Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Mg]Cl)CCC.[Li]CCCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.[O:20]=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>C1COCC1.[NH4+].[Cl-].C1(C)C=CC=CC=1>[Br:19][C:17]1[CH:18]=[C:13]([C:21]2([OH:20])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:25][CH2:26]2)[CH:14]=[N:15][CH:16]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CCCC[Mg]Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cncc(Br)c2)CC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Literature procedure was used to for the selective monosubstitution of dibromoarenes, see: Iida, T.; Wada, T.; Tomimoto, K.; Mase, T. Tetrahedron Lett. 2001, 42, 4841-4844. n-Butylmagnesium chloride in THF (2 M, 0.739 mL, 1.48 mmol) was added to a solution of 1:1 THF:toluene (4.22 mL) and n-BuLi in hexanes (1.6M, 1.85 mL, 2.95 mmol) at −10° C. and stirred for 30 minutes. A solution of 3,5-dibromopyridine (1.00 g, 4.22 mmol) in 1:1 THF:toluene (4.22 mL) was added dropwise over 30 minutes to the reaction mixture and stirred for 1 hour at −10° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (0.841 g, 4.22 mmol) in THF (1.00 mL) was added dropwise to the reaction mixture at −10° C. and warmed to room temperature. The reaction mixture was diluted with saturated aqueous NH4Cl and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrating under reduced pressure. The crude residue was purified by silica gel chromatography (ethyl acetate/hexanes) to yield tert-butyl 4-(5-bromopyridin-3-yl)-4-hydroxypiperidine-1-carboxylate. MS APCI calc'd for C15H22BrN2O3 [M+H]+ 357 and 359. found 357 and 359.
Reaction SMILES: [CH3:1][C@:2]1([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH2:9][CH2:8][CH2:7][C@@:4]2([O:6][CH2:5]2)[CH2:3]1.C(O)(C(F)(F)F)=[O:23].C(Cl)Cl.[OH-].[Na+]>O>[OH:6][C@@:4]1([CH2:5][OH:23])[CH2:7][CH2:8][CH2:9][C@@:2]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)([CH3:1])[CH2:3]1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@]2(CO2)C1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@](O)(CO)C1
Temperature: 18 °C
Reaction time: 2.5 h

Procedure:
To a 3 L flask was added 1-{[(3R,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (94.7 g, 337 mmol). The material was azeotroped two times with EtOAc to remove any trace amounts of MeOH from the SFC. Next, to the residue was added DMF (731 mL) and water (731 mL). The solution was cooled to ˜18° C. (with an ice water bath). Next, a solution of TFA (51.9 mL, 673 mmol) in water (731 mL) added (pre-cooled to ˜10° C.). The entire solution was then cooled with an ice water bath to ˜10° C. The temperature was held around 10° C. for about 2.5 h then allowed to warm to RT and stir overnight. The next day, DCM (500 mL) was added, and the solution was made basic by slowly adding 6N NaOH. The mixture was added to a separatory funnel, the DCM separated and the aqueous layer diluted with 6N NaOH (300 mL), and then extracted with DCM (8×250 mL). The combined organic extracts were concentrated under reduced pressure to remove as much DMF as possible. The residue was dissolved in DCM (250 mL) and stirred at RT to crystallize the trans diol. After stirring overnight, the solution was cooled to ˜10° C., and the solids were filtered off, washed with DCM and dried under reduced pressure. This yielded 49.15 g of 1-{[(1S,3S)-3-hydroxy-3-(hydroxymethyl)-1-methylcyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (trans diol) as a white solid. The filtrate (˜60 g material, a mixture of cis-diol, trans-diol, and elimination side products) was concentrated, loaded onto silica gel and split into 3 equal portions and purified on the ISCO RF (3×330 g column): 0-5% MeOH/DCM over 15 min, hold at 5% for 10 min, then 5-25% over 10 min, then hold at 25%. The trans diol product was combined with the solids from the crystallization and used without further purification. MS (m/z) 300.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.O.O.[Br-].[Na+].[OH-].[K+]>O1CCOCC1.C(OCC)(=O)C.C(OCC)(=O)C.C(O)C>[C:7]1([C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:25][C:26]2[N:30]=[CH:29][NH:28][CH:27]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)[C@H](Cc1c[nH]cn1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
40 mg of L-Nα -[(2S)-3-isopropylthio-2-(1-naphthylmethyl)propionyl]-Nim triphenylmethylhistidine methyl ester was dissolved in 0.6 ml of dioxane. 0.3 ml of a 37 mg/ml sodium bromide trihydrate aqueous solution was added thereto at room temperature. The reaction solution was stirred at room temperature for 15 minutes, and then diluted with 20 ml of ethyl acetate. The reaction solution was washed with 8 ml of water and then with 8 ml of a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The reaction solution was concentrated under reduced pressure to obtain yellow solid. This product was saponified with a solution of 0.4N potassium hydroxide in methanol/water (10/1) to obtain 40 mg of L-Nα -[(2S)-3-isopropylsulfinyl-2-(1-naphthylmethyl)propionyl]-Nim -triphenylmethylhistidine (Rf: 0.48, chloroform/methanol/33% acetic acid=10/1/0.2). This compound was condensed in the same manner as in Example 11 with (2S,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol by a usual DPPA method, further subjected to removal of a triphenylmethyl group by dichloromethane/TFA (3/4). The product was purified by silica gel column chromatography (chloroform/methanol/conc. aqueous ammonia=30/3/0.02) to obtain 20 mg of (2S,3R,4S)-4-{L-Nα -[(2S)-3-isopropylsulfinyl-2-(1-naphthylmethyl)propionyl]histidyl}amino-5-cyclohexyl-1-morpholino-2,3-pentanediol as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.CCN(C(C)C)C(C)C.[CH:29]1[N:33]=[CH:32][N:31]([C:34](N2C=NC=C2)=O)[CH:30]=1.CN(C)CCN>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([NH:33][CH2:29][CH2:30][N:31]([CH3:34])[CH3:32])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Agent: CN(C)CCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.2 %

Procedure:
295 (60 mg, 0.22 mol), DIEA (0.08 mL, 0.44 mmol), and CDI (71 mg, 0.44 mmol) were suspended in DMF (2 mL) and stirred for 4 h at room temperature. N1,N1-Dimethylethane-1,2-diamine (77 mg, 0.87 mmol) was added, and the reaction mixture was stirred for another 3 h. The reaction mixture was quenched with water. The resulting precipitate was filtered, washed with MeOH and H2O, and dried under vacuum to produce provide 296 (61 mg, 81% yield) as a solid. LC-MS (M+H=345, obsd.=345).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[C:17](Cl)=[N:16][C:15]2[C:10](=[CH:11][C:12]([Cl:20])=[C:13]([Cl:19])[CH:14]=2)[N:9]=1>CCO>[N:1]1([C:17]2[C:8]([Cl:7])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([Cl:19])=[C:12]([Cl:20])[CH:11]=3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1cc2nc(Cl)c(Cl)nc2cc1Cl
Solvent: CCO
Product: Clc1cc2nc(Cl)c(N3CCNCC3)nc2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Piperazine (0.69 g, 8.06 mmol) was added to a stirred suspension of 2,3,6,7-tetrachloroquinoxaline (1.08 g, 4.03 mmol) in EtOH (125 mL) at room temperature. The mixture was stirred at room temperature for 8 h and filtered to give the product as a pale yellow solid yield 0.88 g (69%); mp >300° C. MS m/z 316/318 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)=[CH:9][CH2:10][S:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:23])[CH:13]=2)=[CH:4][CH:3]=1.B(O)(O)[C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:36][CH:37]=1.[F-].[K+].[Cl-].[NH4+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1COCC1>[C:2]1([C:41]2[CH:40]=[CH:39][C:38]([C:35]3[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=3)=[CH:43][CH:42]=2)[CH:7]=[CH:6][C:5]([C:8]([C:24]2[CH:29]=[CH:28][C:27]([C:32]3[CH:33]=[CH:34][C:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:36][CH:37]=3)=[CH:26][CH:25]=2)=[CH:9][CH2:10][S:11][C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:23])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)ccc1OCC(=O)O
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(SCC=C(c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)c2ccc(-c3ccc(-c4ccccc4)cc3)cc2)ccc1OCC(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
In an evaporated schlenk flask kept under nitrogen atmosphere were added {4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid (225 mg, 0.41 mmol, example 1, step A–B, biphenylboronic acid (163 mg, 0.8 mmol), KF (79 mg, 1.35 mmol), Pd2(dba)3 (23 mg, 25 mmol) and Pd(P(t-Bu)3)2 (26 mg, 51 mmol). THF (6 ml) was added to the solid mixture keeping the mixture under nitrogen. The reaction mixture was stirred at 50° C. for 2 h, followed by 10 h at 70° C. A saturated solution of ammonium chloride (5 ml) was added, and the mixture was extracted with dichloromethane (2×20 ml). The organic phases were dried and evaporated. The residue was purified by HPLC to give the title compound in 55 mg (19%) yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[N:10]=2)[N:3]=1.[CH3:22][O-:23].[Na+].CO.[Na]>C(Cl)(Cl)Cl.O>[CH3:22][O:23][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2cccc(-c3ccccc3C)n2)n1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C)nc(-c2cccc(-c3ccccc3C)n2)n1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To 4-chloro-6-methyl-2-(6-o-tolyl-2-pyridinyl)pyrimidine (2 g) was added sodium methoxide prepared from methanol (10 ml) and metallic sodium (0.19 g). After the mixture was left to stand at room temperature for 30 minutes, water (30 ml) and chloroform (100 ml) was added thereto, and then extracted. After the extract was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain 4-methoxy-6-methyl-2-(6-o-tolyl-2-pyridinyl)pyrimidine (1.9 g, yield 96%).
Reaction SMILES: C(C1(NC([C@@H]2C[C@@H](S(C3C=CC=CC=3C(F)(F)F)(=O)=O)CN2C2N(C3C=CC=CC=3)N=C(C)C=2)=O)CC1)#N.COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C(=O)CC(=O)C)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.Cl.C1(NN)CCCCC1.[CH3:98][O:99][C:100]([C@H:102]1[CH2:106][C@@H:105]([S:107]([C:110]2[CH:115]=[CH:114][CH:113]=[CH:112][C:111]=2[C:116]([F:119])([F:118])[F:117])(=[O:109])=[O:108])[CH2:104][N:103]1[C:120]1[N:121]([CH:126]2[CH2:131][CH2:130][CH2:129][CH2:128][CH2:127]2)[N:122]=[C:123]([CH3:125])[CH:124]=1)=[O:101]>>[CH3:98][O:99][C:100]([C@@H:102]1[CH2:106][C@@H:105]([S:107]([C:110]2[CH:115]=[CH:114][CH:113]=[CH:112][C:111]=2[C:116]([F:119])([F:117])[F:118])(=[O:109])=[O:108])[CH2:104][N:103]1[C:120]1[N:121]([CH:126]2[CH2:131][CH2:130][CH2:129][CH2:128][CH2:127]2)[N:122]=[C:123]([CH3:125])[CH:124]=1)=[O:101]
Reactant: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCCCC1
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(-c2ccccc2)n1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCCCC1

Procedure:
In analogy to the procedure described in example 308d, a mixture of (2S,4R)-1-(3-oxo-butyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 f) and of (2R,4R)-1-(3-oxo-butyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and cyclohexylhydrazine hydrochloride (CAS Reg. No. 24214-73-1) to give a mixture of the title compound and (2R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester as brown oil. MS (ESI): m/z=500.3 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17](O)=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:20]([F:23])([F:22])[F:21])([O-:3])=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]2)=[CH:6][C:5]=1[C:20]([F:21])([F:22])[F:23])([O-:3])=[O:2]
Reactant: O=C(O)[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](CO)CC2)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanecarboxylic acid (1.63 g, 4.9 mmol, prepared in accordance with Example 42) was suspended in tetrahydrofuran (40 mL). The resulting suspension was cooled to 0° C. with an ice bath. Afterward, a solution of lithium aluminium hydride in tetrahydrofuran (4.9 mL, 1 M in THF) was added under stirring. The resulting solution was allowed to reach room temperature, and then sonicated for 3 hr. After allowing the mixture to react overnight at room temperature, the mixture was heated to 60° C. to ensure complete conversion of the starting material. After cooling to room temperature, the mixture was acidified with 1M HCl and then diluted with ethyl acetate (50 mL). This formed a precipitate. The suspension was centrifuged, and the supernatant was collected and washed with water (10 mL). The organic layer was washed with saturated aqueous ammonium chloride (20 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The desired product was obtained as a solid (1.3 g, 83% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)([OH:3])=O.ClC(OCC)=O.C(N(CC)CC)C.[NH2:27][C:28]([CH3:32])([CH3:31])[CH2:29]O.S(Cl)(Cl)=O>CC(C)=O.O>[CH3:29][C:28]1([CH3:32])[CH2:31][O:3][C:1]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[C:9](=[O:10])[O:8][CH2:7]3)=[N:27]1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC1(C)COC(c2ccc3c(c2)COC3=O)=N1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
Acetone (40 ml) is stirred and 5-carboxyphthalide (2 g ,0.01 1 mol) are added at about 20° C. The mixture is cooled to −10° C. and ethyl chloroformate (1.18 ml, 0.012 mol) is added. At the end of the addition, a solution of triethylamine (1.56 ml ,0.011 mol) in acetone (3.50 ml) is added keeping the temperature of the mixture at or below −10° C. The temperature of the mixture is allowed to rise to 10-13° C. and, after 30 minutes, it is brought to −10° C. and a solution of 2-amino-2-methyl-1-propanol (3.0 g ,0.034 mol) in acetone (5 ml) is quickly added to the mixture. The temperature is allowed to rise to 15-20° C., whereby the reaction is completed as it may be verified by HPLC. To the mixture thus obtained, cooled to −5° C., thionyl chloride (2.5 ml, 0.034 mol) is added, the temperature is allowed to rise to about 20° C. and after 30 minutes the ring closure is completed. The reaction mixture is concentrated in vacuo leaving a residue, which is treated with water (20 ml). The mixture is concentrated again and a further amount of water (10 ml) is added to the residue, the pH is made basic by addition of 25% ammonia and the mixture is cooled to 5° C. The product is filtered off, washed with water and dried in vacuo. Yield: 1.70 g. Total yield: 66.8%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].[O-:10][C:11]#[N:12].[Na+].FC(F)(F)C(O)=O.O>C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6](=[O:9])[CH2:7][O:8][C:11](=[O:10])[NH2:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)CO
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)OCC(=O)COC(N)=O
Reaction time: 3 h

Procedure:
To a stirred mixture of 1-acetoxy-3-hydroxy-2-propanone (10.8 g., 0.1 mole) and sodium cyanate (13.0 g., 0.2 mole) in benzene (50 ml.) is slowly added trifluoroacetic acid (15.5 ml., 0.21 mole). The reaction mixture is stirred for three hours, then water (15 ml.) is added. The organic layer is separated, dried and the solvent removed under reduced pressure to afford 1-acetoxy-3-carbamoyloxy-2-propanone.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([CH:8]1[CH2:10][N@@:9]1[S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C[C@H]2CN2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)S(=O)(=O)[N@@]1CC1Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)[N@]1CC1Cc1ccccc1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
To a cooled (−10° C.) solution of (S)-2-benzylaziridine (100 g, 0.751 mol) and N,N-dimethylsulfamoyl chloride (84.5 mL, 0.787 mol) dichloromethane (100 mL) was added N,N-diisopropylethylamine (131 mL, 0.751 mol). The resulting yellow solution was stirred at −10° C. for a minimum of 16 hours. After this period, a 0.5M solution of citric acid (500 mL) was added and the phases were separated. The organic phase was then washed with 1.0 M sodium bicarbonate solution (500 mL). The organic phase was then solvent exchanged into tert-butyl methyl ether (500 mL). The solution was then cooled to 0° C., and heptane (100 mL) was added dropwise over a period of 2 hours. The mixture was then aged for an additional 2 hours at 0° C., and then cooled (−10° C.), to allowed compound IIa to precipitate out as a white, crystalline solid (27.8 g, 77%). Tlc assay: Rf 0.53 (SiO2; 1:1 heptane:ethyl acetate. KMnO4). 1H NMR (400 MHz, CDCl1): δ 7.20-7.29 (m, 5H), 2.94 (dd, J=14, 5 Hz, 1H), 2.80-2.88 (m, 1H), 2.70 (dd, J=14, 7 Hz, 1H), 2.66 (s, 6H), 2.56 (d, J=7 Hz, 1H), 2.14 (d, J=4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 137.4, 129.3, 128.9, 127.2, 40.6, 38.3, 38.1, 33.0.
Reaction SMILES: F[B-](F)(F)F.[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O+:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:30]1(=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=[O:36].C(O)(=O)C.C(N(CC)CC)C>CO>[CH2:17]([C:16]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[C:14]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:32]2[CH2:33][CH2:34][CH2:35][C:30](=[O:37])[C:31]=2[O:36]1)[C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:13]
Reactant: c1ccc(-c2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1
Reactant: O=C1CCCCC1=O
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=C1CCCC2=C1OC(CC(=O)c1ccccc1)(c1ccccc1)C=C2c1ccccc1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A suspension of 13.51 g of 2,4,6-triphenylpyryliumtetrafluoroborate (34.1 mmol) and 4.78 g of cyclohexane-1,2-dione (42.6 mmol) is heated to boiling point in methanol, then a solution of 4.56 g of acetic acid (75.9 mmol) and 7.68 g of triethylamine (75.9 mmol) in a little methanol is added dropwise. After heating at reflux for 7 h, the solution is allowed to cool to room temperature. A light yellow precipitate is extracted by suction, washed in portions with 100 ml of ice-cold methanol and dried to constant weight. 11.37 g of a light yellow powder (79.3%) with a melting point of 178-179° C. (lit.: 182-184° C.) is obtained.
Reaction SMILES: CC(N)[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@@](O)(C)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)CC1.[CH3:33][CH:34]([NH:64][CH3:65])[C@H:35]1[O:40][C@H:39]([O:41][C@H:42]2[C@H:47]([OH:48])[C@@H:46]([O:49][C@H:50]3[O:55][CH2:54][C@@:53]([OH:57])([CH3:56])[C@H:52]([NH:58][CH3:59])[C@H:51]3[OH:60])[C@H:45]([NH2:61])[CH2:44][C@@H:43]2[NH2:62])[C@H:38]([NH2:63])[CH2:37][CH2:36]1.C[C@@]1(O)[C@H](NC)[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC1.OS(O)(=O)=O.[OH-].[Ba+2].[OH-].[OH-].[K+].S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].P([O-])([O-])([O-])=O.[Na+].[Cl-]>O>[CH3:33][C@@H:34]([NH:64][CH3:65])[C@H:35]1[O:40][C@H:39]([O:41][C@H:42]2[C@H:47]([OH:48])[C@@H:46]([O:49][C@H:50]3[O:55][CH2:54][C@@:53]([OH:57])([CH3:56])[C@H:52]([NH:58][CH3:59])[C@H:51]3[OH:60])[C@H:45]([NH2:61])[CH2:44][C@@H:43]2[NH2:62])[C@H:38]([NH2:63])[CH2:37][CH2:36]1
Reactant: CNC(C)[C@@H]1CC[C@@H](N)[C@@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3OC[C@](C)(O)[C@H](NC)[C@H]3O)[C@H](N)C[C@@H]2N)O1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](C(C)N)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Agent: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H](CN)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Solvent: O
Product: CN[C@@H]1[C@@H](O)[C@@H](O[C@@H]2[C@@H](O)[C@H](O[C@H]3O[C@H]([C@@H](C)NC)CC[C@H]3N)[C@@H](N)C[C@H]2N)OC[C@]1(C)O
Temperature: 75 °C

Procedure:
50 mg of gentamicin sulfate in 5 mL of water is neutralized by adding barium hydroxide until no further precipitate is formed. The precipitate, barium sulfate, is removed by centrifugation. The supernatant is added to a mixture of 5 mL of the polystyrene/polyglycidyl methacrylate polymer particle prepared in Example 4 and 5 mL of a 0.1% suspension of "Schercozoline" S (a substituted imidazoline from stearic acid, available from Scher Chemical Co.) at a pH of 8.5 adjusted with potassium hydroxide. The mixture is warmed to 75° C. for approximately 30 min, diluted with 200 mL of water, and deionized using a mixed bed ion exchange resin. 0.4 mL of the resulting particle reagent is added to 20 mL of 0.1% sodium dodecyl sulfate (SDS) followed by the addition of 0.2 mL of 0.020 M phosphate buffer (pH 7.43) containing 0.3 m NaCl and 0.1% SDS.