Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([OH:21])[CH2:17][CH:18]([CH3:20])[CH3:19])=[N:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[N:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CC(O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Temperature: 70 °C
Yield: 102.6 %

Procedure:
Add manganese dioxide (240 mg) to a solution of 5-tert-butoxycarbonylaminomethyl-2-(1-hydroxy-3-methyl-butyl)-pyridine (60 mg, 0.2 mmol) in anhydrous 1,4-dioxane (1 mL) at room temperature. Heat the reaction mixture at 70° C. for 2 h. Filter the reaction mixture over Celite® and concentrate in vacuo to afford the desired intermediate (60 mg, 99%).
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH:12]2[CH2:16][O:15][C:14](=[O:17])[NH:13]2)(=O)=O)=CC=1.[C:19]([O-])(=[S:21])[CH3:20].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)=O>[C:19]([O:10][CH2:11][CH:12]1[CH2:16][O:15][C:14](=[O:17])[NH:13]1)(=[S:21])[CH3:20]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(=O)N2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(C)=O
Product: CC(=S)OCC1COC(=O)N1
Yield: 75 %

Procedure:
A solution of 2-oxo-1,3-oxazolidin-4-ylmethyl p-toluenesulfonate (1.22 g., 0.0045 mole) and tetrabutylammonium thioacetate (1.71 g, 0.0054 mole) in 75 ml. acetone was refluxed under nitrogen for 90 min. The reaction mixture was concentrated to dryness and the residue was chromatographed on silica gel (250 g). Elution with 4:1 ethyl acetate-hexane yielded 580 mg. of the title compound (75% yield). NMR (CDCl3): 2.38 (s, 3H); 3.06 (d, 2H); 3.84-4.67 (c, 3H); and 6.3 (b, 1H)ppm.
Reaction SMILES: [C:1]1([Mg]Br)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][C@@:14]12[C:22](=[O:23])[CH2:21][C@@H:17]([C:18]1([CH3:20])[CH3:19])[CH2:16][CH2:15]2>C1COCC1>[C:1]1([C:22]2([OH:23])[CH2:21][CH:17]3[C:18]([CH3:19])([CH3:20])[C@:14]2([CH3:13])[CH2:15][CH2:16]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2
Reactant: Br[Mg]c1cccc2ccccc12
Solvent: C1CCOC1
Product: CC1(C)C2CC[C@]1(C)C(O)(c1cccc3ccccc13)C2

Procedure:
The resulting THF solution of 1-naphthylmagnesium bromide was cooled to room temperature. Then, a THF (200 ml) solution of (-)-camphor (50 g, 0.328 mol) was added thereto, and the whole was heated under reflux for 72 hours. The reaction was terminated by cooling with ice-water and adding saturated ammonium chloride aq solution. Then, the organic layer was filtered off, and the solid residue was treated with 10% hydrochloric acid and extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate and, after filtration, concentrated to give 121 g of a crude (1S)-2-(1-naphthyl)-1,7,7-trimethylbicyclo [2.2.1]-heptan-2-ol as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(Cl)[Cl:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([Cl:16])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(CC(=O)O)cc1OC
Product: COc1ccc(CC(=O)Cl)cc1OC

Procedure:
(3,4-dimethoxyphenyl)acetyl chloride is prepared according to the method described in Example 8 using 3,4-dimethoxyphenylacetic acid (2.85 g, 14.5 mmol) to give a brown oil which is dissolved in chloroform (10 mL). This solution is refluxed for 3 hours with a solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanethiol (2.8 g, 14 mmol) in chloroform (10 mL) under nitrogen. The reaction mixture is partitioned between 1M sodium hydroxide solution (100 mL) and dichloromethane (80 mL). The organic layer is separated and the aqueous is washed with more dichloromethane (2×50 mL). The combined dichloromethane extracts are dried over sodium sulfate, and the solvent is removed to leave the crude free ester. This is purified by column chromatography and converted to the hydrochloride salt by treatment with HCl in ether. The product is recrystallised from hot ethyl acetate/methanol to yield the title compound.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:15](=[O:17])[N:14](COCC[Si](C)(C)C)[N:13]=[CH:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]=1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH:46]2[CH2:48][CH2:47]2)[CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([C:8]1[C:16]2[C:15](=[O:17])[NH:14][N:13]=[CH:12][C:11]=2[N:10]([CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:9]=1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH:46]2[CH2:48][CH2:47]2)[CH:36]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(Cc3ccccc3)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCc2ccccc2)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]ncc2c1c(Cc1ccccc1)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To 278 mg (0.413 mmol) of 3-benzyl-1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 19-(a) was added 3.3 ml of 1,4-dioxane solution containing 4N hydrogen chloride, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, to the obtained solid were added 8.6 ml of methanol and 4.3 ml of 28% aqueous ammonia, and the mixture was stirred at room temperature for 1 hour. Then, the solution was concentrated under reduced pressure, water was added to the obtained concentrate, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 198 mg of the title compound as a white solid. (Yield: 88%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2.[H-].[Na+].Cl.Cl[CH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH3:26].CO>CN(C)C=O.O.ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH3:26])[CH2:9][CH2:8][CH2:7]2
Reactant: O=[N+]([O-])c1cc(F)c2c(c1)CCCN2
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCCC1CCN1CCCc2cc([N+](=O)[O-])cc(F)c21
Temperature: 90 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a stirred solution of 8-fluoro-6-nitro-1,2,3,4-tetrahydroquinoline (500 mg, 2.55 mmol) in N,N-dimethylformamide (11 ml), cooled to 0° C. was added sodium hydride, 60% (326 mg, 8.16 mmol) with vigorous stirring. When the bubbling subsided, 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (938 mg, 5.10 mmol) was added and the reaction mixture (dark red) was stirred at 90° C. for 1 h. TLC analysis showed that the reaction mixture was complete. The mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate (3×). The combined organics were then washed with a 1:1 mixture of brine and water (3×), then brine (1×), dried over sodium sulfate, filtered and concentrated. The residue was chromatographed in ethyl acetate, then 10% methanol in 1:1 ethyl acetate:dichloromethane, giving the desired 8-fluoro-1-(2-(1-methylpyrrolidin-2-yl)ethyl)-6-nitro-1,2,3,4-tetrahydroquinoline (665 mg, 2.164 mmol, 85% yield). 1H NMR (DMSO-d6) δ 7.77 (dd, J=15, 2.7 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 3.43-3.32 (m, 4H), 2.94-2.88 (m, 1H), 2.78-2.73 (m, 2H), 2.19 (s, 3H), 2.06-1.97 (m, 2H), 1.91-1.83 (m, 4H); 1.64-1.56 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([C:15]([CH:23]([CH3:25])[CH3:24])(O)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:26])(=[O:5])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH3:27][N:2]([CH3:1])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([C:15](=[C:23]([CH3:24])[CH3:25])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:26])(=[O:4])=[O:5]
Reactant: CC(C)C(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)N(C)C)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)=C(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)N(C)C)c2c1

Procedure:
When the procedure of Example 72 was repeated using 1.2 g. (3.2 mmoles) of 1-dimethylaminosulfonyl-2-amino-6-(α-isopropyl-α-hydroxybenzyl)benzimidazole, 750 mg. of p-toluenesulfonic acid, and 100 ml. of chloroform, there was obtained 1-dimethylaminosulfonyl-2-amino-6-(α-isopropylidenebenzyl)benzimidazole.
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[S:12][CH:13]=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:34]([NH:36][C:37]1[S:38][C:39]([Br:49])=[C:40]([C:42](=[N:46][O:47][CH3:48])[C:43](O)=[O:44])[N:41]=1)=[O:35]>C(OCC)(=O)C.CN(C)C=O>[CH:34]([NH:36][C:37]1[S:38][C:39]([Br:49])=[C:40]([C:42](=[N:46][O:47][CH3:48])[C:43]([NH:1][CH:2]2[C:19](=[O:20])[N:4]3[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]4[S:12][CH:13]=[N:14][N:15]=4)[CH2:7][S:8][C@H:3]23)=[O:44])[N:41]=1)=[O:35]
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(NC=O)sc1Br
Yield: 59.6 %

Procedure:
A solution of 7-amino-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.) and trimethylsilylacetamide (3.4 g.) in dry ethyl acetate (30 ml.) and a mixture of dimethylformamide (0.3 ml.), phosphoryl chloride (0.35 ml.), 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 1.0 g.) and dry ethyl acetate (30 ml.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:20][CH3:21]
Reactant: BrCCBr
Reactant: COc1cc(C=O)cc(-c2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(-c2ccccc2)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
Under N2, tetrakis-triphenylphosphinepalladium(0) was added to a mixture of the above dioxolane (10 g, 31 mmoles), benzeneboronic acid (4.5 g, 37 mmoles), toluene (67 mL), 2 M aqueous sodium carbonate (33 mL) and methanol (20 mL). The resulting mixture was heated at reflux under N2 for 16 hours. After cooling the mixture was diluted with water (150 mL) and washed with heptane (400 mL). The aqueous phase was made acidic with 3N hydrochloric acid and extracted with ethyl acetate (3×300 mL). The combined organic extracts were dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography over silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:2) to afford 5.49 g (77%) of 4-hydroxy-3-methoxy-5-phenylbenzaldehyde. M.p. 107-108° C. 1,2-Dibromoethane (41 mL, 0.48 moles) was added to a mixture of the above 4-hydroxy-3-methoxy-5-phenylbenzaldehyde (5.49 g, 24 mmoles) and potassium carbonate (17 g, 123 mmoles) in DMF (80 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (200 mL), dried over MgSO4 and evaporated in vacuo to afford 8.1 g (100%) of 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C@H:8]([NH:13][C:14](=[O:38])[CH:15]([CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)[CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:9](OC)=[O:10])=[CH:5][N:4]=[CH:3]1.[CH3:39][NH2:40]>CO.O1CCCC1>[CH3:39][NH:40][C:9]([C@@H:8]([NH:13][C:14](=[O:38])[CH:15]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[CH2:7][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)=[O:10]
Reactant: CN
Reactant: COC(=O)[C@H](Cc1cncn1C)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)[C@H](Cc1cncn1C)NC(=O)C(Cc1cccc2ccccc12)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 611 mg (1.2 mmol) of the product from Example 6 in 20 mL MeOH and 10 mL tetrahydrofuran was cooled in ice and saturated with gaseous methylamine. The cooling was removed and the solution allowed to stir at room temperature overnight. The solvent was removed under reduced pressure and the residue triturated with acetonitrile to give 529 mg of the pure product, mp 250-252° C. The structure was confirmed by NMR and mass spectroscopy; (m+H)+ =505.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([C@H:20]1[CH2:27][C:24]2([CH2:26][CH2:25]2)[CH2:23][NH:22][C@@H:21]1[C:28](O)=[O:29])=[O:19])([CH3:16])([CH3:15])[CH3:14].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([O-])(O)=O.[Na+]>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:28]([C@@H:21]3[C@@H:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:27][C:24]4([CH2:25][CH2:26]4)[CH2:23][NH:22]3)=[O:29])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN[C@@H]1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
1-Phenylpiperazine (124 mg, 0.76 mmol) was added to a mixture of (6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acid (180 mg, 0.70 mmol) and BOP (320 mg, 0.75 mmol) in DMF (4 mL) at 0° C. The mixture was stirred at 0° C. for 10 min, then N-methylmorpholine (300 μL) was added. The resulting mixture was stirred at RT for overnight, diluted with 5% NaHCO3 and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated brine and dried over Na2SO4. The solution was filtered and concentrated to afford 248.4 mg of the tert-butyl(6S,7S)-6-[(4-phenylpiperazin-1-yl)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[CH:31][CH:32]=[N:33]2)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:38])=[O:5])(=[O:13])=[O:14])=[C:16]([O:25][CH2:26][CH2:27][C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][CH:32]=[N:33]3)[CH:17]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)OC(C)(C)C)c(OCCc2cccc3ncccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2cccc3ncccc23)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68 %

Procedure:
3-[4-Acetylamino-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (130 mg, 0.24 mmol) was dissolved in 2 mL methylene chloride and 2 mL trifluoroacetic acid. The reaction was stirred at room temperature for 90 minutes. The reaction was concentrated in vacuo, and chased with toluene to yield 110 mg (68%) of the desired product.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]([C:8]1[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=1[O:10][C:11]1[C:25]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][C:14]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:17][C:13]=2[CH:12]=1)#[N:7]>>[C:6]([C:8]1[CH:36]=[CH:35][CH:34]=[CH:33][C:9]=1[O:10][C:11]1[C:25]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:24][C:14]2[NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:17][C:13]=2[CH:12]=1)(=[O:2])[NH2:7]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1cccnc1
Product: NC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1cccnc1

Procedure:
A 80% sulfuric acid solution of 3.5 mg of 5-(2-cyano-phenoxy)-2-pyridin-2-yl-6-(pyridin-3-yloxy)-1H-benzimidazole obtained in Example 5 was stirred overnight at 50° C. The reaction mixture was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was evaporated away under reduced pressure to obtain the entitled compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[O:9](C(OC(C)(C)C)=O)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:10](=[O:9])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1cccc(Br)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 6-bromopyridin-2-amine (15 g, 86.49 mmol, 1 eq.) in 250 ml of DCM cooled to 0° C. were added DMAP (1.05 g, 8.67 mmol, 0.1 eq.), TEA (9.65 g, 95.36 mmol, 1.1 eq.) and BOC2O (22.70 g, 104.03 mmol, 1.2 eq.) portionwise. The reaction was stirred at 0° C. for 5 h and quenched with sat. aqueous NH4Cl. The aqueous layer was extracted with DCM, and the organics were combined, dried over MgSO4 and concentrated. The crude residue was purified by chromatography on silica gel to give impure tert-butyl (6-bromopyridin-2-yl)carbamate (mix 80/20 of mono and bis BOC) as a white solid. A chemical purification was then done. This solid was dissolved in 250 ml of THF cooled to 0° C. then iPrMgCl.LiCl (2 M, 51.89 ml, 103.78 mmol, 1.2 eq.) was added dropwise. The solution was stirred 30 min and quenched with aqueous sat. NH4Cl. The aqueous layer was separated and extracted with DCM. The organics were combined, dried over MgSO4 and concentrated to give tert-butyl (6-bromopyridin-2-yl)carbamate (15.96 g, 68%) as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:6]=1.[C:18]([C:21]1[CH:22]=[CH:23][C:24]([F:30])=[C:25](B(O)O)[CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[F:30][C:24]1[CH:25]=[CH:26][C:21]([C:18](=[O:20])[CH3:19])=[CH:22][C:23]=1[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)c2)cc1
Reactant: CC(=O)c1ccc(F)c(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc(F)c(-c2cn(-c3ccc(OC(F)(F)F)cc3)cn2)c1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
4-Bromo-1-(4-trifluoromethoxyphenyl)-1H-imidazole (200 mg, 0.651 mmol), 5-acetyl-2-fluorophenylboronic acid (178 mg, 0.977 mmol), tetrakis(triphenylphosphine)-palladium(0) (7 mg, 0.007 mmol), a 2 N aqueous solution of potassium carbonate (0.651 mL) and dioxane (8 mL) were combined and added to a microwave vessel. The reaction mixture was heated in the microwave with stirring to 150° C. for 20 min. LC-MS indicated 88% anticipated product; TLC (1:1 hexanes:EtOAc) indicated the presence of starting material plus 3 other materials. EtOAc and H2O were added to the reaction mixture. The aqueous layer was extracted with EtOAc, and the organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by chromatography with gradient elution (100% hexanes to 100% EtOAc) resulting in an off-white solid (90 mg): mp 129° C.; ESIMS m/z 265.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][O:26]CC2C=CC=CC=2)=[O:24])[S:13][CH:14]=1)([O-])=O.Cl.Cl[Sn]Cl.[OH-].[Na+]>CO.O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][OH:26])=[O:24])[S:13][CH:14]=1
Reactant: O=C(CCCCCCC(=O)Nc1nc(-c2ccccc2[N+](=O)[O-])cs1)NOCc1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccccc1-c1csc(NC(=O)CCCCCCC(=O)NO)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a mixture of compound 15 (0.040 g, 0.083 mmol) in methanol (2 ml) was added 1 ml of concentrated HCl. The suspension was cooled to 0° C. Then SnCl2 (0.094 g, 0.49 mmol) was added and the reaction mixture was stirred overnight at room temperature. The mixture was then diluted with 5 ml of water, adjusted to pH 10 with 5N NaOH and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with water, dried over K2CO3 and concentrated in vacuo. The crude product was purified by reverse phase HPLC to afford Octanedioic acid hydroxyamide [4-(2-amino-phenyl)-thiazol-2-yl]-amide 16 (0.016 g, 53% yield). NMR (400 MHz, DMSO-d6 cont 5% TFA) δ (ppm) 12.13 (1H, s), 7.56 (1H, d, J=7.0 Hz), 7.40 (1H, s), 7.09 (1H, t, J=7.0 Hz), 6.83 (1H, d, J=7.0 Hz), 6.72 (1H, m), 3.75-3.39 (4H, brs), 2.44 (2H, t, J=7.3 Hz), 2.29 (2H, t, J=7.3), 1.61 (2H, m), 1.51 (2H, m), 1.30 (4H, m).
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[O:13]CC1C=CC=CC=1)(=[O:6])=[O:5])[CH3:3]>[Pd].C(O)C>[OH:13][CH:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[NH:7][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5]
Reactant: CC(C)S(=O)(=O)NC1CCCC1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)S(=O)(=O)NC1CCCC1O

Procedure:
Scheme IA, step B: [(Methylethyl)sulfonyl][2-(phenylmethoxy)cyclopentyl]amine (2.00 g, 6.72 mmol), palladium on carbon (250 mg) and ethanol (50 mL) were combined and placed on the power shaker under a hydrogen atmosphere at 60 psi's overnight. In the morning, the solution was filtered over a Celite® mat and the resulting filtrate was concentrated under reduced vacuum to yield 1.50 g as a viscous oil. TLC showed material was very pure and was used without further purification. Yield=Quantitative. Ion spray M.S. 206 (M*−1). Analysis calculated for C8H17NO3S: Theory: C, 46.35; H, 8.26; N, 6.75. Found: C, 46.27; H, 7.97; N, 6.70.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16](C3C(=O)NC(=O)N(C4C=CN=C(NCC(NC5SC=C(CC(O)=O)N=5)=O)N=4)C=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:45]=1)[CH3:2].C(OC(=O)C)(=[O:48])C.C(Cl)(=O)C.C(OC(=O)CC)(=O)CC.C(Cl)(=O)CC.C(O)(=O)CC>C(O)(=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[O:48])[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:45]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Agent: CCC(=O)Cl
Agent: CCC(=O)OC(=O)CC
Solvent: CCC(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CCc1ccc2c(c1)CCc1oc(C)nc1C2=O

Procedure:
The subtitle compound was prepared from the product of step (v) (9.20 g) according to the method of example 1 step (v) using acetic anhydride (4.9 ml), acetyl chloride (7.2 ml) and acetic acid (47 ml) (instead of propionic anhydride, propionyl chloride, and propionic acid).