Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CN(C(O[N:28]1N=N[C:30]2[CH:31]=CC=C[C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)CC>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:28][CH2:29][CH2:30][CH3:31])=[O:7])=[CH:4][C:3]=1[B:11]1[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[O:15]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (524 mg, 2 mmol, 1 eq) was added HBTU (642 mg, 2 mmol, 1 eq) in DMF (5 mL). DIPEA (700 uL, 4 mmol, 2 eq) was then added in 100 uL portions. After 10 min propylamine (328 uL, 4 mmol, 2 eq) was then added and the mixture was stirred overnight at room temperature. The solvent was then removed in vacuo. The residue was then dissolved in chloroform and purified by aminopropyl SPE: LC-MS m/z 304 (M+H)+, 3.37 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:15]([OH:17])=O)[CH2:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:18][C:19]1(C)OC(=O)CC(=O)[O:20]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19](=[O:20])[CH:18]=[C:15]([OH:17])[CH:11]2[CH2:12][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCC[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1C(O)=CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.1 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)norvaline (4.0 g), Meldrum's acid (2.40 g) and 4-(N,N-dimethyl)aminopyridine (2.90 g) in tetrahydrofuran (60 mL) was added N,N′-carbonyldiimidazole (3.08 g) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (60 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate to give the title compound as colorless crystals (yield: 1.89 g, 43%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[Br:10])=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: O=C(O)c1cc2cccc(Br)c2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(Br)c2oc1=O
Temperature: 25 °C

Procedure:
DIEA (35.6 μL, 0.2 mmol) was added to 8-bromo-3-carboxy-coumarin (50 mg, 0.19 mmol) and HATU (77.73 mg, 0.2 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (38.89 mg, 0.19 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to the final product: LCMS (ESI) m/z 461 (MH+).
Reaction SMILES: I[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.C1(P([C:41]2[CH:46]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:25][Si:24]([CH3:27])([CH3:26])[CH2:23][CH2:22][O:21][CH2:20][N:4]1[C:5]2[CH:6]=[N:7][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:9](=[O:11])[C:10]=2[C:2]([C:41]#[C:46][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:3]1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(I)cn2COCC[Si](C)(C)C)c1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 60 °C
Reaction time: 24 h
Yield: 439.2 %

Procedure:
To 50 ml of tetrahydrofuran solution containing 16.6 g (purity: 78.4%, 25.0 mmol) of 3-iodo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 18-(b) were added 880 mg (1.25 mmol) of bis(triphenylphosphine)palladium dichloride, 620 mg (3.25 mmol) of cuprous iodide, 1.31 g (5.00 mmol) of triphenylphosphine and 10.5 ml (75.3 mmol) of triethylamine, and the mixture was degassed under reduced pressure and replaced with argon. Then, 11 ml of trimethylsilylacetylene was added to the mixture, and the mixture was stirred at 60° C. for 24 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1→4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 10.8 g of the title compound as a yellowish solid. (Yield: 88%)
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:32][C:33](=[O:49])[C@@H:34]([NH2:48])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>>[C:39]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:41][C:36]([CH2:35][C@H:34]([NH:48][C:26]([C:15]2[N:16]=[C:17]([CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:18]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[C:10]([O:9][C:8]2[CH:29]=[CH:30][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=2)[CH:19]=3)=[O:27])[C:33]([OH:32])=[O:49])=[CH:37][CH:38]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@@H](Cc4ccc(-c5ccccc5)cc4)C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 93.1 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid was reacted with (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (34.8 mg, 0.13 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 70 mg of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[CH2:3][OH:4].[NH2:7][S:8]([C:11]1[C:12]([Cl:27])=[CH:13][C:14]([NH:20][CH2:21][C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([CH:19]=1)[C:16](O)=[O:17])(=[O:10])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.C1(C)C=CC=CC=1>[NH2:7][S:8]([C:11]1[C:12]([Cl:27])=[CH:13][C:14]([NH:20][CH2:21][C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([CH:19]=1)[C:16]([O:4][CH2:3][C:2]([Cl:6])([Cl:5])[Cl:1])=[O:17])(=[O:9])=[O:10]
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Reactant: OCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1cc(C(=O)OCC(Cl)(Cl)Cl)c(NCc2ccco2)cc1Cl

Procedure:
Benzene (30 mL) (or toluene) and 2,2,2-trichloroethanol (0.024 mole) are added to a round-bottomed flask. Furosemide (10) (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid, Aldrich) (0.025 mole), benzene (30 mL), and p-toluenesulfonic acid (0.001 mole) catalyst are added to the flask. A Dean-Stark trap is filled with benzene, and the contents of the flask are refluxed with stirring for several hours or until no additional water is collected in the trap. The reaction is cooled, extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo to give 2,2,2-trichloroethyl 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoate. See Sandler et al., Organic Functional Group Preparations, (1968) p. 249.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].Br.Br.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][CH:26]2[CH2:27][CH2:28][N:29]([CH2:2][C:3](=[O:5])[CH3:4])[CH2:30][CH2:31]2)=[CH:11][CH:10]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: CC(=O)CCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 50 °C
Yield: 39.5 %

Procedure:
A mixture of 9.25 parts of 1-chloro-2-propanone, 48.6 parts of 1-(4-fluorophenylmethyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine dihydrobromide, 32 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 50° C. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 15 parts (39.5%) of 1-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]-2-propanone (intermediate 130).
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[S:7][C:8]([C:11]([NH2:13])=[NH:12])=[CH:9][N:10]=1.[Cl:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=O.C([O-])(=O)C.[Na+]>C(O)C>[CH3:5][C:6]1[S:7][C:8]([C:11]2[NH:13][C:26]([CH3:28])=[C:25]([C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:17]([C:16]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:15]=3[Cl:14])[N:12]=2)=[CH:9][N:10]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: Cc1ncc(C(=N)N)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(c2cnc(C)s2)=NC1c1ccc(F)cc1Cl
Yield: 30.5 %

Procedure:
2 mmol 2-Methylthiazol-5-formamidine acetate, 2 mmol 2-chloro-4-fluorobenzaldehyde, 2 mmol ethyl acetoacetate and 2.2 mmol sodium acetate were reacted under reflux in 10 ml anhydrous ethanol for 20 hr, concentrated, and then ethyl acetate and water were added to separate the layers. The ethyl acetate layer was dried over anhydrous sodium sulfate, and separated by a column chromatography to obtain 0.24 g of a yellowish solid with mp 107-111° C.; 1H-NMR (400 MHz, DMSO-d6) δ 1.0-1.04 (3H, m); 2.43 (3H, s); 2.59 (3H, s); 3.89-3.93 (2H, m); 5.90 (1H, s); 7.14-7.43 (3H, m); 9.52 (1H, s); MS (EI) 393.0 (M+).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].FC(F)(F)S(O[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:36])[CH:32]=2)[N:27]=1)(=O)=O.CCN(C(C)C)C(C)C.O>CS(C)=O>[F:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([N:15]1[CH2:16][CH2:17][CH:12]([N:5]3[C:6]4=[N:7][CH:8]=[CH:9][N:10]=[C:11]4[C:3]([CH3:19])([CH3:2])[C:4]3=[O:18])[CH2:13][CH2:14]1)[CH:35]=[CH:34]2
Reactant: O=S(=O)(Oc1ccc2cc(F)ccc2n1)C(F)(F)F
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C(=O)N(C2CCN(c3ccc4cc(F)ccc4n3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 50 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.117 g, 0.414 mmol), 6-fluoroquinolin-2-yl trifluoromethanesulfonate (0.134 g, 0.455 mmol), and DIEA (0.253 ml, 1.448 mmol) in DMSO (3 mL) was heated at 110° C. in 1 h. The reaction mixture was cooled, H2O was added, and the mixture was extracted with DCM (3×). The organic extracts were dried over Na2SO4, filtered, concentrated, and purified by ISCO (0-30% EtOAc/DCM) to give the title compound (81 mg, 50%). MS (M+1): 392.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.11-8.13 (1 H, m), 8.08-8.10 (1 H, m), 8.05 (1 H, d, J=9.2 Hz), 7.60 (1 H, dd, J=9.2, 5.3 Hz), 7.52 (1 H, dd, J=9.4, 2.9 Hz), 7.40-7.45 (1 H, m), 7.35-7.40 (1 H, m), 4.71 (2 H, d, J=13.5 Hz), 4.48-4.63 (1 H, m), 3.02 (2 H, t, J=12.1 Hz), 2.36-2.48 (2 H, m), 1.79 (2 H, d, J=9.8 Hz), 1.27-1.36 (6 H, m).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5][C:6]1[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][N:7]=1.NN>C(Cl)Cl>[CH3:1][N:2]([C:12]([NH:11][C:9]1[S:10][C:6]([S:5][CH3:4])=[N:7][N:8]=1)=[O:13])[NH2:3]
Reactant: CSc1nnc(N=C=O)s1
Reactant: CNN
Agent: NN
Solvent: ClCCl
Product: CSc1nnc(NC(=O)N(C)N)s1

Procedure:
A solution of methylhydrazine (0.3 mole) in methylene chloride (150 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 5-Methylthio-1,3,4-thiadiazol-2-yl isocyanate dimer (0.1 mole) is then added, with stirring, at room tempertaure. After the addition is completed the reaction mixture is heated at reflux for a period of about 4 hours. After this time the reaction mixture is stripped of solvent and excess hydrazine to yield the desired product 2-methyl-4-(5-methylthio-1,3,4-thiadiazol-2-yl) semicarbazide as the residue.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[O-:19][CH2:20][CH3:21].[Na+].[Na]>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([O:19][CH2:20][CH3:21])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: CC[O-]
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Yield: 95 %

Procedure:
2-Chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g) was added to an ethanol solution of sodium ethoxide prepared from sodium (0.35 g) and ethanol (15 ml), and stirred under reflux for 30 minutes. The solvent was evaporated, and water was added to the residue, which was then acidified with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-ethoxy-5-oxazolepropionic acid (1.40 g, 95%). This was recrystallized from ethanol to give colorless prisms. mp 148-149° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]1[S:15][N:14]=[C:13]2[CH:16]=[C:17]([CH:20]=O)[CH:18]=[CH:19][C:12]=12.C([O:24][C:25](=O)[C:26](=[O:33])[CH2:27][C:28]([CH:30]1[CH2:32][CH2:31]1)=[O:29])C>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:20]([C:17]4[CH:18]=[CH:19][C:12]5=[N:11][S:15][N:14]=[C:13]5[CH:16]=4)[C:27]([C:28]([CH:30]4[CH2:32][CH2:31]4)=[O:29])=[C:26]([OH:33])[C:25]3=[O:24])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=Cc1ccc2nsnc2c1
Solvent: CCO
Product: O=C(C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc2nsnc2c1)C1CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and Benzo[1,2,5]thiadiazole-5-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 4-Cyclopropyl-2,4-dioxo-butyric acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:18]C(OCC2C=CC=CC=2)=O)([CH:14]([CH3:17])[CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH2:18])([CH:14]([CH3:17])[CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(CO)C1(NC(=O)OCc2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(CO)C1(N)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(2-hydroxy-1-methylethyl)piperidine-1-carboxylic acid tert-butyl ester (21.0 g) in methanol (400 ml) was added 10% palladium carbon (2.1 g), and the mixture was hydrogenated at room temperature under ordinary pressure for 90 minutes. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the titled compound (13.8 g).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Br:22][C:23]1[N:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[Br:22][C:23]1[N:24]=[C:25]([CH2:28][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)[S:26][CH:27]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1nc(Br)cs1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(Br)cs4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (289 mg), (4-bromo-1,3-thiazol-2-yl)methanol (399 mg) and triphenylphosphine (808 mg) in THF (8 ml) was added bis(2-methoxyethyl) azodicarboxylate (722 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (128 mg) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20](F)[N:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2].[NH:25]1[CH2:31][CH:30]([OH:32])[CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[N:19]=[C:20]([N:25]5[CH2:31][CH:30]([OH:32])[CH2:29][NH:28][CH2:27][CH2:26]5)[CH:21]=[CH:22][CH:23]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Reactant: OC1CNCCNC1
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCNCC(O)C3)n2)c1
Yield: 12 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 6-(5-ethylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepan-6-ol, 106 was obtained as an off-white solid (49.4 mg, 12%). MS (ESI) m/z: 416.1 [M+H]+
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1CC)=[NH:12])C.[O-]CC.[Na+].C([O:27][CH:28]=[C:29]([C:35](OCC)=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])C>CO>[CH:1]1([N:7]2[C:28](=[O:27])[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][N:12]=[C:11]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=N)c1ccccc1CC
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1cnc(-c2ccccc2)n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
Cyclohexylamine (0.58 g, 5.8 mmol) was added to a solution of ethyl benzenecarboximidic acid ethyl ester (1.0 g, 5.4 mmol) in methanol (10 mL), which was then stirred at room temperature for 16 h. The reaction mixture was then concentrated under reduced pressure and then redissolved in ethanol (10 mL). Sodium ethoxide solution (21% w/w in ethanol, 1.8 g, 5.5 mmol) and diethyl ethoxymethylenemalonate (1.2 g, 5.5 mmol) were added and the mixture was heated to reflux for 16 h before being concentrated under reduced pressure and purified by medium pressure liquid chromatography on silica gel eluting with 0 to 100% ethyl acetate in hexanes to provide 1.41 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[O:16]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23](Cl)=O)=[CH:17]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51]>C(OCC)(=O)C>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[O:16]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:5]3[CH:13]=[CH:14][C:2]([CH3:1])=[CH:3][C:4]=3[N:15]=2)=[CH:17]1
Reactant: Cc1ccc(Nc2ccccn2)c(N)c1
Reactant: O=C(Cl)/C=C/c1ccoc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)nc(/C=C/c1ccoc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methyl-2-amino-N-(2-pyridyl)aniline and (E)-3-(3-furyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate-hexane yielded the titled compound. MW: 391.38; mp: 197.0-198.0° C.; 1H-NMR (DMSO) δ: 8.78-8.74 (1H, m), 8.16 (1H, td, J=7.7, 2.2 Hz), 8.05 (1H, br.s), 7.77 (1H, d, J=15.8 Hz), 7.70-7.67 (2H, m), 7.65-7.59 (1H, m), 7.51 (1H, br.s), 7.32 (1H, d, J=8.4 Hz), 7.10-7.06 (1H, m), 6.89 (1H, d, J=15.8 Hz), 6.81 (1H, br.s), 2.44 (3H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[C:25]1([C:31]2[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[C:25]1([C:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: C1=C(c2ccccc2)CCNC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CC=C(c2ccccc2)CC1
Temperature: 20 °C
Yield: 26.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.5 g), triethylamine (3.4 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (3.9 g) in toluene (150 cc). The mixture is heated for 9 hours at boiling point, then cooled to a temperature of about 20° C. After purification 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 recrystallization from boiling acetonitrile (10 cc), 2-[2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (2.5 g) is obtained, m.p. 106° C.