Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].C[O-].[Na+].[CH2:16](I)[CH2:17][CH2:18][CH3:19].CS(C)=O>C(OCC)(=O)C>[CH2:16]([O:6][C:5]1[C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[O:8][C:2](=[O:1])[C:3]=1[OH:4])[CH2:17][CH2:18][CH3:19]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CCCCI
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A reaction mixture was prepared containing the following ingredients: 33 g. of L-ascorbic acid, 10.2 g. of sodium methylate, 34.5 g. of n-butyl iodide and 250 ml. of DMSO. The reaction mixture was stirred at ambient temperature and the progress of the reaction monitored by thin layer chromatography. After 24 hours, the reaction mixture was added to 500 ml. of ethyl acetate. 3-O-n-Butyl-L-ascorbic acid formed in the above reaction precipitated and was separated by filtration. Further precipitation was caused by adding 300 ml. of toluene to the filtrate. These crystals were also collected and the combined crystals dissolved in 500 ml. of methanol. (weight=about 20 g.) 45 g. of silica gel was added to this solution. The solution was evaporated to dryness in vacuo.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C@H:30]([NH:40][CH3:41])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:21]([N:28]1[CH2:32][C@@H:31]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)[C@H:30]([N:40]([CH3:41])[C:14](=[O:15])[C:13]([C:5]2[CH:4]=[C:3]([C:2]([F:20])([F:19])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)([CH3:18])[CH3:17])[CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(F)cc1
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (the preparation of which is described in WO2002079134) (0.88 g, 2.76 mmol) in CH2Cl2 (5 ml) was added drop wise to a stirred solution of rac-[(3S,4R)-1-benzyl-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-amine (0.72 g, 2.53 mmol) and ethyl-diisopropyl-amine (0.64 ml, 3.78 mmol) in CH2Cl2 (5 ml). The reaction mixture was stirred 1 h, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc/H, 1:4) yielded 1.06 g (74%) of the title product as colorless foam. ES-MS m/e: 567.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH:4]=[CH:3]1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:3]1
Reactant: O=S(=O)(O)Cl
Reactant: Cn1ccc(=O)c2ccccc21
Product: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccccc21
Temperature: 25 °C

Procedure:
1-Methyl-4-quinolone (2 g) was heated with chlorosulphonic acid (5 ml) at 125° for 2.5 hours. The reaction mixture was cooled to room temperature and then carefully poured onto crushed ice (300 ml). The precipitated solid was collected by filtration and then dried to give the novel compound 1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride, m.p. 313°-315°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>ClCCl.C(Cl)(=O)C(Cl)=O.CN(C)C=O>[CH2:11]([NH:12][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=2)=[CH:15][C:16]=1[F:23])[C:14]1[CH:22]=[CH:21][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1F
Reaction time: 0.17 h
Yield: 154.1 %

Procedure:
In a solution of 0.15 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-fluoro benzoic acid in 10 ml of dichloromethane, 0.3 ml of oxalyl chloride and 2 drops of N,N-dimethylformamide were added at room temperature, and stirred at the same temperature for 10 minutes. After the completion of the reaction, the solvent was distilled off under reduced pressure, the remaining white solid was dissolved in 10 ml of chloroform, and 0.3 ml of benzylamine and then 0.3 ml of triethylamine were added under cooling with ice, after the completion of the addition, continued to stir at room temperature for further 20 minutes. After the completion of the reaction, 40 ml of water was poured in the reaction mixture, and extracted with ethyl acetate (50 ml×1). The organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.14 g of the aimed product as white crystal.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([N:13]2[C:14]3[C:10](=[CH:9][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Brc1ccc(Br)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Brc1cccc(-n2ccc3ccccc32)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 74.2 %

Procedure:
To a mixture of 4 (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)1H-indole (3, 2.43 g, 10 mmol), and 1,4-dibromobenzene (11.8 g, 50 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 2.02 g (74%) of the product 4 (3-bromo-phenyl)-1H-indole as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH3:9][N:10]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][C:11]1=[O:17]>C1(C)C=CC=CC=1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]2[CH2:13][C:14]([CH3:16])([CH3:15])[N:10]([CH3:9])[C:11]2=[O:17])=[N:3][CH:4]=1
Reactant: Fc1ccc(I)cn1
Reactant: CN1C(=O)CCC1(C)C
Solvent: Cc1ccccc1
Product: CN1C(=O)C(c2ccc(I)cn2)CC1(C)C
Temperature: -4 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
A solution of 2-fluoro-5-iodopyridine (260 mg, 1.17 mmol) and 1,5,5-trimethyl-pyrrolidin-2-one (148 mg, 1.17 mmol) in 6 ml of dry toluene was purged with Argon and cooled to −4° C. A 1M solution of sodium hexamethyldisilylamide (NaHMDS) in toluene (2.33 ml, 2.33 mmol) was added dropwise maintaining the temperature below 0° C. The red solution was stirred for 2 h at 0° C., quenched by addition of 5 ml of saturated ammonium chloride solution. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue (400 mg) was taken up in ethyl acetate, adsorbed onto 5 g of silicagel which was loaded onto a 20 g prepacked flash chromato-graphy column. After elution with a 0% to 75% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 145 mg (38%) of the title compound as a yellow viscous oil, MS: m/e=331.0 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:38](=[O:40])[CH3:39])[CH2:21]3)[C:15]([C:26]([NH2:28])=[O:27])=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCNC3)n2)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCC3CCCN(C(C)=O)C3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.3 %

Procedure:
To a mixture of 2-(3-acetamidophenylamino)-4-(piperidin-3-ylmethylamino)pyrimidine-5-carboxamide (40 mg, 0.104 mmol) and DIEA (0.100 mL, 0.575 mmol) in CH2Cl2 (2 mL), acetic anhydride (0.040 mL, 0.423 mmol) was added. The mixture was stirred at room temperature for 4 h. It was then purified by HPLC to give the titled compound (5 mg). MS 426.5 (M+H); UV 248.6 nm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:18]([OH:20])=O)[N:15]([CH3:17])[CH:16]=2)=[O:10])=[CH:4][C:3]=1[F:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:46]1[CH:51]=[CH:50][CH:49]=[C:48]([CH2:52][NH2:53])[CH:47]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:21][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:18]([NH:53][CH2:52][C:48]3[CH:47]=[N:46][CH:51]=[CH:50][CH:49]=3)=[O:20])[N:15]([CH3:17])[CH:16]=2)=[O:10])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(NC(=O)Nc2cn(C)c(C(=O)O)n2)cc1F
Reactant: NCc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)Nc2cn(C)c(C(=O)NCc3cccnc3)n2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60 mg (0.2 mmol) of 4-({[(4-methyl-3-fluorophenyl)amino]carbonyl}amino)-1-methyl-1H-imidazole-2-carboxylic acid (Example 18A) are dissolved in 4 ml of DMF and, after addition of 150 mg (0.39 mmol) of HATU and 36 mg (0.3 mmol) of DMAP, stirred at room temperature for 15 minutes. 43 mg (0.39 mmol) of (pyridin-3-ylmethyl)amine are added dropwise to this solution, and the mixture is stirred overnight. The reaction mixture is purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[N:26][NH:25][C:24]2=[O:28])=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:25]1[C:24](=[O:28])[N:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[CH:27]=[N:26]1)[CH3:13]
Reactant: COc1ccc(-n2cn[nH]c2=O)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: COc1ccc(-n2cnn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c2=O)cc1
Yield: 33.7 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.73 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl] ethanol and 1.32 g of 4-(4-methoxyphenyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-methoxyphenyl)-3(2H,4H)-1,2,4-triazolone (869 mg) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=1[Br:18].Cl[CH2:20][CH:21](OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Br:18][C:3]1[C:2]2[N:7]([CH:20]=[CH:21][N:1]=2)[N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:4]=1
Reactant: COC(=O)c1cccc(-c2cc(Br)c(N)nn2)c1
Reactant: CCOC(CCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COC(=O)c1cccc(-c2cc(Br)c3nccn3n2)c1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
A solution of methyl 3-(6-amino-5-bromopyridazin-3-yl)benzoate (1 g, 3.25 mmol), 2-chloro-1,1-diethoxyethane (0.6 g, 3.9 mmol), PTSA (0.62 g, 3.9 mmol) in isopropanol (10 mL) was heated to 80° C. for 40 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting mixture was treated with a saturated NaHCO3 solution (50 mL), extracted with dichloromethane (50 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (0.6 g, 56%) as a white solid. LC-MS: [M+H]+, 332.0, 333.9, tR=1.520 min.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=N)[C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][N:25](C=O)C>>[CH2:1]([C:5]1[N:6]([CH2:15][CH2:16][CH3:17])[C:7](=[CH:24][NH2:25])[C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCc1nc2sccc2c(=N)n1CCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCC1=Nc2sccc2C(=CN)N1CCC

Procedure:
In a sulfonation flask 3.74 g (0.015 mol) 2-butyl-3-propyl-3H-thieno [2,3-d]pyrimidine-4-ylideneamine, 2.84 g (0.03 mol) Mel, 4.15 g (0.03 mol) powdered sodium carbonate and 50 ml abs. DMF are stirred for 4 hours at an internal temperature of 70° C. Then DMF is distilled off in vacuum and the residue taken up in ethylacetate. The organic phase is washed with water and after drying the organic phase over Na2SO4 the solvent is removed in a water jet vacuum. The raw material is purified by column chromatography over silica gel (eluant: hexane/THF 1:1). Yield: 2.7 g of (2-butyl-3-propyl-3H-thieno [2,3-d]pyrimidin-4-ylidene) methylamine in the form of yellow crystals, m.p. 45-47° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[C:22](=O)(O)[O-:23].[Na+].C(Cl)(Cl)=O>C(Cl)Cl>[N:21]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:2]([CH3:1])[CH:3]=1)=[C:22]=[O:23]
Reactant: O=C([O-])O
Reactant: Cc1cc(N)ccc1Oc1ncccc1-c1ccncn1
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N=C=O)ccc1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 3-methyl-4-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (93 mg, 0.33 mmol) in CH2Cl2 (8 mL) was added saturated sodium bicarbonate (4 mL) followed 5 minutes later by phosgene (20% solution in toluene, 0.27 mL, 0.50 mmol). The mixture was stirred for 15 minutes at RT, diluted with CH2Cl2 and extracted with water. The organic layer was dried over sodium sulfate, filtered, concentrated and used without purification.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][CH2:35][C:36]([OH:38])=[O:37]>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)CCC1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CCC(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 55.1 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.95 g, 2 mmol) was reacted with 3-(morpholin-3-yl)propanoic acid hydrochloride (0.39 g, 2 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.61 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][S:11]([C:14]1[CH:43]=[CH:42][C:17]([O:18][C:19]2[C:20]([N:34]3[CH2:38][CH2:37][CH2:36][CH:35]3[CH:39](O)[CH3:40])=[CH:21][C:22]3[NH:26][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[N:24][C:23]=3[CH:33]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:7][CH:39]([CH:35]1[CH2:36][CH2:37][CH2:38][N:34]1[C:20]1[C:19]([O:18][C:17]2[CH:42]=[CH:43][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:15][CH:16]=2)=[CH:33][C:23]2[NH:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[N:26][C:22]=2[CH:21]=1)[CH3:40]
Reactant: CC(O)C1CCCN1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(F)C1CCCN1c1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
0.007 ml of diethylaminosulfur trifluoride was added to a chloroform (1 ml) solution of 21 mg of 1-(1-(6-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-3H-benzimidazol-5-yl)-pyrrolidin-2-yl)-ethanol diastereomer A obtained in Example 354, at −78° C., and the reaction liquid was stirred at −78° C. for 1 hour. The reaction liquid was heated up to room temperature, and aqueous saturated sodium bicarbonate was added to the reaction liquid, and then extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][C:9]=1[OH:23])=[O:6].[OH-].[NH4+:26]>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2])=[C:9]([OH:23])[CH:10]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1O
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1O
Yield: 23 %

Procedure:
Prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-2-hydroxy-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield=23%. Colorless solid. MS: m/e=319.4 (M++H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([Sn](CCCC)(CCCC)CCCC)[CH:13]=[CH2:14].[K+].[Br-]>>[CH2:14]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [K+]
Product: C=CCc1ccc(N)c([N+](=O)[O-])c1
Yield: 96 %

Procedure:
Prepared from 4-bromo-2-nitroaniline 17 (1.70 g, 7.84 mmol) and allyltributyltin (3.38 g, 10.2 mmol) as a yellow solid in 96% yield as described above for 5: mp 29°-31° C.; IR (KBr) 3490, 3374, 1638, 1518, 1341, 1253; 1H NMR δ7.90 (1H, d, J=2.0), 7.19 (1H, dd, J=8.5, 2.0), 6.77 (1H, d, J=8,5), 6.05 (NH, brs), 6.00-5.80 (1H, m), 5.11 (1H, dd, =1.4, 1.4), 5.04 (1H, ddd, J=6.6, 3.0, 1.5), 3.28 (1H, d, J=6.6); 13C NMR δ143.81, 137.13, 129.34, 125.59, 119.49, 116.95, 39.18; HRMS (EI) calcd for C9H10N2O2 178.0742, found 178.0746.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=1[S:7]([NH2:10])(=[O:9])=[O:8].CS[C:18](SC)=[C:19]1[C:28](=[O:29])[C@@:27]([CH2:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:30])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:37]>C1(C)C=CC=CC=1>[CH3:34][C:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][C@:27]1([CH3:30])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:37])=[C:19]([C:18]2[NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:11][O:12][CH2:13][O:14][CH3:15])[C:6]=3[S:7](=[O:8])(=[O:9])[N:10]=2)[C:28]1=[O:29]
Reactant: CSC(SC)=C1C(=O)c2ccccc2[C@@](C)(CCC(C)(C)C)C1=O
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Solvent: Cc1ccccc1
Product: COCOCc1csc2c1S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)(C)C)C1=O)N2
Yield: 84.7 %

Procedure:
A solution of the product of Example 10E (2.02 g, 7.9 mmol) and the product of Example 49E (2.49 g, 6.9 mmol) in 200 mL of toluene was warmed to reflux for 5 h, cooled, and concentrated in vacuo. The crude material was chromatographed on silica gel with methanol/dichloromethane (1:99) to afford the title compound (3.03 g, 85% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (td, J=12.59, 3.13 Hz, 1H) 0.72 (s, 9H) 0.82 (m, 1H) 1.57 (s, 3H) 2.04 (m, 1H) 2.22 (td, J=12.69, 4.41 Hz, 1H) 3.33 (s, 3H) 4.63 (s, 2H) 4.71 (s, 2H) 7.40 (s, 1H) 7.53 (m, 1H) 7.74 (d, J=4.04 Hz, 2H) 8.13 (d, J=7.72 Hz, 1H) 14.00 (s, 1H); MS (APCI−) m/z 517 (M−H)−; Analysis calc'd for (C25H30N2O6S2): C, 57.89; H, 5.83; N, 5.40. Found: C, 57.82; H, 6.12; N, 5.05.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[C:3]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:11](=[O:13])[CH3:12])[C:3]1=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCN(CCO)C1=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCN1CCN(C)C1=O

Procedure:
Reaction of 1-methyl-3-(2-hydroxyethyl)-2-imidazolidinone (13 g) with acetic anhydride (9.2 g) in dichloromethane (60 ml) in the presence of triethylamine (9 g) and 4-dimethylaminopyridine (0.1 g) for 18 hours at ambient temperature gave 1-methyl-3-(2-acetoxyethyl)-2-imidazolidinone as an oil.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:15]([OH:16])[C@@H:14]([OH:17])[C:12](=[O:13])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[NH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[CH2:36]([NH:37][C:12]([C@@H:14]([C@H:15]([C@@H:9]([C@@H:10]([CH2:18][OH:19])[OH:11])[O:8][C@@H:6]1[O:7][C@H:2]([CH2:1][OH:23])[C@@H:3]([OH:22])[C@H:4]([OH:21])[C@H:5]1[OH:20])[OH:16])[OH:17])=[O:13])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:12]([C@@H:14]([C@H:15]([C@@H:9]([C@@H:10]([CH2:18][OH:19])[OH:11])[O:8][C@@H:6]1[O:7][C@H:2]([CH2:1][OH:23])[C@@H:3]([OH:22])[C@H:4]([OH:21])[C@H:5]1[OH:20])[OH:16])[OH:17])=[O:13]
Reactant: O=C1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Reactant: NCCCCCCCCCCCCN
Product: O=C(NCCCCCCCCCCCCNC(=O)[C@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO)[C@H](O)[C@@H](O)[C@H](O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO
Yield: 22.7 %

Procedure:
2.04 g of cellobiono-1,5-lactone (H. W. Diehl et al., Carbohydr. Res. 38, 364 (1974)) are reacted with 0.60 g of 1,12-diaminododecane analogously to Example 5 and 0.60 g of the title compound are obtained.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16]C)[CH2:7]1)=[O:4].Cl.N1C=CC=CC=1>O>[C:3]([CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[OH:16])[CH2:7]1)([OH:4])=[O:2]
Reactant: COC(=O)CC1CCc2c(cccc2OC)C1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)CC1CCc2c(O)cccc2C1
Temperature: 190 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methoxycarbonylmethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.0 g) and pyridine hydrochloride (40 g) was stirred for 2 h at 190° C. The mixture was cooled to room temperature, dissolved into water. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and evaporated to give the title compound having the following physical data. The obtained residue was used for the next step without purification.