Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[Cl:46])(C)(C)C.O>C1C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:46])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OCl
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Reaction time: 1 h
Yield: 90 %

Procedure:
A 200 mg quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 6 ml of benzene. To the solution was added with stirring 51 μl of t-BuOCl at room temperature and the mixture was further agitated for 1 hour. Water was added to the reaction mixture and the resulting mixture was subjected to the same subsequent procedure as in Example 12, giving 19.2 mg of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 90% yield.
Reaction SMILES: [Cl-].[NH4+].C(O)(C)C.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([N+:17]([O-])=O)=[CH:11][C:10]=1[S:20]([OH:23])(=[O:22])=[O:21]>O>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([NH2:17])=[CH:11][C:10]=1[S:20]([OH:23])(=[O:22])=[O:21]
Reactant: COc1cc(OC)c(S(=O)(=O)O)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc(OC)c(S(=O)(=O)O)cc1N

Procedure:
A mixture solution prepared by adding 15 g of reduced iron, 0.3 g of ammonium chloride and 50 ml of isopropyl alcohol to 10 g of 2,4-dimethoxy-5-nitrobenzenesulfonic acid obtained in Step (2) above, was heated at 70° to 80° C. on a water bath with stirring, and 50 ml of water was added thereto. After stirring at 80° C. for 1 hour, the mixture was filtered while hot. To the filtrate, 20 ml of hydrochloric acid (d=1.18) was added. The crystals thus-precipitated were collected by filtration and washed with 20 ml of iropropyl alcohol.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4](S(OCCCCCC)(=O)=O)=[CH:3][CH:2]=1.[C:18]([C:20]1[C:21]([C:28]#[N:29])=[C:22]([CH:24]=[CH:25][C:26]=1[OH:27])[OH:23])#[N:19].[OH-].[Na+]>>[CH2:5]([O:27][C:26]1[CH:25]=[CH:24][C:22]([OH:23])=[C:21]([C:28]#[N:29])[C:20]=1[C:18]#[N:19])[CH2:6][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1c(O)ccc(O)c1C#N
Reactant: CCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCOc1ccc(O)c(C#N)c1C#N
Reaction time: 7 h
Yield: 27.5 %

Procedure:
11.3 g (44.1 mM) of n-hexyl p-toluenesulfonate was added to the mixture of 5.0 g (31.3 mM) of dicyanohydroquinone and 37.5 ml of 5% NaOH aqueous solution, followed by 7 hours of stirring under refluxing. After the reaction, the reaction mixture was washed with toluene and the aqueous layer was acidified with HCl. The resultant precipitate was recovered through filtration and dried. To the precipitate, 1 liter of toluene was added. After the insoluble substrate was filtered out, the filtrate was subjected to recrystallization in a refrigerator and further subjected to recrystallization from a mixture solvent of water/methanol to obtain 2.1 g of an objective product (yield: 27.5%). m.p.: 150°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23].[NH4+].[N:25]#[C:26][S-:27].BrBr>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([F:23])=[CH:18][C:19]2[N:22]=[C:26]([NH2:25])[S:27][C:20]=2[CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc2nccc(Oc3cc4sc(N)nc4cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenylamine (1.00 g, 3.18 mmol) was dissolved in AcOH (8.0 ml), to which was added NH4SCN (486 mg, 6.38 mmol) and the mixture cooled in an ice bath. Br2 (0.33 ml, 6.42 mmol) in AcOH (0.33 ml) was added dropwise with stirring. After addition was complete, the reaction mixture was stirred at room temperature. After one hour, more NH4SCN (1.0 g, 13.1 mmol) was added, followed by more Br2 (0.33 ml, 6.42 mmol) in AcOH (0.33 ml), dropwise with stirring. The reaction mixture was then heated to reflux for several minutes. Upon cooling to room temperature, solids were filtered and washed with AcOH, followed by H2O. The volume of the filtrate was reduced in vacuo and the pH adjusted to pH 9-10 with 1.0N NaOH. The resulting solids were filtered, washed with H2O, and dried under high vacuum to give 6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (568 mg, 48%). 1H-NMR (400 MHz, DMSO): 8.45 (d, 1H), 7.82 (d, 1H), 7.73 (br s, 2H), 7.53 (s, 1H), 7.38 (m, 2H), 6.44 (d, 1H), 3.94 (s, 6H). LC/MS Calcd for [M+H]+ 372.1, found 372.2
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][CH:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C-:20]#[N:21].[Na+]>CN(C=O)C.C(OCC)C>[OH:19][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:20]#[N:21]
Reactant: CCCCCC(O)CCCCCCCCCCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCC(O)CCCCCCCCCCCC#N
Temperature: 90 °C
Yield: 91.8 %

Procedure:
To 17-bromoheptadecan-6-ol (1.0 g, 2.98 mmol) in dry DMF, was added NaCN (175 mg, 3.58 mmol) and the resulting reaction mixture heated at 90° C. for 16 hours. After cooling to room temperature, the mixture was diluted with diethyl ether (100 ml), the organic layer was washed with cold water (3×20 ml), brine solution, dried over MgSO4 and concentrated. The crude product was purified over a silica gel column (10% EtOAc in hexane) to give 13-hydroxyoctadecanenitrile as a colorless liquid (0.77 g, 92%).
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[C:11]([NH:18][CH2:19][CH2:20][NH2:21])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(OCC)(=O)C>[C:11]([NH:18][CH2:19][CH2:20][NH:21][C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CSC(SC)=C(C#N)C#N
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCOC(C)=O
Product: CSC(NCCNC(=O)OC(C)(C)C)=C(C#N)C#N
Temperature: 0 °C

Procedure:
A mixture of 59.8 g (351.2 mmol) of 3,3bis-methylmercapto-2-cyano-acrylonitrile, 56.3 g (351.4 mmol) of N-Boc-ethylenediamine [for preparation see: J. Org. Chem. 60, 4305 (1995)] and 500 ml of ethyl acetate is stirred under reflux for 3 hours and then concentrated in vacuo to approximately half its original volume. The reaction mixture is cooled to 0° C.; 300 ml of diethyl ether are added and the mixture is stirred for a further 0.5 hour and filtered. After washing the filter residue with diethyl ether, 3-[2-(Boc-amino)-ethylamino]-2-cyano-3-methylmercapto-acrylonitrile is obtained; m.p. 123-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][NH2:25])[N:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](Cl)=[O:36])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][NH:25][C:35](=[O:36])[CH2:34][C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[N:13]=2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)c2cccc(-c3ccccc3CN)n2)cc1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CC(=O)NCc2ccccc2-c2cccc(C(=O)Nc3ccc(OC)cc3)n2)cc1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
39 mg (0.12 mmol) of 6-(2-Aminomethylphenyl)-pyridine-2-carboxylic acid-(4-methoxyphenyl)-amide were dissolved in 3 ml of dichloromethane, treated with 27 μl (0.144 mmol) of 4-methoxyphenylacetyl chloride and 19 mg (0.144 mmol) of DIPEA and the mixture was stirred overnight. It was diluted with 20 ml of dichloromethane and washed with an NaHCO3 solution. The organic phase was dried, concentrated and purified by RP-HPLC. 56 mg (78%) of the compound of Example 20 were obtained in the form of its trifluoroacetate.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.C(=O)(O)[O-].[Na+:29]>O.C(O)C>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[CH:13]=[C:12]([C:17]([O-:19])=[O:18])[O:11][C:10]=2[C:9]([CH2:22][CH2:23][CH3:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[Na+:29]
Reactant: CCCc1c2ccccc2c(O)c2c(=O)cc(C(=O)OCC)oc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c2ccccc2c(O)c2c(=O)cc(C(=O)[O-])oc12

Procedure:
The product of step (a) (6 g) was heated at 100° with sodium bicarbonate (1.55 g) in a mixture of water (50 ml) and ethanol (5 ml), for 4 hours. The ethanol was removed, in vacuo, and the remaining aqueous solution was filtered and cooled. The sodium salt (1.8 g) crystallised from this solution as orange needles.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:2]1.[CH2:17](I)[CH2:18][CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:17]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:2]1)[CH2:18][CH3:19]
Reactant: CCCI
Reactant: O=C1Cc2c(cccc2C2CCCNC2)N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN1CCCC(c2cccc3c2CC(=O)N3)C1

Procedure:
1,3-dihydro-4-(piperidin-3-yl)-2H-indole-2-one and n-propyl iodide in dimethylformaimide were reacted in the presence of sodium carbonate to obtain 1,3-dihydro-4-(1-propyl-piperidin-3-yl)-2H-indole-2-one. A solution of the latter in ether was admixed with an ether solution saturated with hydrogen chloride and the recovered product after crystallization from an isopropanol-methanol mixture melted at 260° C.
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[NH2:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1.[C:21]([O:25][C:26]([NH:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:30]=1[CH2:31]Cl)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CC(C)=O>[C:21]([O:25][C:26]([NH:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:30]=1[CH2:31][NH:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CCl
Reactant: Cc1nc2c(N)cccn2c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OC(C)(C)C)c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C

Procedure:
5.5 g of sodium iodide and 8.0 g of sodium carbonate are added at RT to a solution of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine (4.8 g) and 2-tert-butoxycarbonylamino-6-methylbenzyl chloride (9.2 g) in acetone (250 ml) and the mixture is then heated to boiling under reflux for 6 h. After cooling the solution to RT and concentrating it, the residue is dissolved in a mixture of 200 ml of ethyl acetate and 200 ml of water and the organic phase is separated off. After three further extractions with 100 ml each of ethyl acetate, the combined organic phases are dried over magnesium sulfate and then concentrated. The title compound crystallizes as a slightly yellow solid. After chromatographic purification on silica gel (eluent: toluene/dioxane=20:1) and recrystallization from diisopropyl ether, 7.1 g (62%) of the title compound of m.p. 149-152° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH:5]=O.[CH3:12][O:13][CH:14]([O:25][CH3:26])[CH2:15][NH:16]CC1C=CC(F)=CC=1>>[CH3:12][O:13][CH:14]([O:25][CH3:26])[CH2:15][NH:16][CH2:5][C:4]1[CH:3]=[C:2]([F:1])[C:9]([F:10])=[C:8]([F:11])[CH:7]=1
Reactant: COC(CNCc1ccc(F)cc1)OC
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: COC(CNCc1cc(F)c(F)c(F)c1)OC

Procedure:
Starting from 3,4,5-trifluorobenzaldehyde, the title compound was prepared following the method described for 2,2-dimethoxy-ethyl)-(4-fluoro-benzyl)-amine (3). Rt=0.79 min (Method #4). Detected mass: 250.1 (M+H+).
Reaction SMILES: CO[C:3](=[O:34])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[N:13][C:14]([S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[CH:15][CH:16]=2)[CH:7]=[C:6]([O:22][C@@H:23]([CH3:33])[CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH:5]=1.[NH2:35][C:36]1[CH:40]=[CH:39][N:38]([CH3:41])[N:37]=1>>[CH2:20]([S:17]([C:14]1[N:13]=[CH:12][C:11]([O:10][C:8]2[CH:9]=[C:4]([CH:5]=[C:6]([O:22][CH:23]([CH3:33])[CH2:24][OH:25])[CH:7]=2)[C:3]([NH:35][C:36]2[CH:40]=[CH:39][N:38]([CH3:41])[N:37]=2)=[O:34])=[CH:16][CH:15]=1)(=[O:18])=[O:19])[CH3:21]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(C(=O)OC)c2)cn1
Reactant: Cn1ccc(N)n1
Product: CCS(=O)(=O)c1ccc(Oc2cc(OC(C)CO)cc(C(=O)Nc3ccn(C)n3)c2)cn1

Procedure:
The compound of Production Example 117 was obtained as a colorless amorphous substance using the obtained 3-((1S)-2-(t-butyldimethylsiloxy)-1-methyl-ethoxy)-5-(6-ethanesulfonyl-pyridin-3-yloxy)-benzoic acid methyl ester and 3-amino-1-methylpyrazole, by the same method as in Production Example 2, a corresponding method, or a combination thereof with an ordinary method.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([O:23]C)=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11].B(Br)(Br)Br.O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19])(=[O:12])=[O:11]
Reactant: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)ccc1O
Temperature: -78 °C

Procedure:
Methyl 5-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)-2-methoxybenzoate (1.485 g, 3.66 mmol) was dissolved in dichloromethane (DCM) (10 mL) and this was cooled to −78° C. A solution of boron tribromide in DCM (1M, 18.31 mL, 18.31 mmol) was then added dropwise and the reaction stirred under nitrogen. The reaction was then allowed to warm to room temperature and stirred overnight. Water (20 mL) was added dropwise to the reaction mixture and the crude product extracted to the organic phase of an aqueous work up between DCM and water. The aqueous phase was washed twice with DCM. The organic phase was then dried and concentrated in vacuo to give the crude product. LCMS [LCMS2] Rt 1.42 min, m/z (ES+) 392 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#N)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.CC(C[AlH]CC(C)C)C.Cl.C([O-])(O)=[O:22].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:3]([CH:9]=[O:22])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C([O-])O
Reactant: N#Cc1ncc(F)cc1F
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ncc(F)cc1F
Temperature: 78 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 3,5-difluoro-pyridine-2-carbonitrile (0.440 g, 3.14 mmol) (Niewoehner, U. et al. PCT Int. Appl. (2001), WO 2001068647) in dry CH2Cl2 (20 mL) cooled at −78° C., was added DIBAL-H (1.0 M in CH2Cl2, 3.2 mL, 3.2 mmol). After the mixture was stirred a t−78° C. for 1 h, aqueous HCl (3 N, 10 mL) was added, and the mixture was warmed to room temperature. Saturated aqueous NaHCO3 (20 mL) was added, and the mixture was extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (CH2Cl2), affording afford 3,5-difluoro-pyridine-2-carbaldehyde as a colorless crystalline solid (0.0880 g, 20%). 1H NMR (CDCl3) δ 7.32-7.39 (m, 1H), 8.53 (d, 1H, J=2.4 Hz), 10.16 (s, 1H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:27]([O:28]C(=O)C)[C@H:26]([O:32]C(=O)C)[C@@H:25]([CH2:36][O:37]C(=O)C)[O:24][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][CH:16]=1)(=O)C.C[O-].[Na+]>CO>[O:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][CH:16]=1)[C@@H:6]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:32])[C@H:27]([OH:28])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(C(N)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(2-hydroxybenzyl)benzamide (0.063 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (0.33 g) in toluene (3 mL) was added boron trifluoride diethyl ether complex (0.11 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) to give 2-(4-carbamoylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside. To a solution of the obtained 2-(4-carbamoylbenzyl)phenyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside in methanol (5 mL) was added sodium methoxide (0.005 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/ethanol=5/1) to give 2-(4-carbamoylbenzyl)phenyl β-D-glucopyranoside (0.068 g).
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH:15]=[N:14][N:13]=[N:12]1.C(N(CC)CC)C>>[O:7]([C:8]([C:15]1[NH:14][N:13]=[N:12][N:11]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1nnn[nH]1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)c1nnn[nH]1
Reaction time: 0.25 h

Procedure:
The title compound was prepared according to the procedure described in Tetrahedron Letters, 1977, 1935. Accordingly, phenylchloroformate (6.73 g, 43 mmol) was added dropwise into a solution of tetrazole (42.84 mmol, 3 wt % in 100 mL acetonitrile) containing triethylamine (4.35 g, 43 mmol) at 0° C. The mixture was stirred for 15 minutes and the solvent was removed without heating at reduced pressure. Ethyl acetate (80 mL) was added to the white solid and passed through a plug of silica gel, eluting with 3% triethylamine in ethyl acetate to afford phenoxycarbonyltetrazole in 85% yield (6.9 g). 1H-NMR (CDCl3): δ 7.34-7.54 (m, 5H); 9.34 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53])=[O:6]
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(C)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)C)cc2Cl)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 2-chloro-4-isopropylbenzoic acid (100 mg, 0.50 mmol) in dichloromethane (50 mL) were added 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (190 mg, 0.50 mmol) and triethylamine (175 mg, 1.73 mmol). The resultant reaction mixture was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified through pre-HPLC and the obtained solution was freeze-dried to afford 2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropylbenzamide (40 mg, 23.9%) as a white solid. LRMS (M+H+) m/z: calcd 333.13. found 333. HPLC purity (214 nm): 96.2% 1H NMR (300 MHz, DMSO) δ 7.37 (d, J=7.8 Hz, 1H), 7.30 (d, J=1.5 Hz, 1H), 7.23 (dd, J1=7.8 Hz, J2=1.5 Hz, 1H), 6.11 (s, 1H), 4.49 (s, 2H), 2.93 (m, 1H), 2.38 (s, 3H), 2.25 (s, 3H), 1.25 (d, J=6.9 Hz, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:23]1([S:29]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:15]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2c[nH]c3ccccc23)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(C2CCCNC2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (75 mg, 0.25 mmol) and phenylsulfonyl chloride (50 mg, 0.27 mmol) in tetrahydrofuran (THF) at room temperature is treated with potassium tert-butoxide (0.275 mL, 1 M solution in THF, 0.275 mmol), shaken at room temperature for 16 hours, treated with HCl (4 N in dioxane, 0.5 mL), shaken for 2 hours and concentrated in vacuo to give a residue. Purification of the residue by HPLC1 affords the title product, characterized by HPLC and mass spectral analyses [M+H] 341.45, LCMS2 retention time 1.67 min.
Reaction SMILES: Br[CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[Ca+2].[CH2:24]([OH:27])[CH2:25][CH3:26].O>C1COCC1>[CH2:24]([O:27][CH:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[Cl:16])[C:9](=[O:17])[C:8]2[C:7]([Cl:18])=[CH:6][CH:5]=[CH:4][C:3]1=2)[CH2:25][CH3:26]
Reactant: O=C1c2cccc(Cl)c2C(Br)c2cccc(Cl)c21
Reactant: CCCO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Product: CCCOC1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21

Procedure:
To a solution of compound (6) (2.0 mmol) and anhydrous calcium carbonate (0.5 g) in dry THF (20 ml) was added dropwise a solution of an appropriate propanol (10 ml) in dry THF (10 ml) under N2. The reaction mixture was refluxed for 3 hours. Water (250 ml) was added and then extracted with dichloromethane. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting precipitate was collected by filtration, washed with water and further purified by crystallization (CH3CN).