonate solution (20 ml) followed by washing with brine (20 ml). The organic layer obtained was dried over anhydrous sodium sulphate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography over silica gel (100-200 mesh) using 90% ethyl acetate in hexanes as an eluent to obtain the title compound (0.94 g, 88.1%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCCCCl)c2)cc1
Reactant: C1CCNCC1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCCCN3CCCCC3)c2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 139 using tert-butyl N-[3′-(3-chloropropoxy)biphenyl-4-ylmethyl]carbamate instead of 3-(3-chloropropoxy)-4-phenylbenzonitrile and piperidine instead of pyrrolidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([OH:19])=[C:6]([CH:18]=1)[C:7]([N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C=O)C>[C:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:19][C:5]1[CH:4]=[C:3]([Cl:20])[C:2]([Br:1])=[CH:18][C:6]=1[C:7](=[O:8])[N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: Cc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1OCCCC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 82.7 %

Procedure:
To 5-bromo-4-chloro-2-hydroxy-N-methyl-N-o-tolyl-benzamide (2.6 g, 7.3 mmol) in dry DMF (30 mL), was added K2CO3 (2.0 g, 7.6 mmol), followed by addition of t-butyl 4-bromobutyrate (2.0 g, 8.8 mmol). The mixture was heated at 60° C. for 12 hrs and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, and dried over MgSO4. After filtration, concentration and purification by silica gel column chromatography eluting with ethyl acetate in hexanes (3/7) gave 4-[4-bromo-5-chloro-2-(methyl-o-tolyl-carbamoyl)-phenoxy]-butyric acid tert-butyl ester (3.0 g). MS: 496.3 (M+H)+; tR=2.81 min (method 1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][OH:15].C(OCC)(OCC)OCC>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>[CH2:1]([O:8][CH2:9][C:10]1([CH3:11])[O:15][CH2:14][CH2:13][O:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)COCc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: O
Product: CC1(COCc2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 61.5 h
Yield: 90.5 %

Procedure:
A mixture of 1-benzyloxy-2-propanone (4.94 g, 30.1 mmol), ethylene glycol (20 ml, 359 mmol), triethyl orthoformate (5 ml, 30.1 mmol), and p-toluenesulfonic acid monohydrate (130 mg, 0.683 mmol) was stirred at room temperature for 61.5 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (20 ml) was added and the mixture was extracted twice with chloroform (50 ml) and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=1/0 to 4/1 gradient). Desired fractions were concentrated to obtain the title compound (5.67 g, 90.5% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[C:11]([S:22]CCC(OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1.Br[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH3:31]>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH3:31])[CH:10]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Sc2ccccc2Cl)c1
Reactant: CC(Br)c1ccccn1
Product: Cc1csc(Nc2ncc(SC(C)c3ccccn3)cc2Sc2ccccc2Cl)n1
Product: Cl

Procedure:
Prepared according to the method of Example 16 from methyl 3-(5-(2-chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 49), and 2-(1-bromoethyl)pyridine. 1H NMR (d6-DMSO) δ 8.54 (d, 1H), 8.19 (bs, 1H), 7.97 (m, 1H), 7.61 (dd, 1H), 7.50 (m, 2H), 7.37 (m, 2H), 7.04 (bs, 2H), 6.52 (s, 1H), 4.56 (q, 1H), 2.18 (s, 3H), 1.59 (d, 3H); Mass spectrum (esi) m/z=471.2 (M+H-2HCl).