Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH2:2]([CH:9]([NH3+:28])[CH:10]([OH:27])[CH2:11][N:12]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[O:36]1[CH:40]2[O:41][CH2:42][CH2:43][CH:39]2[CH:38]([O:44][C:45](=O)[O:46]N2C(=O)CCC2=O)[CH2:37]1>>[O:36]1[CH:40]2[O:41][CH2:42][CH2:43][CH:39]2[CH:38]([O:44][C:45](=[O:46])[NH:28][CH:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]([OH:27])[CH2:11][N:12]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:37]1
Reactant: O=C(OC1COC2OCCC12)ON1C(=O)CCC1=O
Reactant: CC(C)CN(CC(O)C([NH3+])Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-benzyl-3-(benzyloxycarbonyl-isobutyl-amino)-2-hydroxy-propyl-ammonium chloride (4) (29.70 g, 72.90 mmol, 1 equiv), triethylamine (22.00 g, 220 mmol, 3 equiv) and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester (19.80 g, 73.00 mmol, 1 equiv) in 120 mL of dichlomethane were stirred at ambient temperature. Due to the incompleteness of the reaction, carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester (5.00 g, 18.43 mmol) was added to the solution. The solution was stirred at room temperature for 24 h. The solution was washed twice with 300 mL of water and once with 300 mL of saturated NaHCO3 solution. The organic layer was dried on MgSO4, filtered, and evaporated to dryness to obtain the desired product as a white solid. (37.04 g, 70.34 mmol, 96.4%). LRMS (ES+): m/z 527 [M+H]+.
Reaction SMILES: [O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([O-:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4].[K+]>O>[O:1]=[C:2]([OH:14])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([C:11]([OH:13])=[O:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: [K+]
Solvent: O
Product: O=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Reaction time: 4 h

Procedure:
Monopotassium D-glucarate (30.0 g, 120.87 mmol) was spooned into a 2 L Erlenmeyer flask containing deionized water (300.0 mL) and mixed well. Dowex 50WX8 ion-exchange resin (H+ form, 72.0 mL, 2.1 meq/mL) was washed with deionized water until the aqueous wash was colorless. The resin was added to the Erlenmeyer flask and the mixture stirred for 4 h. The resin was removed by filtration, washed with deionized water and stored for regeneration. The filtrate was concentrated to a syrup using a freeze dryer (20.8 g, 108.28 mmol, 89.6%, calculated as 100% D-glucaric acid) and, without further purification, redissolved in deionized water to give a D-glucaric acid (1) aqueous solution (ca. 1 M, 108.3 mL).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CN(C=O)C.[OH-].[Na+].[CH2:19]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH:27]1[CH2:32]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOC(C)=O>[CH2:19]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH:27]1[CH2:32][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCC1COCCN1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1COCCN1Cc1ccccc1)C(=O)OCC
Temperature: 80 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
Diethyl malonate (1.78 g, 11.1 mmol), DMF (25 mL), sodium hydroxide (0.22 g, 5.55 mmol) and 4-benzyl-3-(bromomethyl)morpholine (1 g, 3.7 mmol) (The compound was synthesized according to the procedure as described in Helvetica Chimica Acta, 87, 2004) were added to a dried flask in turn. The mixture was stirred at 80° C. for 4 hours under N2, and cooled to 25° C. The reaction mixture was diluted with EtOAc (200 mL). The organic layer was washed with brine (100 mL×6), dried over unhydrous Na2SO4. The crude product was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=15/1) to give the title compound as colorless oil (1.15 g, 89%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH:38]=[CH2:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.B(Cl)(Cl)Cl>ClCCl>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH:38]=[CH2:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(N)ncnc21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C=C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 34.8 %

Procedure:
To a solution of the compound from Step C (60 mg) in dichloromethane at −78° C. was added boron trichloride (1M in dichloromethane) dropwise. The mixture was stirred at −78° C. for 2.5 h, then at −30° C. to −20° C. for 3 h. The reaction was quenched by addition of methanol/dichloromethane (1:1) and the resulting mixture stirred at −15° C. for 0.5 h, then neutralized with aqueous ammonia at 0° C. and stirred at room temperature for 15 min. The solid was filtered and washed with methanol/dichloromethane (1:1). The combined filtrate was evaporated and the residue purified by flash chromatography (SiO2, 10% methanol in EtOAc containing 0.1% triethylamine). The fractions containing the product were evaporated to give the title compound as a white solid (10 mg).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][C@@:7]([OH:12])([CH3:11])[C:8](O)=[O:9].[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[C:23]([F:26])([F:25])[F:24])([O-:15])=[O:14]>CC(N(C)C)=O>[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:8](=[O:9])[C@:7]([OH:12])([CH3:11])[CH2:6][Br:5])=[CH:18][C:17]=1[C:23]([F:24])([F:25])[F:26])([O-:15])=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: C[C@](O)(CBr)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: C[C@](O)(CBr)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 80.8 %

Procedure:
Thionyl chloride (8.6 g, 72 mmol) was added dropwise under argon to a solution of bromoacid R-131 (11.0 g, 60 mmol) in 70 mL of DMA at −5 to −10° C. The resulting mixture was stirred for 2 h under the same conditions. A solution of 4-nitro-3-trifluoromethyl-aniline (12.4 g, 60 mmol) in 80 mL of DMA was added dropwise to the above solution, and the resulting mixture was stirred overnight at room temperature. The solvent was removed on Rotavapor using high vacuum oil pump; the residue was diluted with saturated NaHCO3 solution, and extracted with ethyl ether (100 mL×3). Combined extracts were dried over anhydrous Na2SO4, filtered through Celite, and purified by flash chromatography on silica gel, using methylene chloride as eluent to afford 18.0 g (80%) of the desired compound: mp 98-100° C. (Rf=0.2, silica gel, CH2Cl2); 1H NMR (300 MHz, DMSO-d6) δ 10.54 (s, 1H, NH), 8.54 (d, J=2.1 Hz, 1H, ArH), 8.34 (dd, J=9.0 Hz, J=2.1 Hz, 1H, ArH), 8.18 (d, J=9.0 Hz, 1H, ArH), 6,37 (s, 1H, OH), 3.82 (d, J=10.4 Hz, 1H, CHHam,) 3.58 (d, J=10.4 Hz, 1H, CHHb), 1.48 (s, 3H, Me); 13C NMR (75 MHz, DMSO-d6) δ 173.6 (C═O), 143.0, 127.2, 123.2, 122.6 (q, J=33.0 Hz), 122.0 (q, J=271.5 Hz), 118.3 (q, J=6.0 Hz), 74.4, 41.4, 24.9; IR (KBr) 3344 (OH), 1680 (C═O), 1599, 1548 (C═C, Ar), 1427, 1363, 1161 cm−1; MS (ESI): m/z 370.8 (M)+; Anal. Calcd. for C11H10BrN2O4: C 35.60, H 2.72, N 7.55. Found: C 35.68, H 2.72, N 7.49.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[S:8][C:4]=2[CH:3]=1.Cl.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C:9]3[N:34]([C:31]4[CH:30]=[CH:29][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:33][CH:32]=4)[N:35]=[C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(C(=O)CC(=O)C(F)(F)C(F)(F)F)sc2c1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2nc(-c3cc(C(F)(F)C(F)(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)sc2c1
Yield: 45 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-methylbenzothiazol-2-yl)-4,4,5,5,5-pentafluoropentane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-methyl-2-[1-(4-methylsulfonylphenyl)-3-pentafluoroethyl-1H-pyrazol-5-yl]benzothiazole (yield, 45%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1>C(O)(=O)C>[CH3:15][C:11]1[CH:10]=[C:9]([NH:8][C:5](=[O:7])[CH3:6])[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(C)c1
Yield: 96.9 %

Procedure:
To a stirred solution of 11.2 grams (g) (0.11 mole) of acetic anhydride in 100 milliliters (mL) of acetic acid, was added 10.7 g (0.1 mole) of m-toluidine. The solution exothermed to 35° C. and, ten minutes (min) after all the m-toluidine was added, the product solution was concentrated in vacuo. The residue was taken up in EtOAc and was washed with H2O. The organic layer was dried over MgSO4 and concentrated in vacuo to give 14.46 g (97%) of product as a white powder (m.p. 65°-66° C). 1H NMR (CDCl3) 8:9.2 (1H, s, NH), 7.2 (2H, d, 8 Hz, aromatic), 7.0 (1H, t, 8 Hz, aromatic), 6.7 (1H, d, 8.0 Hz, aromatic).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[N:15]=[C:14]([CH:17]([CH3:19])[CH3:18])[NH:13][C:12]=3[CH:11]=[C:10]([C:20]([O:22][CH3:23])=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[C:24](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[N:15]=[C:14]([CH:17]([CH3:19])[CH3:18])[N:13]([CH3:24])[C:12]=3[CH:11]=[C:10]([C:20]([O:22][CH3:23])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(-c2ccc(F)cc2)c2nc(C(C)C)[nH]c2c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(-c2ccc(F)cc2)c2nc(C(C)C)n(C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To a solution of methyl 4-(4-fluorophenyl)-2-isopropyl-1H-benzimidazole-6-carboxylate (10.0 mg, 32.0 μmol) and cesium carbonate (26.1 mg, 80.0 μmol) in N,N-dimethylformamide (64 μL) was added iodomethane (3.0 μL, 48.0 μmol). The mixture was stirred at ambient temperature for 15 min. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (6.4 mg): LC-MS [M+1]=327.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].Br[C:9]1[N:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH:30]4[CH2:32][CH2:31]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1>>[CH:30]1([C:26]2[CH:27]=[C:28]([CH3:29])[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][C:2]5=[O:7])=[N:14][CH:13]=4)=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=2)[CH2:31][CH2:32]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: O=C1CCCCN1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCCC3=O)nc2)CC1
Yield: 38.3 %

Procedure:
Using piperidin-2-one (14 mg) and (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (50 mg) described in Preparation Example 144 and by the reaction and treatment in the same manner as in Example 1, the title compound (20 mg) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:25])(=[O:24])[N:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].O[Li].O>O1CCOCC1.O>[C:20]([N:18]([CH3:19])[S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1)(=[O:25])=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(-c2ccc(S(=O)(=O)N(C)C(C)(C)C)cc2)cc1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Procedure T′: A 15 mL dioxane/H2O (2:1) mixture of 4′-(tert-butyl-methyl-sulfamoyl)-biphenyl-4-carboxylic acid methyl ester (318 mg, 0.88 mmol) and LiOH—H2O (46 mg, 1.1 mmol) is stirred at room temperature overnight. The reaction mixture is concentrated, is diluted with EtOAc, shaken with 1 NHCl, and the layers are separated. The 1 N HCl layer is extracted with EtOAc and the combined organic layers are washed with brine, then dried over Na2SO4 and evaporated to give the intermediate 4′-(tert-butyl-methyl-sulfamoyl)-biphenyl-4-carboxylic acid (270 mg, 88% yield). MS (ES−) 346.1 (M−H)−
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[N:8]=[C:7]3[C:14]2[N:15]=[C:16]3[C:22]([C:23](O)=[O:24])=[CH:21][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:17]3=[N:18][CH:19]=2)[CH2:3][CH2:2]1.Cl.[CH3:35][O:36][CH2:37][C@@H:38]([NH2:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:35][O:36][CH2:37][C@@H:38]([NH:40][C:23]([C:22]1[C:16]2[C:17](=[N:18][CH:19]=[C:14]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[CH:5]=4)[N:9]([CH3:13])[N:8]=3)[N:15]=2)[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[CH:21]=1)=[O:24])[CH3:39]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(C3CC3)ccc21
Reactant: COC[C@H](C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C5CC5)cc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(5-cyclopropyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (70 mg, 0.15 mmol), (S)-1-methoxypropan-2-amine hydrochloride (21 mg, 0.16 mmol), and HATU (63 mg, 0.16 mmol). Then added acetonitrile (2 mL) followed by N,N-diisopropylethylamine (0.08 mL, 0.45 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography over silica gel (gradient: 15% to 100% EtOAc in heptane) to afford 34 mg (42%) of 2-(5-cyclopropyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as a white solid.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:13])[CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[CH:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1>CN(C=O)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][CH:4]1[O:3][B:2]([OH:1])[C:6]2[CH:7]=[C:8]([O:13][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[CH:9]=[C:10]([O:11][CH3:12])[C:5]1=2)[CH3:19]
Reactant: Clc1cnccn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(OC)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(OC)c21
Temperature: 90 °C
Yield: 81 %

Procedure:
A mixture of ethyl 2-(1,6-dihydroxy-4-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.15 g, 0.56 mmol), cesium carbonate (0.37 g, 1.12 mmol) and 2-chloropyrazine (96 mg, 0.84 mmol) in DMF (2 mL) was heated to 90° C. for 3 hr. The reaction mixture was quenched by saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (15 mL×2). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/2) on silica gel to give the title compound as a light yellow solid (156 mg, Y: 81.2%). MS (ESI) m/z=345 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])[N:8]=[C:5]2[S:6][CH:7]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]2[N:4]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N+:17]([O-:19])=[O:18])[N:8]=[C:5]3[S:6][CH:7]=2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccccc1-c1cn2c(CCl)csc2n1
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2csc3nc(-c4ccccc4[N+](=O)[O-])cn23)CC1
Temperature: 110 °C

Procedure:
Displacement: 3-Chloromethyl-6-(2-nitro-phenyl)-imidazo[2,1-b]thiazole (126 mg, 0.300 mmol) in 2 ml of 1-methyl-piperazine was microwave heated at 110° C. for 30 minutes. The reaction mixture was concentrated to dryness, and chased with methanol to obtain crude 3-(4-Methyl-piperazin-1-ylmethyl)-6-(2-nitro-phenyl)-imidazo[2,1-b]thiazole.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[ClH:11].[Cl:12][CH2:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([S:22][CH2:23][CH2:24][CH2:25][Cl:26])[CH:17]=[CH:16][N:15]=1>C(O)(C)C.O>[ClH:12].[ClH:11].[Cl:26][CH2:25][CH2:24][CH2:23][S:22][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:19]=1[O:20][CH3:21]
Reactant: COc1c(SCCCCl)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Yield: 67 %

Procedure:
2-Mercapto-1 H-benzimidazole (10 g) and 2-chloromethyl-4-(3-chloropropylthio)-3-methoxypyridine hydrochloride (1 equivalent) are stirred at 80° C. for 5 h in 150 ml of isopropanol and 15 ml of water, the mixture is cooled, and precipitated solid is filtered off and recrystallized from isopropanol/water. The title compound is obtained as a light brown powder; m.p. 117°-119° C. (dec.); yield: 67% of theory.
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([CH2:20][CH3:21])([OH:19])[CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])C.O.[OH-].[Na+].Cl>O1CCOCC1>[CH2:12]([CH:6]([C:7]([OH:9])=[O:8])[C:5]([CH2:20][CH3:21])([OH:19])[C:4]([OH:22])=[O:3])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(O)(CC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(O)(C(=O)O)C(Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
The 3-Benzyl-2-ethyl-2-hydroxysuccinic acid diethyl ester thus obtained was dissolved in 1,4-dioxane (5 mL), added with water (5 mL) and 5 M sodium hydroxide aqueous solution (15 mL), and stirred at 100° C. for 15 h. The reaction mixture was cooled to room temperature, adjusted to pH 1 with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer having been washed with 1 M hydrochloric acid and brine was dried over anhydrous magnesium sulfate and then filtered. The organic layer was concentrated under reduced pressure to give 1.0 g (quantitative) of 3-benzyl-2-ethyl-2-hydroxysuccinic acid as a solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:27])=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:36][N:35]=[N:34][N:24]=4)=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:27])=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(OCC#N)cc3)c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(OCc4nnn[nH]4)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1-benzyl-3-methyl-2-phenyl-1H-indol-4-yl)-phenoxy]-acetonitrile (0.270 g, 0.630 mmol) was reacted with NaN3 (0.205 g, 3.150 mmol) and NH4Cl (0.168 g, 3.150 mmol) in DMF (5 ml) to give the product (0.211 g, 0.447 mmol, 71%) as a white solid, mp 174-177° C. 1H NMR (DMSO-d6) δ 1.71 (s, 3H), 5.30 (s, 2H), 5.52 (s, 2H), 6.84 (d, J=7.0 Hz, 1H), 6.88 (d, J=7.0 Hz, 2H), 7.10-7.13 (m, 3H), 7.16 (t, J=7.0 Hz, 1H), 7.22 (t, J=7.0 Hz, 2H), 7.32-7.35 (m, 3H), 7.37-7.47 (m, 5H); IR (solid) 3020, 2910, 2860, 1605, 1510, 1480, 1440 and 1230 cm−1; [ESI(−)], m/z 470 (M−H)−; Anal. Calcd. for C30H25N5O: C, 76.41; H, 5.34; N, 14.85; Found: C, 76.42; H, 5.21; N, 14.95.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]([NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([S:17](Cl)(=O)=O)=[CH:16][C:10]=2[N:9]=1)=[O:6].[CH3:21][CH2:22][CH2:23]Br>[Fe]>[CH3:3][O:4][C:5]([NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([S:17][CH2:21][CH2:22][CH3:23])=[CH:16][C:10]=2[N:9]=1)=[O:6]
Reactant: CCCBr
Reactant: COC(=O)Nc1nc2cc(S(=O)(=O)Cl)ccc2[nH]1
Agent: [Fe]
Agent: Cl
Product: CCCSc1ccc2[nH]c(NC(=O)OC)nc2c1
Reaction time: 1 h

Procedure:
Into 100 ml. of a 10% aqueous hydrochloric acid solution 1.5 g. of Sn powder are added at 0° to 10° C., followed by the addition of 10.8 g. (0.033 moles) of 2-[(methoxycarbonyl)amino]-1H-benzimidazol-5-sulfonic acid chloride hydrochloride. The reaction mixture is stirred at the same temperature for one hour. Thereafter 10 g. of Fe powder are added and it is stirred at 25° to 30° C. for 6 hours. The metals are dissolved and 2-[(methoxycarbonyl)amino]-1H-benzimidazole-5-thiol precipitates. The precipitate is filtered off, dissolved in a 10% aqueous potassium hydroxide solution and is subsequently reacted with 6 ml. of n-propyl bromide at 40° to 45° C.
Reaction SMILES: [CH:1]12[C:7](=[O:8])[O:6][C:4](=O)[CH:2]1[CH2:3]2.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([CH2:15][NH:16][NH2:17])=[CH:13][CH:12]=1>C(#N)C>[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([CH2:15][N:16]2[NH:17][C:4](=[O:6])[CH:2]3[CH:1]([CH2:3]3)[C:7]2=[O:8])=[CH:13][CH:12]=1
Reactant: COc1ccc(CNN)cc1
Reactant: O=C1OC(=O)C2CC12
Solvent: CC#N
Product: COc1ccc(CN2NC(=O)C3CC3C2=O)cc1
Temperature: 25 °C

Procedure:
1.0 g (8.92 mmol) 1,2-cyclopropanedicarboxylic acid anhydride is dissolved in 5 ml acetonitrile, 1.5 g (9.86 mmol) 4-methoxy-benzyl-hydrazine dissolved in 5 ml acetonitrile are added dropwise and the mixture is refluxed overnight. During cooling to RT a precipitate is formed, which is filtered off, washed with acetonitrile and dried in the vacuum dryer at 50° C.
Reaction SMILES: C(OC(C1C=CC=CC=1O[C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[NH:39]1[CH2:46][CH2:45][CH2:44][C@@H:40]1[C:41]([NH2:43])=[O:42]>>[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][C:23]2[C:9]([N:39]3[CH2:46][CH2:45][CH2:44][C@@H:40]3[C:41]([NH2:43])=[O:42])=[CH:10][C:11]3[NH:15][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:13][C:12]=3[CH:22]=2)=[CH:26][CH:27]=1)(=[O:32])=[O:33]
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: NC(=O)[C@H]1CCCN1
Product: CS(=O)(=O)c1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2N2CCC[C@@H]2C(N)=O)cc1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 15 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14, and D-prolinamide.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:26][CH2:27]1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Reactant: c1ccc(N2CCNCC2)nc1
Product: CC(=O)NC1(c2ccc(CN3CCN(c4ccccn4)CC3)cc2)CC1

Procedure:
By similar reaction and treatment to that in Example 1(5) using N-(1-(4-chloromethylphenyl)cyclopropyl)acetamide obtained in Example 71(1) instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(2-pyridyl)piperazine instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=145-147° C.