Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:22]=1[N+:29]([O-:31])=[O:30]>C1COCC1>[F:27][C:26]1[C:25]([F:28])=[CH:24][CH:23]=[C:22]([N+:29]([O-:31])=[O:30])[C:21]=1[NH:4][C:3]1[CH:5]=[CH:6][C:7]([I:9])=[CH:8][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-fluoro-4-iodoaniline (11.40 g, 47 mmol) in 100 ml anhydrous THF at 0° C., 47 ml of a 1M solution of LHMDS in THF (47 mmol) was added dropwise. The color of the solution turned dark purple. The solution was transferred via cannula to a dropping funnel, and the solution (containing the amine free base) was added in small portions to a solution of 2,3,4-trifluoronitrobenzene (8.321 g, 47.0 mmol) in anhydrous THF (50 ml) at 0° C. After completion of addition the mixture was stirred under argon at room temperature for 15 hours. The volume of the solvent was reduced, followed by extraction using ethyl acetate and brine. The organic layer was dried over sodium sulfate, the solvent was removed, and the obtained dark oil was purified by flash chromatography (EtOAc/hexane 1:5, Rf=0.58) yielding the crude product, which became a brown solid upon drying in vacuo (yield: 6.23 g, 33.6%). m/z=393 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccn1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccccn1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and commercial 2-acetylpyridine, 3-(4-chlorophenyl)-1-(2-pyridinyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[Br:22][C:23]1[CH:24]=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:27][C:28]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:28]3[CH:27]=[CH:26][C:25]([C:30]([F:33])([F:32])[F:31])=[CH:24][C:23]=3[Br:22])[CH:14]=2)=[CH:8][C:7]=1[CH3:20]
Reactant: COC(=O)CCc1ccc(Oc2cccc(O)c2)cc1C
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Temperature: 100 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
A mixture of 3-[4-(3-hydroxy-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (8.18 g, 28.6 mmol), 3-bromo-4-fluorobenzotrifluoride (6.80 g, 28.0 mmol) and 325 mesh potassium carbonate (4.64 g, 33.68 mmol) in dry DMSO (80 mL) is heated to 100° C. and stirred for about 6 hours under N2. The reaction is cooled and acidified with 1 N HCl. The mixture is then diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 15/1 hexanes/ethyl acetate to afford about 11.74 g (81%) of the titled compound. Rf=0.76 (9/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C24H20O4F3Br 509, found 526 and 528 (M+NH4, 100%).
Reaction SMILES: O[CH:2]1[C:6]2[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:23])[CH3:22].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C.CCCCCC>[CH3:17][C:16]([CH3:18])([CH3:19])[CH2:15][C:14]([NH:13][C:8]1[C:7]([CH3:21])=[C:6]([CH3:2])[C:5]2[O:4][C:3]([CH3:23])([CH3:22])[CH:11]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:10]=2[C:9]=1[CH3:12])=[O:20]
Reactant: C1CCNC1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(O)C(C)(C)O2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(N1CCCC1)C(C)(C)O2
Yield: 36 %

Procedure:
Using N-(3-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 234 and pyrrolidine, the title compound was synthesized in the same manner as in Example 297. Yield: 36%. Melting point: 197-198° C. (ethyl acetate-hexane). 1H-NMR (CDCl3) δ: 1.16 (9H, s), 1.23 (3H, s), 1.49 (3H, s), 1.58-1.72 (4H, m), 2.09 (3H, s), 2.13 (6H, s), 2.30 (2H, s), 2.48-2.80 (4H, m), 4.02 (1H, s), 6.55 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:17])[CH2:9][CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12]C2)[CH:5]=[CH:6][CH:7]=1.[C:18]([NH:20][C:21]([NH2:23])=[NH:22])#[N:19].[CH2:24](OCCOCCO)C>>[NH2:22][C:21]1[N:20]=[C:18]([NH2:19])[C:13]2[CH2:12][CH:9]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)([CH3:17])[CH3:24])[CH2:10][CH2:15][C:14]=2[N:23]=1
Reactant: CC(CC1CCC(=O)CC1)c1cccc(Cl)c1
Reactant: N#CNC(=N)N
Reactant: CCOCCOCCO
Product: CC(C)(c1cccc(Cl)c1)C1CCc2nc(N)nc(N)c2C1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.2 grams (0.013 mole) of 4-[2-(3-chlorophenyl)propan-yl]cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-[2-(3-chlorophenyl)propan-2-yl]-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][O:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].[N:15]#[C:16]Br>>[C:9]1([CH:7]([O:6][CH2:5][C@H:2]2[CH2:3][O:4][C:16]([NH2:15])=[N:1]2)[CH3:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(OC[C@H](N)CO)c1ccccc1
Reactant: N#CBr
Product: CC(OC[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1d (R)-2-amino-3-(1-phenyl-ethoxy)-propan-1-ol was reacted with cyanogen bromide to give (4S)-4-(1-phenyl-ethoxymethyl)-4,5-dihydro-oxazol-2-ylamine. Light yellow oil. MS (ISP): 221.3 ([M+H]+)).
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7](=[O:19])[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])C#N)C.S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[CH2:8][C:7](=[O:19])[CH2:6][CH2:5][C:4]([OH:20])=[O:3]
Reactant: CCOC(=O)CCC(=O)C(C#N)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCC(=O)Cc1ccc(Cl)cc1Cl
Yield: 80 %

Procedure:
A 1-liter 1-neck R.B. flask was charged with 156.61 g (0.50 Mol) of ethyl-5-(2',4'-dichlorophenyl)-5-cyano-4-ketopentanoate, 153 ml of concentrated sulfuric acid, 153 ml of water, and 440 ml of glacial acetic acid. The reaction mixture was stirred and refluxed for 24 hours. l g, 80% yield) was obtained as a viscous dark-colored oil.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[N:4]1.[F:25][C:26]([F:47])([F:46])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[CH3:2][N:3]1[C:7]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:34][CH2:33][C:30]4[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:46])[F:47])=[CH:32][CH:31]=4)[CH2:20]3)=[O:16])[CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[N:4]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C(F)(F)F)cc2)cc1
Reactant: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCNC2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(CCc3ccc(C(F)(F)F)cc3)C2)c1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A mixture of 1-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-piperidin-3-ylmethylurea hydrochloride (50 mg, 142 μmol), toluene-4-sulfonic acid 2-(4-trifluoromethyl-phenyl)-ethyl ester (90% pure, 55 mg, 142 μmol), triethylamine (60 μL, 426 μmol) and acetonitrile (1.5 mL) was heated at reflux for 16.5 hours and cooled to room temperature. The mixture was concentrated, and the residue was purified by flash chromatography, eluting with 3% methanol in dichloromethane containing 0.3% aqueous ammonium hydroxide, to provide a white amorphous solid (30 mg, 45%). 1H NMR (300 MHz, CDCl3) δ8.26 (s, !H), 7.87 (d, J=8 Hz, 1H), 7.76 (s, 1H), 7.51 (d, J=8 Hz, 1H), 7.39 (t, J=8 Hz, 1H), 7.28 (d, J=8 Hz, 2H), 7.20 (d, J=8 Hz, 1H), 6.06 (bm, 1H), 4.15 (s, 3H), 3.23 (t, J=6 Hz, 2H), 3.03 (m, 1H), 2.86 (m, 2H), 2.61 (m, 2H), 2.1-1.5 (m, 7H), 1.05 (m, 1H). Mass spec (ES+) m/z 488.5 (M+H+, 100%).
Reaction SMILES: C(N(CC)CC)C.[C:8](=[O:43])([O:12][CH2:13][CH2:14][N:15]([C:17]([N:19]1[C:23]2[CH:24]=[C:25](OC)[CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[S:30]([CH2:32][C:33]1[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=1)=[O:31])=[O:18])[CH3:16])[O:9][CH2:10][CH3:11].[O:44]1CCC[CH2:45]1>>[C:8](=[O:43])([O:12][CH2:13][CH2:14][N:15]([C:17]([N:19]1[C:23]2[CH:24]=[CH:25][C:26]([O:44][CH3:45])=[CH:27][C:22]=2[N:21]=[C:20]1[S:30]([CH2:32][C:33]1[C:38]([CH3:39])=[C:37]([O:40][CH3:41])[C:36]([CH3:42])=[CH:35][N:34]=1)=[O:31])=[O:18])[CH3:16])[O:9][CH2:10][CH3:11]
Reactant: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2ccc(OC)cc21
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.291 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 1 hr under ice-cooling, and ethyl 2-(methylamino)ethyl carbonate hydrochloride (0.551 g) obtained in Reference Synthetic Example 14 was added thereto. A solution of triethylamine (0.418 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 2 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (15 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). To the solution were added 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.817 g), triethylamine (0.661 mL) and 4-dimethylaminopyridine (0.012 g), and stirred at 60° C. for 12 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (20 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give a mixture of 3:2 of title compound and ethyl 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as pale yellow amorphous solid (0.92 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22].[H-].[Na+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].O>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5](=[O:23])[N:6]2[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][C:13]=1[S:21][CH3:22]
Reactant: CSc1cc(C(C)C)ccc1-n1c(=O)[nH]c2c(Cl)nc(C)nc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(-c2ccc(C(C)C)cc2SC)c2nc(C)nc(Cl)c21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97.4 %

Procedure:
In 5 ml of dimethylformamide, 0.70 g of 6-chloro-9-(4-isopropyl-2-methylthiophenyl)-2-methyl-8,9-dihydropurin-8-one was dissolved, and 80 mg of sodium hydride in an oil was added thereto with ice-cooling, followed by stirring for 40 minutes. Subsequently, 0.39 g of ethyl bromoacetate was added thereto, and the reaction mixture was warmed up to room temperature and was stirred for 20 minutes. Water was poured into the reaction mixture. The reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and was then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to yield 0.85 g of ethyl 2-[6-chloro-2-methyl-8-oxo-9-(4-isopropyl-2-methylthiophenyl)-8,9-dihydropurin-7-yl]acetate as an oil.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)#[CH:9]>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]#[C:9][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: Ic1cccnc1
Reactant: C#Cc1ccc(F)cc1
Product: Fc1ccc(C#Cc2cccnc2)cc1
Yield: 40.6 %

Procedure:
Prepare essentially as described in PREPARATION 10 using 3-iodopyridine (153 mg, 0.75 mmol) and 1-ethynyl-4-fluorobenzene (100 mg, 0.83 mmol) to give the title compound (60 mg, 40%).
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5]CC)=[O:4].[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]>C1COCC1.C(OCC)(=O)C.[Zn]>[F:9][C:2]([F:8])([CH:13]([OH:14])[C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[CH3:10])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Cc1ccccc1C=O
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(O)C(F)(F)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
A solution of ethyl bromodifluoroacetate (5.6 g) and 2-methylbenzaldehyde (3 g) in THF (25 mL) is added dropwise to a refluxing suspension of activated zinc dust (2.1 g) in THF (25 mL) and refluxing continued for a further 4 hours. The reaction is allowed to cool to ambient temperature, filtered through hyflo and concentrated in vacuo to give a yellow solid. The solid is taken up in ethyl acetate (50 mL) and washed with brine which leads to the formation of a white precipitate which is filtered off then partitioned between ethyl acetate (50 mL) and 1 N HCl (50 mL). The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated in vacuo to give (RS)-2,2-difluoro-3-hydroxy-3-(2-methylphenyl)propanoic acid as a yellow solid (2.4 g)
Reaction SMILES: C[C@@]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](N)C[C@H]2N)OC1.CC(N)C1OC(OC2C(O)C(OC3OCC(O)(C)C(NC)C3O)C(N)CC2N)C(O)C(O)C1O.C[C@@:69]1([OH:100])[C@H:74]([NH:75][CH3:76])[C@@H:73]([OH:77])[C@@H:72]([O:78][C@@H:79]2[C@@H:84]([OH:85])[C@H:83]([O:86][C@H:87]3[O:92][C@H:91]([CH2:93][OH:94])[C@@H:90]([OH:95])[C@H:89]([OH:96])[C@H:88]3[NH2:97])[C@@H:82]([NH2:98])[CH2:81][C@H:80]2[NH2:99])[O:71][CH2:70]1.CN[C@@H]1C(O)[C@@H](OC2[C@@H](O)[C@H](O[C@H]3OC(CO)[C@@H](O)[C@H](O)C3NO)C(N)C[C@H]2N)OC[C@H]1O>>[CH3:76][NH:75][CH:74]1[CH:73]([OH:77])[CH:72]([O:78][CH:79]2[CH:84]([OH:85])[CH:83]([O:86][CH:87]3[O:92][CH:91]([CH2:93][OH:94])[CH:90]([OH:95])[CH:89]([OH:96])[CH:88]3[NH2:97])[CH:82]([NH2:98])[CH2:81][CH:80]2[NH2:99])[O:71][CH2:70][CH:69]1[OH:100]
Reactant: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: CNC1C(O)C(OC2C(N)CC(N)C(OC3OC(C(C)N)C(O)C(O)C3O)C2O)OCC1(C)O
Agent: CN[C@@H]1C(O)[C@@H](OC2[C@H](N)CC(N)[C@@H](O[C@H]3OC(CO)[C@@H](O)[C@H](O)C3NO)[C@@H]2O)OC[C@H]1O
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)[C@@H](O)[C@H](O)[C@H]3O)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Product: CNC1C(O)COC(OC2C(N)CC(N)C(OC3OC(CO)C(O)C(O)C3N)C2O)C1O

Procedure:
In like manner, the sulfate salt of gentamicin B, gentamicin B1 and gentamicin X may be prepared. In order to prepare sulfate salts of a mixture of gentamicin A, B, B1 and X, the lyophilised or spray dried product of Example 2 is treated as described in this example.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].Cl[C:13]1[C:14]2[CH2:24][CH2:23][CH2:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[C:15]=2[N:16]=[C:17]([NH2:19])[N:18]=1>>[NH2:19][C:17]1[N:18]=[C:13]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:14]2[CH2:24][CH2:23][CH2:22][C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[C:15]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Product: CC(C)(C)OC(=O)NCCNc1nc(N)nc2c1CCCc1ccccc1-2

Procedure:
tert-Butyl 2-aminoethylcarbamate (595 mg, 3.71 mmol) and the product from Example 1C (702 mg, 2.86 mmol) were treated under the conditions described in Example 1D to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H) 1.97-2.08 (m, 2H) 2.15 (t, J=6.27 Hz, 2H) 2.43-2.49 (m, 2H) 3.15 (q, J=6.22 Hz, 2H) 3.33-3.42 (m, 2H) 5.84 (s, 2H) 6.68 (s, 1H) 6.89 (t, J=5.43 Hz, 1H) 7.20-7.27 (m, 1H) 7.27-7.37 (m, 2H) 7.49-7.57 (m, 1H); MS (ESI+) m/z 370.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH:13]([C:15]([CH3:17])=[O:16])=[CH2:14].[CH3:18]COCC>>[C:1]([C:5]1[CH:11]=[C:10]2[C:9]([CH2:14][CH2:13][C:15]([O:16][CH3:18])([CH3:17])[O:12]2)=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(O)ccc1O
Reactant: CCOCC
Reactant: C=CC(C)=O
Product: COC1(C)CCc2cc(O)c(C(C)(C)C)cc2O1

Procedure:
Reaction of tert-butyl-hydroquinone with methyl vinyl ketone by the procedure of Example 1 gave (±)-7-tert-butyl-6-hydroxy-2-methoxy-2-methylchroman as a white solid, m.p. 115°-117° from ether-30°-60° petroleum ether.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[CH3:39][C:40]1[O:44][N:43]=[C:42]([C:45](Cl)=[O:46])[CH:41]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:45]([C:42]1[CH:41]=[C:40]([CH3:39])[O:44][N:43]=1)=[O:46])[CH:29]=3
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)Nc2cc3cc(c2)Nc2nc(ncc2Cl)Nc2cccc(c2)CC3)no1
Yield: 42 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 42% yield. LCMS for C23H20ClN6O2(M+H)+: m/z=447.2. 1H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 9.59 (s, 2H), 8.17 (s, 1H), 7.88 (m, 1H), 7.59 (m, 1H), 7.49 (m, 1H), 7.35 (m, 1H), 7.11 (dd, 1H), 6.89 (m, 1H), 6.84 (m, 1H), 6.64 (m, 1H), 2.88 (m, 4H), 2.48 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7]1)=[O:5])[CH3:2].Cl[C:28]([O:30][CH:31]=[CH2:32])=[O:29]>ClCCCl>[CH:31]([O:30][C:28]([N:8]1[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1)=[O:29])=[CH2:32]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc([N+](=O)[O-])cc1
Reactant: C=COC(=O)Cl
Solvent: ClCCCl
Product: C=COC(=O)N1CC(C(=O)OCC)C(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
A stirred solution of 1-benzyl-4-(4-nitro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (9.56 g, Reference Example 6) in 1,2-dichloroethane (25 ml), at 25° C. and under an atmosphere of argon, was treated dropwise with vinyl chloroformate (2.5 ml). The resulting mixture was heated at reflux for 20 hours then evaporated (40° C. and 2.7 kPa). The residue was subjected to flash chromatography on silica (0.045-0.020 mm particle size) eluting with a mixture of cyclohexane and ethyl acetate (50:50, v/v) affording the title compound (8.38 g) as a white solid. 1H-NMR [500 MHz, (CD3)2SO]: δ 1.07 (m, 3H); 3.35 to 3.70 and 3.70 to 4.00 (2 m, 6H); 4.03 (m, 2H); 4.54 and 4.56 (2 d, J=6 Hz, 1H); 4.79 and 4.85 (2 d, J=14 Hz, 1H); 7.16 (dd, J=14 and 6 Hz, 1H); 7.69 (d, J=8 Hz, 2H); 8.23 (d, J=8 Hz, 2H). MS (EI): 334 [M]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:30]3([OH:33])[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[N:3]=1
Reactant: O=C1CCOCC1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CCOCC1)n2C
Temperature: -78 °C
Yield: 80.9 %

Procedure:
To (S)-4-(2-chloro-9-methyl-9H-purin-6-yl)-3-methylmorpholine (100.0 mg, 0.374 mmol) in anhydrous THF (4.0 mL) at −78° C. under N2 was added freshly prepared lithium diisopropylamide in THF (2.0 eq.), and the reaction mixture was stirred at −78° C. After stirring for 2 h tetrahydro-4H-pyran-4-one (68.6 μL, 0.75 mmol, 2.0 eq.) was added. The reaction was then stirred at RT for 16 h and quenched with saturated aqueous sodium ammonium chloride solution. Volatile solvent was evaporated in vacuo, and the crude was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 5 to 100% ethyl acetate in hexane). Crystallization from ether-hexane afforded the product (b-1) as a solid (111.3 mg, 81.0%). 1H NMR (CDCl3, 400 MHz). δ ppm 5.3 (broad s, 1H), 4.98 (broad s, 1H), 4.00 (dd, J=3.4 Hz, 1H), 3.97 to 3.79 (m, 7H), 3.79 to 3.71 (m, 2H), 3.60 (td, J=11.6, 2.7 Hz, 1H), 3.45 (broad s, 1H), 2.39 (m, 2H), 1.86 (d, J=13.2 Hz, 2H), 1.38 (d, J=6.8 Hz, 3H); LC-MS m/z (method A)=368/370 [M+H]+, RT=1.93 min.