Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=[C:8]2[C:7]3[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=3)[NH:10][C:9]2=[O:14])=[CH:16]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1c[nH]c2ccccc12
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1c[nH]c3ccccc13)C(=O)N2

Procedure:
5-Aminosulfonyl-2-oxindole was condensed with indole-3-carboxaldehyde to give the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][NH:22][CH3:23])[C@@H:17]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38].CCN(C(C)C)C(C)C>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([CH2:21][N:22]([CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH3:23])[C@@H:17]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:8]=1
Reactant: CNC[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: COC(=O)CCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCN(C)C[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 65 mg of 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-2-(R)-(4-fluorophenyl)-3-(R)-((methylamino)methyl)cyclopentane from Example 18, Step B in 1 mL of acetonitrile was added 0.019 mL of methyl 4-chlorobutyrate and 0.037 mL of DIPEA. The reaction was heated at 50° C. for 48 hours, then an additional 0.038 mL of methyl 4-chlorobutyrate, 0.074 mL of DIPEA and 3 mg of tetrabutylammonium iodide were added and heating continued at 70° C. for 48 hours. The reaction was evaporated under a stream of nitrogen and the residue purified by prep TLC (10% methanol in ethyl acetate) to give 41 mg of title compound and 17 mg of recovered starting material. Mass spec (ESI): 564 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]3[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=3[CH:35]([CH3:37])[CH3:36])=[O:24])=[N:14][C:13]=2[CH:38]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C:26]3[C:31]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:29]=[CH:28][C:27]=3[CH:35]([CH3:37])[CH3:36])=[O:24])=[N:14][C:13]=2[CH:38]=1
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCSc1nc2cc(OCc3ccccc3)ccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCCCCSc1nc2cc(O)ccc2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Under cooling in ice bath, 6-(5-benzyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (514 mg, 2.0 mmol) was dissolved in trifluoroacetic acid (20 ml), followed by addition of thioanisole (1.24 g, 10 mmol), with stirring at ambient temperature for 12 hours. The solvent was distilled off from the reaction solution; the resulting residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed sequentially with a saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, and was dried over anhydrous magnesium sulfate, from which the solvents were distilled off. The residue was purified by silica gel column chromatography (30 g of silica gel; elution solvents:hexane:acetone=5:1 to 5:2), to recover the objective compound (459 mg at a yield of 97%) as a pale red amorphous. IR (KBr) cm−1: 3247, 2963, 1649, 1445, 1153. 1H-NMR (d6-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.48-1.91 (6H, m), 2.35 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.31 (2H, t, J=7.1 Hz), 6.70 (1H, dd, J=8.8, 2.4 Hz), 6.92 (1H, d, J=2.4 Hz), 7.09 (1H, d, J=8.3 Hz), 7.10 (1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz), 7.31 (1H, d, J=8.8 Hz), 8.68 (1H, br s), 8.92 (1H, s). EIMS m/z (relative intensity): 440 (M+, 100). Elementary Analysis: C25H32N2O3S Required: C, 68.15; H, 7.32; N, 6.36; S, 7.28. Found: C, 68.16; H, 7.45; N, 6.26; S, 6.86.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[C:21](=[O:22])([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[O:23][CH3:24]
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
2-(Trifluoromethoxy)phenol (6.0 g, 32.7 mmol) was dissolved in methylene chloride and triethylamine (9.1 mL, 65.4 mmol). The mixture was cooled to 0° C. and methyl chloroformate (2.8 mL, 36.0 mmol) was added dropwise. The mixture was stirred for 2 h at room temperature then quenched with saturated NH4Cl. The reaction was diluted with water and the aqueous layer extracted with dichloromethane (2×30 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to provide methyl 2-(trifluoromethoxy)phenyl carbonate (7.1 g, 92% yield). 1H NMR (400.0 MHz, DMSO-d6) δ7.36-7.26 (m, 4H), 3.93 (s, 31-1).
Reaction SMILES: [OH:1][CH:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[C:5](=[O:17])[C:4]2[S:18][CH2:19][CH2:20][S:21][C:3]1=2.[H-].[Na+].Cl[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26].C>CN(C)C=O.C(#N)C>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:17][CH:5]2[N:6]([C:7]3[CH:16]=[CH:15][C:14]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:8]=3)[C:2](=[O:1])[C:3]3[S:21][CH2:20][CH2:19][S:18][C:4]2=3)=[O:26])[CH2:28][CH2:29]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc2cccnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3cccnc3n2)CC1
Temperature: 0 °C
Yield: 49.1 %

Procedure:
5-Hydroxy-6-(1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (8.45 g.) is added, at 0°C, to a suspension of sodium hydride (0.8 g.) in anhydrous dimethylformamide (125 cc.). The reaction mixture is stirred for half an hour at 0°C, and 1-chlorocarbonyl-4-methylpiperazine (8.45 g.) dissolved in anhydrous dimethylformamide (50 cc.) is then added. After stirring for two and a half hours at 5°C., the reaction mixture is diluted with ice-water (500 cc.). The precipitate which has appeared is filtered off, washed four times with distilled water (total 200 cc.) and twice with diethyl ether (total 50 cc.) and then dissolved in methylene chloride (300 cc.). The organic solution is washed four times with distilled water (total 160 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (0.2 g.) and evaporated. When the residual liquid reaches a volume of 50 cc., boiling acetonitrile (200 cc.) is added. After cooling for two hours at 2°C., the crystals which have appeared are filtered off, washed three times with ice-cold acetonitrile (total 15 cc.) and dried under reduced pressure (20 mm. Hg). The crystals thus isolated (8.0 g.) are dissolved in boiling acetonitrile (270 cc.), decolourising charcoal (0.2 g.) is added to the boiling solution and the whole is filtered. After twenty-four hours at 2°C., the crystals which have appeared are filtered off, washed three times with ice-cold acetronitrile (total 10 cc.) and dried under reduced presssure (20 mm. Hg). 5-(4-Methylpiperazin-1-yl)carbonyloxy-6-(1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (5.8 g.), melting at 255°C., is thus obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[CH:17]=1.C(N=C=NCCCN(C)C)C.O[N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=CC=2N=N1.C1(CN)CC1.C(N(CC)CC)C>CN(C=O)C>[CH:44]1([CH2:43][NH:39][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)=[CH:26][CH:25]=2)[CH2:46][CH2:45]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NCC3CC3)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
To a solution of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) in DMF (2 mL), was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (85.9 mg, 0.45 mmol) and N-hydroxybenzotriazole (60.7 mg, 0.45 mmol), followed by adding cyclopropylmethylamine (26 mg, 0.36 mmol) and triethylamine (75 mg, 0.75 mmol). The reaction mixture was stirred at room temperature overnight. Purification by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient afforded the title compound (14 mg, 13%) which was obtained as a white solid. MS m/e=398.9 [M+H]+.
Reaction SMILES: N([O-])=[O:2].[Na+].[Cl:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][O:16][CH2:17][CH2:18][OH:19])=[C:8](N)[N:7]=1>C(O)(=O)C>[Cl:5][C:6]1[NH:7][C:8](=[O:2])[C:9]2[N:10]=[CH:11][N:12]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]=2[N:14]=1
Reactant: Nc1nc(Cl)nc2c1ncn2COCCO
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]c(Cl)nc2c1ncn2COCCO
Reaction time: 2 h
Yield: 49.8 %

Procedure:
Solid sodium nitrite (0.97g) was added at room temperature with stirring over a period of one hour to a solution of 2-chloro-9-(2-hydroxyethoxymethyl)adenine (0.5g) in glacial acetic acid (10ml). The reaction mixture was stirred for an additional 41/2 hours. The white solid was removed by filtration, washed with cold acetic acid and then well triturated with cold water to remove the sodium acetate present. The solid product was retained. The combined acetic acid filtrate and wash was evaporated at reduced pressure and 40° C. bath temperature and the residual oil triturated with cold water. The resulting solid material was combined with the previously isolated solid and the combined solids dried and recrystallized from ethanol to give 2-chloro-9-(2-hydroxyethoxymethyl) hypoxanthine (0.25g), m.p. >310° C. Elemental analysis and NMR spectrum were consistent with this structure.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:8]=2)[CH2:3][CH2:2]1.C[O:24][C:25](=[O:35])[C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[C:28]([CH2:33]Br)[CH:27]=1>>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]([OH:35])=[O:24])=[CH:27][C:28]=1[CH2:33][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccncc1
Product: O=C(O)c1ccc(Br)c(CN2CCC(c3cn(Cc4ccncc4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 1.5 g (50 mmol) of 3-piperidin-4-yl-1-pyridin-4-ylmethyl-1H-indole and 1.7 g (55 mmol) of 4-bromo-3-bromomethyl-benzoic acid methyl ester. After standard work-up and recrystallisation with ethyl ether, 1.7 g (68% of yield) of the expected acid were obtained.
Reaction SMILES: [OH:1]O.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[O:10]>C(O)=O>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([OH:1])=[O:10]
Reactant: OO
Reactant: O=Cc1ccccn1
Solvent: O=CO
Product: O=C(O)c1ccccn1

Procedure:
To mention specific examples of the reaction conditions, one to two equivalent amount of hydrogen peroxide is added to the pyridine-2-carbaldehyde derivative (8) in a formic acid solvent, and the mixture can be treated at room temperature for about 1 hour to 2 days, thus to produce the pyridine-2-carboxylic acid derivative (9).
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:16][CH3:17])=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:20]1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]2[C:29](=[O:30])[NH:31][C:3](=[O:18])[C:4]=2[C:6]2[CH:7]=[CH:8][C:9]([O:16][CH3:17])=[C:10]3[C:14]=2[N:13]([CH3:15])[CH:12]=[CH:11]3)=[CH:20]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1ccc(OC)c2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2c1ccn2C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a mixture of (1-methyl-4-methoxyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.27 g, 1.10 mmol) and 2-(1H-indol-3-yl-acetamide (0.17 g, 1 mmol) in DMF (5 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 4.0 mL, 4.0 mmol) at room temperature. The reaction mixture was heated at 60° C. for 4 hrs, cooled to room temperature, and quenched with hydrochloric acid (1.0 N). After stirring at room temperature for 30 min, the mixture was extracted with ethyl acetate and the extract was washed with water, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and evaporated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3-(1H-indol-3-yl)-4-(4-methoxy-1-methyl-1H-indol-7-yl)-pyrrole-2,5-dione (270 mg, 72.7%). 1H NMR (d6-DMSO, 400 MHz) 3.65 (s, 3H), 3.84 (s, 3H), 6.46˜6.55 (m, 4H), 6.78 (d, J=7.6 Hz, 1H), 6.95 (t, J=7.2 Hz, 1H), 7.13 (d, J=3.2 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.86 (d, J=3.2 Hz, 1H), 11.05 (s, 1H), 11.79 (s, 1H); MS (ES, m/z): C22H17FN3O3: 372.19(M++1), 370.29 (M+−1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.[NH2:18][CH2:19][CH:20](O)[CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH2:21]([CH:20]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:18][CH2:19]1)[CH2:22][CH3:23]
Reactant: CCCC(O)CN
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCC1CN=C2C=CC(c3cccc(C(F)(F)F)c3)=NN21
Temperature: 130 °C

Procedure:
A mixture of 3.0 g of 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine and 5.0 g of 1-amino-2-pentanol is heated at 130° C. for 18 hours, cooled, diluted with water and extracted with dichloromethane. As for Example 3, the obtained product is reacted with thionyl chloride and the ring is closed with potassium carbonate in ethanol to give 2,3-dihydro-3-propyl-6-[3-(trifluoromethyl)phenyl]imidazo[1,2-b]pyridazine which is dehydrogenated with lead tetraacetate to give the product of the Example.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].C(N(C(C)C)CC)(C)C.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][S:21](=[O:23])(=[O:22])[N:20]([CH3:25])[CH3:19]
Reactant: COc1ccccc1O
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COc1ccccc1OS(=O)(=O)N(C)C
Yield: 5.4 %

Procedure:
A solution of 24.8 g (0.2 mole) of guaiacol (Aldrich) and 34.9 g (0.27 mole) of diisopropylethylamine (Hunig's base, Aldrich) in 200 ml of toluene was added to a solution of 29 ml (0.27 mole) of dimethylsulfamoyl chloride (Aldrich) in 75 ml of toluene and the stirred reaction mixture was heated at reflux for 12 hr. The reaction mixture was successively washed with four 300 ml portions of 6N hydrochloric acid solution, 400 ml of water, three 200 ml portions of 20% sodium hydroxide solution, 400 ml of water and dried (magnesium sulfate). The solvent was evaporated under reduced pressure to give a brown, viscous oil that solidfied upon standing. The solid was recrystallized from ethyl ether-petroleum ether and was collected by filtration. The filtrate was evaporated under reduced pressure and the viscous, brown oil was purified by chromatography (4.5×90 cm glass column, 5.30 g of silica gel, ethyl acetate-hexanes, 1:8). Fractions containing the desired compound were combined and the solvents evaporated under reduced pressure to yield 2.5 g (5%) of the title compound as a light yellow liquid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH2:17]([O:19][C:20](=[O:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:32])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:29])=[O:30])=[CH:24][CH:23]=1)[CH3:18]
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-methylpiperazine (9.23 g, 10.21 ml, 0.092 mol), DIEA (13 g, 17.4 mL, 0.10 mol) and DCM 80 mL is cooled to 0° C., and to this is added a solution of the title B compound, (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (22 g, 0.083 mol) in 50 mL of DCM within 30 min. Reaction mixture stirred at 0° C. for 2 h, and the reaction mixture is washed with water (100 mL), followed by 0.1 N aqueous hydrochloric acid solution (1×200 mL). The organic layer dried over sodium sulfate, filtered and concentrated under vacuo to give crude [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester. Column chromatography over silicagel (60-120 mesh), using ethyl acetate afforded pure [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester as white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 1.3 (t, J=7.4, 3H), 2.3 (s, 3H), 2.5 (m, 4H), 3.0 (br s, 4H), 3.7 (s, 2H), 4.2 (q, J=7.4, 2H), 7.4 (d, J=8.3, 2H), 7.7 (d, J=7.3, 2H); MS 327 [M+1]+.
Reaction SMILES: C(N[C@H](C(O)=O)CC(C)C)(=O)C.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C@H:24]([NH2:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14].[C:31]([NH:34][C:35]1[CH:45]=[CH:44][CH:43]=[C:37]2[C:38]([O:40][C:41](=O)[C:36]=12)=[O:39])(=[O:33])[CH3:32].C(O)(=O)C.C=CCl>CCO>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:24]([N:30]2[C:41](=[O:40])[C:36]3[C:37](=[CH:43][CH:44]=[CH:45][C:35]=3[NH:34][C:31](=[O:33])[CH3:32])[C:38]2=[O:39])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH3:14]
Reactant: CCOc1cc([C@H](N)CS(C)(=O)=O)ccc1OC
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: C=CCl
Agent: CC(=O)N[C@@H](CC(C)C)C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 75 %

Procedure:
A 500 mL 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser. The reaction vessel was charged with (S)-2-(3-ethoxy-4-methoxyphenyl)-1-(methylsulphonyl)-eth-2-ylamine N-acetyl-L-leucine salt (25 g, 56 mmol, 98% ee), 3-acetamidophthalic anhydride (12.1 g 58.8 mmol), and glacial acetic acid (250 mL). The mixture was refluxed over night and then cooled to <50° C. After the solvent was removed in vacuum, the residue was dissolved in ethyl acetate. The resulting solution was washed with water (250 mL×2), saturated aqueous NaHCO3 (250 mL×2), and brine (250 mL×2), and then dried over anhydrous sodium sulfate. After the solvent was evaporated in vacuum, the residue was recrystallized from a binary solvent containing a mixture of ethanol (150 mL) and acetone (75 mL). The solid was isolated by vacuum filtration and washed with ethanol (100 mL×2). The product was dried in vacuum at 60° C. to a constant weight, affording 19.4 g (75% yield) of (S)-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-inoisoindoline-1,3-dione with 98% ee. Chiral HPLC (15/85 EtOH/20 mM KH2PO4 @pH 0.5, Ultron Chiral ES-OVS from Agilent Technology, 150 mm×4.6 mm, 0.4 mL/min., @240 nm): 25.4 min (S-isomer, 98.7%), 29.5 min (R-isomer, 1.2%). The product in CDCl3 was characterized by a 1H NMR spectrum showing the following chemical shifts (6 in ppm): 1.47 (t, 3H), 2.26 (s, 3H), 2.87 (s, 3H), 3.68-3.75 (dd, 1H), 3.85 (s, 3H), 4.07-4.15 (q, 2H), 4.51-4.61 (dd, 1H), 5.84-5.90 (dd, 1H), 6.82-8.77 (m, 6H), 9.46 (s, 1H). The product in DMSO-d6 was characterized by a 13C NMR spectrum showing the following chemical shifts (δ in ppm): 14.66, 24.92, 41.61, 48.53, 54.46, 55.91, 64.51, 111.44, 112.40, 115.10, 118.20, 120.28, 124.94, 129.22, 131.02, 136.09, 137.60, 148.62, 149.74, 167.46, 169.14, 169.48.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClC(Cl)C.[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[CH:25]=[C:24]1[CH3:33].[C:35]1([S:41]([C:44]2[CH:48]=[CH:47][S:46][C:45]=2[CH:49]=O)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(=O)([O-])O.[Na+]>[CH3:19][O:20][C:21](=[O:34])[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([Cl:32])=[CH:29][CH:30]=2)[C:25]([CH2:49][C:45]2[S:46][CH:47]=[CH:48][C:44]=2[S:41]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:43])=[O:42])=[C:24]1[CH3:33]
Reactant: O=Cc1sccc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(Cl)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A mixture of triethylsilane (2.7 g), trifluoroacetic acid (1.6 g) and dichloroethane (8.0 mL) at −20° C. was treated dropwise with a mixture of (5-chloro-2-methylindol-1-yl)acetic acid methyl ester (0.36 g), 3-phenylsulphony-2-thiophenealdehyde (0.39 g) and dichloroethane (8.0 mL), and the resulting mixture was warmed to room temperature over a period of 1.5 hours. The mixture was treated with additional triethylsilane (2.7 g) and trifluoroacetic acid (1.6 g) and then stirred at room temperature for 1 hour. The mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic extract was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate (1:0 to 0:1 by volume) to afford the title compound (0.55 g).