Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[OH-:15].C([N+](C)(C)C)C1C=CC=CC=1.O=O.C>N1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(c1)Cc1ccccc1-2
Reactant: [OH-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=O
Solvent: c1ccncc1
Product: O=C1c2ccccc2-c2ccc(F)cc21

Procedure:
2-Fluorofluorene (824.7 g, 4.48 mol) was dissolved in pyridine (4 L) and stirred. A 40% solution of Triton B (100 mL of benzyltrimethylammonium hydroxide 40% in pyridine according to a general procedure of U. Sprinzak, J. Amer. Chem. Soc. 80 (1958) 5449) was added and oxygen was bubbled into the vigorously stirred solution. This exothermic reaction was run for 20 hours whereupon an additional portion of the Triton B solution (50 mL) was added with continued stirring and oxygen addition for an additional 24 hours. The resulting dark green reaction mixture was treated with Norite (100 g, neutralized charcoal), stirred for 30 minutes and filtered through a Celite pad (diatomaceous earth filter aid). The filter pad was then washed with pyridine (1 L). The combined filtrates were concentrated to a small volume in vacuo with heat. A 5% solution of hydrochloric acid in water (1 L) was added and the pyridine was azeotrophed in vacuo with heat. This process was repeated until a total of 6-8 L of water were evaporated. The granular product was filtered and washed with water (4 L) and air dried. The yellow-orange product was distilled through a large bore short path distillation apparatus (bp 167°-170° C.; 1.5 mm Hg) to yield into a chilled receiving flask the bright yellow 2-fluoro-9-fluorenone (600 g) with a m.p. 113°-115° C. and m/e+. 198 for C13H7FO.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][CH2:15][C:14](=[O:17])[N:13]([CH3:20])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CI
Reactant: COc1ccc(C2CNC(=O)CO2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2CN(C)C(=O)CO2)cc1OC
Temperature: 25 °C
Yield: 96.9 %

Procedure:
2-(3,4-dimethoxyphenyl)morpholin-5-one (0.10 g, 0.42 mM) produced in Example 1, sodium hydride (60%) (0.02 g, 0.46 mM), and methyl iodide (0.07 g, 0.51 mM) were dissolved in dry N,N-dimethylformamide (2 ml) and the mixture was stirred at room temperature for one night. Water was added to the reaction solution, the solution was extracted with methylene chloride, the extract was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product as a yellow oil. The crude product was purified by flash chromatography (SiO2: eluted by 3% methanol/methylene chloride) to obtain the above-described compound (yield 96.9%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=O)[CH:10]=[N:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1.C([O-])(=O)C.[NH4+:27]>C(O)(=O)C>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[N:11][CH:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:27]=2)=[CH:15][CH:16]=1
Reactant: O=C(NN=CC(=O)c1c(F)cccc1F)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Fc1cccc(F)c1-c1cnnc(-c2ccc(Br)cc2)n1
Temperature: 25 °C

Procedure:
A mixture of 1.85 g of 4-bromobenzoic acid [2-(2,6-difluorophenyl)-2-oxoethylidene] hydrazide and 0.77 g of ammonium acetate is heated in 15 ml of glacial acetic acid at 10° C. for 14 h. After cooling to room temperature, the reaction mixture is poured into ice-water and extracted with ethyl acetate, and the organic phase is washed with saturated sodium hydrogen carbonate and saturated sodium chloride solution. After the organic phase has been dried over sodium sulfate, filtering and concentration in a rotary evaporator are carried out. The residue is purified by means of flash chromatography (5% ethyl acetate in toluene). In this way the title compound is obtained in the form of yellow crystals.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[I:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[OH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[OH:49][CH:50]1[CH2:55][CH2:54][N:53]([C:30]([C:29]2[CH:33]=[CH:34][C:26]([I:25])=[CH:27][C:28]=2[NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])=[O:31])[CH2:52][CH2:51]1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCC(O)CC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-iodo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 4, Step D) and 4-hydroxypiperidine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C20H19IN4O4S, 538.0; m/z found, 539 [M+H]. HPLC (reverse phase): RT=7.77 min. 1H NMR (400 MHz, CDCl3, rotameric broadening): 9.07 (d, J=1.8 Hz, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.90 (br s, 1H), 8.50 (dd, J=7.0, 1.5 Hz, 1H), 8.37 (dd, J=8.4, 1.4 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.89 (dd, J=8.4, 7.4 Hz, 1H), 7.39 (dd, J=8.0, 1.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 3.94-3.90 (m, 1H), 3.80-3.75 (m, 1H), 3.2-2.8 (m, 3H), 2.05-2.01 (m, 2H), 1.7-1.3 (m, 3H).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:27]1[CH:32]=[CH:31][C:30]2=[N:33][N:34]=[C:35]([C:36]([F:39])([F:38])[F:37])[N:29]2[N:28]=1>C(O)C>[CH2:2]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:27]3[CH:32]=[CH:31][C:30]4=[N:33][N:34]=[C:35]([C:36]([F:39])([F:37])[F:38])[N:29]4[N:28]=3)[CH2:14][CH:15]2[CH2:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)c1nnc2ccc(N3CC4CN(Cc5ccccc5)CC4C3)nn12
Temperature: 70 °C
Yield: 83 %

Procedure:
2-Benzyl-3,3a,4,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole hydrochloride (0.129 g, 0.54 mmol) and then diisopropylethylamine (0.070 g, 0.54 mmol) were added sequentially to a solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (0.080 g, 0.36 mmol) in ethanol (2 mL). The reaction mixture was heated at 70° C. for 4 hours and then evaporated to leave an involatile residue. The residue was purified by preparative hplc using a Phenomenex Luna C18 100A column (10% silica, 21 mm diameter, 150 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% trifluoroacetic acid) and acetonitrile as eluents to give a partially purified product that was further purified by ion exchange chromatography an SCX column eluted with 7M aqueous ammonia in methanol as eluents to give 6-(5-benzyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-2-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[3,4-f]pyridazine (0.116 g, 83%) as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].Br[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16]>C(O)C>[CH2:13]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: Oc1ccccc1
Reactant: CC(C)CCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CCOc1ccccc1

Procedure:
Phenol (0.5 mole) was added to a solution of sodium ethoxide in ethanol (2 N; 250 ml) and 1-bromo-3-methylbutane (0.5 mole) was added dropwise while stirring. The mixture was heated under reflux for three hours and most of the solvent was then distilled off. Water was added to the residue and the organic layer was separated, washed twice with 10% aqueous NaOH, water, dilute H2SO4 and water, and was then dried over MgSO4. It was distilled in vacuo to give the title compound, b.p. 89°-92° C. at 14 mm Hg pressure. The identity and purity was confirmed by thin layer chromatography (TLC) and NMR and IR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Cl>C(COC)OC.O.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)CCCOc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(=O)c2ccc(OCCCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
41 g of methyl 4-[4-(4-methoxybenzoyl)phenoxy]butyrate from Example 2 are dissolved in 600 ml of dimethoxyethane/water 4:1, and 63 ml of 2N sodium hydroxide solution are added. The mixture is stirred at room temperature for 4 hours, then acidified to pH 3 with 3N hydrochloric acid, and the organic solvent is removed in vacuo. The acid which has separated out is filtered off and dried over phosphorus pentoxide in vacuo.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].[CH3:15][C:16]([C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)=[O:17]>CC(C)=O>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])=[CH:20][CH:19]=1)(=[O:17])[CH3:15]
Reactant: CC(C)OC(=O)CBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCC(=O)OC(C)C)cc1

Procedure:
Potassium carbonate (17.0g.) was added to a solution of isopropyl bromoacetate (24.0g.) and 4-hydroxyacetophenone (17.7g.) in acetone (200ml.). The mixture was heated under reflux for 24 hours, cooled and filtered. The filtrate was evaporated to an oil which was dissolved in ether (150ml.). The solution was washed with sodium bicarbonate solution (2 × 30ml.), water (2 × 30ml.), dried and evaporated. The residual oil was distilled to give isopropyl 4-acetylphenoxyacetate, I.R. peaks at 1750 and 1670 cm-1.
Reaction SMILES: [C:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]#[CH:22]>CC(C)=O>[C:1]([N:3]([CH2:22][C:21]#[CH:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)#[N:2]
Reactant: C#CCBr
Reactant: N#CNc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN(C#N)c1cccc(C(F)(F)F)c1
Yield: 63.1 %

Procedure:
To a solution of N-cyano-3-trifluoromethylaniline (5.0 g) in acetone (100 ml), potassium carbonate (7.4 g) and propargyl bromide (3.5 g) were added, and the resultant mixture was stirred at room temperature for 10 hours, followed by filtration of the reaction mixture. The solvent was removed from the filtrate by distillation under reduced pressure, and the residue was subjected to column chromatography to give N-cyano-N-propargyl-3-trifluoromethylaniline (3.8 g). The thus obtained N-cyano-N-propargyl-3-trifluoromethylaniline (1 g) and a catalytic amount of triethylamine were dissolved in methanol (30 ml), and the resultant mixture was cooled to 0° C. Hydrogen sulfide was gradually introduced into the mixture for 20 minutes while keeping the temperature at 0° C., followed by introduction of nitrogen gas to remove hydrogen sulfide. The solvent was removed by distillation, and the residue was subjected to column chromatography to give 0.2 g of 2-imino-3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (Compound (ix)).
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].CI.[C:21](OCC)(=O)C>CN(C=O)C>[CH3:21][O:1][CH:2]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)c1ccc2ccccc2c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(OC)c1ccc2ccccc2c1
Reaction time: 24 h
Yield: 53 %

Procedure:
To a stirred solution of methyl 2-hydroxy-2-(naphthalen-2-yl)acetate (0.63 g, 1 eq) in dry DMF was added NaH (0.45 g, 4 eq) and methyl iodide (0.74 mL, 4.1 eq). Stirring was then continued for 24 hours. The reaction mixture was then poured into ethyl acetate and washed with H2O. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an oil that was purified by column chromatography using ethyl acetate and hexanes to yield an oil (0.358 g, 53%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([O:24][C:25](=[O:30])[CH2:26][CH2:27][O:28][CH3:29])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:32])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:31])[CH:6]=[CH:5]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([O:24][C:25](=[O:30])[CH2:26][CH2:27][O:28][CH3:29])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:32])[C:9](=[CH:8][C:7](=[O:31])[CH:6]=[CH:5]2)[CH2:10][CH2:11]3)[CH2:14][CH2:15]1)(=[O:35])[CH3:34]
Reactant: COCCC(=O)O[C@]1(C(=O)CO)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Reactant: CC(=O)OC(C)=O
Product: COCCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
As described in Example 5(c), 1.0 g of 11β,21-dihydroxy-17-(3-methoxypropionyloxy)-1,4-pregnadiene-3,20-dione is reacted with acetic anhydride at room temperature, worked up, and purified, thus isolating 810 mg of 21-acetoxy-11β-hydroxy-17-(3-methoxypropionyloxy)-1,4-pregnadiene-3,20-dione.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH2:41][CH2:42][CH2:43][CH2:44][N:45]1[CH:49]=[CH:48][N:47]=[CH:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][NH:41][CH2:42][CH2:43][CH2:44][N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: NCCCn1ccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(-c3ccc(CNCCCn4ccnc4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.6 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 1-(3-aminopropyl)imidazole (0.034 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of 1-(3-aminopropyl)imidazole (0.1 mL) and sodium triacetoxyborohydride (0.086 g, 0.40 mmol) were added and the reaction mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 4 days. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 14.0-15.7 min was collected, concentrated, and lyopholyzed to afford N1-(4-{4-amino-1-[4-{([3-(1H-1-imidazolyl)propyl]amino}methyl)phenyl]-1H-pyrazolo [3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.040 g, 0.061 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.35-8.40 (2H, m), 8.16 (2H, d, J=7.6 Hz), 7.99 (1H, t, J=7.6 Hz), 7.89 (1H, d, J=10.0 Hz), 7.75 (1H, d, J=8.4 Hz), 7.59 (1H, s), 7.52 (2H, d, J=3.8 Hz), 6.45 (1H, s), 7.40 (1H, d, J=8.0 Hz), 7.16 (1H, s), 6.87 (1H, s), 4.04 (2H, t, J=7.0 Hz), 3.96 (3H, s), 3.77 (2H, S), 2.45-2.46 (2H, m), 1.91 (3H, s), and 1.86-1.90 (2H, m); RP-HPLC (Hypersil C18, 5 μm 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.28 min. MS: MH+660.2.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH:9]([S:14]([OH:17])(=[O:16])=[O:15])[CH2:10][C:11]([OH:13])=[O:12].C(Cl)CCl.O[N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29]>CC(N(C)C)=O>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[CH2:8][CH:9]([S:14]([OH:17])(=[O:15])=[O:16])[CH2:10][C:11]([O:13][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CC(CN1C(=O)C=CC1=O)S(=O)(=O)O
Solvent: ClCCCl
Solvent: CC(=O)N(C)C
Product: O=C(CC(CN1C(=O)C=CC1=O)S(=O)(=O)O)ON1C(=O)CCC1=O
Yield: 74.4 %

Procedure:
4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-sulfobutanoic acid (110 mg, 0.418 mmol), EDC (240 mg, 1.25 mmol) and N-hydroxysuccinimide (58 mg, 0.504 mmol) was stirred in 10 ml of DMA for overnight, evaporated and purified on SiO2 chromatography eluted with CH3OH/CH2Cl2/HAc (100:900:1 to 100:600:1) to afford 112 mg (75%) of the title product. 1H NMR (DMF-d7) 6.93 (s, 2H), 4.06 (dd, 1H, J=4.8, 13.1 Hz), 3.80 (dd, 1H, J=10.7, 13.9 Hz), 3.35 (dd, 1H J=3.3, 17.8 Hz), 3.25 (m, 1H), 3.10 (dd, 1H, J=2.2, 16.4 Hz), 2.87 (m, 4H); 13C NMR 172.27, 170.88, 169.29, 135.55, 55.28, 40.22, 32.69, 26.66; ESI MS m/z− 261.70 (M−H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:11])[CH2:8][CH2:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[O:11]=[C:7]([C:5]1[NH:1][C:2](=[O:6])[NH:3][CH:4]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)Cl
Reactant: O=c1[nH]cc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCC(=O)c1c[nH]c(=O)[nH]1
Reaction time: 2 h

Procedure:
In 10 ml of dichloromethane is placed 1.0 g of 1,3-dihydro-2H-imidazol-2-one, 1.28 g of butyryl chloride and 4.8 g of aluminum chloride. The mixture is refluxed and stirred for 2 hours after which it is poured into water. The precipitate is collected, washed with water, and recrystallized from ethanol:water, to give the title compound, m.p. 268°-270° C.
Reaction SMILES: [OH-].[K+].[OH:3][C@@H:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[CH2:10])[C:6]([O:8]C)=[O:7]>O.CO>[OH:3][C@@H:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=[CH2:10])[C:6]([OH:8])=[O:7]
Reactant: C=C(C(=O)OC)[C@@H](O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C(=O)O)[C@@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of potassium hydroxide (2.27 g, 0.040 mol, 1.3 eq) in water (45 mL) was added drop wise to a solution of 1a (6 g, 0.031 mol, 1 eq) in methanol (15 mL) (see FIG. 4). The mixture was stirred at room temperature for 15 h. The solution was then concentrated under vacuum. The aqueous phase was washed with ether (2×100 mL), acidified with 6N aqueous HCl solution and extracted with ether (3×100 mL). The combined organic extracts were washed with brine (100 mL) and dried over sodium sulfate. Evaporation of the solvent afforded a colorless oil which crystallized upon standing. The desired product 9a was obtained as a solid (5.34 g, 96%). Rf 0.26 (hexane/EtOAc=6:4).). 1H NMR δ (DMSO-d6) 5.41 (s, 1H), 5.61 (s, 1H), 5.93 (s, 1H), 6.15 (s, 1H), 7.22 (m, 5H), 12.45 (s, 1H). [M−H]− 177.2: tR=1.28 min; purity: 88%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:25]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:26][C:27]([O-])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:22][C:21]([CH3:24])([O:20][C:18]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:28])[CH2:26][C:25]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:19])[CH3:23]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCN)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(=O)NCCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
After stirring for 0.5 hour, a solution of 1.04 g (3×10-3 mol) of 1,1-dimethylethyl 10-amino-6-[(1,1-dimethylethoxy)carbonyl]-2,6-diazadecanoate in 5 ml of anhydrous chloroform is added dropwise at 0° C. The mixture is stirred for 5 hours at room temperature and 1.06 g (8×10-3 mol) of ethyl malonate and 1.64 g (8×10-3 mol) of 1,3-dicyclohexylcarbodiimide are added. The mixture is stirred for 1 hour and the solvent is evaporated off under reduced pressure. The pasty residue obtained is chromatographed on silica using an ethyl acetate/hexane mixture (1/1 v/v) and then ethyl acetate as the eluent to give 0.95 g (yield: 69%) of the expected product in the form of an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[CH2:14]O)([CH3:3])[CH3:2].C1C=CC(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[N:30]([CH2:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])=[N+:31]=[N-:32]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To 8B (190 mg, 0.89 mmol) in THF (5 mL) at 0° C. was added DPPA (300 mg, 1.1 mmol) in THF (1 mL) and DBU (170 mg, 1.9 mmol). The cold bath was removed and the reaction was stirred at rt overnight. The reaction was then concentrated and purified via silica gel chromatography (0-15% ethyl acetate/hexane) to provide 8C (160 mg, 90%) and starting material (8B) (30 mg). 8C: LC-MS: 237.16 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]([C:31]3[S:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)=[N:29][CH:30]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:30]=[N:29][C:28]([C:31]3[S:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)=[CH:27][CH:26]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4s3)nc2)OC1(C)C
Reactant: Brc1ccc(-c2nc3ccccc3s2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2sc(-c3ccc(-c4ccc(-c5nc6ccccc6s5)nc4)cn3)nc2c1
Temperature: 80 °C

Procedure:
A mixture of 9 (0.591 g, 2.03 mmol), 16 (0.700 g, 2.07 mmol), tetrakis(triphenylphosphine)palladium(0) (117 mg, 102 μmol), Na2CO3 (1.59 g, 15.0 mmol), H2O (15 mL) and THF (25 mL) was degassed with argon for about 20 min while stirring. The stirring reaction mixture was then maintained under argon at about 80° C. for about 19 h. Upon completion, the mixture was cooled to RT, filtered and the precipitate collected as a white solid (0.83 g, 97%). This compound was found to be insoluble in numerous common organic solvents.