Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1.[Br:19]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([Br:19])=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: Cc1nn(-c2cc(Br)c(Cl)cc2F)c(=O)n1C(F)F
Yield: 62.1 %

Procedure:
This compound was prepared in the manner of Example 1 with 7.6 grams (0.027 mole—1.0 equiv.) of 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, 10.0 grams (0.056 mole—2.1 equiv.) of N-bromosuccinimide, and 50 mL of concentrated sulfuric acid (% wt/vol. triazole to solvent—15.2%) as reagents. A yield of 6.06 grams of 92.4% pure 1-(4-chloro-2-fluoro-5-bromophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (62.1% yield) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[CH:12][C:13]([N+:20]([O-:22])=[O:21])=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(OCC)C>[N+:20]([C:13]1[CH:12]=[CH:11][C:10]([O:9][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[CH:15][C:14]=1[C:16]([F:17])([F:18])[F:19])([O-:22])=[O:21]
Reactant: Nc1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)ccn1
Temperature: 150 °C
Yield: 16.3 %

Procedure:
To a solution of 2-amino-4-chloropyridine (2.0 g, 15.6 mmol) in N-methylpyrrolidone (16 ml) were added 5-hydroxy-2-nitrobenzotrifluoride (4.85 g, 23.4 mmol) and diisopropylethylamine (8.15 ml, 46.8 mmol), followed by stirring under a nitrogen atmosphere to heat at 150° C. for 62 hrs. The reaction mixture was cooled down to room temperature and the diisopropylethylamine was evaporated under a reduced pressure. The resultant residue was partitioned between ethyl acetate:tetrahydrofuran=1:1 (300 ml) and a 1 N aqueous solution of sodium hydroxide (100 ml). The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; heptane/ethyl acetate=1/2, ethyl acetate, then ethyl acetate/methanol=20/1). The crude product was subjected to silica gel filtration (Fuji Silysia NH) The filtrate was concentrated to give a solid, which was then suspended in diethyl ether:hexane=1:1, filtered, and dried under aeration to provide the titled compound (760 mg, 16.3%) as a brown solid.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:16][C:15](=[O:17])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]2[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[CH2:3][CH:2]=1.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>O1CCOCC1>[CH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:15](=[O:17])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH:2]=1
Reactant: COC(=O)C1=CN(c2ccc(O)cc2)C(C2CC=CCC2)CC1=O
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: C1COCCO1
Product: COC(=O)c1cn(-c2ccc(O)cc2)c(C2CC=CCC2)cc1=O
Temperature: 80 °C
Yield: 70.4 %

Procedure:
In 20 ml of dioxane was dissolved 1.0 g of methyl 6-(cyclohexen-4-yl)-1-(4-hydroxyphenyl)-4-oxo-1,4,5,6-tetrahydronicotinate, and the resulting solution was heated to 80° C. To this solution was added dropwise a solution of 0.83 g of 2,3,5,6-tetrachloro-p-benzoquinone in 20 ml of dioxane at 80° C., followed by reaction at the same temperature for 1 hour. After completion of this reaction, the reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with 50 ml of dioxane to obtain 0.7 g of methyl 6-(cyclohexene-4-yl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinate having a melting point of 250° C. or more.
Reaction SMILES: NC1SC=C(C(=NOC2CC2)C(N[C@@H:11]2[C:28](=[O:29])[N:13]3[C:14]([C:25]([O-])=[O:26])=[C:15]([CH2:18][N+:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:16][S:17][C@H:12]23)=O)N=1.[ClH:35]>O>[ClH:35].[N+:19]1([CH2:18][C:15]2[CH2:16][S:17][C@@H:12]3[CH2:11][C:28](=[O:29])[N:13]3[C:14]=2[C:25]([Cl:35])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)cs1
Agent: Cl
Solvent: O
Product: O=C(Cl)C1=C(C[n+]2ccccc2)CS[C@@H]2CC(=O)N12

Procedure:
To a solution of 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylate (syn isomer) (750 mg) in water (50 ml) was added concentrated hydrochloric acid (0.265 ml). The solution was lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-cyclopropyloxyimino)acetamido]-3-(1-pyridinio)methyl-3-cephem-4-carboxylic acid chloride hydrochloride (syn isomer) (874 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Cl:40])[CH:39]=1)[C:34](Cl)=[O:35]>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:33]2[CH:32]=[C:31]([Cl:30])[CH:39]=[C:38]([Cl:40])[CH:37]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 4 ml of methylene chloride, 0.28 ml of triethylamine and 255 mg of 3,5-dichlorobenzoyl chloride are mixed together then agitation is carried out at ambient temperature for 30 minutes. Then 2 ml of water is added, followed by extracting with methylene chloride, drying and evaporating the solvents. In this way 454 mg of expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14](=[O:31])[CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:18])[CH:6]=[C:7]([I:13])[C:8]=1[O:9][CH2:10][CH2:11][OH:12].O1CCCC1.CO.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([OH:31])[CH2:15][CH2:16][CH:17]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[OH:18])[CH:6]=[C:7]([I:13])[C:8]=1[O:9][CH2:10][CH2:11][OH:12]
Reactant: COc1cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc(I)c1OCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc(I)c1OCCO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 101 %

Procedure:
1-(3-Methoxy-4-hydroxyethoxy-5-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanedione (11.6 g, 21.3 mmol), was added to 120 mL tetrahydrofuran and 240 mL methanol. To this solution was added dropwise sodium borohydride (1.45 g, 38.4 mmol), in 60 mL water. The reaction mixture was stirred at room temperature for 2.5 hours, and then cooled, quenched with water, and the aqueous layer extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and evaporated in vacuo to provide the product (11.8 g, 98.8%). 1H NMR (CDCl3) δ1.84 (m, 4 H); 3.84 (m, 2 H); 3.86 (s, 3 H); (s, 9 H); 4.15 (t, 2 H); 4.68 (m, 2 H); 6.57 (s, 2 H); 6.91 (9, 1 H); 7.32 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH2:13][CH3:14])[N:11](OC)[C:10]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].N.[Na].[Cl-].[NH4+]>>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH2:13][CH3:14])[NH:11][C:10]1=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: CC[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 102.6 %

Procedure:
(trans)-3-t-Butoxycarbonylamino-4-ethyl-1-methoxy-2-azetidinone (3 g) is added to 170 ml of liquid ammonia at -78° C. under nitrogen and 1.68 g of sodium is added in 5 portions with stirring over a 5 minute period. Stirring is continued for 30 minutes. Ammonium chloride is then added slowly until the blue color of the reaction mixture disappears. After removal of the ammonia under nitrogen the solid is extracted with two 100 ml portions of ethyl acetate. Removal of the solvent followed by drying in vacuo yields 2.7 g of the title compound.
Reaction SMILES: [C:1](Cl)(=O)C.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:8][C:7]=1[F:19]>CO>[CH3:1][O:16][C:15](=[O:17])[C:14](=[O:18])[CH:13]=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([Br:5])=[C:7]([F:19])[CH:8]=1
Reactant: O=C(O)C(=O)C=Cc1ccc(Br)c(F)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C(=O)C=Cc1ccc(Br)c(F)c1
Yield: 32.7 %

Procedure:
Acetyl chloride (2.9 mL, 41.0 mmol) was slowly added at 0° C. to methanol (15.0 mL) under stirring. A solution of 4-(4-bromo-3-fluoro-phenyl)-2-oxo-3-butenoic acid (3.2 g, 11.7 mmol) prepared in Step 1 in methanol (5.0 mL) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 1 hour, additionally at 80° C. for 16 hours, and then filtered at room temperature to give 1.1 g of the titled compound as a pale yellow solid.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].[I:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2N)=[CH:11][CH:10]=1>C(O)C>[I:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[N:7]=[C:2]2[CH3:3])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1Nc1ccc(I)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: Cc1nc2ccccc2n1-c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl acetimidate hydrochloride (6.757 g, 54.9 mmol) was added to a suspension of N-(4-iodophenyl)-1,2-diaminobenzene (6.812 g, 22.0 mmol) in absolute ethanol (30 ml) at room temperature. After 2 hours, 50 ml of ice cold 2N aqueous sodium hydroxide was added and the product was extracted into ethyl acetate (2×100 ml). The extracts were washed with water (3×100 ml), dried (MgSO4) and concentrated under reduced pressure to give 1-(4-iodophenyl)-2-methylbenzimidazole, 6.695 g as a white solid, m.p. 136°-7° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:28]=[CH:27][C:26]3[C:17]4[NH:18][C:19](=[O:25])[C:20]5[N:21]([CH:22]=[CH:23][N:24]=5)[C:16]=4[C:15](=[CH:29][C:30]([OH:32])=[O:31])[C:14]=3[CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>O>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:28]=[CH:27][C:26]3[C:17]4[NH:18][C:19](=[O:25])[C:20]5[N:21]([CH:22]=[CH:23][N:24]=5)[C:16]=4[CH:15]([CH2:29][C:30]([OH:32])=[O:31])[C:14]=3[CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C=c1c2cc(NC(=O)Nc3cccc(F)c3)ccc2c2[nH]c(=O)c3nccn3c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC1c2cc(NC(=O)Nc3cccc(F)c3)ccc2-c2[nH]c(=O)c3nccn3c21
Yield: 46.5 %

Procedure:
The process is performed as in Example 62 but starting with 0.3 g of 8-[3-(3-fluorophenyl)ureido]-10-(carboxymethylene)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one hydrochloride, 15 ml of water and 1 ml of 1N sodium hydroxide. After removal of the catalyst, the filtrate is acidified with 2 ml of 1N hydrochloric acid and the precipitate formed is filtered off, washed with distilled water and dried under vacuum (1 mnHg; 0.13 kPa). 0.14 g of 8-[3-(3-fluorophenyl)ureido]-10-(carboxymethyl)-5H,10H-imidazo[1,2-a)indeno[1,2-e]pyrazin-4-one hydrochloride is obtained in the form of a light brown solid melting above 260° C. (1H NMR spectrum (300 MHz; (CD3)2SO-d6 ; δ in ppm]: 2.60 and 3.27 (2 dd, J=16.5 and 9 Hz and J=16.5 and 3.5 Hz respectively, 1H each: CH2); 4.47 (dd, J=9 Hz and 3.5 Hz, 1H: CH 10); 6.80 (dt, J=8.5 and 2 Hz, 1H: aromatic H ortho to the F and para to the ureido); 7.13 (broad d, J=8.5 Hz, 1H: aromatic H para to the F and ortho to the ureido); 7.32 (dt, J=8.5 and 8 Hz, 1H: aromatic H meta to the F and meta to the ureido); 7.44 (dd, J=8.5 and 1.5 Hz, 1H: H 7); 7.53 (d mt, J=12 Hz, 1H: aromatic H ortho to the F and ortho to the ureido); 7.75 and 8.26 (2 broad s, 1H each: H of the imidazole); 7.79 (d, J=8.5 Hz, 1H: H 6), 7.87 (broad s, 1H: H 9); 9.18 and 9.23 (2 broad s, 1H each: NHCONH); 12.65 (s 1H: NH 5)).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CO.CS(C)=O>[CH2:10]([O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrCc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
3.3 g of sodium were dissolved in 60 ml of methanol and stirred with 15 g of 5-hydroxy-2-methylpyridine in 230 ml of DMSO for 1 hour at a temperature of 80° to 90° C. The methanol was spun or rotated out after cooling the mixture. 23.5 g of benzylbromide were then added, followed by stirring for 20 hours at room temperature. The reaction mixture was then acidified with 2N HCL and mixed with 1500 ml of water. The mixture was then extracted with diethyl ether and the ether phase was discarded. The pH-value of the aqueous phase was then adjusted to approximately 8 and the solution was extracted with ether. The organic phase was evaporated. 24.1 g of 5-benzyloxy-2-methylpyridine were obtained. The latter was dissolved in 200 ml of glacial acetic acid, mixed with 12 ml of hydrogen peroxide (30%) and refluxed for 2 hours. The mixture was then neutralized with 40% caustic soda solution and 1000 ml of water were added. The solution was extracted with dichloromethane and the organic phase evaporated. 25 g of 5-benzyloxy-2-methylpyridine-N-oxide were obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:43]([C:45]1[N:50]=[CH:49][NH:48][C:47](=O)[CH:46]=1)[CH3:44].[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C>[C:52]([O:56][C:57]([N:59]1[CH2:64][CH2:63][N:62]([C:47]2[CH:46]=[C:45]([CH2:43][CH3:44])[N:50]=[CH:49][N:48]=2)[CH2:61][CH2:60]1)=[O:58])([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1cc(=O)[nH]cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
4 mL DIPEA and 3 g PYBOP was added to 2.9 g 6-ethyl-3H-pyrimidin-4-one in 10 mL DMF. The reaction was stirred 5 min at ambient temperature and 1.1 g piperazine-1-carboxylic acid tert-butyl ester was added. The reaction was stirred overnight at RT. The solvent was removed and the residue was purified by HPLC to give 1 g of the desired compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:14].[OH:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: BrCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)c1ccc(OCCCCCCCCCCCCBr)cc1
Yield: 82 %

Procedure:
A solution of 150 mmol (49.2 g) of 1,12-dibromododecane, 50 mmol (10.6 g) of benzyl 4-hydroxybenzoate, and 0.3 mol (41.5 g) of potassium carbonate in 500 ml of acetone was refluxed for 6 hours. The reaction solution was then filtered and concentrated, and the resulting crude product was purified by column chromatography to obtain the objective ester compound of the following formula. (yield: 82%) ##STR34##
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:18])([CH3:20])[CH3:19])=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CCCCC=NS(=O)C(C)(C)C
Reactant: COc1cccc(OC)c1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) yellow solution of 2-iodo-1,3-dimethoxybenzene (6.337 g; 24.00 mmol) in anh. THF (130 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (15.0 ml; 24.00 mmol). The resulting yellow solution was further stirred at −78° C. for 15 min. A yellow solution of ethyl 6-((tert-butylsulfinyl)imino)hexanoate (5.018 g; 19.20 mmol) in anh. THF (12 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 50 min. The resulting orange reaction mixture was treated successively with aq. sat. NH4Cl (65 ml), Et2O (200 ml) and water (60 ml). The separated yellow organic layer was then washed with brine (60 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 6-(2,6-dimethoxyphenyl)-6-(1,1-dimethylethylsulfinamido)hexanoate as a yellow oil. LC-MS (conditions B): tR=0.91 min.; [M+H]+: 400.05 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([N:7]1[CH2:11][CH2:10][CH:9]([NH:12]C(OC(C)(C)C)=O)[CH2:8]1)=[O:6])[CH3:2].[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[CH2:1]([O:3][C:4](=[O:20])[C:5]([N:7]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8]1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N1CCC(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(=O)N1CCC(N)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
106.2 (3-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-oxo-acetic acid ethyl ester (1.5 g) was dissolved in CH2Cl2 (7 ml) and TFA (7 ml) was added. The mixture was stirred at 25° C. for 3 h, evaporated to dryness to yield crude (3-amino-pyrrolidin-1-yl)-oxo-acetic acid ethyl ester trifluoroacetate as red brown oil (1.57 g). MS 187.3 ([M+H]+)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH3:37])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)[CH3:37])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: CC(Oc1cccc(Br)n1)C1CCCCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OC(C)C5CCCCC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(1-cyclohexyl-ethoxy)-pyridine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[F:17][C:18]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:19]=1[CH2:20][N:21]([CH:42]([CH3:44])[CH3:43])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([N:34]2[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:18]([F:17])[C:19]=1[CH2:20][N:21]([CH:42]([CH3:44])[CH3:43])[C:22](=[O:23])[NH:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([N:34]2[CH2:35][CH2:36][CH:37]([CH2:40][NH:1][CH2:2][C@@H:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH2:38][CH2:39]2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CC(C)N(Cc1c(F)cccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N(Cc1c(F)cccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.159 g, 0.65 mmol), 1-(2,6-difluoro-benzyl)-3-[4-(4-formyl-piperidine-1-sulfonyl}-phenyl]-1-isopropyl-urea (0.6 mol),and glacial acetic acid (0.037 g, 0.65 mmol) in 5 mL methanol was stirred for 1 hour over 4A molecular sieves. In one portion sodium cyanoborohydride (0.041 g, 0.65 mmol) was added and the mixture stirred over night at ambient temperature. The sieves were filtered and the filtrate was preabsorbed on silica gel. The solids were purified by flash chromatography (CH2Cl2—CH3OH, 19:1) to give 0.12 g of product as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=[O:9])[N:6]=1.[Br:21]N1C(=O)CCC1=O>CO>[NH2:1][C:2]1[S:3][C:4]([Br:21])=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1nc(N)sc1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 12 g of 2-(2-aminothiazol-4-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetic acid and 9.54 g of N-bromosuccinimide in 100 ml of methanol is stirred at 60° C. for 2 hours.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]([CH2:42][CH3:43])[C:11]([NH:13][C:14]1[C:15]([C:25]2[NH:29][C:28]3[CH:30]=[C:31]([N:35]4[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]4)[C:32]([F:34])=[CH:33][C:27]=3[N:26]=2)=[N:16][N:17](C2CCCCO2)[CH:18]=1)=[O:12])[CH3:9]>ClCCl>[CH2:42]([N:10]([CH2:8][CH3:9])[C:11]([NH:13][C:14]1[C:15]([C:25]2[NH:29][C:28]3[CH:30]=[C:31]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)[C:32]([F:34])=[CH:33][C:27]=3[N:26]=2)=[N:16][NH:17][CH:18]=1)=[O:12])[CH3:43]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCN(C)CC3)cc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCN(C)CC3)cc2[nH]1
Temperature: 22 °C
Reaction time: 72 h
Yield: 48.1 %

Procedure:
0.7 mL of trifluoroacetic acid is added to a solution of 250 mg of 1,1-diethyl-3-[3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]urea in solution in 2 mL of dichloromethane. The reaction medium is stirred at 22° C. for 72 hours. The reaction medium is concentrated under vacuum in a rotary evaporator. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-12 cartridge. The elution is carried out in pure dichloromethane for 15 min and then in dichloromethane containing 10% of ammoniacal methanol. 100 mg of 1,1-diethyl-3-{3-[5-fluoro-6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}urea are obtained in the form of a beige solid. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.18 (t, J=7.0 Hz, 6H); 2.90 (s, 3H); 3.05 (m, 2H); 3.28 (m, 2H); 3.38 (q, J=7.0 Hz, 4H); 3.54 (m, 4H); 7.24 (d, J=8.0 Hz, 1H); 7.46 (d, J=11.5 Hz, 1H); 8.00 (s, 1H). EI mass spectrum: m/z=414 (M)+.; m/z=341 (M−C4H11N)+; m/z=114 CF3CO2H+. relative to TFA; m/z=72 C4H10N+; m/z=69 CF3+ relative to TFA; m/z=45 CO2H+ relative to TFA, base peak; m/z=43 C2H5N+.