Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([CH2:21][O:22][C:23]([CH3:28])([CH3:27])[C:24](O)=[O:25])[C:9]=2[CH3:29])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.FC1C(O)=C(F)C(F)=C(F)C=1F.[NH2:54][CH2:55][C:56]1[CH:64]=[CH:63][C:59]([C:60]([OH:62])=[O:61])=[CH:58][CH:57]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([CH2:21][O:22][C:23]([CH3:27])([CH3:28])[C:24]([NH:54][CH2:55][C:56]3[CH:57]=[CH:58][C:59]([C:60]([OH:62])=[O:61])=[CH:63][CH:64]=3)=[O:25])[C:9]=2[CH3:29])=[CH:6][CH:7]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: Cc1c(COC(C)(C)C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(COC(C)(C)C(=O)NCc2ccc(C(=O)O)cc2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 710 mg of 2-[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic acid in 5 ml of DMF, 360 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 345 mg of pentafluorophenol and 392 mg of NEM were added and the reaction mixture was stirred for 3 h at room temperature. Then, 353 mg of 4-Aminomethyl-benzoic acid and 540 mg of NEM in 5 ml of DMF were added. After 16 h the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 288 mg.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(CO)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(COS(C)(=O)=O)cn1
Reaction time: 0.5 h

Procedure:
To a solution of (6-Methyl-pyridin-3-yl)-methanol (24.36 kg, 198 mol) dissolved in tetrahydrofuran (80 kg) under nitrogen at −3° C. was added triethylamine (22.14 kg, 218.8 mol) over 30 mins followed by methanesulphonyl chloride (23.16 kg, 202.2 mol) over 3 hr and the slurry stirred for an additional 30 mins. The slurry was then filtered to remove triethylamine hydrochloride and the cake washed four times with tetraydrofuran (21.6 kg). An aliquot was removed and concentrated and analysed.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(NCCC[CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])=O>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:33][C@H:32]([C:34]([OH:36])=[O:35])[CH3:31])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O

Procedure:
N-Benzyloxycaronbyl-L-phenylalanyl-Nε -trifluoroacetyl-L-lysine (m.p. 143°-147° C.) from N-benzyloxycarbonyl-L-phenylalanine and Nε -trifluoroacetyl-L-lysine (A. T. Moore, et al., J. Chem. Soc. (C), 2349-2359 (1966)).
Reaction SMILES: [OH-:1].[K+].C(C[C:6]1[C:14]2[O:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1)#N.[CH2:22]([OH:24])[CH3:23]>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:10]=[C:9]3[CH:8]=[CH:7][CH:6]=[C:14]3[O:13][C:12]=2[CH2:23][C:22]([OH:1])=[O:24])=[CH:20][CH:19]=1
Reactant: CCO
Reactant: [OH-]
Reactant: N#CCc1cccc2c(-c3ccc(F)cc3)coc12
Agent: [K+]
Product: O=C(O)Cc1oc2cccc-2cc1-c1ccc(F)cc1

Procedure:
Potassium hydroxide (85%, 49 g.), 7-cyanomethyl-3-(4-fluorophenyl)benzofuran (48.8 g., 0.194 mole) and 95% ethanol (500 ml.) are mixed and heated at reflux temperature overnight under a nitrogen atmosphere. The mixture is then concentrated by evaporation in vacuo, diluted with water and extracted with diethyl ether. The aqueous phase is filtered, then acidified by the slow addition of hydrochloric acid. The solid is collected by filtration and recrystallized from aqueous ethanol (65%) with treatment with decolorizing charcoal, giving yellow crystals. Another recrystallization from an ethanol-petroleum ether mixture (about 5:1) gives yellow crystals of 3-(4 -fluorophenyl)-7-benzofuranacetic acid, m.p. 169°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:16]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[O:17])(=[O:11])=[O:10].Cl[C:36]1C=CC(Cl)=C[C:37]=1S(Cl)(=O)=O>>[CH2:36]([O:24][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH:14]=2)=[CH:27][CH:26]=1)[CH3:37]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(NS(=O)(=O)c2cc(Cl)ccc2Cl)c1OC
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3cc(Cl)ccc3Cl)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(2,5-Dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=523.1 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using 2,5-dichloro-benzenesulfonyl chloride and yielded 4-[3-(2,5-dichloro-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F-].[Cs+].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:17][C@H:18]1[O:20][CH2:19]1)(=O)=O.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:17][C@H:18]2[O:20][CH2:19]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OC[C@@H]2CO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
3-Nitrophenol (0.92 g, 6.6 mmol) was dissolved in 5 ml anhydrous DMF, and cesium fluoride (3.02 g, 19.9 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature, and (S)-glycidyl nosylate (1.71 g, 6.6 mmol) was added. The reaction mixture was stirred for 20 hours at room temperature. Water (150 ml) was added, and the solution was extracted with ethylacetate. The organic phase was dried over MgSO4 and evaporated. The residue was purified with column chromatograph using ethylacetate:hexane (50:50) solvent to give (S)-glycidyl m-nitrophenyl ether (1.02 g 80% yield, m.p 44-5° C.) as a yellowish solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)[CH:10]=[CH:9][N:8]=1)=[O:5])[CH3:2].[Br:20]NC(=O)CCC(N)=O>CN(C=O)C>[Br:20][C:10]1[C:11]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:8][CH:9]=1
Reactant: CCNC(=O)Nc1cc(-c2cncc(F)c2)ccn1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2cncc(F)c2)c(Br)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of N-ethyl-N′-(5-fluoro-3,4′-bipyridin-2′-yl)urea (Intermediate 29, 386 mg, 1.48 mmol) in DMF (7 mL), N-bromosuccinamide (396 mg, 2.22 mmol) was added. The resulting solution was heated to 80° C. and stirred at that temperature for 8 hours. The reaction mixture was partitioned between water and ethyl acetate. The layers were separated and the organic layer was washed with 5% sodium thiosulfate solution, water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting solid was washed with acetonitrile and dried to give the title compound as an off-white solid (340 mg). MS (ESP): 340 (M+H+) for C13H12BrFN4O; NMR: 1.06 (t, 3H), 3.14 (q, 2H), 7.35 (t, 1H), 7.69 (s, 1H), 7.91-7.97 (m, 1H), 8.48 (s, 1H), 8.51 (t, 1H), 8.71 (d, 1H), 9.37 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.FC(F)(F)C(O)=O.[CH3:28][N:29]([CH3:34])[CH2:30][C:31](Cl)=[O:32].Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:16])[CH2:15][CH2:14][N:13]([C:31](=[O:32])[CH2:30][N:29]([CH3:34])[CH3:28])[CH2:12][CH2:11]1
Reactant: CN(C)CC(=O)Cl
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCNCC2)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)N1CCC(F)(COc2ncc(S(N)(=O)=O)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide, 2.trifluoroacetic acid (0.131 g), 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139 g), and sodium carbonate (0.048 g) were combined in a 5-mL vial with N,N-dimethylformamide (3 mL) and stirred overnight at room temperature. Additional sodium carbonate (0.048 g) was added followed by 2-(dimethylamino)acetyl chloride, hydrochloric acid (0.139 g) and stirring was continued over a second night. The reaction mixture was concentrated under high vacuum, slurried in CH2Cl2, filtered, concentrated, chromatographed on amine functionalized silica gel with 0 to 4% methanol in CH2Cl2 as the eluent and dried in a vacuum oven at 80° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:28])[N:17]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2CC(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[7-(2-Butynyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (50 mg) and potassium carbonate (20 mg) were dissolved in N,N-dimethylformamide (1.5 ml) and methyl bromoacetate (14 μl) was added to the solution while cooling on ice. After the mixture was stirred at room temperature overnight, the mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After the organic layer was concentrated by distillation, the residue was purified by silica gel column chromatography to give 26 mg of the title compound from the elution fraction of hexane-ethyl acetate (1:1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[C:10]([C:17]#[N:18])=[CH:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([CH3:23])([O-])=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:8][C:9]([C:10]1([C:17]#[N:18])[CH2:23][CH:11]1[CH:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C=C(C#N)C(=O)OCc1ccccc1)CC
Reactant: C[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(CC)C1CC1(C#N)C(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 66.4 %

Procedure:
To a solution of 2-cyano-4-ethyl-hex-2-enoic acid benzyl ester (3.76 g, 14.6 mmol) in 80 mL acetonitrile was added nitromethane (3.95 mL, 73 mmol), followed by DBU (2.18 mL, 14.6 mmol) resulting in an orange solution. The reaction was heated to 60° C. for 16 hours, then cooled and partitioned between Et2O and 1N HCl (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography of the residue (5→10% EtOAc/hexanes) afforded 2.63 g (66%) of 1-cyano-2-(1-ethyl-propyl)-cyclopropanecarboxylic acid benzyl ester as a pale yellow oil. 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.22 (m, 2H), 1.86 (dd, J=9.0, 4.6 Hz, 1H), 1.72 (m, 1H), 1.45–1.57 (m, 4H), 1.42 (dd, J=8.3, 4.6 Hz, 1H), 1.14 (m, 1H), 0.93 (m, 6H). 13C NMR δ 168.21, 135.12, 128.88, 128.73, 128.16, 117.77, 68.25, 42.41, 36.72, 26.18, 25.97, 25.20, 19.33, 11.19, 10.84. LRMS: m/z 272.1 (M+1). IR (neat) 2245, 1734 cm−1. Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.44; H, 7.83; N, 5.22.
Reaction SMILES: [CH2:1]([N:3]([C:14]1[N:19]=[C:18]([N:20]([CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[CH2:21][CH3:22])[N:17]=[C:16]([O:33][CH2:34][CH2:35][OH:36])[N:15]=1)[CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[NH:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)[CH3:2].[C:37]([O:45][CH3:46])(=[O:44])[CH2:38][CH2:39][C:40]([O:42]C)=O.[CH3:47][OH:48]>C1(C)C=CC=CC=1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:21]([N:20]([C:18]1[N:19]=[C:14]([N:3]([CH:4]2[CH2:9][C:8]([CH3:10])([CH3:11])[NH:7][C:6]([CH3:13])([CH3:12])[CH2:5]2)[CH2:1][CH3:2])[N:15]=[C:16]([O:33][CH2:34][CH2:35][O:36][C:40](=[O:42])[CH2:39][CH2:38][C:37]([O:45][CH2:46][CH2:47][O:48][C:16]2[N:17]=[C:18]([N:20]([CH2:21][CH3:22])[CH:23]3[CH2:28][C:27]([CH3:29])([CH3:30])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]3)[N:19]=[C:14]([N:3]([CH:4]3[CH2:5][C:6]([CH3:13])([CH3:12])[NH:7][C:8]([CH3:10])([CH3:11])[CH2:9]3)[CH2:1][CH3:2])[N:15]=2)=[O:44])[N:17]=1)[CH:23]1[CH2:24][C:25]([CH3:32])([CH3:31])[NH:26][C:27]([CH3:30])([CH3:29])[CH2:28]1)[CH3:22]
Reactant: CCN(c1nc(OCCO)nc(N(CC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reactant: COC(=O)CCC(=O)OC
Reactant: CO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CCN(c1nc(OCCOC(=O)CCC(=O)OCCOc2nc(N(CC)C3CC(C)(C)NC(C)(C)C3)nc(N(CC)C3CC(C)(C)NC(C)(C)C3)n2)nc(N(CC)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1

Procedure:
1.60 g of 2,4-bis-[N-ethyl-N-(2,2,6,6-tetramethyl-4-piperidyl)amino]-6-(2-hydroxyethoxy)-1,3,5-triazine [prepared as described in Preparation 3(B)] and 0.22 g of dimethyl succinate were dissolved in 20 ml of toluene, and a catalytic amount of tetraisopropyl titanate was added to the resulting solution. The resulting mixture was first agitated at 100° to 105° C. for 3 hours whilst the methanol generated was removed by distillation, and then the temperature was elevated to 130° C. to remove the toluene. When this removal was complete, a mixture of ethyl acetate and water was added to the residue, and then the mixture was shaken. The ethyl acetate layer was then separated, dried and concentrated by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (using a 10:3:1 by volume mixture of diethyl ether, ethanol and triethylamine as eluent), to obtain 920 mg of the title compound as crystals melting at 85° C.
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[C:3](=[O:9])[CH2:2]1.[BH4-].[Na+].Cl.N(CCO)CCO>C(O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([OH:9])[CH2:2]1
Reactant: O=C1COC2OCCC12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: OCCNCCO
Product: OC1COC2OCCC12
Reaction time: 1 h
Yield: 155.3 %

Procedure:
Generally in accordance with the procedure described by Ghosh et al in J. Org. Chem. 2004, 69, 7822-7829, tetrahydrofuro[2,3-b]furan-3(2H)-one (950 mg, 7.42 mmol, 1 eq.) was dissolved at 0° C. in 50 mL of ethanol. NaBH4 (302.4 mg, 8 mmol, 1.07 eq.) was added in one portion to the mixture. After a 1 hour stirring period, diethanolamine hydrochloride salt (3.2 g, 8 mmol, 1.07 eq.) was added and the mixture was stirred overnight at room temperature. The heterogeneous mixture was filtered over dicalite and washed with 20 mL of warm AcOEt. After evaporation of the organic solvents under reduced pressure to afford 1500 mg of hexahydrofuro[2,3-b]furan-3-ol with a quality (area %) of 40%; max yield: 60%. diastereoisomeric excess: exo(3S,3aS,6aR)/endo (3R,3aS,6aR): 18.5/81.5.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][N:11]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([CH3:19])=[N:12]1>>[CH3:10][N:11]1[C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:6]([O-:9])=[O:7])[C:13]([CH3:19])=[N:12]1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C(=O)O)n(C)n1
Agent: O=S(=O)(O)O
Product: Cc1nn(C)c(C(=O)O)c1[N+](=O)[O-]

Procedure:
One-hundred and twelve grams concentrated sulfuric acid is added to 42 ml 90% nitric acid at 70°-80° C. To this 39 grams 1,3-dimethylpyrazole-5-carboxylic acid is added in portions over one hour such that temperature does not go over 90° C. After 2.5 hours the reaction mixture was cooled and poured over ice. The resulting percipitate was filtered, dried, and recrystallized in ethanol, to produce 1,3-dimethyl-4-nitropyrazol-5-carboxylic acid having mp 141°-142° C.
Reaction SMILES: [C:1]1(=[O:16])[CH2:15]CCCCCC[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:17](OC(=O)C)(=O)C.C[C:25](=[O:33])[CH:26]=[CH:27]CCCCC.C(OC(=O)CC)(=O)CC>>[C:25]([O:16][C:1](=[CH:2][CH:3]([CH3:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:15])(=[O:33])[CH2:26][CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=CCCCCCCCCCCCC1
Reactant: CCCCCC=CC(C)=O
Agent: CCC(=O)OC(=O)CC
Product: CCCCCC(C)C=C(C)OC(=O)CC
Yield: 83 %

Procedure:
The same procedure as described in Example 1 (a) was carried out, except that 2-cyclopentadecenone and acetic anhydride were replaced with 3-nonen-2-one and propionic anhydride, respectively, to produce 4-methyl-2-nonene-2-yl propionate in 83% yield. E/Z=13/87.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl>[CH2:37]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:6]=2)[CH2:1]1)[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=CCc1ccccc1
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CCN(CCc1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A 400 mg (1.01 mmole) sample of compound (II), phenylacetaldehyde (121 mg, 1.01 mmole), sodium triacetoxyborohydride (320 mg, 1.52 mmole) and acetic acid (61 mg, 1.01 mmole) were stirred in 10 mL of 1,2-dichloroethane for 12 hrs. at ambient temperature. The reaction was diluted with methylene chloride, washed with 1N NaOH, water and brine. Purification was carried out with silica gel chromatography using 50% ethyl acetate/hexanes as the eluent.
Reaction SMILES: CC[O-].[Na+].Cl.[C:6]([NH2:9])(=[NH:8])[CH3:7].[F:10][C:11]([F:27])([F:26])[C:12]([CH:14]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:15](OCC)=[O:16])=O.CCOCC.CCCCCC>CCO>[CH3:7][C:6]1[NH:9][C:15](=[O:16])[C:14]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:12]([C:11]([F:10])([F:27])[F:26])[N:8]=1
Reactant: CC(=N)N
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)C(F)(F)F
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)Cc1c(C(F)(F)F)nc(C)[nH]c1=O
Yield: 26.9 %

Procedure:
A mixture of NaOEt (0.074 mol) in EtOH (prepared from 1.7 g of Na and 75 mL of EtOH), acetamidine hydrochloride (3.5 g, 0.037 mol), and diethyl 2-trifluoroacetylsuccinate (10.0 g, 0.037 mol) was heated under reflux for 20 h. The mixture was concentrated, taken up in water, acidified to pH 4 with conc. HCl, and extracted with EtOAc. The extracts were washed with brine, dried (MgSO4), and concentrated to give an oily solid. Trituration with ether/hexane gave 2.63 g (27%) of product as a white solid. An analytical sample was recrystallized from ether/hexane, mp 108°-110° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:18][C@H:17]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][NH:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:34](Cl)(=[O:36])[CH3:35]>C1COCC1.C([O-])(O)=O.[Na+]>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:18][C@H:17]([O:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:16][N:15]3[C:34](=[O:36])[CH3:35])=[O:13])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C([C@@H]1C[C@H](Oc2ccc(F)cc2)CN1)N1CCCN(C2CCC2)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@@H](Oc2ccc(F)cc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Reaction time: 48 h
Yield: 20.1 %

Procedure:
To a solution of (2S,4S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(4-fluoro-phenoxy)-pyrrolidine (102 mg, 0.85 mmol) and Et3N (0.197 mL) in THF (2.82 mL) was added acetyl chloride (60 μL, 0.85 mmol). After 48 h, the mixture was diluted with saturated (satd.) aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried and evaporated. The residue was purified by FCC, followed by reverse phase HPLC (5-99% CH3CN/20 mM NH4OH) to give the desired product (69 mg, 61%). MS (ESI): mass calcd. for C22H30FN3O3, 403.23; m/z found, 404.3 [M+H]+. 1H NMR (CDCl3): 7.02-6.92 (m, 2H), 6.87-6.77 (m, 2H), 4.92-4.79 (m, 2H), 4.12-3.96 (m, 1H), 3.84-3.47 (m, 5H), 2.92-2.77 (m, 1H), 2.66-2.51 (m, 2H), 2.50-2.41 (m, 2H), 2.39-2.30 (m, 1H), 2.22-2.12 (m, 1H), 2.10 (d, J=2.1 Hz, 3H), 2.07-1.98 (m, 2H), 1.92-1.72 (m, 4H), 1.71-1.54 (m, 2H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])[OH:8])[OH:6])[OH:4].[CH3:13][N:14](C)C=O>>[CH3:13][NH:14][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: CN(C)C=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
20 g of polifungin and 6 g of glucose were dissolved in 100 ml of dimethyl formamide and then the further procedure was carried out as in the Example IV till the moment of washing with water of precipitated N-glycosyl polifungin. The washed precipitate was suspended in 1200 ml of methanol of the temperature of 50° C., then was stirred and 7 g of N-methylglucamine, dissolved in 70 ml of water, were added. After dissolving the solution was filtered, 800 ml of n-amyl alcohol were added and the whole was concentrated under the reduced pressure at the temperature of 40° C. till the moment of removal of methanol and water. The resulting precipitate was filtered and washed with acetone. The precipitate was dried at a room temperature under the reduced pressure. 16.3 g of N-methylglucamine salt of N-glycosyl polifungin of biological activity of 1980 U/mg, E1 cm1% =572 at 304 nm were obtained. Original antibiotic exhibited E1 cm1% =720 at 304 nm.