Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:22][O:23][CH2:24][CH2:25][OH:26]>>[CH3:22][O:23][CH2:24][CH2:25][O:26][C:12](=[O:13])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1
Reactant: COCCO
Reactant: CC(C)Cc1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: COCCOC(=O)Cc1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
To a solution of 3.5 g of p-isobutylphenylacetic acid chloride in 5.9 g of 2-methoxyethanol was added 1.6 g of triethylamine, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, an inorganic substance produced was filtered off. The filtrate was extracted with ether, and the extract was washed, dehydrated and applied over a column of silica gel. The adsorbates was eluted with ether, and the eluates were freed of ether to give an oily product. Distillation of the product in vacuo gave 2.8 g of p-isobutylphenylacetic acid-2-methoxyethyl ester as a colorless oil, boiling at 97°-98° C./1 mmHg. Analysis-Calculated for C15H22O3 : C, 71.97; H, 8.86. Found: C, 71.63; H, 8.90. Mass spectrum: parent ion 250 m/e.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH:6]=[CH:7][CH:8]=[O:9]>[C].[Pd].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH:8]=[O:9])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20]
Reactant: COc1cc(C=CC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(CCC=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
A mixture of 3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (5.6 g), palladium-carbon (5%, 0.5 g) and tetrahydrofuran (THF) (160 ml) was subjected to catalytic hydrogenation at room temperature under 1 atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate -hexane (1:1), was obtained 3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propionaldehyde, which was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.80-81° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C@@H:7]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9])=[O:5])[CH3:2].[N:18]([O-])=[O:19].[Na+]>O.C(O)(=O)C>[CH2:1]([N:3]([N:18]=[O:19])[C:4]([NH:6][C@@H:7]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9])=[O:5])[CH3:2]
Reactant: O=N[O-]
Reactant: CCNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 96.4 %

Procedure:
1-ethyl-3-(β-D-glucopyranosyl)urea (930 mg) was dissolved in a mixture of water (4.3 ml) and acetic acid (4.3 ml), and to the solution was added 370 mg (1.5 mol. equivalents) of sodium nitrite in small portions under stirring. The mixture was stirred overnight at ambient temperature to complete the nitrosation. The reaction mixture was then treated with 4 ml of a cation-exchange resin, Amberlite IR-120 (H+ form), to remove the sodium ion therefrom. The reaction mixture was subsequently freeze-dried, affording 1.0 g of the titled compound as an amorphous substance of pale yellow color. [α]D26 -2° (c 1.0, H2O). This substance gave a single spot at Rf 0.82 in a thin layer chromatography on silica gel using chloroform-methanol (3:2 by volume) as eluent.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26](O)=[O:27])=[CH:19][C:18]=3[CH:29]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].S(Cl)(Cl)=O.[CH3:34][N:35]([CH2:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1)[CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(N(CC)CC)C>C1COCC1.CN(C=O)C.O>[CH3:34][N:35]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([NH:47][C:26]([C:20]2[CH2:21][CH2:22][S:23](=[O:24])(=[O:25])[C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[CH:9][CH:10]=4)=[CH:29][C:18]=3[CH:19]=2)=[O:27])=[CH:48][CH:49]=1)[CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
In THF (98 ml) was dissolved 7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (4.9 g). To the mixture were added under ice-cooling thionyl chloride (1.3 ml) and DMF (3 drops), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added dropwise a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (2.93 g) and triethylamine (6.6 ml) in THF (88 ml), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 97) (2.9 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(CC)CC)C.[CH3:20][Si:21]([CH3:29])([CH3:28])[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([S:24]([CH2:23][CH2:22][Si:21]([CH3:29])([CH3:28])[CH3:20])(=[O:26])=[O:25])[N:9]=2)[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1
Reactant: Cc1cc(C=O)cc2cn[nH]c12
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)cc2cn(S(=O)(=O)CC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a suspension of 7-methylindazole 5-aldehyde (3.0 g, 18.7 mmol) in methylene chloride (150 mL) was added triethylamine (7.83 mL, 56.2 mL, 3 equiv) followed by dropwise addition of neat 2-trimethylsilanyl-ethanesulfonyl chloride (5.60 g, 28.1 mmol, 1.5 equiv). The mixture gradually became homogeneous and was allowed to stir at room temperature for 16 h. The solution was concentrated to a minimum amount of methylene chloride and then subjected to flash column chromatography on silica gel (1:4 ethyl acetate/hexanes) to give 4.7 g (77%) of the product as a pale yellow solid. 1H-NMR (CDCl3, 300 MHz) δ 9.98 (s, 1H), 8.77 (s, 1H), 8.09 (s, 1H), 7.64 (s, 1H), 3.64-3.58 (m, 2H), 2.65 (s, 3H), 0.88-0.82 (m, 2H), 0.01 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[NH2:17])[CH:7]=[CH:6]2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[O-2].[Mg+2].C1C=CC=CC=1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@:13]1([CH3:19])[CH2:14][O:15][C:16](=[O:18])[NH:17]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)COC(N)=O)ccc2c1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: c1ccccc1
Product: COc1ccc2cc([C@]3(C)COC(=O)N3)ccc2c1

Procedure:
A mixture of carbamic acid (S)-2-(6-methoxy-naphthalen-2-yl)-propyl ester (5.4 g, 0.0208253 mol), iodobenzene diacetate (9.46 g, 0.0294 mol; Acros) and magnesium monoxide (1.93 g, 0.0479 mol; Aldrich), and rhodium(II) acetate dimer (500 mg, 0.001 mol; Janssen) in benzene (250 mL, 2.8 mol; Aldrich) was refluxed overnight under N2. TLC (EtOAc-hexanes 2:3) showed a slow moving spot. The solution was diluted with EtOAc and filtered through CELITE™ and washed with EtOAc and MeOH. Silica gel was added to the solution, which was then concentrated and purified on a 120 g silica gel column with 10-50% EtOAc/hexanes to give precipitate.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:11]1[O:17][C@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[C@H:14]([OH:15])[C@H:12]1[OH:13]>C(N(CC)CC)C.C(Cl)Cl>[C:2]([O:13][C@@H:12]1[C@@H:14]([O:15][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[C@@H:16]([C@@H:18]([CH2:20][O:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[O:19][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[O:17][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC[C@@H](OC(=O)c1cccnc1)[C@H]1OC[C@H](OC(=O)c2cccnc2)[C@H]1OC(=O)c1cccnc1)c1cccnc1

Procedure:
23.8 g of nicotinoyl chloride-hydrochloride are added in portions in the course of 15 minutes to a suspension of 5.0 g of 1,4-anhydro-D-glucitol (Arlitan) in 30 g of triethylamine and 100 ml of methylene chloride, at 40°, whilst stirring and with the exclusion of atmospheric moisture. After the reaction mixture has been allowed to react for a further 30 minutes, it is filtered and the bulk of the methylene chloride is distilled off from the filtrate. The residue which is thus formed from the filtrate is dissolved in methylene chloride and the solution is washed with water. After drying over sodium sulphate, evaporating under a waterpump vacuum and degassing the residue under a high vacuum, pure 2,3,5,6-tetra-O-nicotinoyl-1,4-anhydro-D-glucitol is obtained as a viscous, brownish oil which has an optical rotation [α]D20 = + 16° ± 1° (c = 1.099 in chloroform), IR: carbonyl band at 1,730 cm-1, and a Rf value of 0.26 on silica gel thin layer plates in the system: methylene chloride/ethyl acetate (85:15).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:28][N:29]=[C:30]=[O:31]>O1CCCC1>[CH3:28][NH:29][C:30](=[O:31])[O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([N:12]([CH2:19][CH2:20][CH3:21])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH:3]=[C:2]2[CH3:1]
Reactant: CCCN(c1ccncc1)n1cc(C)c2cc(O)ccc21
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1cc(C)c2cc(OC(=O)NC)ccc21
Reaction time: 2.3 h

Procedure:
To a stirred solution consisting of 3-methyl-1-(propyl-4-pyridinylamino)-1H-indol-5-ol (2.06 g) and tetrahydrofuran (49 ml) was added milled K2CO3 (1.06 g) followed by dropwise addition of methyl isocyanate (0.48 ml) at room temperature under nitrogen. Stirring was continued for 2.3 hours at which time the reaction mixture was filtered through a pad of celite and the solids washed with EtOAc. Concentration afforded the crude product. Purification via flash column chromatography (silica gel, 2% Et3N/EtOAc) afforded 2.30 g of the desired carbamate as an oil. The product was crystallized from ether, m.p. 147°-149° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>O1CCCC1>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([NH:25][CH2:2][C:3]2[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Reactant: Nc1ccc(N)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CNc2ccc(N)cc2)cc(C(C)(C)C)c1O

Procedure:
4-Bromomethyl-2,6-di-tert-butyl-phenol (2.42 g, 0.008 mole) was dissolved in 50 mL of dry tetrahydrofuran. In a separate conical flask benzene-1,4-diamine (p-PDA) (1.728 g, 0.016 mole) was dissolved in 25 mL of tetrahydrofuran and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottom flask containing solution of 4-Bromomethyl-2,6-di-tert-butyl-phenol was kept in oil-bath at 85° C. Solution in the flask was continuously stirred with the help of magnetic stirrer. Benzene-1,4-diamine solution was added drop-by-drop, from funnel to the flask in acidic medium for a span of 4-5 hours till all the solution was poured out. The reaction was terminated after that and the final reaction mixture was allowed to attain room temperature. The product was purified using silica gel column chromatography. Product was identified by 1H-NMR. The yield of 4-[(4-Amino-phenylamino)-methyl]-2,6-di-tert-butyl-phenol was 2.24 g (85%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[S:10]1[C:14]2[CH:15]=[C:16]([S:19](Cl)(=[O:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[CH:11]1>>[Br:9][C:3]1[C:2]([NH:1][S:19]([C:16]2[CH:17]=[CH:18][C:13]3[N:12]=[CH:11][S:10][C:14]=3[CH:15]=2)(=[O:20])=[O:21])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(N)c(Br)n1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Product: Cc1ccc(NS(=O)(=O)c2ccc3ncsc3c2)c(Br)n1
Yield: 35 %

Procedure:
By working in a manner similar to that of Preparation VII, starting with 3-amino-2-bromo-6-methylpyridine and 6-benzothiazolesulfonyl chloride, the expected product is obtained in the form of a beige-colored paste (yield=35%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8](C)[C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([O-:13])=O)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:18]([N:20]([CH2:23][CH2:24][NH2:25])[CH2:21][CH3:22])[CH3:19]>>[CH2:18]([N:20]([CH2:21][CH3:22])[CH2:23][CH2:24][NH:25][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:7]=[CH:8][C:9]=1[O:15][CH3:16])[CH3:19]
Reactant: CCCC(=O)c1cc(C)c(OC)c(C(=O)[O-])c1
Reactant: CCN(CC)CCN
Product: CCCC(=O)c1ccc(OC)c(C(=O)NCCN(CC)CC)c1
Temperature: 100 °C

Procedure:
In a flask equipped with a Dean-Stark device, there are introduced 10 g of the ester obtained in Example 3 and 10 g of diethylaminoethylamine and the mixture is heated to 100° C. for 3 hours. There are thus obtained 10.3 g of an oily product which is converted to hydrochlorate in the ethanol-ether mixture. The product obtained has a melting point of 155° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].Br[C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C=O)C.C(O)C.O>[CH3:18][C:12]([O:10][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[F:9])([CH3:19])[C:13]([OH:15])=[O:14]
Reactant: Oc1c(F)cc(F)cc1F
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(Oc1c(F)cc(F)cc1F)C(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,4,6-trifluorophenol (5.00 g) was dissolved in DMF (100 ml), ethyl 2-bromo-2-methylpropanoate (15 ml) and potassium carbonate (7.00 g) were added thereto, followed by stirring at 80° C. overnight. The reaction solution was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution and then 1M hydrochloric acid in this order, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=19:1) to obtain a colorless oily product. The oily product thus obtained was dissolved in ethanol (150 ml), a 1M aqueous sodium hydroxide solution (70 ml) was added thereto, followed by stirring at room temperature for one hour. The reaction solution was concentrated under reduced pressure and water was added to the resulting residue, followed by washing with ethyl acetate. 1M hydrochloric acid was added to the aqueous layer, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 2-methyl-2-(2,4,6-trifluorophenoxy)propanoic acid (7.83 g) as a colorless oily product.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[OH:6][C@@H:7]1[C@@H:12]([OH:13])[C@H:11]([OH:14])[C@@H:10]([CH2:15][OH:16])[O:9][C:8]1=[O:17].CN1CCOCC1.C1(C)C=CC=CC=1>C1COCC1.O>[CH3:1][Si:2]([CH3:4])([CH3:3])[O:6][C@@H:7]1[C@@H:12]([O:13][Si:2]([CH3:4])([CH3:3])[CH3:1])[C@H:11]([O:14][Si:2]([CH3:4])([CH3:3])[CH3:1])[C@@H:10]([CH2:15][O:16][Si:2]([CH3:4])([CH3:3])[CH3:1])[O:9][C:8]1=[O:17]
Reactant: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: C[Si](C)(C)Cl
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Solvent: O
Product: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At −7° C., TMSCl (71 mL) was added into a solution of (3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one (14.2 g) and N-methylmorpholine (80 mL) in dry THF (120 mL), and then the mixture was slowly warmed up to room temperature and stirred overnight. At 10° C., toluene (160 mL) and H2O (300 mL) were poured into the mixture, and then the organic phase was washed with H2O (120 mL), 1M HCl (150 mL×4) and brine (120 mL). The organic phase was dried over Na2SO4, and concentrated to obtain the crude product, then the crude product was purified by silica-gel column chromatography (PE/EA=10/1) to obtain 30 g of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one.
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[H-].[Na+].Cl[CH2:15][C:16](OCC)=[O:17].Cl.N>C1(C)C=CC=CC=1.O.C(O)C>[Cl:11][C:9]1[N:10]=[C:5]([CH:2]2[O:1][CH2:15][C:16](=[O:17])[NH:4][CH2:3]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NCC(O)c1cccc(Cl)n1
Reactant: CCOC(=O)CCl
Agent: Cl
Agent: N
Agent: [H-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C1COC(c2cccc(Cl)n2)CN1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
6 g (0.0347 mol) of 2-hydroxy-2-(2-chloro-pyridin-6-yl)-ethanamine are dissolved in 160 ml of absolute toluene and mixed with 2.2 g (0.047 mol) of 50% sodium hydride in oil and stirred for 40 minutes at ambient temperature. Then 4.16 g (0.034 mol) of ethyl chloroacetate are added dropwise. The reaction mixture is stirred for 18 hours at ambient temperature and then carefully mixed with 10 ml of ethanol and 30 ml of water and subsequently acidified with dilute hydrochloric acid. The reaction solution is made alkaline with ammonia and extracted with methylene chloride. The organic phase is dried over sodium sulphate, concentrated by evaporation and the residue is purified over a silica gel column using ethyl acetate as eluant.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[C@@H:19]([C:20]([NH:22][C@H:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[CH3:24])=[O:21])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[O:1]([CH2:8][CH2:9][N:10]1[C@@H:19]([C:20]([NH:22][C@H:23]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[CH3:24])=[O:21])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2CCOc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@H]1Cc2ccccc2CN1CCOc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 5 °C
Yield: 64.6 %

Procedure:
Stir a mixture of methyl 4-[(1S)-1-[[(3R)-2-(2-phenoxyethyl)-3,4-dihydro-1H-isoquinoline-3-carbonyl]amino]ethyl]benzoate (41.5 g, 90.5 mmol), THF (291 mL), and 2 M aqueous sodium hydroxide (181 mL, 360 mmol) at 40° C. overnight. Concentrate under reduced pressure to remove the THF. Add water (200 mL), then wash the aqueous layer with TBME (2×200 mL). Cool the aqueous layer to 5° C. and add concentrated aqueous hydrochloric acid with stirring until the pH reaches 2 (as estimated by pH paper analysis). With stirring, allow the mixture to warm to room temperature over 30 minutes, then isolate the solids by filtration. Add the solids to water (500 mL) and heat to 80° C. for one hour. Cool the mixture to room temperature, isolate the solids by filtration, and dry the solids in a vacuum oven at 45° C. overnight. Add the solids to isopropyl acetate (300 mL) and stir vigourously for 5 h. Isolate the solids by filtration, and dry the solids under reduced pressure to furnish the title compound as a white solid (26 g, 60% yield). Mass spectrum (m/z): 445 ([M+H]+).
Reaction SMILES: C([O:4][C:5]1([O:14][CH2:13][C@:11]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([OH:12])[C@:9]([C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([OH:10])[C@@:7]1([C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[OH:8])O)CC.[BrH:39].C(O)(=O)C.ClCCl>O>[Br:39][C:5]1([O:14][CH2:13][C@:11]([C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([OH:12])[C@:9]([C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([OH:10])[C@@:7]1([C:31](=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:8])[OH:4]
Reactant: CCCOC1(O)OC[C@@](O)(C(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)[C@]1(O)[C@](O)(C(=O)c2ccccc2)COC(O)(Br)[C@@]1(O)C(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 6 h
Yield: 80 %

Procedure:
While the internal temperature of the reactor containing 2.622 kg (5.20 mol) of 1-propoxy-2,3,4-tribenzoyl-L-arabinopyranose was maintained at 0-20° C., 4.21 kg of a 30-33% hydrogen bromide/acetic acid solution was added dropwise thereto, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, 1.296 liters of dichloromethane was added to the reaction solution, which was then stirred for 30 minutes. The stirred solution was added dropwise to a reactor containing 4.162 liters of purified water and stirred for 30 minutes. Then, the stirred solution was separated into layers. The water layer was back-extracted with 1.296 liters of dichloromethane. The oil layer was washed two times with 0.195 kg of aqueous saturated sodium chloride solution and one time with 0.248 kg of aqueous saturated sodium bicarbonate solution, and then dried with sodium sulfate, and the solvent was removed by concentration. To the concentrated residue, 1.30 liters of dichloromethane was added, and the solution was stirred for 2-3 hours. 6.50 liters of hexane was added to the stirred solution, which was then cooled to a temperature of 0-5° C., stirred for 3-4 hours, and filtered. The filtered solids were washed with 2.76 liters of hexane and dried in a vacuum, thus obtaining 2.185 kg (80% yield) of 1-bromo-2,3,4-tribenzoyl-L-arabinopyranose. 1H NMR (CDCl3): δ 8.20-7.90 (dd, 4H), 7.90-7.80 (d, 2H), 7.70-7.20 (m, 9H), 6.93 (d, 1H), 5.97 (dd, 1H), 5.82 (m, 1H), 5.70 (dd, 1H), 4.50 (d, 1H), 4.25 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([F:31])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[C:22]([F:31])[CH:21]=2)[CH2:9]/[C:10](=[N:34]\[OH:35])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:32])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OS(C)(=O)=O)c(F)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(OS(C)(=O)=O)c(F)c1

Procedure:
In analogy to example 151, step 3, methanesulfonic acid 4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-2-fluoro-phenyl ester was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=493.1 [M+H]+.