Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]12[CH:8]([C:9]([OH:11])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C([O-])(O)=O.[Na+].[Na+].[Cl-].[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[N:2]12[CH:8]([C:9]([O:11][CH2:19][CH3:20])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(O)C1C2CCN1CC2
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1C2CCN1CC2

Procedure:
A solution of 1-azabicyclo[2.2.1]heptane-7-carboxylic acid hydrochloride (1.20 g, 6.76 mmol) in absolute ethanol (10 mL) and concentrated sulfuric acid (2 mL) was refluxed for 8 h. The reaction mixture was cooled and then basified with saturated aqueous NaHCO3 to pH 8-9. The solution was saturated with solid NaCl and extracted with chloroform (4×20 mL). The combined chloroform extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to give a light brown liquid. This was purified by Kugelrohr distillation at 120° C. and 2.5 mm pressure to afford 1.00 g (90%) as a colorless liquid.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([N+:25]([O-:27])=[O:26])=[C:12]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:13]=2)=[CH:5][CH:4]=1)=O.[CH2:28]([CH2:30][NH2:31])[OH:29].C([O-])([O-])=O.[K+].[K+].C(O)(C)C>ClCCCl.C(Cl)Cl.C(N(CC)CC)C.CO>[OH:29][CH2:28][CH2:30][NH:31][CH2:1][C:3]1[S:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([N+:25]([O-:27])=[O:26])=[C:12]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:13]=2)=[CH:5][CH:4]=1
Reactant: NCCO
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccc(C=O)s3)ccc2[N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCCl
Product: COc1ccc(C(=O)Nc2cc(-c3ccc(CNCCO)s3)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.2 %

Procedure:
A solution of aldehyde 191 (0.155 g, 0.41 mmol) in 1,2-dichloroethane (3.0 mL) was treated with ethanolamine (0.06 mL, 1 mmol) and the mixture was allowed to stir at room temperature for 6 h. The mixture was then treated with solid NaHB(OAc)3 (0.354 g, 1.67 mmol), more 1,2-dichloroethane (3 mL) and stirred a further 17 h at room temperature. The mixture was treated with 10% aqueous K2CO3, extracted with DCM, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (eluent: 5 to 10% isopropanol in DCM with 1% triethylamine then 5 to 10% MeOH in DCM with 1% triethylamine, to give title compound 192 (77.5 mg, 44% yield).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[C:14]([Cl:27])=[CH:15][C:16]([F:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH:18]=2)=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[C:14]([Cl:27])=[CH:15][C:16]([F:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])[CH:18]=1)[N:10]=2
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2cc(NC(=O)C(F)(F)F)c(F)cc2Cl)nc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3cc(NC(=O)C(F)(F)F)c(F)cc3Cl)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Potassium thiocyanate (5.98 g, 61.5 mmol) was dissolved in acetic acid (280 mL), N-{5-[(5-aminopyridin-2-yl)oxy]-4-chloro-2-fluorophenyl}-2,2,2-trifluoroacetamide (5.20 g, 14.9 mmol) was added thereto, and the mixture was stirred at room temperature for 30 min. To the solution was added dropwise a solution (40 mL) of bromine (2.54 g, 15.9 mmol) in acetic acid, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), the solution was washed with saturated aqueous sodium hydrogen carbonate solution (200 mL×3) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The dried organic layer was concentrated under reduced pressure. The precipitate was collected by filtration to give the title compound (5.78 g, 96%) as a pale-yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:28])[C:9](=[O:27])[C:10]([C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:3]=1.C(N(C(C)C)C(C)C)C.[C:45]([O:48][CH2:49][C:50](Cl)=[O:51])(=[O:47])[CH3:46]>ClCCl>[F:22][C:19]([F:20])([F:21])[C:17]1[CH:18]=[C:13]([C:10]([CH3:12])([CH3:11])[C:9]([N:8]([CH3:28])[C:5]2[C:4]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])=[CH:3][C:2]([NH:1][C:50]([CH2:49][O:48][C:45](=[O:47])[CH3:46])=[O:51])=[N:7][CH:6]=2)=[O:27])[CH:14]=[C:15]([C:23]([F:26])([F:24])[F:25])[CH:16]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of 100 mg (0.20 mmol) N-(6-amino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 3 ml dichloromethane were added 27 mg (0.21 mmol) N-ethyldiisopropylamine and 30 mg (0.21 mmol) acetoxy acetyl chloride. After stirring overnight, the solvent was evaporated and the residue was purified by flash-chromatography to give 62 mg (52%) of the title compound as white solid.
Reaction SMILES: C[Sn](C)C.C[Sn](C)C.Br[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[N:19]([CH3:29])[C:20]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][CH3:26])=[CH:21][N:22]=2)=[CH:12][CH:11]=1.Br[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1.[F-].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][C:24]([CH3:28])([CH2:25][CH3:26])[CH2:23][C:20]1[N:19]([CH3:29])[C:18]([CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=3)=[CH:11][CH:12]=2)=[N:22][CH:21]=1
Reactant: CCC(C)(C)Cc1cnc(CCc2ccc(Br)cc2)n1C
Reactant: Fc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Agent: [F-]
Solvent: C1COCCO1
Product: CCC(C)(C)Cc1cnc(CCc2ccc(-c3ccc(F)cn3)cc2)n1C
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Hexamethylditin (174 mg, 0.53 mmol) was added to a solution of 2-[2-(4-bromophenyl)ethyl]-5-(2,2-dimethylbutyl)-1-methyl-1H-imidazole (186 mg, 0.53 mmol), 2-bromo-5-fluoropyridine (94 mg, 0.53 mmol), and tetrakis(triphenylphosphine)palladium (0), (62 mg, 0.053 mmol) in 1,4-dioxane (25 mL). The mixture was stirred overnight at 110° C. KF on Celite (1:1) was added and the solution was stirred at rt for 1 h. The mixture was filtered, and the filtrate was washed with water, dried (MgSO4), filtered, and concentrated in vacuo to give a residue. The residue was purified by flash column chromatography on silica gel eluting with 0-50% EtOAc/hexanes to provide the title compound. LC-MS: m/e 366 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][C:7]=1[CH3:20].[H-].[Na+].[CH3:24]I.OS([O-])(=O)=O.[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH3:24])=[CH:8][C:7]=1[CH3:20]
Reactant: CI
Reactant: COC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1C
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N(C)C(=O)OC(C)(C)C)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled and stirred solution of 22.8 g (77 mmol) of the above prepared (4-tert-butoxycarbonylamino-2-methyl-phenoxy)-acetic acid methyl ester in 230 ml DMF was added within 10 min 3.7 g (55% in oil, 85 mmol) of NaH and, after 1 h, 14.5 ml (232 mmol) of CH3I. The reaction was stirred at 0° C. for 2 h, neutralized with aqueous 10% KHSO4, and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over sodium sulfate, and evaporated to give 25.8 g of [4-(tert-butoxycarbonyl-methyl-amino)-2-methyl-phenoxy]-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].C(=O)([O-])O.[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[O:23][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: O=C(COc1cc(OCc2ccccc2)ccc1OCc1ccccc1)c1ccccc1
Temperature: 22 °C

Procedure:
A mixture of 2,5-bis(benzyloxy)phenol (0.28 g), 2-bromoacetophenone (0.22 g), potassium hydrogen-carbonate (0.25 g) and 18-Crown-6 (3 mg) in acetonitrile (4.2 ml) was stirred at 22° C. for one week. The mixture was filtered and evaporated to dryness under reduced pressure. The residue was triturated with the mixture of ether (8.2 ml) and water (1.4 ml) at the ice bath temperature. The product was collected by filtration, washed with cold ether and dried under reduced pressure. Yield is 0.14 g. 1H NMR (DMSO-d6) δ=4.98 (s, 2H), 5.06 (s, 2H), 5.58 (s, 2H), 6.51 (dd, J=8.9, 2.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.94 (d, J=8.9 Hz, 1H), 7.28-8.03 (m, 15H).
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][N:10]2[N:13]=[CH:14][CH:15]=[C:9]2[N:8]=1.[Br:16]Br.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>C(O)(=O)C>[Br:16][C:15]1[CH:14]=[N:13][N:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[N:8][C:9]=12
Reactant: BrBr
Reactant: Clc1ccn2nccc2n1
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
Sodium acetate [127-09-3] (24.1 g, 293.9 mmol) was added to a solution of 5-chloro-pyrazolo[1,5-a]pyrimidine [29274-24-6], (30.1 g, 195.7 mmol) in glacial acetic acid (395 mL) and allowed to stir at ambient temperature until all of the solid had dissolved. An ice bath was then put in place, and the solution chilled to 0° C. Bromine [7726-95-6] (11.0 mL, 214.7 mmol) was added drop by drop into the 0° C. buffered acetic acid reaction solution over 35 minutes which gradually became a thick stirred suspension. Upon completion of the bromine addition, the suspension was allowed to stir for a further 15 minutes then was slowly poured into an aqueous (5% w/v) solution (1 L) of sodium metabisulfite [7681-57-4] stirred in an ice bath. Solid sodium hydroxide [1310-73-2] pellets were added to the stirred suspension, at a rate to maintain an internal temperature of less than 40° C., until pH of the supernatant was determined to be approximately 8 by pH paper. Precipitated product was isolated by filtration, the filter cake washed with water, and allowed to dry to afford 39.8 g of light yellow powder, mp. 173-174° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.22 (d, J=7.33 Hz, 1H) 8.44 (s, 1 H) 9.21 (d, J=7.07 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 82.84, 109.99, 138.94, 143.76, 145.61, 151.18. LRMS (ESI) m/z 231.8/233.8/235.8 [(M+H)]+, calc'd for C6H3BrClN3: 232.47.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[C:28]([CH3:36])[CH:27]=2)O1>CO.Cl[Pd]Cl>[CH3:36][C:28]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:31]=[CH:30][C:29]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)c(C)c2)c1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
Methyl 2-chloroisonicotinate (0.996 g, 5.80 mmol), potassium carbonate (1.042 g, 7.54 mmol), 4,4,5,5-tetramethyl-2-(3-methyl-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (1.66 g, 5.80 mmol) and PdCl2 (dppf) (0.105 g, 0.15 mmol) were mixed in methanol (20 mL) in two microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The solution was partitioned between water and ethyl acetate. The organic layer was isolated, dried over Na2SO4, filtered through celite and the solvent was evaporated. Automated column chromatography using the Biotage equipment. Gradient eluation using heptane-ethyl acetate, 0% to 50%. Methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)-isonicotinate (1.22 g, 71%) was isolated. 1H NMR (600 MHz, cdcl3) δ 2.57 (s, 3H), 3.99 (s, 3H), 7.70 (d, 1H), 7.81 (dd, 1H), 7.91 (d, 1H), 7.98 (s, 1H), 8.29 (s, 1H), 8.84 (d, 1H).
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[C:39]([C:42]1[CH2:43][CH2:44][N:45]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[O:49])[CH2:46][CH:47]=1)(=[O:41])[CH3:40]>ClCCl.O.C(OCC)(=O)C>[CH2:51]([O:50][C:48]([N:45]1[CH2:44][CH:43]=[C:42]([C:39](=[O:41])[CH2:40][C@H:5]2[NH:8][C:7](=[O:9])[C@@H:6]2[C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH3:11])[CH2:47][CH2:46]1)=[O:49])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CC(=O)C1=CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)C1=CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (3.96 g) and triethylamine (2.03 ml) in dichloromethane (60 ml) was added dropwise trimethylsilyl trifluoromethanesulfonate (3.5 ml) at -70° C. under nitrogen atmosphere. To this solution was added dropwise at -70° C. a reaction mixture, which had been prepared by stirring a solution of 4-acetyl-1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridine (3.268 g), triethylamine (1.94 ml) and trimethylsilyl trifluoromethanesulfonate (2.6 ml) in dichloromethane at -70° C. under nitrogen atmosphere. After the mixture was warmed to ambient temperature, the mixture was stirred for 2 hours. The reaction mixture was poured into a mixture of ethyl acetate (200 ml) and water (100 ml), and the solution was stirred for 30 minutes. The organic layer was separated, washed with brine (100 ml), dried over magnesium sulfate and concentrated to give an oil, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (2:1-1:5, V/V) to give (3S,4R)-4-[2-(1-benzyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-2-oxoethyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (4.65 g).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: CCOC(=O)COc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(OCCCCBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 2-(4-hydroxy-2-nitrophenoxy)acetate 9 (0.17 g, 0.0007 mol) in 10 mL acetone was added potassium carbonate (0.39 g, 0.0028 mol). The reaction mixture was stirred at room temperature for 10 min. Then 1,4-dibromobutane 10 (0.33 mL, 0.0028 mol) was added. The resulting mixture was heated at reflux for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC). Acetone was evaporated and the residue was diluted with water, extracted with ethyl acetate and dried over sodium sulfate to give ethyl 2-(4-(4-bromobutoxy)-2-nitrophenoxy)acetate 11 which was purified by silica gel column chromatography using 0-20% gradient of hexane and ethyl acetate. Yellow oil (0.52 g, 92%). 1H NMR (400 MHz, CDCl3): δ 1.26 (t, J=6.8 Hz, 3H); 1.91-1.98 (m, 2H); 2.02-2.09 (m, 2H); 3.48 (t, J=6.8 Hz, 2H); 3.99 (t, J=6.0 Hz, 2H); 4.26 (q, J=6.8 Hz, 2H); 4.70 (s, 2H); 6.99-7.02 (m, 2H); 7.38 (d, J=3.2 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]#[N:26])[CH2:21][CH2:20]4)[CH2:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:28][NH:29][C:30](=N)[CH2:31][CH2:32][CH3:33]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][CH:17]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]5[O:28][N:29]=[C:30]([CH2:31][CH2:32][CH3:33])[N:26]=5)[CH2:23][CH2:24]4)[CH2:16][C:15]=3[CH:27]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(C#N)CC2)O3)cc1
Reactant: CCCC(=N)NO
Product: CCCc1noc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ccc4O3)CC2)n1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Example 2. LC (method 2): tR=1.40 min; Mass spectrum (ESI+): m/z=468 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.O>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[N:13][CH:14]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-n2ccnc2)nc1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
204 mg (corresponding to 3.00 mmol) of imidazole was dissolved in 5 mL of dimethylformamide. Then, 200 mg (corresponding to 1.00 mmol) of 5-acetyl-2-bromopyridine and 414 mg (corresponding to 3.00 mmol) of potassium carbonate were added thereto. The resulting solution was heated at 100° C. for 3 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, supplemented with a saturated ammonium chloride aqueous solution and water, and extracted 3 times with dichloromethane. The combined dichloromethane layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent: dichloromethane/ethyl acetate=4/1), to obtain 87 mg (corresponding to 0.462 mmol) of 5-acetyl-2-(1H-imidazole-1-yl)pyridine (FIG. 3, step 1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[C:21]1([NH:27]N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.B(F)(F)F.CCOCC>C(O)(=O)C>[C:14]1([C:12]2[NH:27][C:21]3[C:26]([C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NNc1ccccc1
Reactant: CS(=O)(=O)c1ccc(CC(=O)c2ccccc2)cc1
Agent: Cl
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccccc3)[nH]c3ccccc23)cc1
Temperature: 130 °C

Procedure:
The mixture of 0.9 g (3.3 m mol) of 4-methylsulfonylphenyl-actophenone prepared in Example 97 and 0.5 g (3.3m mol) of phenylhydrazine hydrochloride were heated at 130° C. for 0.5 h. After cooling, 20 ml of acetic acid and 0.2 g of BF3.Et2O was added and heated to reflux for 1 h. Acetic acid was removed in vacuo, the resulting residue was suspended in water, filtered, dried and purified by column chromatography using petroleum ether/ethyl acetate 3:1 as elutant, 0.45 g of the title compound was obtained as white crystal, yield, 39.5%, m.p. 239-241° C. The data of Nuclear Magnetic Resonance shown that: 1HNMR (300 MHz, DMSO)δ: 3.24 (s, 3H, SO2CH3), 7.05-7.90 (m, 13H, Ar—H), 11.77 (s, 1H, N—H); Anal. Calcd for: C21H17NO2S: C 72.60, H 4.93, N 4.03; Found: C 72.35, H 5.03, N 4.25.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:72][C@@H:73]1[C:76](=[O:77])[NH:75][C@@H:74]1[CH2:78][N:79]1[N:83]=[C:82]([C@@H:84]([NH:95][C:96](=[O:102])[O:97][C:98]([CH3:101])([CH3:100])[CH3:99])[CH2:85][CH2:86][NH:87][C:88](=[O:94])[O:89][C:90]([CH3:93])([CH3:92])[CH3:91])[CH:81]=[N:80]1>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[C:35]([O:34][C:32]([NH:31][C:28]1[S:29][CH:30]=[C:26](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([O:14][CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:16])[CH2:18][CH2:19]2)/[C:23](=[O:24])[NH:72][C@H:73]2[C@@H:74]([CH2:78][N:79]3[N:83]=[C:82]([C@H:84]([CH2:85][CH2:86][NH:87][C:88](=[O:94])[O:89][C:90]([CH3:93])([CH3:91])[CH3:92])[NH:95][C:96](=[O:102])[O:97][C:98]([CH3:101])([CH3:100])[CH3:99])[CH:81]=[N:80]3)[NH:75][C:76]2=[O:77])[N:27]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)c1cnn(C[C@H]2NC(=O)[C@H]2N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)c1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
A mixture of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (582 mg, 1.028 mmol), DIPEA (0.269 mL, 1.543 mmol) and HATU (430 mg, 1.131 mmol) in DCM/DMF (12 mL, 5:1) was stirred at 0° C. for 30 min. To this mixture was added di-tert-butyl ((S)-1-(2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2H-1,2,3-triazol-4-yl)propane-1,3-diyl)dicarbamate (1.03 mmol). After stirring for an additional 30 min at 0° C., it was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (760 mg, 77%). LCMS: Rt=1.12 min, m/z=959.6 (M+1) Method 2m_acidic.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[C:23]1([O:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:37][CH2:36][CH2:35][CH2:34][O:33][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCOc1cccc2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCOc2cccc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(1-naphthyloxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-(1-naphthyloxy)butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.