Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]([CH3:37])([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:26]([C:27](=[O:35])[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24][O:23][C:22]=3[CH:36]=2)=[CH:14][N:13]=1)[C:6]([O:8]C)=[O:7].O1CCCC1.O>CO>[CH3:4][C:5]([CH3:37])([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[N:26]([C:27](=[O:35])[NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24][O:23][C:22]=3[CH:36]=2)=[CH:14][N:13]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(c2)OCCN3C(=O)Nc2ccccc2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(COc1ccc(-c2ccc3c(c2)OCCN3C(=O)Nc2ccccc2)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
Lithium hydroxide monohydrate (14.3 mg, 0.342 mmol) was added to a solution of methyl 2,2-dimethyl-3-(5-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)propanoate B-3 (ca. 62.0 mg, 0.114 mmol) in 1:1:1 tetrahydrofuran:water:methanol (1.14 mL) at room temperature. After 12 h of vigorous stirring at room temperature, lithium hydroxide monohydrate (14.3 mg, 0.342 mmol) was added, and the reaction mixture was heated at 65° C. under microwave irradiation for 30 mins. The clear solution was then quenched with a 1 N aqueous solution of hydrogen chloride (1.0 mL) and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on C18 reverse phase (water:acetonitrile gradient with 0.05% formic acid) to give white crystalline 2,2-dimethyl-3-(5-(4-(phenylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)propanoic acid B-4 (36.6 mg, Yield=72% over 2 steps). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.23 (s, 6H), 3.88 (t, J=4.10 Hz, 2H), 4.28 (s, 2H), 4.30 (t, J=4.10 Hz, 2H), 6.86 (d, J=8.51 Hz, 1H), 7.01 (dt, J=1.10, 7.41 Hz, 1H), 7.16-7.21 (m, 2H), 7.29 (t, J=7.72 Hz, 2H), 7.50 (d, J=8.20 Hz, 2H), 7.60 (d, J=8.51 Hz, 1H), 7.98 (br d, J=8.51 Hz, 1H), 8.44 (s, 1H), 9.16 (s, 1H), 12.37 (br s, 1H); MS (ESI) [M+1]+ 448.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:13][CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:5][CH:4]=1.Br.[CH3:16][N:17]1[C:22]2[CH:23]=[C:24]([OH:27])[CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1.[OH:28]O>O.N.CC(C)=O.C(OCC)(=O)C>[CH2:13]([N:9]([CH:10]([CH3:11])[CH3:12])[C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:25]2[C:24](=[O:27])[CH:23]=[C:22]([N:17]([CH2:18][CH2:19][OH:28])[CH3:16])[C:21](=[O:20])[CH:26]=2)=[CH:8][CH:7]=1)[CH3:14]
Reactant: CCN(c1ccc(N)cc1)C(C)C
Reactant: CN1CCOc2ccc(O)cc21
Reactant: OO
Agent: Br
Agent: Cl
Agent: N
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(c1ccc(NC2=CC(=O)C(N(C)CCO)=CC2=O)cc1)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1.07 g (0.005 mol) of N-(4-aminophenyl)-N-ethyl-N-isopropylamine hydrochloride in 5 ml of water and 2 ml of 20% aqueous ammonia is added a solution of 1.22 g (0.005 mol) of 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-ol hydrobromide in 2 ml of water, 1 ml of 20% aqueous ammonia and 15 ml of acetone. 17 ml of aqueous hydrogen peroxide solution are added and the mixture is stirred at room temperature for 4 hours. An oil forms. After 24 hours at 6° C., the oil forms a gum. This gum is taken up in ethyl acetate. After drying and concentrating this organic phase, 0.86 g of 2-[4-(ethylisopropylamino)phenylamino]-5-[(2-hydroxyethyl)methylamino][1,4]benzoquinone (compound 2) is obtained in the form of a black powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](O)=O)=[CH:22][C:17]=2[NH:16][CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1.O=P(Cl)(Cl)Cl>>[NH:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[S:35][C:4]([CH2:5][CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:3][N:2]=3)=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: NCC(=O)CCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(CCc2cnc(-c3ccc4[nH]cnc4c3)s2)cc1

Procedure:
The compound was synthesized starting from amino-4-phenylbutan-2-on-hydrochloride (163 mg; 1 mmol), benzimidazol-5-carboxylic acid (248 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol), TEA (0.22 ml, 0.3 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described above; yield: 0.042 g (13.8%); MS m/z: 306.1 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 2.98 (t, 2H, 3J=7.5 Hz); 3.20 (t, 2H, 3J=7.5 Hz); 7.17-7.22 (m, 1H); 7.25-7.31 (m, 4H); 7.62 (s, 1H); 7.80 (d, 1H, 3J=8.7 Hz); 7.90 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 8.16 (d, 1H, 4J=1.7 Hz); 9.02 (s, 1H); HPLC (METHOD [A]): rt 13.73 min (97.4%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[OH:16].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28](OS(C)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:16][C:7]2[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[O:17])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C(C)(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 104 %

Procedure:
3-(4-tert-Butyl-2-hydroxyphenyl)acrylic acid methyl ester (24.7 mg, 0.105 mmole), 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (58.7 mg, 0.210 mmol), potassium carbonate (43.7 mg, 0.316 mmol) was added in DMF. The reaction mixture was stirred overnight. The reaction mixture was purified according to step 1 of Example 30 to give solid (45.6 mg, 100%).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([S:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>CO>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([S:14][C:5]([CH3:13])([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([OH:23])=[O:3])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(C)(Cc1ccccc1)Sc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(SC(C)(Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid ethyl ester (4.12 g, 12 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml) was added. The reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated, diluted with 1:1 hexane:diethyl ether and extracted with H2O. The water layer was cooled with ice and is acidified to pH 3. The acid was then extracted with chloroform and the organic layer was dried over MgSO4, filtered and concentrated to afford of 2-(4-methoxy-phenylsulfanyl)-2-methyl-3-phenyl-propionic acid as a low melting solid. Yield 580 mg, 16%; MS: 303.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30](O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[N:38](C(OCC)=O)=NC(OCC)=O>ClCCl>[CH2:30]([O:10][C:5]1[CH:6]=[CH:7][C:8]([NH2:38])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Nc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Yield: 85 %

Procedure:
To a solution of 4-amino, 2-nitrophenol (1 mmol), triphenyl phosphine (1.2 mmol) and benzyl alcohol (1.2 mmol) in dry dichloromethane (5 ml) at ambient temperature, under a nitrogen atmosphere, was added a solution of diethyl azodicarboxylate (1.2 mmol) in dry dichloromethane (2 ml). The resultant mixture was stirred at ambient temperature for 18 hr. Evaporation under reduced pressure afforded a gum that was purified by column chromatography (SiO2; diethyl ether) to give 4-benzyloxy-3-nitro-aniline, yield 85%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)NC=[C:5]2C=O.P([O-])([O-])(O)=O.[NH4+:18].[NH4+].[N+:20]([CH2:23][CH2:24][CH3:25])([O-])=O>C(O)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:8](=[C:4]([CH3:5])[CH:3]=1)[NH:20][CH:23]=[C:24]2[C:25]#[N:18]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: CCC[N+](=O)[O-]
Reactant: [NH4+]
Agent: O=P([O-])([O-])O
Solvent: CC(=O)O
Product: Cc1cc(Br)cc2c(C#N)c[nH]c12
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of 5-bromo-indole-3-carboxaldehyde (0.7 g, 2.94 mmol), diammonium hydrogen phosphate (2.05 g, 15.5 mmol) in 1-nitropropane (9 mL) and acetic acid (3 mL) were heated at reflux for 16 h. After cooling to room temperature, the solvents were removed under reduced pressure and water added to the dark residue. After a short while, 5-bromo-1H-indole-3-carbonitrile precipitated rapidly, was filtered, washed severally with water and dried for several hours to afford 0.6 g (87%) of the desired nitrile. LC/MS: tR=1.71 min, 235.01 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[C:24]([Cl:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[Cl:26])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:26][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([Cl:25])[C:15]=1[O:14][CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cc(Cl)c(OCC2CCCN2C(=O)OC(C)(C)C)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)c(OCC2CCCN2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirred solution of methyl 4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3,5-dichlorobenzoate (988 mg, 3.248 mmol) in CH2Cl2 (20 mL) was added TFA (5 mL) at 0° C., and the reaction mixture was stirred at room temp for 2 hr. The solvent was removed under a reduced pressure and the residue was treated with 1N NaOH. The solution was extracted with CHCl3. The extract was washed with brine, dried over Na2SO4, and concentrated under a reduced pressure to afford 672 mg (68%) methyl 3,5-dichloro-4-(2-pyrrolidinyl)methoxybenzoate as a pale yellowish oil. 1H-NMR (400 MHz, CDCl3) δ1.62-1.69 (m, 1H), 1.78-1.86 (m, 2H), 1.89-199 (m, 1H), 2.92-2.98 (m, 1H), 3.04-3.09 (m, 1H), 3.55-3.60 (m, 1H), 3.91 (s, 3H), 4.01 (dd, J=6.8, 8.8 Hz, 1H), 4.08 (dd, J=4.9, 8.8 Hz, 1H), 7.97 (s, 2H); MS (FAB) m/z 304 (M++1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:34]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[C:42]([CH2:51]OS(C)(=O)=O)[C:43](=[O:50])[N:44]([CH2:46][CH:47]([CH3:49])[CH3:48])[N:45]=2)=[CH:36][CH:35]=1.CN1CCNCC1>>[C:34]1([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[C:42]([CH2:51][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)[C:43](=[O:50])[N:44]([CH2:46][CH:47]([CH3:49])[CH3:48])[N:45]=2)=[CH:36][CH:35]=1
Reactant: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(COS(C)(=O)=O)c1=O
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(CN2CCN(C)CC2)c1=O
Yield: 68.2 %

Procedure:
Following the procedure of Example 1 (10), 6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 68.2%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH2:14]2)=[O:12])[CH2:10][CH2:9]1)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][C:8]1([C:11]([N:13]2[CH2:16][CH:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH2:14]2)=[O:12])[CH2:9][CH2:10]1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C4(NC(=O)OC(C)(C)C)CC4)C3)ccc1-2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)C4(N)CC4)C3)ccc1-2
Reaction time: 18 h
Yield: 58.5 %

Procedure:
To a suspension of (1-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carbonyl}-cyclopropyl)-carbamic acid tert-butyl ester (225 mg, 0.41 mmol) in MeOH (3.1 mL) was added 4N HCl/dioxan (1.0 mL, 4.1 mmol) and the reaction mixture was stirred for 18 hours. The resulting solid was filtered off and washed with diethyl ether before being partitioned between DCM and an aqueous saturated sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with DCM (×2). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-8% 2N NH3/MeOH in DCM). The resulting solid was suspended in ether and collected by filtration to give 425 as a white solid (108 mg, 59%). LCMS: RT=7.96 min, [M+H]+=451. 1H NMR δ (ppm) (DMSO-d6): 8.35 (1 H, d, J=8.20 Hz), 8.02 (1 H, s), 7.20 (1 H, dd, J=8.22, 1.81 Hz), 7.05 (1 H, s), 5.86-5.78 (1 H, m), 4.59 (2 H, t, J=9.01 Hz), 4.40 (2 H, t, J=5.07 Hz), 4.20 (2 H, d, J=7.67 Hz), 3.85 (1 H, t, J=7.50 Hz), 3.44 (2 H, t, J=5.08 Hz), 2.18 (2 H, s), 1.58 (6 H, d, J=6.59 Hz), 1.09-1.06 (2 H, m), 0.70 (2 H, q, J=3.28 Hz)
Reaction SMILES: [CH2:1]1[C@H:6]([NH2:7])[C@@H:5]([O:8][C@H:9]2[O:14][C@H:13]([CH2:15][NH2:16])[C@@H:12](O)[C@H:11](O)[C@H:10]2O)[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]2[OH:32])[C@@H:2]1[NH2:33].O.C([N:37](CC)CC)C.C(OC(N=[N+]=[N-])=O)(C)(C)C>N1C=CC=CC=1>[CH2:12]1[C@@H:13]([CH2:15][NH2:16])[O:14][C@H:9]([O:8][C@H:5]2[C@H:4]([OH:20])[C@@H:3]([O:21][C@H:22]3[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([NH2:31])[C@H:23]3[OH:32])[C@H:2]([NH2:33])[CH2:1][C@@H:6]2[NH2:7])[C@H:10]([NH2:37])[CH2:11]1
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CCN(CC)CC
Agent: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: O
Solvent: c1ccncc1
Product: NC[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
For instance, 6'-N-t-butoxycarbonylkanamycin may be prepared in a high yield by reacting kanamycin in solution in a mixture of pyridine, water and triethylamine with a 1 to 3 molar proportion of t-butoxycarbonyl azide added dropwise thereto under agitation, stirring the admixture at ambient temperature overnight, concentrating the reaction mixture to dryness in vacuo and then purifying the solid residue in a column chromatography with a cation-exchange resin such as Amberlite CG 50 (NH4 form), while recovering the unreacted kanamycin. Moreover, 2',6'-di-N-t-butoxycarbonylkanamycin B or 3',4'-dideoxykanamycin B may be prepared in a high yield, for example, by reacting kanamycin B or 3',4'-dideoxykanamycin B in solution in a mixture of pyridine, water and triethylamine with a 2-3 molar proportion of t-butoxycarbonyl azide added dropwise thereto under agitation, stirring the admixture at ambient temperature overnight, concentrating the reaction mixture to dryness in vacuo, and then purifying the solid residue in column chromatography with a cation-exchange resin such as Amberlite CG 50 (NH4 form). When this preparation procedure is repeated with 2 molar proportions or less of t-butoxycarbonyl azide, there may be obtained 6'-N-t-butoxycarbonyl-kanamycin B or 3',4'-dideoxykanamycin B in a high yield. 6'-N-t-butoxycarbonyl-kanamycin B or 3',4'-dideoxykanamycin B once isolated may also be converted into the 2',6'-di-N-t-butoxycarbonyl derivative by further reacting with 1 to 2 molar proportions of t-butoxycarbonyl azide in a similar manner. The compounds of the formula (IV) prepared in the above procedures may be employed as a starting compound in the process of this invention without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.[C:20]([CH2:22][C:23](O)=[O:24])#[N:21].C(Cl)CCl.C(N(CC)CC)C>C1COCC1>[NH2:1][C:2]1[C:7]([NH:8][C:23](=[O:24])[CH2:22][C:20]#[N:21])=[CH:6][N:5]=[C:4]([O:9][C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:3]=1
Reactant: COC(=O)c1cccc(Oc2cc(N)c(N)cn2)c1
Reactant: N#CCC(=O)O
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(Oc2cc(N)c(NC(=O)CC#N)cn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step 3 in THF (150 mL), was added cyanoacetic acid (870 mg, 10.2 mmol), EDC (4.32 g, 22.5 mmol) and triethylamine (8 ml, 51 mmol). This mixture was then stirred at rt for overnight. The reaction mixture was concentrated, taken up in EtOAC (300 mL), washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in AcOH (100 ml), and then heated to 115° C. for 24 h. The reaction mixture was concentrated to afford the title compound, which was used directly to next step without further purification. MS (ES+) m/e 309 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][C@H:24]([CH2:26]Cl)[N:23]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:22][C@H:21]1[CH3:35])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@H:24]([CH2:26][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:23]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:22][C@H:21]1[CH3:35])=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCOCC2)CN1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
K2CO3 (12.4 g, 90.0 mmol), KI (8.29 g, 51.0 mmol) and morpholine (3.9 mL, 45.0 mmol) were added to a solution of (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (10.0 g, 30.0 mmol) in acetonitrile (150 mL). The reaction was stirred at 70° C. for 18 h. The solids were filtered off and the solvent was removed in vacuo. The residue was partitioned between DCM (150 mL) and water (150 mL). The organic phase was dried (MgSO4) and evaporated. Chromatography (SiO2, eluted with petrol-EtOAc 0-50%) gave the title compound (9.0 g, 77%) as a white solid. MS: [M+H]+=390.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH2:5]([C:12]1[CH:13]=[C:14]([N:18]2[CH2:22]C=CC2)[CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C[N+]1([O-])CC[O:27]CC1.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Os](=O)(=O)(=O)=O.C(O)(C)(C)C.O>[CH2:5]([C:12]1[CH:13]=[C:14]([N:18]2[CH2:4][C@H:2]([OH:3])[C@H:1]([OH:27])[CH2:22]2)[CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1=CCN(c2cccc(Cc3ccccc3)c2)C1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O[C@@H]1CN(c2cccc(Cc3ccccc3)c2)C[C@@H]1O
Reaction time: 8 h

Procedure:
While stirring 20 ml of an acetone solution of 2.1 g of 1-(3-benzylphenyl)-2,5-dihydropyrrole on an ice bath, 2.2 ml of a 50% aqueous solution of N-methylmorpholine-N-oxide, 4 ml of water and 0.5 ml of a 2.5% t-butanol solution of osmium tetroxide were successively added thereto, followed by stirring as it was at room temperature overnight. After adding 2 ml of a 1 M aqueous solution of sodium thiosulfate, the reaction mixture was extracted with ethyl acetate-water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography with 10–50% ethyl acetate/hexane, to give 1.15 g of the title compound.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C@@H:13]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:14]([N:30]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.O.C(=O)(O)[O-].[Na+]>Cl.O1CCOCC1>[NH2:8][C@@H:12]([C@@H:13]([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C@@H:14]([N:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:17]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cccc(OCc3ccccc3)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N[C@H](CO)[C@@H](OCc1ccccc1)[C@H](Cc1cccc(OCc2ccccc2)c1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Dissolve 4-(R)-[1-(S)-benzyloxy-3-(3-benzyloxyphenyl)-2-(S)-dibenzylaminopropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (16.01 g, 22.0 mmol) in 4 M hydrogen chloride in 1,4-dioxane (130 mL) and stir for 30 minutes. Add water (65 mL) and stir for 18 hours. Slowly add sodium bicarbonate (50 g) and water (˜50 mL). Extract with ethyl acetate, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate to give the crude desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[I:14]Cl.C([O-])(O)=O.[Na+]>Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:10])([F:11])[F:12])=[CH:4][C:3]=1[I:14]
Reactant: Nc1ccc(C(=O)C(F)(F)F)cc1
Reactant: ClI
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(C(=O)C(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a stirred solution of 1-(4-aminophenyl)-2,2,2-trifluoroethanone (1.0 g, 5.28 mmol) in 1M aqueous HCl solution (70 mL) was added iodine monochloride (0.77 g, 4.76 mmol). The reaction mixture was stirred at r.t. for 2 h, then basified with the addition of aqueous sat. NaHCO3 solution and extracted with EtOAc (2×100 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 15-20% EtOAc/hexanes) gave the title compound (0.983 g, 59%) as a cream solid. δH (CDCl3) 8.40 (1H, d, J 1.0 Hz), 7.92-7.85 (1H, m), 6.76 (1H, d, J 8.6 Hz), 4.91 (2H, br. s). LCMS (ES+) RT 2.86 minutes (Method 2).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:8][Si:9](Cl)([CH3:11])[CH3:10]>C[Si](N[Si](C)(C)C)(C)C>[Si:9]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][Si:9]([CH3:11])([CH3:10])[CH3:8])([CH3:11])([CH3:10])[CH3:8]
Reactant: C[Si](C)(C)Cl
Reactant: OCCCCCO
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)OCCCCCO[Si](C)(C)C
Temperature: 50 °C

Procedure:
1,5-Pentanediol (65 g, 0.62 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.4 mL trimethylsilyl chloride. A portion of HMDS (ca. 20 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (130 mL, 0.71 mol total) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50° C. Heating was continued at 100° C. (1 h), and 150° C. (2.5 h). GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 139 g of colorless oil, bp 47°-49° C./0.1 mm. 1H NMR (CDCl3): 3.60 (t, J=7Hz, 4H), 1.57 (m, 4H), 1.40 (m, 2H), 0.12 (s, 18H), consistent with the assigned structure.