Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8](Cl)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])[CH2:4][CH2:3]1
Reactant: CCCCCCCCCCCCCl
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCN1CCN(C)CC1
Yield: 65.9 %

Procedure:
100 g (1 mole) of 1-methyl-piperazine were heated to 100° C and a total of 204.5 g (1 mole) of dodecyl chloride was added in 3 portions. After a reaction time of 15 minutes, 40 g (1 mole) of solid sodium hydroxide was added in several portions and the mixture was allowed to react for 2 hours at 140°-150° C. The reaction product was then separated from the solid inorganic residue by filtering the reaction mixture whilst hot. The inorganic residue was extracted twice with 200 ml of benzene, the benzene phase was separated off and concentrated and the residue was added to the main filtrate. The product was subjected to a fractional distillation. 177 g (66% of theory) of 1-methyl-4-dodecyl-piperazine of boiling point 90°-115° C/0.01 mm Hg were thus obtained.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1([NH2:27])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:27][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NN1CCOCC1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.23 g, 0.83 mmol) in dry DCM (15 mL) were added morpholin-4-amine 209 (0.13 g, 1.25 mmol), 1-hydroxybenzotriazole (0.19 g, 1.41 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.24 g, 1.25 mmol) and 4-dimethylaminopyridine (0.15 g, 1.23 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-N-(morpholin-4-yl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 210 (0.255 g, 85%) as a clear thick oil.
Reaction SMILES: N([O-])=O.[Na+].N[C@@H:6]([C:13]([OH:15])=[O:14])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1.[OH-].[NH4+].[ClH:18]>O>[Cl:18][C@H:6]([CH2:7][C:8]1[N:12]=[CH:11][NH:10][CH:9]=1)[C:13]([OH:15])=[O:14]
Reactant: N[C@H](Cc1c[nH]cn1)C(=O)O
Reactant: Cl
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](Cl)Cc1c[nH]cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cold solution of sodium nitrite (2.63 g, 38 mmol) in water (5 ml) was added dropwise to a stirred suspension of D-histidine (2 g, 11.5 mmol) in concentrated hydrochloric acid (30 ml) at −5° C. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 17 hours. The mixture was cooled and basified with aqueous ammonium hydroxide solution (2N) until pH=4-5. The solvent was then removed by evaporation under reduced pressure to afford (2R)-2-chloro-3-(1H-imidazol-4-yl)propanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:18]=[C:17]([NH:19]C(=O)C)[CH:16]=[C:15]([CH3:23])[CH:14]=3)[NH:8][C:5]2=[N:6][CH:7]=1.N>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[C:15]([CH3:23])[CH:14]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Nc1cc(C)cc(/C=C/c2nc3cc(Br)cnc3[nH]2)n1
Agent: N
Agent: O=S(=O)(O)O
Product: Cc1cc(N)nc(/C=C/c2nc3cc(Br)cnc3[nH]2)c1
Temperature: 0 °C
Yield: 82.7 %

Procedure:
1.20 g of N-{6-[(E)-2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-vinyl]-4-methyl-pyridin-2-yl}-acetamide (compound B10) are suspended in 12 ml of aqueous sulphuric acid (10% strength) at 115° C. for 17 h. Subsequently, the mixture is cooled to 0° C. and conc. aqueous ammonia is added until pH=10. Thereafter, the mixture is extracted 3 times each with 70 ml of ethyl acetate. The combined organic layers are dried using sodium sulphate, filtered with suction, and evaporated to dryness to yield 880 mg of the title compound as an oil, which solidifies upon standing. M.p. 280° C. ESI-MS: 330.2/332.2 (MH+; 100%/90%). TLC: Rf=0.35 (dichloromethane/methanol 10:1).
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10](Cl)=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.N1C(C)=CC=CC=1C>C(OCC)(=O)C.O1CCCC1.[Pd]>[S:1]1[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(Cl)c1cccc2nnsc12
Agent: [Pd]
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cccc2nnsc12

Procedure:
99 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride are dissolved in 1.2 l of ethyl acetate, the mixture is treated at 0°-5° C. with a solution of 58.7 g of 2,6-lutidine in 200 ml of tetrahydrofuran as well as 33 g of palladium/charcoal catalyst (5% Pd), and hydrogenated under low pressure (104Pa) with a further addition of a total of 57 g of palladium/charcoal catalyst and 500 ml of tetrahydrofuran in 5 portions. The catalyst is subsequently removed by filtration and washed with tetrahydrofuran, and the filtrate is evaporated. The residue is purified on silica gel (CH2Cl2) and gives the title compound of m.p. 134°-136° C.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[F:16][C:17]([F:35])([F:34])[C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]3[CH:27]=[C:28](O)[CH:29]=[CH:30][C:31]=3[CH2:32][C@H:21]12)=[O:19].C(N(CC)CC)C.O>CN(C)C1C=CN=CC=1.ClCCl>[F:35][C:17]([F:16])([F:34])[C:18]([N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]3[CH:27]=[C:28]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:29]=[CH:30][C:31]=3[CH2:32][C@H:21]12)=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(N1CCC[C@@H]2c3cc(O)ccc3C[C@@H]21)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21)C(F)(F)F
Temperature: 25 °C

Procedure:
Trifluoromethanesulfonic anhydride (5.6 mL) is added dropwise to a solution of 2,2,2-trifluoro-1-(cis-6-hydroxy-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridin-1-yl)-ethanone (7.3 g), triethylamine (7.2 mL), and 4-dimethylaminopyridine (50 mg) in dichloromethane (60 mL) chilled in an ice bath. The solution is stirred with cooling for 1 h and at room temperature for 2 h. Water (100 mL) and dichloromethane (100 mL) are then added and the organic phase is separated. The organic phase is washed with water (50 mL), dried (MgSO4), and concentrated to give the title compound as a dark oil. Yield: 10.7 g (quantitative); TLC: rf=0.50 (silica gel, cyclohexane/ethyl acetate 3:1); Mass spectrum (ESI+): m/z=418 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:19]([OH:21])=O)[N:15]=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:46][O:47][C:48]([C:50]1[C:58]2[N:57]=[C:56]([NH2:59])[NH:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49]>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:46][O:47][C:48]([C:50]1[C:58]2[N:57]=[C:56]([NH:59][C:19]([C:14]3[N:15]=[CH:16][C:17]4[C:12]([CH:13]=3)=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:18]=4)=[O:21])[NH:55][C:54]=2[CH:53]=[CH:52][CH:51]=1)=[O:49]
Reactant: O=C(O)c1cc2ccc(OCc3ccccc3)cc2cn1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c(NC(=O)c3cc4ccc(OCc5ccccc5)cc4cn3)nc12
Yield: 88.4 %

Procedure:
0.70 g (2.5 mmol) of 7-benzyloxy-isoquinoline-3-carboxylic acid synthesized above, 1.0 g (2.7 mmol) of HBTU in a mixture of 7.5 ml of DMF and 1.7 mL of DIEA was reacted with 0.48 g (2.5 mmol) of 2-Amino-3H-benzoimidazole-4-carboxylic acid methyl ester (Intermediate A) as described in general procedure A. 2-[(7-Benzyloxy-isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester (1.0 g, 88%) was isolated after column chromatography using 1:1 ethyl acetate and hexane as an eluents. LCMS: 453 (M+1)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([N:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCNCC1)C1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1cc(C2(CN3CCNCC3)CCCCC2)ccc1OCCCN1CCCC1
Yield: 59 %

Procedure:
The title compound (187 mg, 59%) was prepared using 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}carbonyl)piperazine and lithium aluminium hydride similarly to the procedure used for example 142. 1H NMR (400 MHz, CDCl3) δ 1.30-1.33 (m, 3H), 1.46-1.54 (m, 4H), 1.78-1.81 (m, 4H), 1.98-2.05 (m, 4H), 2.09-2.12 (m, 6H), 2.23 (s, 2H), 2.53-2.57 (m, 4H), 2.62-2.71 (m, 6H), 4.01 (t, 2H), 6.83 (d, 2H), 7.26 (d, 2H). LRMS APCI+ m/z 386 [MH]+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:18])=[C:10](S(CC)(=O)=O)[N:11]=2)[C:6](=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4]1)[CH3:2].[C:25]([CH2:28][NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)(=[O:27])[CH3:26]>C(#N)C>[C:25]([CH2:28][NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:10]2[N:11]=[C:12]3[C:7]([C:6](=[O:19])[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:18])[CH2:31]1)(=[O:27])[CH3:26]
Reactant: CC(=O)CNC1CCNC1
Reactant: CCOC(=O)c1cn(CC)c2nc(S(=O)(=O)CC)c(F)cc2c1=O
Solvent: CC#N
Product: CCOC(=O)c1cn(CC)c2nc(N3CCC(NCC(C)=O)C3)c(F)cc2c1=O
Yield: 78.2 %

Procedure:
A mixture containing ethyl 1-ethyl-7-ethylsulfonyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.78 g), 3-(N-acetylmethylamino)pyrrolidine (2.13 g), and acetonitrile (70 ml) was heated under reflux for 3 hours. After cooling the mixture, the resulting precipitate was collected and recrystallized from acetonitrile to yield 1.58 g of ethyl 7-[3-(N-acetylmethylamino)-1-pyrrolidinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 212°-213° C.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([C:21](=[O:23])[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:20][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[C:21](=[O:23])[CH3:22])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)C1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 3 h
Yield: 63.2 %

Procedure:
To a solution of 1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanone (IX-1) 4.00 g (9.20 mmol) dissolved in CH3CN (50 mL) was added 2.48 mL (18.40 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 3 hours at RT. Volatiles were removed under vacuo, and the crude residue was dissolved in AcOH (30 mL) before a total of 1.5 g of Zn dust was added portionwise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and column chromatography (SiO2, CH2Cl2/MeOH 9:1 to 8:2) yielded 1.50 g (63%) of the title compound as a colorless oil. ES-MS m/e: 258.0 (M+H+).
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6](C(O)=O)/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9]O.COC(OC)N(C)C.C>O1CCCC1.C1(C=CC(O)=CC=1)O>[CH:8]([C:7]1[O:11][C@H:2]2[N:3]([C:4](=[O:5])[CH2:1]2)[CH:6]=1)=[CH2:9]
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: COC(OC)N(C)C
Agent: Oc1ccc(O)cc1
Solvent: C1CCOC1
Product: C=CC1=CN2C(=O)C[C@H]2O1
Yield: 83.3 %

Procedure:
Clavulanic acid (3.0 mmole) in dry tetrahydrofuran (10 ml) and N,N-dimethylformamide dimethylacetal (0.4 g., 3.35 mmole) in dry tetrahydrofuran (10 ml) were added simultaneously to a rapidly stirred solution of hydroquinone (20 mg) in tetrahydrofuran (20 ml) at room temperature. After addition was complete (5 minutes), the mixture was decolourised using charcoal and filtered, the filter being washed well with more tetrahydrofuran. The solvent was evaporated from the filtrate under reduced pressure to yield (5R)-3-vinyl-7-oxo-4-oxa-1-azabicyclo[3.2.0]-hept-2-ene (340 mg., 2.5 mmole) as a colourless oil, which was immediately dissolved in methyl acrylate (15 ml). The resulting solution was heated at 80° (bath temperature) for 2 hours, then the methyl acrylate was evaporated under reduced pressure and the resulting residue was chromatographed on silica gel using ethyl acetate/protroleum ether (b.p. 60°-80°). Isomer I of the title compound was thus obtained as a colourless gum (84 mg), [α]D 25 =+308.5° (c 1.0, CHCl3). (Found: M+, 223.0839; C11H13NO4 requires 223.0844). νmax (CHCl3): 1795 (β-lactam C=O), 1735 (ester C=O), 1710 (sh)(C=C) cm-1. δ(CDCl3): 1.56 (1, J 12 Hz, 1H, C(11)H), 2.0-2.8 (complex, 4H), 2.93 (d, J 16 Hz, 1H C(4)H), 3.29 (dd, J 16, 2 Hz, 1H, C(4)H), 3.65 (s, 3H, CO2CH3), 4.10 (ddd, J 12, 4, 2 Hz, 1H C(1)H), 5.11 (m, 2H, C(5)H and C(8)H). m/e: 223 (M+, 20%), 195 (33), 192(25), 182(3), 167(10), 164(17), 154(40), 122(30), 121(15), 95(100), 94(24). Isomer II of the title compound was also obtained as a colourless gum (45 mg), [α]D25 =+181.9° (c 1.0, CHCl3). Found: M, 223.0849; C11H13NO4 requires 223.0844). νmax (CHCl3): 1792 (β-lactam C=O), 1735 (ester C=O), 1710 (sh)(C=C) cm-1. δ(CDCl3): 1.55 (dt, J 6, 12 Hz, 1H C(11)H), 2.0-3.0 (complex, 4H) 2.92 (d, J 16 Hz, 1H, C(4)H), 3.28 (dd, J 16, 2 Hz, 1H C(4)H), 3.69 (s, 3H, CO2CH3), 4.05 (ddd, J 12, 5, 2 Hz, 1H, C(1)H), 5.10 (m, 2H, C(5)H, C(8)H). m/e: 223 (M+ , 6%), 195(22), 192(17), 182(14), 167(8), 164(10), 154(3), 122(37), 121(95), 95(52), 94(20), 55(100).
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]2[C:11]([O:13]C)=[O:12]>>[CH:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH2:5][CH:4]2[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C1CC2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CC2CCC1CC2
Reaction time: 16 h

Procedure:
Sodium hydroxide (2.5N, 22.4 mL, 56 mmol) was added to a methanolic solution of methyl bicyclo[2.2.2]octane-2-carboxylate (4.7 g, 28 mmol in 50 mL) at ambient temperature and the mixture was stirred for 16 hours. The solvent was concentrated in vacuo, water added (20 mL) and the solution made acidic with IN aqueous HCl. The product was extracted into dichloromethane (3×50 mL), the combined organic layers washed with water (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator to afford the titled compound of formula (III) as a white solid (4.3 g, 100% yield).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH:11]([CH3:15])[C:12](Cl)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCCC1>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH:11]([CH3:15])[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OC(C)C(=O)Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC(C)C(=O)N2CCOCC2)cc1

Procedure:
7.5 g (30 mmol) of 2-[(4-tolylsulfonyl)oxy]-propionyl chloride are dissolved in 15 ml of tetrahydrofuran in a flask. 6.5 g (80 mmol) of morpholine are then slowly added dropwise at 0°-5° C., with stirring and simultaneous cooling. The mixture is then subsequently stirred at 0° C., poured onto ice and extracted with diethyl ether. The organic phase is separated off, dried with Na2SO4 and concentrated in a rotary vacuum evaporator. The light yellow residue is separated on a silica gel column (eluting agent: hexane/ethyl acetate 1:1). White crystals of melting point 75°-77° C. then result.
Reaction SMILES: [N:1]([C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[O:33][C@H:32]([CH2:34][O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:14]2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([N:43]=[N+]=[N-])[N:5]=1)=[N+]=[N-].C(Cl)(Cl)Cl>CCO.[Pd]>[NH2:1][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@@H:13]2[O:33][C@H:32]([CH2:34][O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:14]2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([NH2:43])[N:5]=1
Reactant: [N-]=[N+]=Nc1nc(N=[N+]=[N-])c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Nc1nc(N)c2ncn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reaction time: 6 h
Yield: 69 %

Procedure:
Pd-C (5%) (500 mg) was added to a solution of 2,6-diazido-9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)purine (IV, 4.8 g, 8.0 mmol) in EtOH (500 ml), and the resulting mixture was hydrogenated at atmospheric pressure for 6 hr. The H2 atmosphere was changed after 30 min. and after 1 hr. The catalyst was removed by filtration and was washed with CHCl3 to dissolve precipitated product. The combined filtrate and washings were evaporated to dryness in vacuo, and the resulting residue was dissolved in boiling EtOH (80 ml). The crystals that formed on cooling the EtOH solution were collected by filtration, washed with EtOH, and dried in vacuo; yield 3.3 g (75%), mp 161°-162°, TLC (19:1 CHCl3 --MeOH). The analytically pure produce was obtained from a previous preparation: yield 69%; mp 162°; [α]D25 +44.4±0.7° (c, 1.06, CHCl3); λmax ]Mμ (ε× 10-3)], pH 1--254 (10.9), 292 (9.0); EtOH--256 (10.8), 283 (9.0); pH 7, 13--256 (9.0), 279 (9.1); vmax (cm-1)3460, 3350, 3310, 3140 (NH, CH), 2940, 2915 2890, 2865 (CH), 1660 (NH), 1590 (C=C, C=N), 1085, 1045, 1015 (COC), 730, 690 (phenyl).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C@@H:17]1[O:38][C@H:37]([CH2:39][OH:40])[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])=[O:4].O=O.[C:43](=O)(O)[O-:44].[Na+]>O.[Pt]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C@@H:17]1[O:38][C@H:37]([C:39]([O:44][CH3:43])=[O:40])[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])=[O:4]
Reactant: COC(=O)CCCCCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Reactant: O=C([O-])O
Agent: [Pt]
Agent: O=O
Agent: [Na+]
Solvent: O
Product: COC(=O)CCCCCCCCCCCO[C@@H]1O[C@H](C(=O)OC)[C@@H](OC(C)=O)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Reaction time: 2 h

Procedure:
A solution of 10 (500 mg)-in 20 mL of water was vigorously stirred with freshly prepared platinum black (200 mg) at 85 C. while oxygen was slowly passed through the suspension. The pH of the reaction was maintained at approximately 8.0 with solid sodium bicarbonate. It took about 2 hours to complete the oxidation. The mixture was cooled after an additional 10 minutes of stirring. After removal of the catalyst by passing the solution through a Nylon-66 0.45 μm pore size filter, the filtrate was lyophilized. The residue was redissolved in 20 mL of ice-water and the solution was adjusted to pH 2 with 12N HCl and extracted with chloroform. The extract was washed with water until neutral, dried over sodium sulfate and concentrated, and the residue was esterfied with ethereal diazomethane. The product was eluted from a column of silica gel (Rf 0.45, hexane-ethyl acetate, 75:25) to give amorphous methyl 1-O-(11-methoxycarbonylundecyl)-3-O-benzyl-2,4-di-O-acetyl-β-D-glucopyranosuronate (11).1H-NMR data: 7.26-7.30 (m, 5 H, arom.), 5.20 (t, 1 H), 5.08 (t,1 H), 4.62(s, 2 H, CH2Bn), 4.45(d, 1 H, anom.), 3.85-3.97 (m, 2 H) 3.73 (s,3 H, COOMe), 3.68(s, 3 H, COOMe), 2.36(t, 2 H, CH2 lipid), 1.98(s, 6 H, 2Ac), 1.20-1.63 (18 H, lipid).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.[H-].[Na+].[CH2:16]([O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[CH2:35]Br)[CH:24]=[CH:23][C:22]=1[Cl:37])[CH3:17]>O1CCOCC1>[CH2:16]([O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[CH2:35][N:3]2[C@@H:2]([CH3:1])[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])[CH:24]=[CH:23][C:22]=1[Cl:37])[CH3:17]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(4S,5R)-(−)-4-Methyl-5-phenyl-2-oxazolidinone (0.062 g, 0.35 mmol) was added to a vial containing sodium hydride (60% in mineral oil; 0.015 g, 0.38 mmol) in 1,4-dioxane (10 mL). After stirring for 30 minutes at room temperature, the mixture was added to a vial containing [5-(4-bromo-2-bromomethyl-phenoxy)-2-chloro-phenyl]-acetic acid ethyl ester (0.15 g, 0.32 mmol) at 10° C. The reaction was stirred at room temperature overnight, and then additional (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (0.062 g, 0.35 mmol), pretreated with sodium hydride (60% in mineral oil; 0.015 g, 0.38 mmol), was added and the reaction was stirred overnight. Once no starting material was observed by analytical LCMS, the mixture was carried forward to the hydrolysis step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:10][N:11]([CH2:13][CH2:14]Cl)[CH3:12].CN(CCOC1C=CC(Br)=CC=1)C>>[CH3:10][N:11]([CH2:13][CH2:14][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:12]
Reactant: CN(C)CCCl
Reactant: Oc1cccc(Br)c1
Agent: CN(C)CCOc1ccc(Br)cc1
Agent: Cl
Product: CN(C)CCOc1cccc(Br)c1
Yield: 73.7 %

Procedure:
3-Bromophenol (5.0 g, 28.9 mmol) and 2-(N,N-dimethylamino)ethyl chloride, hydrochloride (6.24 g, 43.3 mmol) were reacted by the general procedures as described in the preparation of N,N-dimethyl-2-(4-bromophenoxy)ethylamine. The residue was chromatographed on silica gel (dichloromethane/methanol 100:0 to 90:10) to give the title compound (5.2 g, 74%) as a pale yellow liquid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34]>C1COCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:16])[CH2:6][CH2:5]2
Reactant: OCCNCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)N(CCO)CCO)O2
Reaction time: 1.5 h
Yield: 9.3 %

Procedure:
To a solution of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (500 mg, 2.00 mmol) in 10 mL THF was added 356 mg CDI (2.20 mmol). After stiffing for 1.5 h., a solution of diethanolamine (231 mg, 2.2 mmol) in 10 mL THF was added over 1 h and the reaction was stirred overnight. The reaction was concentrated, dissolved into 70 mL CH2Cl2 and washed sequentially with 50 mL 0.62 M HCl, 50 mL 1.0 M NaHCO3, 50 mL saturated NaCl and dried over Na2SO4. The combined aqueous phases were extracted 3×50 mL 3:1 isopropyl alcohol/isopropyl acetate which was dried and concentrated to a brown oil. Flash chromatography yielded 63 mg of 6-hydroxy-N,N-bis(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a yellow oil.