Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>ClCCl.C(N(CC)CC)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[N:10][CH:11]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Br)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(Br)cn1
Temperature: 20 °C
Yield: 55.6 %

Procedure:
A solution of trimethylacetyl chloride (17.5 g, 146 mmol) in dichloromethane (25 ml) was added to a solution of 2-amino-5-bromopyridine (25.0 g, 144 mmol) in dichloromethane (100 ml) and triethylamine (24 ml) dropwise with stirring at 20° C. The reaction mixture was then stirred for 40 minutes, filtered, washed with water, dried and concentrated. Recrystallization from hexanes afforded 20.6 g (70%) of the title product as a white flaky solid. mp 63-64° C. 1H NMR (CDCl3): δ=8.82 (br, 1 H); 8.30 (d, 1 H); 8.19 (m, 2 H); 1.36 (s, 3 H). MS (El): m/z=256, 258 (M+, Br isotopes).
Reaction SMILES: [BH4-].[Na+].B(OC)(OC)OC.[F:10][C:11]1[CH:30]=[CH:29][C:14]([C:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][C:18]=2[C:26](O)=[O:27])=O)=[CH:13][CH:12]=1.O>C1COCC1>[F:10][C:11]1[CH:30]=[CH:29][C:14]([CH:15]2[C:17]3[C:18](=[CH:19][C:20]([CH2:21][OH:22])=[CH:24][CH:25]=3)[CH2:26][O:27]2)=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(F)cc2)c(C(=O)O)c1
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 35 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
To a suspension of sodium borohydride (43.5 g) dispersed in THF (327 ml) was added trimethyl borate (9.1 g) and added dropwise at 20-30° C. a solution of 4-(4′-fluorobenzoyl)isophthalic acid (100.5 g) synthesized in Example 4 in THF (313 ml), and the mixture was heated to 35° C. A boron trifluoride-THF complex (181.7 g) was added dropwise at 35-42° C. After the dropwise addition, the mixture was heated at 40-50° C. for 7 hr, and hydrolyzed with water (101 ml) in an ice bath. THF was evaporated under reduced pressure. To the residue was added 30% sulfuric acid (110 g) and the mixture was stirred at 60° C. for 5 hr. A 25% aqueous solution of sodium hydroxide (200 g) was added and the mixture was extracted with hot toluene (450 ml) at 70° C. The hot toluene layer was washed with warm water (70° C., 60 ml), heptane (450 ml) was added and the mixture was cooled. The precipitated crystals were collected by filtration and dried to give 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (69.0 g, 81%). The various spectrum data of the crystals were the same as those obtained in Example 12.
Reaction SMILES: [P:1]([O:9]CC)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].COC(=O)[O-].[CH3:17][NH+:18]1[CH2:22][CH:21]([CH3:23])[N:20]([CH3:24])[CH:19]1[CH3:25].O>CO>[CH2:4]([O:3][P:1]([O-:9])([O:6][CH2:7][CH3:8])=[O:2])[CH3:5].[CH3:17][NH+:18]1[CH2:22][CH:21]([CH3:23])[N:20]([CH3:24])[CH:19]1[CH3:25]
Reactant: CCOP(=O)(OCC)OCC
Agent: CC1C[NH+](C)C(C)N1C
Agent: COC(=O)[O-]
Solvent: CO
Solvent: O
Product: CCOP(=O)([O-])OCC
Temperature: 100 °C
Reaction time: 20 h

Procedure:
By adding 42 parts of triethyl phosphate (TEP: produced by Daihachi Chemical Industries Co., Ltd.) to the methanol solution of 46 parts of 1,2,3,4-tetramethylimidazolinium methyl carbonate salt obtained in Production Example 1, followed by addition of 5.4 parts of water and stirring at 100° C. for 20 hours, triethyl phosphate was hydrolyzed and a salt exchange reaction was carried out to obtain a methanol solution of 1,2,3,4-tetramethylimidazolinium diethyl phosphate monoanion. The above-described solution was heated under reduced pressure of 1.0 kPa or less at 50° C. to distill methanol until no distillate of methanol was observed. Thereafter, the temperature was raised from 50° C. to 100° C. and heating was continued for 30 minutes to distill and remove monomethyl carbonate (HOCO2CH3), methanol, and carbon dioxide (slight amounts of methanol and carbon dioxide are formed by thermal decomposition of monomethyl carbonate. Hereinafter, these are abbreviated as by-products). Thus, 1,2,3,4-tetramethylimidazolinium diethyl phosphate monoanion, electrolyte (C-2), was obtained. The yield was 99 parts (yield based on the weight of 46 parts of 1,2,3,4-tetramethylimidazolinium methyl carbonate salt; hereinafter the same shall apply). The molecular weight of the electrolyte (C-2) was 280.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1.Cl.[CH3:10][O:11][C:12](=N)[NH:13][N+:14]([O-:16])=[O:15].[OH-].[Na+]>O.C(Cl)(Cl)Cl>[CH3:10][O:11][C:12](=[N:13][N+:14]([O-:16])=[O:15])[NH:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1
Reactant: NCc1cnc(Cl)s1
Reactant: COC(=N)N[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
5-(Aminomethyl)-2-chlorothiazole (7.43 g, 50.0 mmol) was dissolved in water (96 ml), and concentrated hydrochloric acid (4.22 ml, 50.0 mmol) was added. To this reaction mixture was added O-methyl-N-nitroisourea (6.25 g, 52.5 mmol) and chloroform (30 ml), and adjusted to pH 6.7 with aqueous sodium hydroxide solution (0.5 N) using pH meter. After 24 hours of stirring at room temperature, maintaining pH 6.7, the organic phase was separated from the water phase. The water phase was extracted with chloroform (100 ml), and the combined organic phase was concentrated under reduced. Water (50 ml) was added to the residue to stir for a while. The resulting crystals were collected by filtration under reduced pressure, and washed with water. The washed crystals were dried under reduced pressure (80° C., 2 hours) to provide 7.80 g (62.2% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1.Cl.[CH3:10][O:11][C:12](=N)[NH:13][N+:14]([O-:16])=[O:15]>[OH-].[Na+].O>[CH3:10][O:11][C:12](=[N:13][N+:14]([O-:16])=[O:15])[NH:1][CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1
Reactant: NCc1cnc(Cl)s1
Reactant: COC(=N)N[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.6 %

Procedure:
5-(Aminomethyl)-2-chlorothiazole (1.49 g, 10.0 mmol) was dissolved in diluted hydrochloric acid (15 ml, 10.0 mmol), and O-methyl-N-nitroisourea (1.31 g, 11.0 mmol) was added. The pH was 2.1 at this time. This reaction mixture was adjusted to pH 6.2 with aqueous sodium hydroxide solution (0.1 N, 4 ml, 0.40 mmol) using pH meter. Water (1 ml) was added to increase the whole volume to 20 ml. After 16 hours of stirring at room temperature (pH was 7.1 at this time), the resulting white crystals were collected by filtration under reduced pressure, and washed with water. The washed crystals were dried under reduced pressure (80° C., 2 hours) to provide 1.62 g (64.6% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([C:10]2[C:11]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:12]=3[S:13][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Reaction time: 1.3 h
Yield: 77.9 %

Procedure:
To a well stirred solution of 2-(4′-methoxyphenyl)-6-methoxybenzo[b]thiophene (0.305 g, 1.13 mmol) and 4-methoxybenzoyl chloride (0.378 g, 2.22 mmol) in CH2Cl2 (45 ml) was added AlCl3 (0.550 g, 4.12 mmol) portion-wise over a 15 minute period. After 1.3 hours, water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 70:30 EtOAc/hexanes) afforded the title compound (0.3576 g, 0.88 mmol, 78%) as a pale yellow solid. Recrystallization (EtOAc/hexanes) afforded a highly pure, crystalline sample with mp 119-120° C. 1H-NMR (CDCl3, 360 MHz): δ=7.77 (d, J=9.0 Hz, 2H, ArH), 7.52 (d, J=8.9 Hz, 1H, ArH), 7.35 (d, J=8.9 Hz, 2H, ArH), 7.31 (d, J=2.3 Hz, 1H, ArH), 6.95 (dd, J=8.9, 2.4 Hz, 1H, ArH), 6.76 (d, J=9.0, 2H, ArH), 6.75 (d, J=8.9, 2H, ArH), 3.87 (s, 3H, —OCH3), 3.79 (s, 3H,—OCH3), 3.74 (s, 3H, —OCH3); 13C-NMR (CDCl3, 90 MHz): δ=193.2, 193,7, 159.7, 157.6, 142.4, 140.0,134.0, 132.2, 130.5, 130.4, 130.2,126.0,124.0, 114.7, 114.0, 113.6, 104.5, 55.6, 55.4, 55.2. HRMS (EI) M+ calcd for C24H20O4S, 404.1082, found 404.1059. Anal. Calcd for C24H20O 4S: C, 71.27; H, 4.98; S, 7.93. Found: C, 71.39; H, 4;98; S, 7.90.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][C:10]1[N:14]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:13]=[N:12][CH:11]=1.O>CS(C)=O>[CH:9]([C:10]1[N:14]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:13]=[N:12][CH:11]=1)=[O:8]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Cn2cncc2C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (13.8 ml/99.6 mmol) and then SO3-pyridine complex (9.89 g/62.25 mmol) are added in succession to a solution of 4.6 g (24.9 mmol) of the compound obtained in Step A in 120 ml of DMSO, and the reaction mixture is stirred at room temperature for 30 minutes. The whole is then brought to 0° C., hydrolysed with H2O, and then extracted several times with AcOEt. The organic phases are combined, washed with a saturated NaCl solution, dried over MgSO4, and evaporated to dryness to yield the title product.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([OH:9])[N:4]=1.[N:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N12CCN(CC1)CC2.O>CN(C)C=O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:18]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:19])[N:4]=1
Reactant: Oc1nccc(C(F)(F)F)n1
Reactant: O=C(Cl)N1CCOCC1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1nccc(C(F)(F)F)n1)N1CCOCC1
Yield: 79.4 %

Procedure:
A solution of 4-(trifluoromethyl)-2-pyrimidol (0.49 g, 3.00 mmol), 4-morpholinecarbonyl chloride (0.45 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.51 g, 3.00 mmol) in N,N-dimethylformamide (15 ml) was stirred at room temperature for 2 hours. Water was added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70→50:50)) yielding the title compound (0.66 g, 80% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[CH:14]([Li])(CC)[CH3:15].C(I)C>C1COCC1>[CH2:1]([C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7])[CH2:14][CH3:15]
Reactant: [Li]C(C)CC
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Solvent: CCI
Solvent: C1CCOC1
Product: CCCc1cccc2c1C(=O)NS2(=O)=O
Yield: 89 %

Procedure:
Following a procedure similar to that described in Example 28A 10 g (0.051 mol) of 4-methylsaccharin was reacted with 86 ml (0.10 mol) of a 1.18M solution of s-butyl lithium in THF and the resulting solution treated with 4.5 ml (0.050 mol) of ethyl iodide to give 10.15 g (89%) of 4-propylsaccharin, which on reaction with 5.32 ml (0.056 mol) of chloromethyl phenyl sulfide in toluene in the presence of tetrabutylammonium bromide afforded a 65% yield of 2-phenyl-thiomethyl-4-propylsaccharin as an oil, 1.8 g (0.0052 mol) of which, on reaction with 1.25 ml (0.016 mol) of sulfuryl chloride in MDC afforded 0.94 g (66%) of 2-chloromethyl-4-propylsaccharin.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([C:6]([OH:8])=[O:7])[NH2:5].[C:9]([NH:12][C@@H:13]([C:21]([OH:23])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:11])[CH3:10]>CO.O>[C:9]([NH:12][C@@H:13]([C:21]([OH:23])=[O:22])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:11])[CH3:10].[CH3:1][O:2][CH2:3][C@H:4]([C:6]([OH:8])=[O:7])[NH2:5]
Reactant: COCC(N)C(=O)O
Agent: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Solvent: CO
Solvent: O
Product: COC[C@@H](N)C(=O)O
Temperature: 50 °C
Yield: 68 %

Procedure:
Into a 250 mL round-bottomed flask equipped with a stirrer, reflux condenser and thermometer was added O-methyl-D,L-serine (5 g) in 90:10 methanol/water (25 mL). N-Acetyl-D-phenylalanine (8.70 g) was added in one portion and the mixture heated to 50° C. overnight. The suspension was cooled to room temperature and filtered, and the solid was rinsed with 90:10 methanol/water (5 mL) and dried at 40° C. under vacuum for 3 h. The N-acetyl-D-phenylalanine salt of O-methyl-D-serine (3.4 g, 25%) was obtained as a white solid with a chiral purity >90%. Regeneration of the title compound could be effected by adjustment of the pH to 1-2 by treatment with HCl, followed by extraction into an organic solvent and subsequent adjustment of the pH to ˜7 with NaOH.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[NH:13][C:12](=[O:14])[C@H:11]1[NH:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1)=[O:49]>C(#N)C.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[N:13]([CH2:47][C:48]([O:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=2)=[O:49])[C:12](=[O:14])[C@H:11]1[NH:15][C:16]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)CN2C(=O)[C@@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CO[Si](C)(C)C(C)(C)C)cc1
Yield: 75.8 %

Procedure:
(3S,4S)-4-t-Butyldimethylsilyloxymethyl-3-tritylaminoazetidinone (IV), (1.67 g) [H. Mastalerz et al., J. Med. Chem., 1988, 31, 1190] as a suspension in acetonitrile (40 ml) was treated with DMF (20 ml) to obtain a clear solution. Cesium carbonate (1.29 g) followed by 4-methoxybenzyl bromoacetate (1.19 g) were added and the mixture vigorously stirred overnight. T.l.c. analysis showed no starting material, the solution was diluted with ethyl acetate and washed with water (4×), brine and then dried. Removal of solvent in vacuo and purification by flash chromatography afforded the title compound as a pale yellow foam, (1.744 g, 76%), νmax (CH2Cl2) 1760 and 1744 cm-1 ; δH (CDCl3) -0.06 and -0.13 (6H, 2s), 0.81 (9H, s), 1.60 (1H, brs), 2.44 (1H, dd, J 3.3, 11.7 Hz), 3.1 (1H, dd, 2.2, 11.7Hz), 3.29 (1H, m), 3.41 (1H, d, J 18.0 Hz), 3.80 (3H, s), 4.36 (1H, d, J 18.0 Hz), 4.45 (1H, m), 4.97 and 5.05 (2H, ABq, J 11.8 Hz), 6.85 (2H, d, J 8.7 Hz), 7.16-7.30 (15H, m) and 7.52 (2H, d, J 8.7 Hz); [mass spectrum: MH+ (651)].
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].CCN=C=NCCCN(C)C.[CH:29]1[CH:30]=[CH:31][C:32]2[N:37](O)[N:36]=[N:35][C:33]=2[CH:34]=1.CN([CH:42]=[O:43])C>C(OCC)(=O)C>[NH2:1][C:2]1[S:10][C:5]2[CH2:6][N:7]([C:42]([C:29]3[CH:30]=[CH:31][C:32]4[NH:37][N:36]=[N:35][C:33]=4[CH:34]=3)=[O:43])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: Nc1sc2c(c1C(=O)N1CCCC1)CCNC2
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Product: Nc1sc2c(c1C(=O)N1CCCC1)CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 25 °C
Yield: 10 %

Procedure:
Starting material 12 (1.6 g, 6.4 mmol) was dissolved in 20 ml DMF. Then EDCI (1.46 g, 7.6 mmol) and HOBt (1.3 g, 9.5 mmol) were added. Now, one half of 1.04 g (6.4 mmol) 1H-1,2,3-benzothiazole-5-carboxyllic acid was added. The reaction mixture was stirred at ambient temperature over night. Then the other half of the 1H-1,2,3-benzothiazole-5-carboxyllic acid was added and the reaction mixture was again stirred at ambient temperature over night. The reaction mixture was now concentrated in vacuo yielding 7 g crude product. Those were taken up in ethyl acetate and water and the phases were separated. The organic phase was washed with water and the combined aqueous phases were washed with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The desired product 13 was isolated as a brown oil (1.2 g, 20% content, 10% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH:15]=2)=[CH:2]1.[H-].[Na+].[CH3:35]I>CN(C)C=O.O1CCOCC1.O>[CH3:35][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH:11]=2)=[CH:2]1
Reactant: CI
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
A mixture of 2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (11 g) in dimethylformamide (150 cc) is added over 30 minutes to sodium hydride (1.3 g) in a 50% dispersion in vaseline oil, under a current of argon, maintaining the temperature at about 20° C. The reaction medium is stirred for 2 hours at a temperature of about 20° C., then a solution of methyl iodide (3.9 g) in dioxane (50 cc) is added over 15 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The reaction mixture is redissolved in distilled water (250 cc) and the organic phase is extracted with dichloromethane (4×100 cc) and then washed with distilled water (400 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallized from boiling methyl ethyl ketone (70 cc). 2-{3-[4-(1-Methyl-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (3.3 g) is obtained, m.p. 161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:16]=[C:15]([CH3:17])[C:14](=[CH:5][C:4]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(OC)c(C=O)c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1cc(OC)ccc1OC)C(C)=O
Yield: 76.7 %

Procedure:
A stirred solution of 25.0 grams (0.15 mole) of 2,5-dimethoxybenzaldehyde, 22.0 grams (0.17 mole) of ethyl acetoacetate, 2 mL of piperidine, and 3 mL of glacial acetic acid in about 250 mL of toluene is placed in a reaction vessel equipped with a Dean-Stark trap, and heated at reflux for about 12 hours. After this time, the reaction mixture is cooled and washed in turn with water, a cold solution of aqueous 10% hydrochloric acid, aqueous 5% sodium bicarbonate, and aqueous 1% acetic acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. Elution is accomplished using methylene chloride. The column chromatography does not provide product purification as expected. The fractions are recombined and concentrated under reduced pressure to a residual oil. The oil is distilled under vacuum, yielding 32 grams of impure ethyl 3-oxo-2-(2,5-dimethoxyphenylmethylidene)butanoate. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7]([NH:17][CH2:18][C:19](O)=[O:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C=O>[C:11]1([CH2:10][O:9][C:7](=[O:8])[NH:17][CH2:18][C:19](=[O:20])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nn1cccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccccc1)Nn1cccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 18.8 %

Procedure:
To a solution of 1-aminopyrrole (2.46 g) and carbobenzyloxyglycine (6.28 g) in 120 ml of dry DCM and 10 ml of dry dimethylformamide was added DCC (8.00 g). The reaction mixture was stirred at room temperature over a period of 64 hours. The precipitate was removed by filtration and stirred in boiling ethyl acetate. The mixture was filtered and the filtrate was combined with the filtrate of the reaction mixture and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, DCM/methanol 20:1) yielding a first fraction (2.97 g) which was contaminated by DCU. A second fraction recrystallized from ethyl acetate afforded 1.54 g of the product as crystals, m.p. 146°-147° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([Cl:29])=[C:24]([Cl:30])[CH:23]=3)[C:18]([F:21])([F:20])[F:19])=[CH:11][C:8]=2[C:9]#[N:10])[N:3]=1.C(N(CC)CC)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>C(Cl)Cl>[C:9]([C:8]1[CH:11]=[C:12](/[CH:15]=[CH:16]/[CH:17]([C:22]2[CH:23]=[C:24]([Cl:30])[C:25]([Cl:29])=[C:26]([Cl:28])[CH:27]=2)[C:18]([F:19])([F:20])[F:21])[CH:13]=[CH:14][C:7]=1[N:4]1[CH:5]=[N:6][C:2]([NH:1][C:41]([CH:38]2[CH2:40][CH2:39]2)=[O:42])=[N:3]1)#[N:10]
Reactant: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(N)n1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1-n1cnc(NC(=O)C2CC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a stirred solution of (E)-2-(3-amino-1H-1,2,4-triazol-1-yl)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzonitrile (0.15 g, 0.31 mmol) in DCM at 0° C., were added triethylamine (0.1 g, 1 mmol) and cyclopropylcarbonyl chloride (0.04 g, 0.38 mmol) and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with DCM and washed with water and brine and dried over Na2SO4. Concentration under reduced pressure and purification by column chromatography (SiO2, 100-200 mesh) afforded the title compound as a solid (66 mg, 34%): mp 109-112° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.94 (br s, 1H), 8.36 (s, 1H), 8.08 (m, J=8.4 Hz, 1H), 7.91 (s, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.13 (dd, J=15.6, 9.2 Hz, 1H), 6.87 (d, J=15.6 Hz, 1H), 4.92 (m, 1H), 1.99 (br s, 1H), 0.82 (s, 4H); ESIMS m/z 540.04 ([M+H]+); IR (thin film) 3233, 2233, 1699, 1114, 807 cm−1.