Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7](C(O)=O)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:14][CH:15]=1
Reactant: O=C(O)C(Cc1ccc(F)cc1)C(=O)O
Solvent: CCOCC
Product: O=C(O)CCc1ccc(F)cc1

Procedure:
The 4-fluorobenzylmalonic acid is heated to 170° to 175° for 1.5 hours. After cooling, the reaction product is stirred with a little diethyl ether. 41.6 g of 3-(4-fluorophenyl)propionic acid of m.p. 85° to 88° [from ethyl acetate/petroleum ether (1:4)] thereby crystallize out.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:9])[CH2:4][CH2:3]1>C(O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:25]2[CH2:26][CH2:27][N:28]([C:8]([CH2:10][CH3:11])=[O:9])[CH2:29][CH2:30]2)=[O:9])[CH2:6][CH2:7]1
Reactant: CN1CCN(C(=O)c2c(N3CCNCC3)n(-c3ccccc3)c3ccccc23)CC1
Solvent: CCO
Product: CCC(=O)N1CCN(c2c(C(=O)N3CCN(C)CC3)c3ccccc3n2-c2ccccc2)CC1

Procedure:
A mixture of 4 g (10 mmols) of 1 -phenyl-2-(1-piperazinyl)-indole 3-carboxylic acid 4-methyl-piperazide, 10 ml of ethyl chloroformiate and 40 ml of ethanol were heated at the boil for 24 hours. After cooling, the precipitate was suctionfiltered and washed with ethanol. The yield amount of 4.2 g in the form of hydrochloride that decomposed above 300° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8](=[O:20])[CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:4][CH:3]=1.[Br:21]Br>C(O)(=O)C>[Br:21][CH:9]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:20]
Reactant: BrBr
Reactant: Cc1cccc(C(=O)Cc2ccc3ncccc3c2)n1
Solvent: CC(=O)O
Product: Cc1cccc(C(=O)C(Br)c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
To a stirred solution of 1-(6-methyl-pyridin-2-yl)-2-quinolin-6-yl-ethanone of Step C (1.13 g, 4.3 mmol) in acetic acid (40 mL) was slowly added a solution of bromine (0.22 ml, 4.3 mmol, 1 equiv) in acetic acid (5 mL) over 2 minutes. After stirring at the ambient temperature for 3 hours the reaction mixture was concentrated in vacuo, and the residue was triturated with a mixture of ethyl acetate (20 mL) and ether (20 mL). The crude hydrobromide was converted to the free base by treating with saturated aqueous sodium hydrogen carbonate. The product was extracted with ethyl acetate, the combined organics were washed with saturated aqueous sodium chloride and concentrated in vacuo. Silica gel chromatography (9:1 methylene chloride/acetonitrile) provided title compound as a yellow oil (0.95 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:20][CH2:21][CH2:22]Cl)[CH2:18][CH3:19].O>CN(C)C=O>[CH2:17]([O:20][CH2:21][CH2:22][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH3:19]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCOCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.6 %

Procedure:
To a solution of 4-hydroxybenzoic acid (3.04 g) and anhydrous potassium carbonate (5.52 g) in N,N-dimethylformamide (20 ml) was added 2-propyloxyethyl chloride (2.94 g), and the mixture was stirred at room temperature overnight, and then stirred at 80° C. for 8 hours. To a reaction solution was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure to give the title compound (5.21 g; crude).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[F:30])[NH:26][N:25]=[CH:24]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][C:29]=2[F:30])[NH:26][N:25]=[CH:24]3)=[O:19])=[CH:6][CH:7]=1
Reactant: Nc1cc2cn[nH]c2cc1F
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1C
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(Cl)cc2)CC(=O)N1C

Procedure:
The title compound was prepared from the product of Example 56, Step 2 and 5-amino-6-fluoroindazole using the method described in Example 56, Step 3. MS (ES+) m/e 413 [M+H]+
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]3[NH:15][N:16]=[C:17]([NH2:18])[C:12]3=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1>[NH2:18][C:17]1[C:12]2[C:13](=[N:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([NH:2][S:27]([C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[F:19])(=[O:28])=[O:29])=[CH:4][CH:5]=3)=[CH:10][N:11]=2)[NH:15][N:16]=1
Reactant: Cc1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccc(-c2cnc3c(N)n[nH]c3n2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(F)c(S(=O)(=O)Nc2ccc(-c3cnc4c(N)n[nH]c4n3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of 6-(4-amino-phenyl)-1H-pyrazolo[3,4-b]pyrazin-3-ylamine hydrochloride and 397 mg of 2-fluoro-5-methyl-benzenesulfonyl chloride in 4 ml DCM, 0.16 ml pyridine were added and the reaction mixture was stirred for 16 h at RT. Then, the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 220 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:5]=1[NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:5]=1[NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)C(=O)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)Nc1ccc(C(F)(F)F)cc1N

Procedure:
Shake 85 g. of 2'-nitro-4'-trifluoromethylisobutyranilide in 1.0 liter of ethanol containing 3.0 g. of 5% palladium on charcoal in a parr shaker under approximately 50 lbs. per square inch hydrogen pressure for twenty-four hours. Filter, remove the ethanol and recrystallize from a dichloromethane-chloroform-hexane mixture, obtaining the product of this step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:44][CH2:43][CH2:42][C@@:19]3([CH2:23][C@H:22]([O:24][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][C:3](=[O:45])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:44][CH2:43][CH2:42][C@@:19]3([CH2:23][C@H:22]([OH:24])[CH2:21][CH2:20]3)[CH:18]=2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8]
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=C[C@]3(CCC2)CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C3)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC#C[C@@H](CC(=O)OC)c1ccc(OCC2=C[C@]3(CCC2)CC[C@@H](O)C3)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.9 %

Procedure:
To a solution of (3S)-3-{4-[(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en-7-ylmethoxy]-phenyl}-hex-4-ynoic acid methyl ester (738 mg) obtained in step 8 in tetrahydrofuran (3.7 mL) was added tetra-n-butylammonium fluoride (1M tetrahydrofuran solution; 2.97 mL), followed by stirring the mixture at room temperature for 17 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:3) to give (3S)-3-[4-((2R,5R)-2-hydroxy-spiro[4.5]dec-6-en-7-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (395 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10](COCCOC)[N:9]=2)=[CH:4][CH:3]=1>C(O)C.[Pd].[C]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COCCOCn1nc(-c2ccc(F)cc2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
To a solution of 1-{[3-(4-fluorophenyl)-5-nitro(1H-indazolyl)]methoxy}-2-methoxyethane (100 mg, 0.29 mmol) in ethanol (30 mL) was added a scoup of Pd/carbon. The reaction was stirred overnight at room temperature under an atmosphere of hydrogen. It was filtered over celite and the solution concentrated to an oil. The oil was taken up in methanol (20 mL) and 6N HCl (20 mL) and the solution was heated to 75° C. for 3 hours. The solution was concentrated under vacuo, added to saturated bicarbonate (100 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were dried (Na2SO4), concentrated to an oil and chromatographed on silica gel, eluting with 50% ethyl acetate/hexane to give the title compound (35 mg, 53% yield). 1H NMR (CDCl3) δ 10.1 (br s, 1H), 7.89 (dd, 1H), 7.23–7.16 (m, 4H), 6.91 (dd, 1H), 3.6 (br s, 1H); ES-MS (m/z) 228 [M+1]+.
Reaction SMILES: [OH-].[K+].C(O[CH:7]1[C:15]2[C:10](=[C:11]([CH3:21])[C:12]([CH2:17]COC)=[C:13]([CH3:16])[CH:14]=2)[C:9](=[O:22])[CH:8]1[CH3:23])(=O)C>O1CCCC1.[Zn]>[CH3:23][C:8]1[C:9](=[O:22])[C:10]2[C:15]([CH:7]=1)=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[C:11]=2[CH3:21]
Reactant: COCCc1c(C)cc2c(c1C)C(=O)C(C)C2OC(C)=O
Agent: [K+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1=Cc2cc(C)c(C)c(C)c2C1=O

Procedure:
The 2,5,6,7-tetramethyl-1-indenone was prepared by reducing 2,4,5,6-tetramethyl-1,3-indanione with zinc dust at 50° C. Product was purified by chromatography with 1% ethyl acetate in benzene to yield two isomers. The major isomer was treated with 10% potassium hydroxide, then purified by sublimation. The compound has the structure: ##STR8## Dehydropterosin O synthesis: 3-acetoxy-6(beta-methoxy) ethyl-2,5,7-trimethyl-1-indanone was dissolved in tetrahydrofuran and 10% potassium hydroxide and refluxed for two hours. The solution was then extracted three times with ether and the combined extracts chromatographed with 2% ethylacetate in benzene to yield the Dehydropterosin O compound. The compound has the structure: ##STR9## R=H Dehydropterosin B R=CH3Dehydropterosin O
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=C(\C)/CCC(OC)=O)=[C:16]([CH2:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[O:38]=[O+][O-]>C(Cl)Cl.CO>[Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]=[O:38])=[C:16]([CH2:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6- ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (10.6 g) in methylene chloride (150 ml), methanol (150 ml), and pyridine (5 ml) was treated with an excess of ozone at -70° C. The reaction was quenched with dimethylsulfide (20 ml) and stirred for 5 hours at 25° C. The reaction mixture was poured into 1N aqueous sodium hydrogen mullets. Extraction with 1:1 ethyl acetate:hexane gave an oil which on purification by silica gel chromatography gave 2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-acetaldehyde, m.p. 90.9°-91.6° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[CH2:15]([C:22]1[C:27]([Cl:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=1[Cl:32])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCl.C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][C:22]3[C:27]([Cl:28])=[CH:26][C:25]([N+:29]([O-:31])=[O:30])=[CH:24][C:23]=3[Cl:32])=[CH:17][CH:18]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cc2ccccc2)c(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In 15 ml of dichloromethane was suspended 1.30 g of AlCl3, and a solution of 1.43 g of 4-chlorobenzoyl chloride in 3 ml of dichloromethane was added to the suspension for a period of 30 minutes. A solution of 2.00 g of 4-benzyl-3,5-dichloronitrobenzene in 2 ml of dichloromethane was added for a period of 15 minutes, and the reaction mixture was refluxed for 22 hours. The reaction mixture was poured into 25 ml of ice-water, and 30 ml of chloroform and 3 ml of conc. hydrochloric acid were added. The resulting mixture was stirred for 15 minutes at a room temperature, and the organic layer was separated, washed with water and saturated aqueous sodium bicarbonate solution, dried and concentrated to quantitatively give the above-identified compound as oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[C:5]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>ClCCl>[CH2:28]([N:30]([CH2:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:6]2=[C:5]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:31][CH3:32])[CH3:29]
Reactant: CCOC(=O)c1c(CCl)nc2sc(C)c(C)c2c1-c1ccc2c(c1)OCO2
Reactant: CCNCC
Solvent: ClCCl
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc(C)c(C)c2c1-c1ccc2c(c1)OCO2
Reaction time: 14 h

Procedure:
A mixture of ethyl 6-chloromethyl-4-(3,4-methylenedioxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (1.5 g), diethylamine (1.36 g) and dichloromethane (35 ml) was stirred for 14 hours under reflux. The reaction mixture was washed with water and dried (MgSO4), then the solvent was distilled off. The residue was subjected to column chromatography on silica gel. From the fraction eluted with chloroform, was obtained ethyl 6-(N,N-diethylaminomethyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate as an oily product. This oily product was dissolved in ethanol (35 ml), to which was added ethanolic hydrogen chloride (23%, 1.2 g). The mixture was stirred for 15 minutes at room temperature, which was concentrated under reduced pressure to leave hydrochloride of ethyl 6-(N,N-diethylaminomethyl)-4-(3,4-methylenedioxyphenyl)-2,3-dimethylthieno[2,3-b]pyridine-5-carboxylate (0.8 g, 44%) as an amorphous solid product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][C:39]([OH:43])([CH:41]=[CH2:42])[CH3:40]>>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH2:42][CH2:41][C:39]([OH:43])([CH3:40])[CH3:38])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Reactant: C=CC(C)(C)O
Product: CC(C)(O)CCc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 247 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.2 g, 0.352 mmol) and 2-Methyl-3-buten-2-ol (0.110 ml, 1.056 mmol), the title compound was obtained as a solid (83 mg, 38% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 10.76 (s, 1H), 8.28 (d, J=5.49 Hz, 1H), 7.53 (m, 3H), 7.43 (m, 1H), 7.35 (d, J=6.04 Hz, 1H), 7.29 (t, J=7.69 Hz, 1H), 6.31 (d, J=5.49 Hz, 1H), 4.28 (s, 1H), 3.71 (m, 4H), 3.50 (m, 4H), 2.81 (m, 2H), 1.77 (m, 2H), 1.12 (s, 6H); MS (ESI): 620 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:23][CH2:24]2)=[O:18])[C:13]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[CH2:48][CH2:47][N:46]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3ccc(CC)c(CC)c3)NC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 34 from (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[S:4][C:5]([CH3:14])([CH3:13])[CH:6]2[C:10]([OH:12])=[O:11].[Na].[C:16]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]O)=[CH:22][CH:21]=1)(=[O:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH2:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[S:4][C:5]([CH3:14])([CH3:13])[CH:6]2[C:10]([O:12][CH2:24][C:23]1[CH:22]=[CH:21][C:20]([O:19][C:16](=[O:18])[CH3:17])=[CH:27][CH:26]=1)=[O:11]
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Reactant: CC(=O)Oc1ccc(CO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(COC(=O)C2N3C(=O)C(N)C3SC2(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
6-Amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, sodium salt (5 mmole) in 50 ml of dimethylformamide is stirred at room temperature while 2 equivalents of p-(acetyloxy)benzyl alcohol is added. The mixture is cooled to 0° C. after which 5.5 mmole of dicyclohexylcarbodiimide in 10 ml of dimethylformamide is added. This mixture is stirred at 0° C. for 1 hour and at room temperature for 4 hours. Dicyclohexylurea is removed by filtration. The filtrate is diluted with chloroform, washed with water, dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH3:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:25]([C:32]([NH:34][OH:35])=O)C1C=CC=CC=1>C1COCC1>[OH:35][NH:34][C:32]([N:22]1[CH2:21][CH2:20][CH:19]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH3:12])[CH2:24][CH2:23]1)=[O:25]
Reactant: Cc1cnc(CN(C2CCNCC2)C(C)c2ccccn2)c(C)c1
Reactant: O=C(NO)Oc1ccccc1
Solvent: C1CCOC1
Product: Cc1cnc(CN(C2CCN(C(=O)NO)CC2)C(C)c2ccccn2)c(C)c1
Temperature: 25 °C
Yield: 38 %

Procedure:
To a solution of (3,5-Dimethyl-pyridin-2-ylmethyl)-piperidin-4-yl-(1-pyridin-2-yl-ethyl)-amine (0.124 g, 0.38 mmol) in dry THF (4 mL) was added N-(phenoxycarbonyl)hydroxylamine (Stewart, A. O. et al. J. Org. Chem. 1992, 57, 5020-5023) (0.116 g, 0.76 mmol) and the resultant solution was stirred at 60° C. overnight. The mixture was cooled to room temperature and concentrated. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 15:1:1 CH2Cl2-MeOH—NH4OH) provided 59 mg (38%) of COMPOUND 261 as a white solid. 1H NMR (CDCl3) δ 0.97-1.02 (m, 1H), 1.39-1.47 (m, 3H), 1.61-1.67 (m, 3H), 1.83-1.86 (m, 1H), 2.27 (s, 3H), 2.28 (s, 3H), 2.53-2.61 (m, 1H), 2.71-2.80 (m, 1H), 2.92-3.00 (m, 1H), 3.79-3.99 (m, 4H), 6.48-6.85 (m, 2H), 7.11-7.15 (m, 1H), 7.23 (br s, 1H), 7.34-7.40 (m, 1H), 7.58-7.63 (m, 1H), 8.19 (br s, 1H), 8.51 (d, 1H, J=3.9 Hz); 13C NMR (CDCl3) δ 16.42, 18.31, 18.68, 30.14, 30.52, 44.12, 44.18, 51.88, 55.29, 58.52, 122.25, 123.99, 132.19, 133.15, 136.48, 139.60, 146.63, 148.84, 155.08, 161.12, 162.90; ES-MS m/z 384 (M+H). Anal. Calcd. For C21H29N5O2.0.1CH2Cl2.1.0H2O: C, 61.81; H, 7.67; N, 17.08. Found: C, 62.17; H, 7.33; N, 16.74.
Reaction SMILES: [F-].C([N+:6]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:11][CH2:12][CH2:13][CH3:14])CCCC)CCC.[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>>[N:6]1[C:11]([C@H:21]2[CH2:20][C@@H:19]2[CH2:23][OH:22])=[CH:12][CH:13]=[C:14]2[CH2:18][CH2:17][CH2:16][C:15]=12
Reactant: C1CCOC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OC[C@H]1C[C@@H]1c1ccc2c(n1)CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of S-5 (3.19 g, 10.5 mmol) in THF (40 mL) was added tetrabutyl ammonium fluoride solution 1M (10.5 mL, 10.5 mmol). The resulting mixture was stirred 2 hours at room temperature and concentrated. Flash column separation using a 10-100% ethyl acetate/hexane gradient gave S-6 as an oil. (1.44 g, 72%)
Reaction SMILES: [Br:1][C:2]1[C:6](Br)=[C:5]([Br:8])[NH:4][N:3]=1.[CH2:9]([O:11]CC)C.C([Li])CCC.CN(C)C=O>CCCCCC.O>[Br:8][C:5]1[C:6]([CH:9]=[O:11])=[C:2]([Br:1])[NH:3][N:4]=1
Reactant: CCOCC
Reactant: Brc1n[nH]c(Br)c1Br
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1c(Br)n[nH]c1Br
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
81.7 g (0.268 mol) of 3,4,5-tribromopyrazole are introduced with stirring into 1500 mL of diethyl ether at a temperature in the region of 20° C. and under an argon atmosphere. The mixture is cooled to a temperature in the region of −78° C., followed by dropwise addition of 335 mL (0.536 mol) of a 1.6 M solution of n-butyllithium in hexane over 3 hours 15 minutes. The reaction mixture is stirred for 1.5 hours at a temperature in the region of −75° C., followed by dropwise addition of 100 mL (1.34 mol) of dimethylformamide, while keeping the temperature below −70° C. The mixture is stirred for a further 2 hours at a temperature in the region of −75° C., and then for 15 hours at a temperature in the region of 20° C. The reaction medium is then cooled in an ice-water bath and 1000 mL of water are added. After separation of the phases by settling, the aqueous phase is extracted with 500 mL of diethyl ether and with three times 500 mL of ethyl acetate. The aqueous phase is then acidified with citric acid solution to pH 3 (formation of a precipitate is observed) and extracted with twice 1000 mL of diethyl ether. The organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa), and the yellow solid obtained is taken up in 300 mL of water and stirred for 2 hours at a temperature in the region of 20° C. The mixture is then filtered and the solid is washed with twice 50 mL of water, dried in a fume cupboard and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 51.3 g of 3,5-dibromo-1H-pyrazole-4-carboxaldehyde are thus obtained in the form of a yellow powder melting at 173° C.