Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH3:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=2[NH:14][C:13]1=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N+:18]([O-:34])=[C:17]([CH3:19])[C:16]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:15]=2[NH:14][C:13]1=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1=[N+]([O-])C(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Yield: 76.8 %

Procedure:
To a suspension of (3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (3.22 g) in methylene chloride (50 ml) was added m-chloroperbenzoic acid (2.50 g, 1.5 eq. mol) portionwise under stirring at ice-bath cooling. The mixture was stirred for 3 days at ambient temperatures. From the reaction mixture methylene chloride was removed in vacuo and to the residue was added an aqueous solution of sodium bicarbonate and stirred for several minutes. The mixture was extracted with ethyl acetate twice and the combined extract was washed with aqueous sodium bicarbonate, water twice and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford an amorphous mass, which was triturated in methanol and collected by filtration to give (3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one-4-oxide (2.59 g) as a crystalline powder. From the mother liquid, the second crop (0.25 g) of the desired powder was prepared by crystallization in a mixture of methanol and diisopropyl ether (3:1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23](I)[CH:22]=2)=[O:18].C([O-])(=O)C.[K+].Br[C:45]1[CH:50]=[CH:49][N:48]=[N:47][CH:46]=1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.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.O1CCOCC1.ClCCl.CO.CS(C)=O>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([C:45]1[CH:50]=[CH:49][N:48]=[N:47][CH:46]=1)[CH:22]=2)=[O:18]
Reactant: Brc1ccnnc1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(I)cc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(-c4ccnnc4)cc32)cc1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
A mixture of [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-iodo-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (194.9 mg, 0.306 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium (II)/dichloromethane adduct (14.4 mg, 0.015 mmol) bis(pinacol)diborane (100.9 mg, 0.397 mmol), potassium acetate (132.3 mg, 1.35 mmol), and anhydrous dimethylsulfoxide (DMSO) (1.5 ml) was deaerated. Then, the air was replaced three times with argon, and was heated and stirred at 110° C. for six hours. Then, the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (dichloromethane/methanol=15/1). The resulting crude product was mixed with 4-bromo-pyridazine (78.0 mg, 0.491 mol), dichlorobis(triphenylphosphine)palladium (II) (17.2 mg, 0.025 mmol), an aqueous solution of 2 M sodium bicarbonate (0.325 mmol), and dioxane (0.4 ml). After deaeration, the air was replaced three times with argon, and this was microwaved at 150° C. for five minutes. Then, the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (dichloromethane/methanol=1% to 12%). Thus, [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-pyridazin-4-yl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone was obtained as a pale yellow amorphous material (20.0 mg, yield of 11%).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:2]=1.[N:19]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C(O)=O)[C:27]2C=CN=CC=2N=C1.N1(CC2C=CC(C(O)=O)=CC=2)C2C=CN=CC=2N=C1.[K]>>[CH:28]1([N:19]([CH3:27])[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:3]2[C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[N:1]=[CH:2]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)CCCCCCn1cnc2cnccc21
Reactant: O=C(O)CCCCCCn1cnc2ccncc21
Agent: O=C(O)c1ccc(Cn2cnc3cnccc32)cc1
Agent: [K]
Product: CN(C(=O)CCCCCCn1cnc2ccncc21)C1CCCCC1

Procedure:
Utilizing the procedure described in Example 5(b) employing a mixture of 7-(3H-imidazo[4,5-c]pyridin-3-yl)heptanoic acid and 7-(1H-imidazo[4,5-c]pyridin-1-yl)heptanoic acid, potassium salts in lieu of 4-(1H-imidazo[4,5-c]pyridin-1-ylmethyl) benzoic acid, potassium salt yielded an impure mixture of isomers. The mixture was purified by column chromatography (silica gel, 5% ethanol in chloroform) to yield a less polar isomer N-cyclohexyl-N-methyl-7-(3H-imidazo[4,5-c]pyridin-3-yl)heptanamide as a pale-yellow oil, having the following physical characteristics:
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCCc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
To a 0° C. solution of 4-propylbenzoic acid (2 g, 12.18 mmol) in methanol (3.00 mL) and dichloromethane (10 mL) was added trimethylsilyldiazomethane (7.92 mL, 15.83 mmol), dropwise over a period of 5 min. Towards the end of the addition, the reaction mixture was pale yellow. The reaction was stirred at 0° C. for 30 min. and the excess diazo reagent was quenched by the slow addition of acetic acid at 0° C. (˜1.5 mL). The colorless solution was concentrated and partitioned between ether (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ether layer was washed with brine (10 mL), dried over sodium sulfate and concentrated to yield methyl 4-propylbenzoate (2.1 g, 11.78 mmol, 97% yield) as a liquid. 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (d, J=8.28 Hz, 2H) 7.24 (d, J=8.53 Hz, 2H) 3.90 (s, 3H) 2.61-2.67 (m, 2H) 1.59-1.71 (m, 1H) 0.94 (t, J=7.40 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][NH:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:32]4[CH:31]=[C:30]([S:27]([NH:26][CH3:25])(=[O:28])=[O:29])[CH:35]=[CH:34][CH:33]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 23.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(N-methylsulfamoyl)phenylboronic acid (23 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N-methylbenzenesulfonamide (5.88 mg, 24%). 1H-NMR (MeOD): 2.16 (m, 1H), 2.22 (m, 1H), 2.41 (m, 3H), 3.15 (m, 3H), 5.21 (m, 0.2H), 5.83 (m, 0.8H), 6.98 (m, 1H), 7.16 (m, 1H), 7.25 (m, 1H), 7.32 (m, 2H), 7.38 (m, 2H), 7.42 (m, 1H), 7.51 (m, 1H), 7.66 (m, 2H), 7.86 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[OH2:23]>>[F:8][C:7]1[C:2](=[O:23])[NH:3][CH:4]=[CH:5][C:6]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:10]=1
Reactant: O
Reactant: Fc1c(-c2ccnc(NC3CCOCC3)n2)ccnc1Cl
Agent: Cl
Product: O=c1[nH]ccc(-c2ccnc(NC3CCOCC3)n2)c1F
Temperature: 140 °C
Yield: 75.1 %

Procedure:
4-(2-Chloro-3-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.08 g, 0.259 mmol) and 1M HCl (3.89 mL, 3.89 mmol) were added to a microwave vial. The vial was heated in a microwave at 140° C. for a total of 10 hours in 2 hour segments. The reaction mixture was diluted with water, and the desired 3-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.0565 g, 0.195 mmol, 75.1% yield) was collected by vacuum filtration.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[O:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([NH:25][CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: NC1CCOCC1
Product: C(#Cc1cnc(NC2CCOCC2)nc1)c1ccccc1

Procedure:
The title compound, MS: m/e=280.3 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and tetrahydro-pyran-4-ylamine.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:44]=[CH:43][C:22]2[C:23]([N:26](C(OCC(Cl)(Cl)Cl)=O)[C:27](OCC(Cl)(Cl)Cl)=[O:28])=[N:24][O:25][C:21]=2[CH:20]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[F:18][C:19]1[CH:44]=[CH:43][C:22]2[C:23]([NH:26][C:27]([N:15]3[CH2:16][CH2:17][N:12]([C:10]4[S:9][N:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)[CH2:13][CH2:14]3)=[O:28])=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2cc(F)ccc12
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1noc2cc(F)ccc12)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 32 %

Procedure:
A mixture of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (492 mg, 2.00 mmol), bis(2,2,2-trichloroethyl) (6-fluoro-1,2-benzisoxazol-3-yl)imidodicarbonate (502 mg, 1.00 mmol), diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethyl sulfoxide (5 ml) was stirred at 70° C. for 5 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to yield 136 mg (32.1%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:14][CH3:15])[CH2:12][CH3:13])(=[O:10])=[O:9])=[C:6]([OH:16])[C:5]([NH:17][C:18]2[C:21](=[O:22])[C:20](=[O:23])[C:19]=2[O:24][CH2:25][CH3:26])=[CH:4][CH:3]=1.Cl.C(NOC)C.Cl.O1CCCN1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][C:18]2[C:21](=[O:22])[C:20](=[O:23])[C:19]=2[O:24][CH2:25][CH3:26])=[C:6]([OH:16])[C:7]=1[S:8]([N:11]1[CH2:12][CH2:13][CH2:15][O:14]1)(=[O:10])=[O:9]
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(CC)OC)c2O)c(=O)c1=O
Agent: C1CNOC1
Agent: CCNOC
Agent: Cl
Product: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N3CCCO3)c2O)c(=O)c1=O

Procedure:
This compound was prepared analogously to 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Intermediate FA) by replacing N-ethyl-O-methylhydroxylamine hydrochloride (Intermediate G) with isoxazolidine hydrochloride. [M+H]+ 402.9
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH:19]([O:18][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][O:1][C:31]([NH:30][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:29][CH:28]=2)=[O:32])[CH:4]=1)[C:13]([OH:15])=[O:14])([CH3:20])[CH3:21]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1COC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and α,α,α-trifluoro-p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:3]=1[NH2:4].Cl[CH2:12][CH:13]1[O:17][CH2:16][O:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C>[O:17]1[CH:13]([CH2:12][NH:4][C:3]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])[CH2:14][O:15][CH2:16]1
Reactant: COc1cccc(C)c1N
Reactant: ClCC1COCO1
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Product: COc1cccc(C)c1NCC1COCO1

Procedure:
2-Methyl-6-methoxyaniline (0.3 mole), 5-chloromethyl-1,3-dioxolane (0.3 mole), potassium carbonate (0.3 mole) and tetraethylammonium chloride (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of 4 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxolan-5-ylmethyl)-2-methyl-6-methoxyaniline.
Reaction SMILES: C([O:8][C:9]1[CH:41]=[CH:40][C:12]2[N:13]=[C:14]([S:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]([NH:28][C:29]4[C:30]([S:38][CH3:39])=[N:31][C:32]([CH3:37])=[CH:33][C:34]=4[S:35][CH3:36])=[O:27])[CH2:21][CH2:20]3)[NH:15][C:11]=2[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[OH:8][C:9]1[CH:41]=[CH:40][C:12]2[N:13]=[C:14]([S:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]([NH:28][C:29]4[C:30]([S:38][CH3:39])=[N:31][C:32]([CH3:37])=[CH:33][C:34]=4[S:35][CH3:36])=[O:27])[CH2:21][CH2:20]3)[NH:15][C:11]=2[CH:10]=1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccc(OCc4ccccc4)cc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccc(O)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 76.5 %

Procedure:
2-[4-[2-(5-benzyloxybenzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide (115 mg, 0.189 mmol) obtained in Example 150 was dissolved into trifluoroacetic acid (2 ml) and stirred at room temperature for 23 hours. The reaction solution was concentrated in vacuo, and the resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=10:1) to provide 75 mg (yield 76%) of the desired compound as colorless powdery crystals. IR (KBr) cm−1: 3227, 1675, 1600, 1564, 1486. 1H-NMR (CDCl3) δ: 2.36 (3H, s), 2.45 (3H, s), 2.47 (3H, s), 2.50-3.00 (10H, m), 3.10 (2H, s), 3.14 (2H, br s), 6.61 (1H, s), 6.74 (1H, d, J=8.8 Hz), 7.00 (1H, s), 7.29 (1H, d, J=8.8 Hz), 8.41 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:9]=2)[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1N
Yield: 72 %

Procedure:
1-Methyl-4-[3-(3-methyl-thiophen-2-yl)-4-nitro-phenyl]-piperazine (60 mg, 0.18 mmol, as prepared in the previous step) was stirred with 40 mg 5% Pd—C in MeOH (5 mL) under H2 (1 atm) for 2 h. The reaction was filtered through Celite and concentrated in vacuo to afford 40 mg (72%) of 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine as a brown solid, which was used immediately without further purification. Using a procedure similar to Example 9, step (c), 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine (40 mg, 0.13 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (30 mg, 0.19 mmol, as prepared in Example 9, step (c)) in the presence of DIEA (61 μL, 0.34 mmol) to afford 18.9 mg (36%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 2.13 (s, 3H), 2.38 (s, 3H), 2.59-2.62 (m, 4H), 3.24-3.27 (m, 4H), 6.92 (d, 1H, J=2.8 Hz), 7.06 (d, 1H, J=5.1 Hz), 7.15 (d, 1H, J=3.7 Hz), 7.19 (d, 1H, J=3.7 Hz), 7.02 (dd, 1H, J=2.8, 9.0 Hz), 7.42 (d, 1H, J=5.1 Hz), 8.11 (s, 1H), 8.34 (d, 1H, J=9.0 Hz); Mass spectrum (ESI, m/z): Calcd. for C22H22N4O2S, 407.1 (M+H). found 407.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].Cl[C:10]([O:13]C(Cl)=O)(Cl)Cl>O1CCOCC1>[CH3:2][O:3][C:4](=[O:8])[CH:5]([N:6]=[C:10]=[O:13])[CH3:7]
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(C)N=C=O
Temperature: 55 °C
Yield: 83.6 %

Procedure:
L-Alanine methyl ester hydrochloride (6.00 g., 42.99 mmole) was slurried in anhydrous 1,4-dioxane (125 ml.), treated with trichloromethylchloroformate (7.8 ml., 64.66 mmole) and heated at 55° C. for 20.5 hours. The excess trichloromethylchloroformate and 1,4-dioxane were removed from the reaction mixture by distillation under slightly reduced pressure. The resultant residue was subjected to distillation to afford the desired intermediate 2-isocyanatopropionic acid methyl ester (4.64 g., 83.6% yield) as a clear colorless liquid. B.P. 58° C. (15-20 mm Hg.). 1H-NMR (200 MHz, CDCl3) δppm =1.54, d, J=8 Hz., 3H (--CH3), 3.87, s, 3H (--OCH3), 4.13, q, J=8 Hz., 1H(--CH--CH3), IR(neat) 3000, 2960, 2270, 1745, 1455, 1445, 1385, 1305, 1230, 1110 cm-1.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15](F)=[CH:14][C:13]=1F.Cl>O1CCCC1>[CH2:3]([O:10][C:13]1[CH:14]=[C:15]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[F:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
2.82 g (70.6 mmol, 2.5 eq) of sodium hydride at 60% are added to a solution of 7.6 g (70.6 mmol, 2.5 eq) of benzyl alcohol in 100 ml of tetrahydrofuran. The reaction medium is stirred at ambient temperature for 1½ hours and then 5.0 g (28.2 mmol, 1 eq) of 1,2,4-trifluoro-5-nitrobenzene in solution in 50 ml of tetrahydrofuran are added dropwise. The reaction medium is refluxed for 3 hours. The reaction medium is treated with 150 ml of 1M hydrochloric acid and extracted with ethyl acetate. The organic phases are combined, washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica gel, elution being carried out with 90/10 heptane/ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:40](=[O:41])[C:39]3[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=3)[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 72.8 %

Procedure:
3.73 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 40 ml of acetone, and 2.07 g of potassium carbonate are added thereto. 2.04 g of 4-nitrobenzoyl chloride are added at room temperature to the mixture under stirring, and said mixture is stirred at the same temperature overnight. After the reaction, the mixture is treated in the same manner as described in Example 8. 3.8 g of (+)-cis-2-(4-methoxyphenyl)-3-(4-nitrobenzoyloxy)-5-[2-(dimethylamino)-ethyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:18]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=1)[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:39]O.Cl.O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:18]([C:34]([N:36]([CH3:37])[CH3:38])=[O:35])[C:19]1[CH:20]=[CH:21][C:22]([OH:39])=[CH:23][CH:24]=1)[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: OO
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4.0 g (7.50 mmol) of material from Step A above in 75 mL of tetrahydrofuran at 0° C. was added 1.25 mL of an aqueous solution of 30% hydrogen peroxide. After 1 h, the solution was allowed to warm up to ambient temperature and stirring continued for 2 h. The reaction mixture was acidified with 1N hydrochloric acid to pH 4. Additional water was added, and the aqueous layer was extracted with ethyl acetate (three times). The combined organic extracts were washed with saturated brine, dried (magnesium sulfate) and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (silica gel, methanol/ethyl acetate) to afford the title compound. LC-MS 424.2 (M+1).