Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][C:9](=[O:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:30][CH:29]2[CH2:31][CH:26]1[CH2:27][CH2:28]2.O>CN(C)C=O>[CH:26]12[CH2:31][CH:29]([CH2:28][CH2:27]1)[CH2:30][CH:25]2[CH2:24][N:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][C:9]1=[O:20].[CH:26]12[CH2:31][CH:29]([CH2:28][CH2:27]1)[CH2:30][CH:25]2[CH2:24][O:20][C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[N:10]=1
Reactant: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: BrCC1CC2CCC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(OCC3CC4CCC3C4)nc(-c3ccccc3)c2c1
Product: O=c1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1CC1CC2CCC1C2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 11 g of 4-phenyl-6-nitro-2(1H)-quinazolinone in 100 ml of dimethylformamide, was added 2.2 g of 52.9% sodium hydride. After stirring at 50°C for 1 hour, 17 g of 2-bromomethyl norbornane was added and the reaction mixture was heated under reflux for 8 hours. After cooling, the mixture was poured into 1l of water and the resulting mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residual oil was chromatographed on silica gel using chloroform as eluting solvent to obtain 1-(2-norbornylmethyl)-4-phenyl-6-nitro-2(1H)-quinazolinone and 2-(2-norbornylmethoxy)-4-phenyl-6-nitroquinazoline. The former was recrystallized from a mixture of carbon tetrachloride and diethyl ether, to give yellow needles, m.p. 160°- 161°C, and the latter was recrystallized from methylchloroform, to give yellow needles, m.p. 153°- 155°C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][CH2:8][C@H:9]([NH:20][C:21](=[O:35])[C@@H:22]([NH:26][CH2:27][C:28]1[O:29][C:30](=[O:34])[O:31][C:32]=1[CH3:33])[CH2:23][O:24][CH3:25])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:36][C:37]1[S:38][C:39]([C:42](O)=[O:43])=[CH:40][N:41]=1.N1C=CC=CC=1>C(Cl)Cl.Cl>[CH3:6][O:7][CH2:8][C@H:9]([NH:20][C:21](=[O:35])[C@@H:22]([N:26]([CH2:27][C:28]1[O:29][C:30](=[O:34])[O:31][C:32]=1[CH3:33])[C:42]([C:39]1[S:38][C:37]([CH3:36])=[N:41][CH:40]=1)=[O:43])[CH2:23][O:24][CH3:25])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: Cc1ncc(C(=O)O)s1
Reactant: COC[C@H](NCc1oc(=O)oc1C)C(=O)N[C@@H](COC)C(=O)OCc1ccccc1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC[C@H](NC(=O)[C@H](COC)N(Cc1oc(=O)oc1C)C(=O)c1cnc(C)s1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
Referring to FIG. 38, phosphorous oxychloride (323 μL, 3.46 mmol) was added dropwise to (S)-benzyl 3-methoxy-2-((S)-3-methoxy-2-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl)amino)propanamido)propanoate (1.46 g, 3.46 mmol), 2-methylthiazole-5-carboxylic acid (248 mg, 3.46 mmol) and pyridine (1.07 mL, 10 mmol) in DCM (20 ml) at 0° C. The reaction mixture was stirred at 0° C. for 3 hours, diluted with 1N HCl, and extracted with DCM. The organic layer was separated, dried (Na2SO4) and evaporated. The residue was purified by flash column chromatography to give the product as a white solid (346 mg, 22%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:27]4[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([N+:34]([O-])=O)[CH:28]=4)[N:14]3[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)#N.C[O-].[Na+].C(O)(=O)C>CO.CC(O)=O.[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:27]4[CH:32]=[CH:31][C:30]5[N:33]=[C:37]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=6)[NH:34][C:29]=5[CH:28]=4)[N:14]3[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3ccc(N)c([N+](=O)[O-])c3)cc3ccc(N4CCN(C)CC4)cc32)cc1
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc4nc(-c5ccccn5)[nH]c4c3)cc3ccc(N4CCN(C)CC4)cc32)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 26.9 %

Procedure:
The 4-[6-(4-Methyl-piperazin-1-yl)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-2-nitro-phenylamine (0.5 g, 0.99 mmol), was dissolved in 7:3 MeOH/HOAc (100 ml), and hydrogenated in the presence of 5% palladium on carbon (100 mg), overnight. The solution was then filtered through celite, washed with methanol (50 ml), and evaporated. The resulting diamine was dissolved in methanol (20 ml). To this was added a solution of 2-cyanopyridine (154 mg, 1.5 mmol) that had been treated (immediately before) with sodium methoxide (0.15 mmol) in methanol (2 mL) at 40° C. for 1.5 hour under nitrogen. To this mixture, acetic acid (0.21 ml, 3.8 mmol) was added. This mixture was heated at 80° C. overnight under nitrogen followed by cooling to room temperature, and removing the solvents under reduced pressure. Next the residue treated with a 5% aqueous ammonia solution, incubated at 5° C. over one day, decanted the aqueous layer, washed well with water. Resulting light tan solid was isolated and washed with ether to give the product 150 mg (15% yield). The material while not completely pure, could be taken to next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([O-])=O.[Na+].[CH3:12][O:13][CH2:14][C:15](=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].C([O-])(=O)C.[Na+]>Cl.CO.O.O>[CH3:12][O:13][CH2:14][C:15](=[O:21])[C:16](=[N:8][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: O=N[O-]
Reactant: Nc1ccccc1
Reactant: COCC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC(=O)C(=NNc1ccccc1)C(=O)OC
Yield: 82.8 %

Procedure:
To a solution of aniline (50 g) in 6N hydrochloric acid (536 mL) was added dropwise with stirring under ice-cooling an aqueous solution (142 mL) of sodium nitrite (55.6 g). The solution was added dropwise to a mixed solution of methyl 4-methoxy-3-oxobutanoate (78.5 g) and sodium acetate (264 g) in methanol/water (1.4 L/0.35 L) with stirring under ice-cooling. The total amount was added dropwise, and the mixture was stirred at the same temperature for 2 hr. Water was added to the reaction mixture, and the mixture was stirred for 30 min. The precipitated yellow crystals were collected by filtration, washed successively with water, ethanol/diisopropyl ether (1/9) and diisopropyl ether, and dry to give the title compound (111.2 g) as yellow crystals.
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>C(Cl)Cl>[C:19]([Si:16]([CH3:18])([CH3:17])[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2[nH]ccc12
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Imidazole (15.3 g, 225 mmol) was added to a solution of 4-hydroxyindole (20 g, 150 mmol) in 300 mL of anhydrous methylene chloride at ambient temperature. The resulting mixture was treated with tert-butyldimethylsilyl chloride (25 g, 165 mmol). After stirring overnight at ambient temperature, the reaction mixture was poured into 300 mL of water. The layers were separated, and the aqueous phase was extracted with methylene (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to a black oil. The crude residue was purified on a Prep 500 (silica gel; 0% to 5% ethyl acetate/hexanes) to give the title compound as a light purple waxy solid in quantitative yield. MS (ion spray, NH4OAc) m/e [M+1]+ 248, [M−1]− 246.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CS(C)=O.CCN(CC)CC>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[N:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OCc1ccc2[nH]ncc2n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1ccc2[nH]ncc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
1H-pyrazolo[4,3-b]pyridine-5-methanol (240 mg, 1.61 mmol) was dissolved in DCM (24 mL) at rt, and DMSO (5.71 mL, 80.45 mmol) and NEt3 (1.12 mL, 8.05 mmol) were added. After 10 min, SO3-pyridine was added, and the mixture was stirred at rt for ca. 1.5 hr. The reaction was quenched with sat. NH4Cl solution, stirred for 10 min, then extracted with DCM, washed with water and with brine, and dried with Na2SO4. The crude product (orange oil) was purified by a short manual flash column (hex/EtOAc 1:1) to afford 1H-pyrazolo[4,3-b]pyridine-5-carboxaldehyde (62 mg, 26.2%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:6](=[O:7])[O:5][CH:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][C:14]([CH3:23])=[CH:15][C:16]([CH3:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19].[H][H]>CCOC(C)=O.O=[Pt]=O>[OH:1][CH2:2][CH:3]1[C:6](=[O:7])[O:5][CH:4]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([CH3:24])[CH2:13][CH:14]([CH3:23])[CH2:15][C:16]([CH3:22])=[CH:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C=C(C)C=C(C)CC(C)CCCCC1OC(=O)C1CO
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: COC(=O)C=C(C)CC(C)CC(C)CCCCC1OC(=O)C1CO

Procedure:
49 mg (0.144 mmole) of Methyl 11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoate in 5 ml of EtOAc was added 3 mg of platinium oxide. This mixture was hydrogenated at room temperature and 1 atom for N30 minutes (NO. 144 mmole (1 eq) of hydrogen was consumed). The solution was filtered and the filtrate was concentrated to dryness afforded methyl 11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2-undecenoate.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=2)[C@@H:13]([CH3:32])[CH2:12]1)C1C=CC=CC=1>C(O)C>[CH3:30][N:28]([CH3:29])[C:25]1[CH:24]=[CH:23][C:22]([C:21]([N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:11]([NH2:10])[CH2:12][C@@H:13]2[CH3:32])=[O:31])=[CH:27][CH:26]=1
Reactant: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Solvent: CCO
Product: C[C@H]1C[C@@H](N)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Reaction time: 18 h
Yield: 91.8 %

Procedure:
(±)-Cis-[1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic acid benzyl ester (665 mg, 1.49 mmol) was dissolved in ethanol (30 mL). The resulting solution was evacuated and backfilled with argon. A catalytic amount of palladium on carbon (10%) was added. The vessel was once again evacuated and this time was backfilled with hydrogen from a balloon. The reaction was then allowed to react at room temperature over night under a hydrogen atmosphere. Reaction was complete after 18 h. The mixture was carefully filtered and concentrated to 10% volume. The resulting concentrated solution was filtered through an Acrodisc (and concentrated to afford the crude amine (423 mg, 92%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:15][CH:14]2[C:9](C(O)=O)([CH2:10][CH2:11][CH2:12][CH2:13]2)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:27])C=CC=CC=1.C([N:39]([CH2:42]C)CC)C>C1(C)C=CC=CC=1>[N:39]([C:9]12[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2]([CH3:1])([CH3:19])[CH2:15][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:42]=[O:27]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CC2CCCCC2(C(=O)O)c2ccccc21
Solvent: Cc1ccccc1
Product: CC1(C)CC2CCCCC2(N=C=O)c2ccccc21
Yield: 86.5 %

Procedure:
A solution of the compound from Example 44 (0.62 g, 2.4 mmol) and diphenylphosphorylazide (0.73 g, 2.64 mmol) in triethylamine (0.36 g) and 10 ml toluene was refluxed at 110° C. for 30 minutes. Workup and purification on silica gel gave the title compound (0.53 g, 86%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([N:17]=[O:18])[C:5](=O)[O:6]C1C=CC=CC=1[N+]([O-])=O.[NH2:19][C@@H:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]>CN(C)C=O.C(O)C>[C@@H:20]1([NH:19][C:5](=[O:6])[N:4]([CH2:3][CH2:2][Cl:1])[N:17]=[O:18])[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: O=NN(CCCl)C(=O)Oc1ccccc1[N+](=O)[O-]
Reactant: N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
3.28 g (12 mmol) of o-nitrophenyl N-(2-chloroethyl)-N-nitrosocarbamate is dissolved in a mixture of 10 ml anhydrous dimethylformamide and 10 ml anhydrous ethanol, and to this solution is added little by little 1.79 g (10 mmol) of 1-amino-1-deoxy-β-D-glucopyranose powder, while stirring, at 5°-10° C. over 10 minutes. The resultant mixture is, after adding 5 ml of anhydrous dimethylformamide thereto, stirred further at 10° C. for 5 hours, and the thus reacted solution is concentrated at 40° C. and below, under reduced pressure. The crystalline residue obtained is washed with anhydrous ethyl ether and then with acetone, dried under reduced pressure, and recrystallized from anhydrous ethanol-ethyl ether (1:5) to give 2.47 g of 3-(β-D-glucopyranosyl)-1-(2-chloroethyl)-1-nitrosourea. Yield 78.7%. mp 77°-78° C. (decomp.). [α]D25 -10.3° (C 1.0, water). Analysis for C9H16N3O7Cl (MW 313.69):
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CS(C)=O>[CH2:17]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCC=CCCCCCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCC=CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 34.1 %

Procedure:
Sodium hydride (95%, 84 mg, 3.5 mmol) was added to a solution of theobromine (0.595 g, 3.2 mmol) in dimethylsulfoxide (15 ml). After 20 minutes of stirring, 1-bromo-9-octadecene (0.995 g, 3 mmol), prepared above, was added. After 6 hours of stirring at room temperature, the reaction mixture was warmed to 60° C. over 3 hours and then poured into a separatory funnel containing 50 ml of water. The reaction mixture was extracted with five 40 ml aliquots of dichloromethane. The organic extracts were combined, washed with water (50 ml) and brine (50 ml) and dried over anhydrous magnesium sulfate. Removing the solvent under reduced pressure resulted in a crude product further purified by flash chromatography over silica gel using a 30% acetone/petroleum ether eluant, yielding 0.44 g of 1-(9-octadecenyl)-3,7-dimethylxanthine (34% yield).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:27][C:28]([F:56])([C:52]([F:55])([F:54])[F:53])[C:29]([F:51])([F:50])[C:30]([F:49])([F:48])[O:31][C:32]([F:47])([F:46])[C:33]([F:45])([F:44])[O:34][C:35]([F:43])([F:42])[CH2:36][O:37][CH2:38][CH2:39][CH2:40]Br>>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:40][CH2:39][CH2:38][O:37][CH2:36][C:35]([O:34][C:33]([F:44])([F:45])[C:32]([F:46])([F:47])[O:31][C:30]([F:48])([F:49])[C:29]([F:50])([F:51])[C:28]([F:27])([F:56])[C:52]([F:55])([F:54])[F:53])([F:43])[F:42])=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: FC(F)(COCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCOc1ccc(C#Cc2ccc(O)cc2)cc1
Product: CCCCCCCCCCOc1ccc(C#Cc2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 4-decyloxy-4'-hydroxytolane (1.5 g, 4.3 mmol, prepared essentially as described in EP 641850) with 3-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl bromide (2.6 g, 4.7 mmol). The reaction mixture was quenched with water, and the resulting crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (200-220° C. at 0.5 torr), to provide a yield of 2.64 g.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11][CH2:10]1)C.C1COCC1.[OH-].[Li+]>CO.O>[C:23]([O:22][C:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3])[CH2:14][CH2:13]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)CCCCN1CCN(CCCCNC(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCN1CCN(CCCCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-[4-(4-tert-butoxycarbonylaminobutyl)piperazin-1-yl]pentanoic acid ethyl ester (18) (1.62 g, 4.20 mmol) in methanol (12 mL)/THF (10 mL) was added a solution of lithium hydroxide (0.35 g, 8.40 mmol) in water (4 mL). The reaction mixture was stirred at room temperature for 20 h and then concentrated in vacuo. The resulting residue was diluted with water (5 mL) and acidified to pH ˜5 with 1 N aqueous HCl. The aqueous solution was extracted with chloroform/2-propanol (3:1, 3×10 mL). The combined extracts were concentrated under vacuum to dryness. The resulting residue was further co-evaporated with toluene and dried under high vacuum to give the desired acid 19 as a colorless, thick oil (1.42 g, 95%): 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.63 (m, 8H), 2.30 (m, 2H), 2.58 (m, 2H), 2.68 (m, 2H), 2.92 (m, 8H), 3.12 (m, 2H), 4.92 (br, 1H); ESI MS m/z 358 [C18H35N3O4+H]+.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][CH:5]([CH3:18])[CH:6]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)[CH3:7]>O1CCCC1.CO.O>[CH3:4][CH:5]([CH3:18])[CH:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)[CH3:7]
Reactant: COC(=O)c1ccc(C(C)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
Lithium hydroxide hydrate (0.42 g, 10 mmol) was added to a solution methyl 4-(3-methylbutan-2-yl)benzoate (0.20 g, 1.0 mmol) in tetrahydrofuran (9 mL), methanol (3 mL) and water (3 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was removed in vacuo. Hydrochloric acid (3 mol/L) was added to make pH 1-2, and the product was extracted with dichloromethane (50 mL). The combined organic phase was washed with sodium chloride aqueous solution (20 mL×3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give pure product 4-(3-methylbutan-2-yl)benzoic acid (0.18 g, 94%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:11]([CH2:22][CH:23]=[CH2:24])[S:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[NH2:21])(=[O:14])=[O:13])[CH:9]=[CH2:10].[Br:25][C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[S:34](Cl)(=[O:36])=[O:35])=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH2:22]([N:11]([CH2:8][CH:9]=[CH2:10])[S:12]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[NH:21][S:34](/[CH:33]=[CH:32]/[C:29]1[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=1)(=[O:35])=[O:36])(=[O:14])=[O:13])[CH:23]=[CH2:24]
Reactant: C=CCN(CC=C)S(=O)(=O)c1cnccc1N
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C=CCN(CC=C)S(=O)(=O)c1cnccc1NS(=O)(=O)/C=C/c1ccc(Br)cc1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
Triethylamine (0.440 mL, 3.16 mmol) added was to a solution of N,N-diallyl-4-aminopyridine-3-sulfonamide (0.40 g, 1.58 mmol) in pyridine (10 mL), the mixture was stirred for 5 min and (E)-2-(4-bromophenyl)ethenesulfonyl chloride (0.53 g, 1.89 mmol) was added. After stirring over night the pyridine was evaporated, diluted hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was evaporated. Purification by column chromatography, using chloroform/methanol (97:3) as the eluent, gave the title compound in 60% yield.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C@H:5]1[N:8](C(CC2C=CC(OC)=CC=2)CC2C=CC(OC)=CC=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4]>C(#N)C.O.CO>[Cl:1][CH2:2][C:3]([C@H:5]1[NH:8][C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4]
Reactant: C=C(CCl)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Solvent: CC#N
Solvent: CO
Solvent: O
Product: C=C(CCl)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of (3S,4S)-4-(1-chloromethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (320 g) in a mixture of acetonitrile and water (9 : 1) (3.8 liters) was added a solution of ceric ammonium nitrate (702 g) in a mixture of acetonitrile and water (9 : 1) (2 liters) at 5° C. or lower, followed by stirring for 30 minutes. The reaction mixture was diluted with water (5.2 liters) and extracted with ethyl acetate (3.4 liters). The aqueous layer was extracted with a mixture of ethyl acetate (1.7 liters), diethyl ether (1.7 liters) and benzene (1.7 liters). The combined extracts were washed successively with brine, 5l% sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was dissolved in methanol (1.5 liters) with warming and allowed to cool gradually. After filtration to remove crystals, the filtrate was concentrated in vacuo to give an oily residue, which was purified by silica gel chromatography to yield (3S,4S)-4-(1-chloromethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH:29]([CH3:31])[CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]1[CH2:28][CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCCN3CC(C)C)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(2-piperidinyl)propyl]-9H-purin-6-amine and 1-iodo-2-methylpropane.