Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21](C(O)=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39](N)[CH2:40][CH3:41].[O:43]=[C:44]1[N:48](P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH:17]([C:44](=[O:43])[NH2:48])[N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([CH2:39][CH2:40][CH3:41])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Reactant: CCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (190 mg, 0.345 mmol) was dissolved in 10 mL of dichloromethane, and propylamine (163 mg, 2.76 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (176 mg, 0.69 mmol) and triethylamine (105 mg, 1.04 mmol) were then added to the solution. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-propyl-carbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 44a (70 mg, yield 34.3%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.C(=O)([O-])[O-].[K+].[K+].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C.O>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[CH:6][N:5]2[CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cccc2c1ccn2CCCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c1ccn2CCCN1CCOCC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 1-(3-bromopropyl)-4-nitro-1H-indole (8.18 g, 28.9 mmol) in anhydrous N,N′-dimethylformamide (200 mL) was added grounded potassium carbonate (12 g, 87 mmol) in portions. Then a solution of morpholine (12.6 g, 144.8 mmol) in N,N′-dimethylformamide was added dropwise. The mixture was stirred at 80° C. for 12 hours, diluted with water and extracted with ethyl acetate. The organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, filtrated and evaporated to afford the product 4-(3-(4-nitro-1H-indol-1-yl)propyl)morpholine, which was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]([C:10](OCC)=O)=[C:8]([N+:22]([O-])=O)[CH:7]=1.Cl.[C:26](Cl)(=[O:28])C.C([O-])=O.[NH4+:33]>C(O)C.C(N)=O.O=[Pt]=O.O.O>[CH3:21][O:20][CH2:19][CH2:18][O:17][C:16]1[CH:15]=[C:9]2[C:8](=[CH:7][C:6]=1[O:5][CH2:4][CH2:3][O:2][CH3:1])[NH:22][C:26](=[O:28])[N:33]=[CH:10]2
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Reactant: [NH4+]
Reactant: CC(=O)Cl
Agent: O=[Pt]=O
Agent: Cl
Agent: O=C[O-]
Solvent: NC=O
Solvent: CCO
Solvent: O
Product: COCCOc1cc2cnc(=O)[nH]c2cc1OCCOC
Temperature: 20 °C
Reaction time: 6 h

Procedure:
To ethyl 3,4-dihydroxybenzoate (36.4 g, 0.200 mol), K2CO3 (60.8 g, 0.44 mol) and tetrabutylammonium iodide (750 mg) in degassed acetone (400 mL) was added 2-bromoethyl methyl ether (69.5 g, 47 mL). The mixture was stirred under N2 at reflux for 64 hours. Ether (600 mL) was added to the mixture and after stirring 30 minutes at 20° C. the precipitated salts were removed by filtration. The filtrate was concentrated in vacuo and the residue was triturated with hexane (500 mL) for 30 minutes and the white solid ethyl 3,4-bis(2-methoxy-ethoxy)benzoate was filtered and dried in vacuo (55.5 g; 93%; M.P. 50°-51° C.). A portion of this product (45.7 g, 0.158 mol) in acetic acid (150 mL) was treated dropwise with conc. HNO3 (40 mL) at 5° C. and the solution stirred 24 hours before pouring into cold H2O (1.6 L). The mixture was extracted with ethyl acetate (1.1 L), and the organic phase was washed three times with 200 mL H2O, and brine, dried over Na2SO4, filtered and concentrated in vacuo to afford ethyl 4,5-bis-(2-methoxy-ethoxy)-2-nitro-benzoate (54.3 g) as a brown oil. This nitro product (52.0 g, 0.15 mol) was dissolved in ethanol (1000 mL) containing 1 equivalent of HCl (generated in the ethanol by prior addition of 11 mL acetyl chloride), PtO2.H2O (1.0 g) was added, and the mixture was hydrogenated under 45 psi H2 for 6 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo to a thick slurry which was diluted with ether (400 mL). The solid white hydrochloride salt of ethyl 2-amino-4,5-bis-(2-methoxy-ethoxy)benzoate was filtered and dried in vacuo (44.7 g; 88%). A portion of this material (42 g, 0.12 mol) and ammonium formate (7.6 g, 0.12 mol) were dissolved in formamide (63 mL) and the stirred mixture was heated to 160°-165° C. under an atmosphere of N2 for 3 hours. H2O (200 mL) was added and after cooling the precipitated crude title product was recovered by filtration, washed with cold H2O, and dried in vacuo. The filtrate was extracted five times with CHCl3, and the pooled organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue and crude quinazolone precipitate were combined, triturated in hot acetonitrile (250 mL) for 30 minutes, cooled to 20° C. and treated with ether (250 mL). After cooling to 4° C. the white solid was filtered and dried in vacuo (30.4 g, 86%; GC-MS m/z 294 (M+)).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:8]1[N:12]=[CH:11][N:10]([C:13](N2C=NC=C2)=[O:14])[CH:9]=1>O1CCCC1>[N:10]1([C:13]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:14])[CH:9]=[CH:8][N:12]=[CH:11]1
Reactant: CCCCCCO
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCCOC(=O)n1ccnc1
Temperature: 30 °C

Procedure:
A solution of n-hexanol (25.95 g) in tetrahydrofuran (400 ml) was slowly added to solution of N,N-carbonyldiimidazole (48.08 g) in tetrahydrofuran (100 ml) and stirred for 2½ hour at 25-35° C. to provide hexyl 1H-imidazole-1-carboxylate compound of formula-4. 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-6a (100 g), tetrahydrofuran (700 ml), water (800 ml) and potassium carbonate (117 g) were added to the reaction mixture and stirred for 20 hours at 25-30° C. After completion of the reaction, filtered the solid, washed with tetrahydrofuran and then dried to get title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35° C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35° C. to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35° C. to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Further the obtained solid recrystallized from ethyl acetate and ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:19]1([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][NH:29]3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([N:22]4[CH2:23][CH2:24][N:19]([C:25]5[CH:33]=[CH:32][CH:31]=[C:30]6[C:26]=5[CH:27]=[CH:28][NH:29]6)[CH2:20][CH2:21]4)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: O=C1CCN(c2cc(Cl)cc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: Clc1cc(N2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(6-chloro-quinolin-8-yl)-piperidin-4-one (Step 1, 0.13 g) and of 4-piperazino-indole (commercially available, 0.100 g) in 15 mL CH2Cl2 in 10 mL of dichloroethane, was added 0.137 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 100% Ethyl acetate, to give 0.070 g of the desired product. Mp: 224° C.; MS (ES) m/z (relative intensity): 447 (M++−H, 100).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].O.[OH-].[Na+].S(OC)(O[CH3:21])(=O)=O>C(Cl)Cl>[CH3:21][O:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5]
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CON=C(C(C)=O)C(=O)OC(C)(C)C
Yield: 93.3 %

Procedure:
To the tert-butyl 2-hydroxyimino-3-oxobutyrate was added water [6], to which was added 30% sodium hydroxide [800 ml] at 28° C. while stirring to render the pH to 9.0. To the resultant solution was added dimethyl sulfate [1324 g] at 28° to 30° C. in the course of 20 minutes, which was stirred for 4 hours while adding thereto at 25° to 30° C. a 30% aqueous solution of sodium hydroxide [500 ml] to adjust the pH within the range of 8.7 to 9.0. After completion of the reaction, extraction was conducted with methylene chloride [4 l], and the aqueous layer was subjected to further extraction with methylene chloride [2 l]. The methylene chloride layers were combined and washed with a 1N aqueous solution of sodium hydroxide, 1N HCl, a 5% aqueous solution of sodium hydrogencarbonate and water, each one litre portion, successively. The resultant solution was dried over anhydrous sodium sulfate [700 g], followed by concentration under reduced pressure to obtain tert-butyl 2-methoxyimino-3-oxobutyrate [1878 g] as an oily product. The yield was 93.3%. NMR(CDCl3): δ4.08 (3H,s), 2.36(3H,s), 1.53(9H,s)ppm .
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:25]=[CH:24][C:23]2[CH:22]3[CH2:26][C:15]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]4)([C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=2[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:25]=[CH:24][C:23]2[CH:22]3[CH2:26][C:15]([CH2:27][N:28]4[CH2:29][CH2:30][C:31](=[O:34])[CH2:32][CH2:33]4)([C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=2[CH:13]=1
Reactant: OC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (3.06 mL, 35.1 mmol, 2 eq) in methylene chloride (100 mL) under nitrogen was added distilled dimethylsulfoxide (5.00 mL, 70.2 mmol, 4 eq). After 10 min 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidin-4-ol (described in example 1l) (5.96 g, 17.5 mmol) was added as a methylene chloride solution (10 mL). The reaction was stirred at -78° C. for 30 min prior to the addition of triethylamine (19.6 mL, 140 mmol, 8 eq). The cooling bath was removed and the reaction warmed to room temperature over 1.5 h. The reaction was poured into 2.5N NaOH (100 mL) and the aqueous phase extracted with methylene chloride (3×100 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The crude reaction mixture was purified by flash chromatography over silica gel (400 mL, eluent: 20% ethyl acetate in hexane) to yield 5.53 g (93%) of the title compound. TLC analysis (Rf 0.21, 20% ethyl acetate in hexane). 1H NMR (CDCl3, 250 MHz) 7.26 (m, 1H), 7.13 (m, 3H), 6.95 (m, 3H), 4.28 (s, 1H), 3.49 (s, 2H), 2.94 (t, J=6.1Hz, 4H), 2.62 (s, 2H), 2.43 (t, J=6.0 Hz, 4H) MS (CI, CH4) m/z 338 (M+1,100), 340 (35), 366 (M+29,31)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:17][O:18][CH:19]([O:30][CH3:31])[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22](F)[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C.O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([NH:1][C:22]3[CH:21]=[C:20]([CH:19]([O:30][CH3:31])[O:18][CH3:17])[CH:25]=[CH:24][C:23]=3[N+:26]([O-:28])=[O:27])[S:3][C:4]=2[C:14]([NH2:16])=[O:15])=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(N)nc1-c1ccc(Cl)cc1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3ccc(Cl)cc3)c(C(N)=O)s2)c1
Yield: 34.9 %

Procedure:
A mixture of 0.89 g (3.51 mmole) of 2-amino-4-(4-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.18), 0.91 g (4.21 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitrobenzene, 5.70 g (17.55 mmole) of cesium carbonate (5.70 g, 17.55 mmole) and 10 mL of dimethylformamide was heated at 70 degrees for 2 days. The reaction mixture was diluted with ethyl acetate and water. The precipitate was collected by filtration, washed with water and dried under vacuum to give 0.55 g of 4-(4-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.19a).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:11]([CH3:24])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([F:23])[CH:18]=[C:19]([F:22])[CH:20]=2)[NH:15][CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:33]>CN(C)C=O>[CH2:25]([N:10]([CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C@H:11]([CH3:24])[CH2:12][C:13]1[C:21]2[C:16](=[C:17]([F:23])[CH:18]=[C:19]([F:22])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CI
Reactant: C[C@H](Cc1c[nH]c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Cc1cn(C)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
NaH (180 mg of 60% oil dispersion, 4.5 mmol) is added to a solution of dibenzyl-[2-(5,7-difluoro-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine (1.4 g, 3.6 mmol) in 20 ml dimethylformamide under N2 at 0° C. The resulting mixture is stirred for 20 minutes, then is allowed to warm to room temperature over 20 minutes. A 5 ml solution of iodomethane in dimethylformamide (7.2 mmol) is added dropwise and the reaction mixture is stirred for 1 hour. The reaction is quenched with cold aqueous NaHCO3, xtracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated and is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 1.3 g of dibenzyl-[2-(5,7-difluoro-1-methyl-1H-indol-3-yl)-1(R)-methyl-ethyl]-amine (89%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:16])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (1.005 g) and N-hydroxy-benzotriazole (HOBt)(0.642 g) in DMF (30 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(2.76 g) and triethylamine (2.005 ml). The mixture is stirred for 1 h at ambient temperature. This solution is added at 0° C. slowly to a solution of 1,4-diaminobenzene (0.43 g) and triethylamine (0.45 ml) in DMF (5 ml). After completion of the chemical reaction the mixture is evaporated at high vacuum and the residue is partitioned between ethyl acetate and an aqueous saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and the crude product is purified by silica gel flash chromatography. A colorless solid (0.735 g) is obtained in 55% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)[CH:14]=[CH:13][N:12]=1>CN(C=O)C.[H-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:11]2[N:16]=[C:15]([C:17]3[CH:29]=[CH:28][C:20]4[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=4[CH:18]=3)[CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: COc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2nccc(-c3ccc4nc(NC(C)=O)sc4c3)n2)cc1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 37.2 %

Procedure:
4-Methoxythiophenol (0.168 ml, 1.36 mmol) was dissolved in DMF (1.0 mL) and NaH (60% in mineral oil), 66.8 mg, 1.67 mmol) was added. The reaction was stirred under nitrogen at RT for 65 minutes, then N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (48.0 mg, 158 μmol) was added, and the reaction solution was stirred overnight under nitrogen at RT and quenched with water. The suspension was filtered, and the solid was washed with water, MeOH, and Et2O, then collected. The layers of the biphasic filtrate were separated, and the aqueous phase was extracted with 10:1 DCM/MeOH (2×25 mL; 10 mL; 2×25 mL). Organic extracts were combined with the solid, concentrated, and purified on HPLC (10% to 95% MeCN/water with 0.1% TFA over 30 minutes) to afford N-(6-(2-(4-methoxyphenylthio)pyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (24 mg, 38% yield). MS (ESI pos. ion) m/z: 409. Calculated exact mass for C20H16N4O2S2: 408. 1H NMR (400 MHz, DMSO-d6): 12.52 (s, 1H), 8.65 (s, 1H), 8.61 (d, J=8.5 Hz, 1H), 7.80 (m, 2H), 7.58 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 4.85 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:21][C:5]2[S:6][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[C:3]1=[O:22].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[CH3:1][CH:2]1[CH2:21][C:5]2[S:6][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:3]1[OH:22]
Reactant: CC1Cc2sc(-c3ccccc3)c(-c3ccccc3)c2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1Cc2sc(-c3ccccc3)c(-c3ccccc3)c2C1O
Reaction time: 8 h

Procedure:
A solution of 5-methyl-2,3-diphenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-4-one (6.08 g, 20 mmol) in 75 mL of ether was slowly added to a solution of LiAlH4 (0.38 g, 10 mmol) in 50 mL of ether and stirred overnight. The resulting suspension was poured into a mixture of ice and water, the organic layer was isolated, while the water layer was extracted with ether (3×50 mL). The combined organic layers were washed with water, dried over MgSO4 and evaporated off to dryness. The 5-methyl-2,3-diphenyl-5,6-dihydro-4H-cyclopenta[b]thiophen -4-ol so obtained was dissolved in 100 mL of benzene, added of 1 g of p-toluenesulfonic acid and was refluxed for 10 min. Then the reaction mixture was cooled to room temperature and treated with a saturated aqueous solution of Na2CO3. The organic phase was isolated, dried over MgSO4 and evaporated off to dryness giving the crystallized product. Yield 3.46 g (60% with respect to the starting ketone).
Reaction SMILES: [C:1](O)(=O)[CH3:2].[CH2:5]([NH:7][CH2:8][CH3:9])[CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:18]1([CH2:6][CH2:5][N:7]([CH2:1][CH3:2])[CH2:8][CH3:9])[C:17]2[C:16](=[CH:17][CH:18]=[CH:19][CH:16]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)O
Reactant: CCCCCC
Reactant: CCNCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCN(CC)CCc1cccc2ccccc12

Procedure:
The Pt catalyst solution used in these preparations was a solution of Karsted's catalyst in hexane. The solvents used were spectral grade, dried over molecular sieves. 1-(naphthyl)-2-(diethylamino) ethane was prepared according to methods outlined by Chandross and Thomas in Chem. Phys. Letters 9 393(1971). 1-napthylenyl acetic acid was converted to the acid chloride, reacted with diethylamine to make the corresponding amide and reduced to the corresponding amine using lithium aluminum hydride. Extraction from basic aqueous solution into ether gave the desired product in high yield.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([S:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)=[O:19])=[CH:13][CH:12]=1)[CH2:6]2.[OH:25]OS([O-])=O.[K+].[OH2:31]>CO>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([S:10]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)=[O:19])=[CH:13][CH:12]=1)(=[O:25])=[O:31])[CH2:6]2
Reactant: O=S([O-])OO
Reactant: CN1C2CCC1CC(Sc1ccc(NC(=O)c3ccsc3)cc1)C2
Reactant: O
Agent: [K+]
Solvent: CO
Product: CN1C2CCC1CC(S(=O)(=O)c1ccc(NC(=O)c3ccsc3)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-3-thiophenecarboxamide (130 mg) in methanol (5 ml) was added a solution of Oxone (446 mg) in water. The mixture was stirred at room temperature for 30 minutes and then applied directly to an SCX cartridge. The impure product eluted with methanol and was subjected to further clean up by preparative LC-MS to yield N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)sulfonyl]phenyl]-3-thiophenecarboxamide (75 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[CH2:12][CH2:13][N:7]21.[CH2:25]([Mg]Br)[CH3:26].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCn2c1nc1c(Cl)ccc(C=O)c12
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 8-chloro-1-(2,4-dichloro-6-methylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole-5-carbaldehyde (140 mg, 0.368 mmol) in tetrahydrofuran (30 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.50 mL, 15.0 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hr. Water was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (150 mg).