Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])[CH2:12][CH2:11]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCNCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(C(=O)c2ccccc2)CC1

Procedure:
A solution of 0.083 g (0.255 mmol) of 4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)piperidine (Example 2), 0.083 mL (1 mmol) of pyridine and 0.12 mL (1 mmol) of benzoyl chloride in 2 mL of methylene chloride was mixed for 18 hr. The reaction was diluted with methylene chloride and washed with saturated NaHCO3. The organic fraction was dried over MgSO4 and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate) to give the title compound.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.Cl.[N:18]1([C:23](N)=[NH:24])C=CC=N1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C=O)C>[C:23]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:2]1)(=[NH:18])[NH2:24]
Reactant: N=C(N)n1cccn1
Reactant: CS(=O)(=O)Nc1cccc2c1CCNC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cccc2c1CCN(C(=N)N)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A suspension of N-(1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide hydrochloride obtainable by the method of Example 19(b) of WO 98/30560 (15 g, 69 mmol), 1H-pyrazole-1-carboxamidine hydrochloride (10.0 g, 0.57 mol) and diisopropylethylamine (16.2 g, 125 mmol) in DMF (119 ml) was stirred overnight at room temperature. After this time 2N aqueous sodium hydroxide-was added to adjust to pH 12. The resulting white suspension was stirred for three hours, filtered and the solid dried in vacuo overnight at 45° C. to give 14.5 g of the title product (95%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=C([CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)C(N(C)C)=O.CO.C[CH2:20][O:21][C:22]([CH3:24])=[O:23].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.O>[CH3:1][N:2]([CH3:16])[C:3]1[CH:4]=[C:24]([CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1)[C:22]([O:21][CH3:20])=[O:23]
Reactant: CN(C)C(=O)c1cc(CO)nc(N(C)C)c1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(CO)nc(N(C)C)c1
Temperature: 135 °C
Reaction time: 12.5 h
Yield: 65 %

Procedure:
A mixture of 167 mg of 2-(dimethylamino)-6-(hydroxymethyl)-N,N-dimethylisonicotinamide in 2 mL of H2SO4 and 1.2 mL of H2O was stirred at 135° C. for 12.5 h. The temperature was decreased to 95° C., methanol (5 mL) was added, and the solution was heated for 1 h. The solution was added to ice with H2O and EtOAc, and solid NaHCO3 and sat. NaHCO3 solution were added to pH=8. The aqueous layer was extracted with EtOAc (4×), and the combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (30% EtOAc/hexanes) provided 102 mg of methyl 2-(dimethylamino)-6-(hydroxymethyl)isonicotinate as a yellow solid in 65% yield.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.C(N(CC)CC)C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[C:30]([O:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1)(=[O:33])[CH:31]=[CH2:32]
Reactant: O=C1NCC(CO)O1
Reactant: C=CC(=O)Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)OCC1CNC(=O)O1

Procedure:
105 g (0.90 mol.) of 5-hydroxymethyl-oxazolidin-2-one were placed into a one liter, three necked, round bottomed flask equipped with a paddle stirrer and thermometer. This was followed by 500 ml of tetrahydrofuran, 101 g (1.0 mol.) of triethylamine and 0.5 g of phenothiazine. Stirring was started as 90 g (1.0 mol.) of acryloyl chloride were added dropwise in such a way that the contents of the flask were maintained at 30° C. or less. When the addition was complete, the contents were stirred overnight at room temperature. The triethylamine hydrochloride was filtered and the solution was allowed to stand over NaHCO3 and Na2SO4. The solution was filtered, transferred to a one liter, round bottomed flask and placed on a rotoevaporator. The solution was concentrated by purging with a stream of air while rotating the flask. The resulting liquid was confirmed by 13C NMR to contain a mixture of the desired product and unreacted starting material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][NH:5][CH3:6].COC(=O)[C@H](CC1N=CNC=1)NCC1C=CC=CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C=O)C.[C:66]1([CH3:81])[CH:71]=[CH:70][C:69]([S:72](N(CC(O)=O)C)(=[O:74])=[O:73])=[CH:68][CH:67]=1>>[CH3:1][O:2][C:3](=[O:7])[CH2:4][N:5]([S:72]([C:69]1[CH:70]=[CH:71][C:66]([CH3:81])=[CH:67][CH:68]=1)(=[O:74])=[O:73])[CH3:6]
Reactant: CNCC(=O)OC
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COC(=O)[C@H](Cc1c[nH]cn1)NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1

Procedure:
N-(Toluene-4-sulfonyl)sarcosine methyl ester was prepared from sarcosine methyl ester using the procedure described in Method 1. The title compound was prepared by coupling in DMF N-(toluene-4-sulfonyl)sarcosine with (N-benzyl)histidine methyl ester in the presence of BOP and NMM, to give after aqueous workup and flash chromatography, the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Br)c1F)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 54.2 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-bromo-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.3 g, 6.5 mmol) prepared in Example 63a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-3-(3-bromo-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (2 g, 54%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20].Cl>ClC1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([C:4](=[O:5])/[CH:3]=[CH:2]/[C:1]([OH:6])=[O:7])[CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: O=C1C=CC(=O)O1
Reactant: COc1ccccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: COc1ccc(C(=O)/C=C/C(=O)O)cc1Cl
Temperature: 10 °C
Reaction time: 24 h
Yield: 60.5 %

Procedure:
Into a 500 ml four-neck flask were charged 66.9 g (0.682 mol) of maleic anhydride and 150 ml of chlorobenzene under a nitrogen atmosphere. Then, the whole was cooled to 10° C. or lower and 67.6 g (0.507 mol) of aluminum chloride was added thereto. While temperature was maintained at 10 to 15° C., 23.2 ml (0.195 mol) of 1-chloro-2-methoxybenzene was added dropwise, followed by 51 hours of reaction at 20 to 30° C. After termination of the reaction was confirmed by HPLC analysis, the reaction solution was added dropwise to 200 ml of a 1N hydrochloric acid aqueous solution cooled to 0° C. to decompose excess aluminum chloride. Extraction with 400 ml of ethyl acetate was conducted and the organic layer was washed twice with 200 ml of a 1N hydrochloric acid aqueous solution. Then, the organic layer was extracted three times with 200 ml of a saturated sodium hydrogen carbonate aqueous solution to extract (E)-4-(3-chloro-4-methoxyphenyl)-4-oxo-2-butenoic acid into the aqueous layer, followed by adjusting the aqueous layer to pH 2.0. After 24 hours of stirring at 5° C., filtration was carried out to obtain 28.4 g (yield 60.5%) of the aimed compound as light yellow crystals. As a result of HPLC analysis, the purity was found to be 96.3%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[C:18](Cl)(=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O>[N:1]1([C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.7 %

Procedure:
To a solution of ethyl piperidine-3-carboxylate (4 g, 25.4 mmol) in THF (30 mL) and water (30.0 mL) was added Na2CO3 (6.74 g, 63.6 mmol). The resulting suspension was stirred at rt for 20 min. After this time, benzyl carbonochloridate (4.12 g, 24.17 mmol) was added in dropwise. After addition, the stirring solution became milky, then white precipitates formed. After stirring at rt for 2 h, the reaction was partitioned between EtOAc and water. The separated aqueous phase was extracted with EtOAc (2×). The combined organics were washed with water and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The oily residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-40% EtOAc/Hex. The desired fractions were concentrated to afford the desired product, 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (5.68 g, 19.50 mmol, 77% yield) as a colorless oil. Anal. Calcd. for C16H21NO4 m/z 291.3, found: 292.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.41-7.28 (m, 5 H), 5.26-4.97 (m, 2 H), 4.34-4.06 (m, 3 H), 4.06-3.91 (m, 1 H), 3.13 (br. s., 1 H), 2.96-2.81 (m, 1 H), 2.46 (br. s., 1 H), 2.15-1.96 (m, 1 H), 1.78-1.56 (m, 2 H), 1.49 (br. s., 1 H), 1.33-1.17 (m, 3 H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])OC(C)(C)C)[CH2:4][CH2:3]1.[C:16](OC(=O)C(C)C)(=O)[CH:17](C)[CH3:18].[ClH:27].O1CCOCC1>C(Cl)Cl>[ClH:27].[NH2:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9](=[O:15])[CH:17]([CH3:18])[CH3:16])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(C)C(=O)OC(=O)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)C(=O)N[C@H]1CC[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl cis-4-aminocyclohexylcarbamate (500 mg, 2.333 mmol) in DCM (20 mL) was added isobutyric anhydride (0.407 mL, 2.450 mmol). The solution was stirred overnight at RT. After 16 hours, 4 M HCl in dioxane (2.333 mL, 9.33 mmol) was added, and the reaction was stirred at RT overnight. The resulting white precipitate was collected by vacuum filtration and dried in vacuo to generate N-(cis-4-aminocyclohexyl)isobutyramide hydrochloride as an off-white powder (508 mg, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:8]1[NH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:7]=1[CH2:6]2.C([O:32][CH2:33][C:34](Cl)=[O:35])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]([NH:12][C:11]2[C:7]3[CH2:6][C:5]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:8]=3[N:9]([C:33](=[O:32])[CH2:34][OH:35])[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COc1cc2c(cc1OC)-c1[nH]nc(Nc3cccc(F)c3)c1C2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)CO)C2
Yield: 90 %

Procedure:
To a mixture of (6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (Compound 14) (3.6 g, 10.0 mmol), Benzyloxy-acetyl chloride (Compound 27a) (2.2 g, 12.0 mmole) and DMF (50 mL) was added Diisopropylethylamine (5.2 mL, 30 mmole) at room temperature with stirring. The reaction was stirred at room temperature over night. The reaction was quenched with water and extracted with EtOAc. Dried over sodium sulfate and removed solvent in vacuo. The crude material was then taken up into ethanol and 0.5 g of Pd/C was added. The reaction was shaken on the hydrogenator over night. The reaction was filtered through Celite and removed solvent in vacuo. Triturated in a small amount of EtOAc. 3.2 g of ˜90% pure material was produced. 300 mg of the crude material was prepped on the Gilson and lyophilization gave Compound 432 as a white powder. MS m/z 384 (M+H)+;
Reaction SMILES: [C:1]([F:8])([F:7])([F:6])[C:2](Cl)([Cl:4])[F:3].Cl.[CH2:10]([O:12]CC)C>>[C:1]([C:2]([CH2:10][OH:12])([F:3])[Cl:4])([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C(F)(Cl)Cl
Reactant: CCOCC
Agent: Cl
Product: OCC(F)(Cl)C(F)(F)F

Procedure:
The reaction product of CFC-114a, an aldehyde and a reactive metal may be neutralized by diluting the reaction product mixture with a mixture of a solvent, ice, and an aqueous solution of an acid. The solvent can be any commonly used organic solvent, such as diethyl ether. The aqueous solution of an acid may be an aqueous solution of a common mineral acid, such as hydrochloric acid. After stirring the resulting mixture for a period of time, the layer comprising the organic solvent is separated. The organic solvent layer can be subsequently washed with a dilute aqueous solution of an acid, followed by a brine solution. The organic layer is then dried. The drying is accomplished by stirring the organic layer over an anhydrous salt, such as anhydrous magnesium sulfate or anhydrous sodium sulfate. The organic solvent may then be evaporated to afford CF3CClFCH2OH.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[O:7][C:8]1[CH:9]=[C:10]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=1.Cl>C1COCC1.O>[CH:3]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[O:7][C:8]1[CH:9]=[C:10]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)=[O:2]
Reactant: COC(OC)c1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of N-[3-(3-dimethoxymethyl-4-nitrophenoxy)-phenyl]-benzenesulfonamide (0.0083 mol) in THF (12 mL) was stirred at room temperature, then 12N HCl (6 mL) and water (6 mL) were added and the reaction mixture was stirred for 48 hours at room temperature. The mixture was stirred in H2O and extracted with diisopropyl ether. The organic layer was separated, washed with a 10% NaHCO3 solution, separated again, dried, filtered, and the solvent was evaporated. The obtained residue was stirred in diisopropyl ether, and then the desired product was filtered off and dried to yield the title compound as a solid.
Reaction SMILES: O[CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.COCCN(S(F)(F)[F:35])CCOC.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[F:35][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
tert-Butyl 3-hydroxy-4-(4-(methoxycarbonyl)phenyl)piperidine-1-carboxylate described in Production Example 6-2 (518 mg, 1.54 mmol) was dissolved in dichloromethane (15 mL), [bis-(2-methoxyethyl)amino]sulfur trifluoride (0.313 mL, 1.70 mmol) was added at −78° C. over 3 minutes, and the mixture was stirred for 1 hour while warming to room temperature. A saturated aqueous sodium bicarbonate solution and ethyl acetate were serially added to the reaction mixture. The aqueous layer was extracted with ethyl acetate three times and then the organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=19:1-3:2) to obtain the title compound (402 mg, 77%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[C:19]1[C:23]([NH2:24])=[CH:22][NH:21][N:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]=[C:11]1[C:19]1[C:23]([NH:24][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:22][NH:21][N:20]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
A mixture of benzoic acid (34 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (40.5 mg, 0.30 mmol) in DMF (5 ml) was stirred at room temperature for 24 h. The solvent was removed in vacuo, the crude product purified by preparative LC/MS and following reduction of the product-containing fractions N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide was obtained as a brown solid (23 mg, 30%). (LC/MS: Rt 3.66, [M+H]+ 303.67).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(#N)C>[N+:20]([C:3]1[CH:4]=[C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:18]=[CH:19][C:2]=1[NH:30][CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1)([O-:22])=[O:21]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(C(F)(F)F)cc1
Temperature: 80 °C

Procedure:
To a 25 mL round bottom flask under a nitrogen atmosphere were added 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (195 mg, 0.65 mmol), 4-(trifluoromethyl)-benzylamine (112 mg, 0.65 mmol), acetonitrile (1 mL) and DIPEA (0.34 mL, 1.96 mmol). The mixture was heated to 80° C. for 24 h at which point the reaction was cooled to RT and concentrated to dryness. The resulting residue was washed with water (2×20 mL) and then dissolved in EtOAc, dried over Na2SO4, filtered and then concentrated. The material was used without further purification. MS (ESI): mass calcd. for C24H18F3N3O3, 453.13; m/z found, 454.1[M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[Br:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23]C(O)=O>>[Br:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][C:3]1[C:4](=[O:5])[C:6]2[C:11]([C:12](=[O:13])[C:2]=1[CH3:1])=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1ccc(CC(=O)O)c(Br)c1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Product: COc1ccc(CC2=C(C)C(=O)c3ccccc3C2=O)c(Br)c1
Yield: 57 %

Procedure:
As starting materials for the coupling reaction menadione and 2-Bromo-4-methoxyphenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:1, UV), 857 mg (2.31 mmol, 57% yield) of P_TM102 were isolated as yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][C:15]([NH2:17])=[S:16])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:18]=[CH:19][CH:20]=[N:21][C:5]1=2.CI.[C:24](OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][S:16][C:15](=[NH:17])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[N:18]=[CH:19][CH:20]=[N:21][C:5]=3[N:4]([CH2:3][O:2][CH3:1])[C:9]=2[CH:10]=1
Reactant: CCOC(C)=O
Reactant: COCN1c2cc(CC(N)=S)ccc2Sc2nccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COCN1c2cc(CC(=N)SC)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into 15 ml of a solution of 318 mg of (10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)thioacetamide in acetone was dropped 1.5 m of methyl iodide. After stirring at room temperature for 2 hours, the reaction mixture was distributed into ethyl acetate and an aqueous solution of potassium carbonate. The organic layer was extracted and the extract was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 350 mg of the title compound was obtained as a yellow oily substance.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][OH:21])[N:18]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[CH2:23](I)[CH3:24]>O1CCCC1>[Cl:3][C:4]1[C:5]([CH3:22])=[C:6]([S:10]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH2:19][CH2:20][O:21][CH2:23][CH3:24])[N:18]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCO)cs1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCc1csc(NS(=O)(=O)c2cccc(Cl)c2C)n1
Reaction time: 0.25 h

Procedure:
Sodium hydride (95% dry, 80 mg, 3.23 mmol) was added to a stirred solution of EXAMPLE 181A (426 mg, 1.28 mmol) in tetrahydrofuran (10 mL) at room temperature. After stirring for 15 min, the mixture was treated with ethyl iodide (400 mg, 2.56 mmol). The reaction mixture was stirred for 2 h at 55° C. and then quenched with aqueous HCl (1 M, 1 mL) and water was added. The product was extracted with DCM and dried (Sodium sulfate). Evaporation of the solvent gave a residue which was purified by flash chromatography on silica gel eluting with 10% acetone in DCM giving an oil (0.25 g, 54%) which solidified on standing: MS (Ionspray, [M+H]+) m/z 360; Anal. Calcd. (found) for C14H17ClN2O3S2: C, 46.6 (46.5)%; H, 4.7 (4.6)%; N, 7.8 (7.8)%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[C@@H:7]([OH:19])[CH2:6][C@@H:5]1[CH3:20])(=[O:3])[CH3:2].[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([O:19][C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[CH2:6][C@@H:5]1[CH3:20])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)[C@@H](O)C[C@H](C)N2C(C)=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: CCOC(=O)c1ccc2c(c1)[C@H](Oc1ccc([N+](=O)[O-])cc1)C[C@H](C)N2C(C)=O
Yield: 57.4 %

Procedure:
[Step 4] Reactions and treatments were carried out in the same manner as in Step 2 of Example 117, using 89.3 mg of ethyl (2S,4S)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate instead of ethyl (2S,4R)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate, and 4-nitrophenol was used instead of benzoic acid. Thus, 73.6 mg (57.4%) of ethyl (2S,4R)-1-acetyl-2-methyl-4-(4-nitrophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylate was obtained as a white solid.