Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCCCCC.CO>C(Cl)Cl>[C:7]([NH:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC[C@@H](N)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: CC[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.1 %

Procedure:
To a stirred solution of (R)-(−)-2-aminobutan-1-ol (10 g, 112.18 mmol) in CH2Cl2 (500 mL) under Ar at RT, was added Pri2NEt (30 mL, 172.22 mmol) followed by trityl chloride (35.4 mL, 126.98 mmol). The reaction mixture was stirred at RT for 48 h, when TLC (55:40:5 hexane/Et20/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue precipitated from Me2CO (50 mL) with hexane (900 mL) with stirring, the precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in hexane (1 L), filtered, and the filtrate was evaporated in vacuo to afford the title compound as a light yellow oil (32 g, 86%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.56 (t, 3H, J=7.41, —NHCH(CH2CH3)CH2OH), 1.10 (m, 2H, —NHCH(CH2CH3)CH2OH), 2.21 (m, 1H, —NHCH(CH2CH3)CH2OH), 2.72+3.00 (2×m, 2H, —NHCH(CH2CH3)CH2OH), 4.28 (t, 1H, J=5.26 Hz, —NHCH(CH2CH3)CH2OH), 7.14-7.49 (m, 15H, 3×Bz).
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:27])[C:4]1[C:5](=[C:9]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=[C:11]([N+]([O-])=O)[CH:12]=1)[C:6]([OH:8])=[O:7].[C:28]1([S:34]([O-:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Na+]>CN(C=O)C>[CH3:1][N:2]=[C:3]([OH:27])[C:4]1[C:5](=[C:9]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:10]=[C:11]([S:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CCCCCCCCCCSc1cc([N+](=O)[O-])cc(C(O)=NC)c1C(=O)O
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCSc1cc(S(=O)(=O)c2ccccc2)cc(C(O)=NC)c1C(=O)O

Procedure:
2.0 g (5.28 mmols) of 3-n-decylthio-5-nitrophthalic acid N-methylimide, 1.73 g (10.57 mmols) of sodium phenylsulfinate and 20 ml of DMF are stirred for 17 hours at 120° C. The mixture is concentrated and the residue is taken up in methylene chloride/dilute hydrochloric acid. The organic phases are washed with saturated NaCl solution, dried over sodium sulfate and evaporated. After recrystallisation from cyclohexane, 1.83 g (73% of theory) of the title imide, with a melting point of 86°-88° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[CH3:18].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[CH3:18]
Reactant: CCn1ncc(C)c1-c1cc(C(=O)OC)sc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc(C)c1-c1cc(C(=O)O)sc1Cl
Temperature: 50 °C

Procedure:
To a solution of methyl 5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (260 mg, 0.90 mmol) in THF/H2O (2 mL/2 mL) was added KOH (201 mg, 3.6 mmol). The reaction mixture was heated to 50° C. for 4 h. After the mixture was concentrated and diluted with H2O, the pH was adjusted to 3. The mixture was extracted with DCM (5 mL×3). The collected organic layers were concentrated under vacuum to give crude 5-chloro-4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid, which was used directly without further purification: LC-MS (ES) m/z 271 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[C:17]=3[CH3:24])=[C:7]([C:12]([NH2:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:25][CH3:26].BrC[CH2:29][CH2:30][CH2:31][Cl:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:32][CH2:31][CH2:30][CH2:29][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[C:17]=3[CH3:24])=[C:7]([C:12]([NH2:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: COc1cc2c(Nc3cccc(CO)c3C)c(C(N)=O)cnc2cc1O
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cccc(CO)c3C)c(C(N)=O)cnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.4 %

Procedure:
7-Hydroxy-4-[3-(hydroxymethyl)-2-methylanilino]-6-methoxy-3-quinolinecarboxamide (0.90 mg, 2.54 mmol) was dissolved in DMF (10 ml), 1-bromo-4-chlorobutane (0.28 ml, 2.79 mmol) and Cs2CO3 (1.7 g, 5.2 mmol) were added and the mixture was stirred at ambient temperature for three days. The mixture was poured out on water and extracted with methylenechloride. The residue was chromatographed on silica using ethylacetate/methanol (1:0–>5:1) as eluent, affording 550 mg (50% yield) of the titled compound.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.[N:31]12[C:37](=[O:38])[CH2:36][CH2:35][CH:34]1[C:33](=O)[CH:32]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([O:10][C:33]2[CH2:34][CH:35]3[N:31]([C:37](=[O:38])[CH2:36]3)[C:32]=2[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: O=C(OCc1ccccc1)C1C(=O)C2CCC(=O)N21
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccccc3)N3C(=O)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
p-Toluenesulfonic anhydride (326 mg, 1 mμol) and N,N-diisopropylethylamine (192 μl, 1.1 mμol) are added to an ice-cold, stirring solution of benzyl 1-azabicyclo[2.3.0]heptan-3,7-dione-2-carboxylate (259 mg, 1 mμol) in anhydrous methylene chloride (10 ml). The resulting solution is stirred in the cold and under a nitrogen atmosphere for 2.5 hours. The solution is diluted with methylene chloride (20 ml), washed with water (10 ml). 1 M pH3 phosphate buffer (10 ml) and 5% aqueous sodium bicarbonate (2×10 ml) dried with magnesium sulfate, filtered, and evaporated under vacuum to a semi-solid. This material is triturated with ice-cold ethyl acetate (2×2 ml) and diethyl ether (2×5 ml) to provide benzyl 3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (276 mg, 67%) as a white powder. Recrystallization from methylene chloridediethyl ether gives analytically pure product as small white needles: mp 103°-105°; IR (CH2Cl2) 1786, 1723, 1382, and 1190 cm-1 ; NMR (CDCl3) 8 2.44 (s, 3, ArCh3) 3.03 (dd,1,J=3.0 and 17.0,HGβ), 3.16 (dd,1,J=8.5 and 18.7,H4a), 3.32 (dd,1,J=10.0 and 18.7,H46), 3.55 (dd,1,J=5.5 and 17.0, HG), 4.21 (m,1,H5), 5.14 (ABq,2,J=12,CH2Ar), 7.35 (S,5, ArHO, 7.26 and 7.75 (two d's,4,J=9,ArH); UV(dioxane) 283 (E6600) and 277 (E6500) nm.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:11][C:12]#[N:13])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH:11]([C:12]#[N:13])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:20]
Reactant: N#CCC(=O)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(C#N)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
A heptane washed suspension of 7.6 g (0.189 mole) of 60% NaH/mineral oil in 400 ml of anhydrous toluene was treated portion-wise with 25.0 g (0.172 mole) of benzoylacetonitrile under a nitrogen atmosphere. After stirring for 1 hour, 33.0 g (0.189 mole) of ethyl bromoacetate (97%) was added in one portion. The reaction was heated at reflux for 4 hours, then allowed to cool to room temperature and stirred for 20 hours. Water (500 ml) was added, and the toluene layer was extracted with water (500 ml). The toluene layer was dried over MgSO4, filtered, and the solvent evaporated under reduced pressure (42.9 g). The residual oil was fractionally distilled under vacuum to give 21.4 g (54%) of pure product.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:23])([F:22])[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([CH:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[OH:15])[CH:5]=1>C(O)(=O)C.S(=O)(=O)(O)O.O.[O-2].[O-2].[O-2].[Cr+6]>[ClH:1].[NH:19]1[CH2:20][CH2:21][CH:16]([C:14]([C:6]2[CH:5]=[C:4]([C:3]([F:2])([F:22])[F:23])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: OC(c1cc(C(F)(F)F)c2ccccc2c1)C1CCNCC1
Agent: [Cr+6]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1cc(C(F)(F)F)c2ccccc2c1)C1CCNCC1
Reaction time: 0.5 h

Procedure:
A chilled, stirred solution of 124 g (0.4 mole) of α-(4-trifluoromethyl-2-naphthyl)-4-piperidinemethanol hydrochloride in 600 ml of acetic acid, 40 ml of 25% sulfuric acid and 72 ml of water is added with stirring to 26.5 g (0.27 mole) of chromium trioxide in 30 ml of acetic acid over a period of 11/2 hours, during which time an additional 20 ml of water is added. The mixture is stirred for 1/2 hour at a temperature of less than 9° C. The solvent is removed under vacuum and the residue treated with excess sodium hydroxide and extracted with ether and with chloroform. The combined extracts are washed with water, dried over MgSO4 and filtered. To the filtrate is added additional chloroform and ethereal HCl. The resulting precipitate is filtered off and recrystallized from isopropyl alcohol to yield 4-trifluoromethyl-2-naphthyl 4-piperidyl ketone hydrochloride.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=[N:29][NH:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:25][CH2:24]1)(C(C)(C)C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+]>C(O)(=O)C.O1CCCC1>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:24][CH2:25][C:26](=[N:29][NH:30][S:31]([C:34]2[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:27][CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)NN=C2CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3O[Si](C)(C)C(C)(C)C)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)NN=C2CCC(c3ccc(O)cc3O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a round bottomed flask was added N′-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene-4-methylbenzenesulfonohydrazide (100 mg), tetrahydrofuran (5 ml), glacial acetic acid (3 drops) and tetrabutylammonium fluoride hydrate (174 mg), and the resulting solution was stirred at room temperature for 2 hr. Saturated sodium hydrogen carbonate solution (10 ml) was added and stirring was continued for 1 hr. The reaction mixture was partitioned between water (10 ml) and ethyl acetate (20 ml), the layers were separated, and the aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic phases were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether, 7:3 v/v) furnished the title compound (62 mg, 100%) as a cream solid. δH ((CD3)2CO): 1.44-1.63 (2H, m), 1.92-2.01 (3H, m), 2.22-2.32 (1H, m), 2.35-2.43 (2H, m), 2.97 (3H, s), 3.09 (1 H, tt), 6.28 (1 H, dd), 6.37 (1 H, d), 6.87 (1 H, d), 7.38 (2H, d), 7.79 (2H, d), 7.96 (1H, s), 8.13 (1H, s), 8.99 (1H, s); m/z (ES+) 375 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25](=O)[CH2:26][CH3:27]>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][CH2:26][CH3:27])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: CCC=O
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: CCC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 67.2 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with propionaldehyde (0.5 g, 8.6 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 120° C. for 90 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.073 g, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][C@H:8]2[NH2:14])=[O:4].[CH:15]([C:17]1[N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](C)=[CH:20][CH:21]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11]([CH2:10][CH2:9][C@H:8]2[NH:14][CH2:15][C:17]2[N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:13]=1)=[O:4]
Reactant: Cc1ccc(C=O)n1C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NCc1cccn1C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A solution of (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester (A-03) (361 mg, 1.88 mmol, 1 eq.) in methylene chloride (3 ml) was added to a solution of tert-butyl 2-formyl-5-methyl-1H-pyrrole-1-carboxylate (434 mg, 2.08 mmol, 1.1 eq.) in dry methylene chloride (17 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was cooled to 0° C. and then Na(OAc)3BH (1.2 g, 5.66 mmol, 3 eq.) was added portionwise and it was stirred at 25° C. for 14 h. The reaction mixture was diluted with methylene chloride (200 ml) and washed with saturated sodium bicarbonate (50 ml), water (2×50 ml) and brine (50 ml), and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel; 5% EtOAc/hexanes) to give the desired product as a light yellow oil. Yield: 82% (600 mg, 1.56 mmol).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14]Br)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[CH:11][CH:10]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: CC(C)(N)CO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCNC(C)(C)CO)cc1
Yield: 59.1 %

Procedure:
A mixture of 2-amino-2-methylpropanol (4.46 g), 4-methoxyphenethyl bromide (10.76 g), potassium carbonate (13.8 g) and potassium iodide (8.3 g) in acetonitrile (100 ml) was heated under reflux for 20 hours and evaporated. The residue was partitioned between ethyl acetate and water and the organic layer was dried over sodium sulphate and evaporated. The residual solid was recrystallised from ethyl acetate/hexane to give the title compound (6.6 g, 60%), m.p. 114°-115°.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:8])(=O)=O.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][CH2:6][C@@H:7]([NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:8])[CH2:22][CH2:21]1
Reactant: C[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Reactant: NC1CC1
Product: C[C@@H](CNC1CC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
(S)-2-(Benzyloxycarbonylamino)propyl methanesulfonate (48 mmol) and cyclopropyl amine (480 mmol) were mixed together and stirred at room temperature for 48 h. The remaining cyclopropyl amine was removed by rotary evaporator and the residual mixture was added to 500 ml of ethyl acetate and washed with 5% Na2CO3 aqueous solution and brine. After drying (K2CO3) and removal of the solvent, the residual semi-solid was recrystallized from CH2Cl2 and petroleum ether to afford the target compound in 60% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[C:38]([S:42](=[O:45])(=[O:44])[NH2:43])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[C:38]([S:42](=[O:44])(=[O:45])[NH2:43])=[CH:37][C:33]=1[C:34]([N:21]1[CH2:20][CH2:19][N:18]([C:13]2[CH:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:16]=[C:15]([CH3:17])[N:14]=2)[CH2:23][CH2:22]1)=[O:35]
Reactant: COc1ccc(-c2cc(N3CCNCC3)nc(C)n2)cc1OC
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)c(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(N3CCN(C(=O)c4cc(S(N)(=O)=O)c(Cl)cc4Cl)CC3)nc(C)n2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.5 %

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-2-methyl-4-(1-piperazinyl)pyrimidine (0.8 g) in chloroform (10 ml) were added triethylamine (0.39 ml) and 2,4-dichloro-5-sulfamoylbenzoyl chloride (0.74 g), and the mixture was stirred at ambient temperature for 20 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and evaporated. The obtained mixture was chromatographed on silica gel eluting with chloroform-methanol mixture (49:1 v/v), to give 4-[4-(2,4-dichloro-5-sulfamoylbenzoyl)piperazin-1-yl]-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (1.03 g).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:28]=[CH:27][C:14]([CH2:15][C:16]3([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[S:6]1(=[O:30])=[O:29])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:28]=[CH:27][C:14]([CH2:15][C:16]3([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[S:6]1(=[O:30])=[O:29])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CCOC(=O)C1(Cc2ccc(C3=CC(=O)N(C(C)(C)C)S3(=O)=O)cc2)CCC(=O)N1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccc(C3CC(=O)N(C(C)(C)C)S3(=O)=O)cc2)CCC(=O)N1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
Ethyl 2-[4-(2-tert-butyl-1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)benzyl]-5-oxopyrrolidine-2-carboxylate (24 mg, 0.055 mmol) was dissolved in ethanol (2.5 mL) and 10% Pd/C (10 mg, 0.09 mmol) was added. Hydrogen was added to a Parr shaker (58 psi) and shaken overnight. Purification by preparative LCMS gave the desired product as a colorless glass (23 mg, 95%). 1H NMR (400 MHz, CD3OD): δ 7.42 (d, J=8.2 Hz, 2H), 7.32 (d, J=8.2 Hz, 2H), 5.12 (t, J=8.9 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 3.30 (m, 2H), 3.22 (d, J=13.6 Hz, 1H), 3.13 (d, J=13.6 Hz, 1H), 2.38 (m, 1H), 2.21 (m, 2H), 1.92 (m, 1H), 1.61 (s, 9H), 1.28 (t, J=7.0 Hz, 3H); LCMS found for C21H29N2O6S (M+H)+: m/z=437.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:7])[CH3:6].[Cl:19][CH:20]([CH3:24])[C:21](Cl)=[O:22]>ClC(Cl)C>[C:5]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:21](=[O:22])[CH:20]([Cl:19])[CH3:24])=[CH:17][CH:18]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)NCCCCc1ccccc1
Reactant: CC(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)NCCCCc1ccc(C(=O)C(C)Cl)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Under ice cooling, 20.9 g of anhydrous aluminum chloride was added to 200 ml of a dichloroethane solution containing 10.0 g of [4-(acetylamino)butyl]benzene and 9.96 g of 2-chloropropionyl chloride, and the mixture was stirred at 5° C. for 1 hour. The reaction mixture was poured into ice water, and the organic layer was collected by separation. After the organic layer was washed with water and dried, the solvent was removed to obtain 13.71 g of 4-[4-(acetylamino)butyl]-1-(2-chloropropionyl)benzene.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>CO.ClCCl.C(OCC)C>[ClH:22].[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[S:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccs2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: O=S(=O)(c1cccs1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-Thiophenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (759 mg) was dissolved in methanol (10 ml) and dichloromethane (5 ml), 2M HCl in diethyl ether (11.4 ml) was added and the reaction mixture was stirred at room temperature overnight, then cooled in ice bath, the resulted precipitate was filtered, washed with ether to yield 4-(2-thiophenesulfonyl)-piperazine hydrochloride salt (529 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[C:15]([C:20](=[O:60])[N:21]([CH:33]([CH3:59])[CH:34]([CH2:50][O:51][Si](C(C)(C)C)(C)C)[CH2:35][C:36]1[O:37][C:38]([C:41](=[O:49])[NH:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:39][CH:40]=1)[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[O:16][CH2:17][O:18][CH3:19])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])[CH3:2].C1C2C(=CC=CC=2)C=CC=1CNC(C)C(CO[Si](C(C)(C)C)(C)C)CC1OC(C(=O)NC2C=CC=CC=2)=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6](=[C:15]([C:20](=[O:60])[N:21]([CH:33]([CH3:59])[CH:34]([CH2:50][OH:51])[CH2:35][C:36]1[O:37][C:38]([C:41](=[O:49])[NH:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:39][CH:40]=1)[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[O:16][CH2:17][O:18][CH3:19])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)=C(OCOC)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(CO[Si](C)(C)C(C)(C)C)Cc1ccc(C(=O)Nc2ccccc2)o1
Agent: CC(NCc1ccc2ccccc2c1)C(CO[Si](C)(C)C(C)(C)C)Cc1ccc(C(=O)Nc2ccccc2)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)=C(OCOC)C(=O)N(Cc1ccc2ccccc2c1)C(C)C(CO)Cc1ccc(C(=O)Nc2ccccc2)o1
Yield: 42.5 %

Procedure:
400 mg of tert-butyl 3-(ethoxycarbonyl)-4-[N-[(1RS,2RS)-2-(tert-butyldimethylsilyloxymethyl)-1-methyl-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-(2-naphthylmethyl)carbamoyl]-4-methoxymethyloxy-3-butenoate prepared by the same reaction as in Example 1(2) by using N-(2-naphthylmethyl)-[(1RS,2RS)-2-(tert-butyldimethylsilyloxymethyl)-1-methyl-3-{5-(phenylcarbamoyl)-2-furyl}propyl]amine prepared in Reference Example 4 was dissolved in 4 ml of tetrahydrofuran and stirred together with 0.95 ml of 1.0M tetrabutylammonium fluoride in tetrahydrofuran solution at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography [hexane/ethyl acetate=1/1] to give 147 mg (yield: 43%) of the title compound as a colorless oily substance.