Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11]CC=C)[C@H:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:8]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:7][C@H:6]1[O:32][C@H:33]1[C@H:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:45]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:44][C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:34]1[O:64][C:65](=[O:67])[CH3:66])(=[O:3])[CH3:2].C1N2CCN(CC2)C1.ClCCl>C(O)C.C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]([O:4][C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:8]([CH2:23][O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:7][C@H:6]1[O:32][C@H:33]1[C@H:46]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:45]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[O:44][C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:34]1[O:64][C:65](=[O:67])[CH3:66])(=[O:3])[CH3:2]
Reactant: C=CCO[C@@H]1[C@@H](OC(C)=O)[C@H](O[C@@H]2[C@@H](OC(C)=O)[C@H](OCc3ccccc3)O[C@H](COCc3ccccc3)[C@H]2OCc2ccccc2)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Rh]
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)O[C@H]1[C@H](O[C@@H]2[C@@H](OC(C)=O)[C@H](OCc3ccccc3)O[C@H](COCc3ccccc3)[C@H]2OCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1O
Temperature: 25 °C
Yield: 49 %

Procedure:
1.28 g (1 eq.) of benzyl 2-O-acetyl-3-O-allyl-4,6-di-O-benzyl-β-D-gluco-pyranosyl-(1→3)-2-O-acetyl-4,6-di-O-benzyl-β-D-glucopyranoside (M=915) and 1.18 g of Dabco are dissolved in 50 ml of an ethanol/toluene/water (8/3/1; v/v/v) mixture and then 390 mg (0.3 eq.) of Wilkinson's catalyst are added thereto. The reaction medium is heated under reflux for 1 hour 30 minutes and then put to dryness. The mixture is then taken up with dichloromethane and extracted with water, with iced 1/2N HCl, with 5% NaHCO3 and then with water, dried and concentrated. The residue is then redissolved in 30 ml of an acetone/10% aq. HCl (19/1; v/v) mixture which is refluxed for 8 min. After rapid cooling to R.T., the solution is neutralised with a few drops of 5% NaHCO3 and concentrated. The whole is diluted again with dichloromethane and is extracted with water. The product is finally purified over silica gel [flash; eluent: toluene/ethyl acetate (85/15; v/v)] which thus enables isolating 600 mg of benzyl 2-O-acetyl-4,6-di-O-benzyl-β-D-glucopyranosyl-(1→3)-2-O-acetyl-4,6-di-O-benzyl-β-D-glucopyranoside (M=875).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:15]=[CH:14][C:10]2[CH:11]=[CH:12][S:13][C:9]=2[CH:8]=1.CS(O[CH2:21][CH:22]1[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O>[CH3:27][C:24]1([CH3:28])[O:23][CH:22]([CH2:21][O:6][C:7]2[CH:15]=[CH:14][C:10]3[CH:11]=[CH:12][S:13][C:9]=3[CH:8]=2)[CH2:26][O:25]1
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Reactant: Oc1ccc2ccsc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCC(COc2ccc3ccsc3c2)O1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Dimethylformamide (10 mL) was added to a reactor containing 6-hydroxybenzothiophene (22, 619 mg, 4.12 mmol), (R/S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate ((R/S)-18a, 1.04 g, 4.95 mmol) and Cs2CO3(1.61 g, 4.95 mmol). The reaction mixture was agitated at 100° C. for 6 hours and then cooled to room temperature. After adding water, extracting with ethyl acetate, washing with saturated ammonium chloride aqueous solution, and removing water using sodium sulfate, column chromatography yielded 6-[(R/S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyloxy]benzothiophene ((R/S)-25, 1.08 g, 99%) as a liquid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[N+](C)=CCl.[Cl-].[O:12]1[C:17]([C:18](=[N:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]([OH:21])=O)=[CH:16][S:15][CH2:14][CH2:13]1.C[Si](CC(N)=O)(C)C.[NH2:38][CH:39]1[C:57](=[O:58])[N:41]2[C:42]([C:54]([OH:56])=[O:55])=[C:43]([CH2:46][S:47][C:48]3[N:52]([CH3:53])[N:51]=[N:50][N:49]=3)[CH2:44][S:45][C@H:40]12>C(OCC)(=O)C.O.CN(C)C=O>[O:12]1[C:17]([C:18](=[N:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:19]([NH:38][CH:39]2[C:57](=[O:58])[N:41]3[C:42]([C:54]([OH:56])=[O:55])=[C:43]([CH2:46][S:47][C:48]4[N:52]([CH3:53])[N:51]=[N:50][N:49]=4)[CH2:44][S:45][C@H:40]23)=[O:21])=[CH:16][S:15][CH2:14][CH2:13]1
Reactant: CCCCCCON=C(C(=O)O)C1=CSCCO1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)C1=CSCCO1
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
Phosphoryl chloride (1.214 g.), N,N-dimethylformamide (0.579 g.) and ethyl acetate (3 ml.) were treated in a conventional manner to prepared a Vilsmeier reagent. To the reagent was added 2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetic acid (syn isomer, 2.00 g.) at -10° C., and stirred at the same temperature for 20 minutes. On the other hand, trimethylsilylacetamide (6.93 g.) was added to a suspension of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.18 g.) in ethyl acetate (50 ml.), and stirred at 40° C. for an hour. To the solution was added the activated acid solution at -10° C. and stirred at the same temperature for an hour. Water (20 ml.) was added to the resultant solution and the organic layer was separated. The solution was washed with water (20 ml.) twice and dried. After concentrating the solution in vacuo, the residue was pulverized with diisopropyl ether (50 ml.). The precipitates were collected by filtration and dried to give 7-[2-(2,3-dihydro-1,4-oxathiin-6-yl)-2-n-hexyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 3.4 g.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[CH3:18][N:19]([CH3:31])[CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:29][C:26]1[CH:25]=[CH:24][C:23]([N:22]([CH2:21][CH2:20][N:19]([CH3:31])[CH3:18])[CH3:30])=[CH:28][CH:27]=1
Reactant: CN(C)CCN(C)c1ccc(N)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCN(C)c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 54.1 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.28 g, 1.0 mmol) and N-[2-(dimethylamino)ethyl]-N-methylbenzene-1,4-diamine hydrochloride (0.30 g, 1.0 mmol) were stirred in N,N-dimethylformamide (5 mL) with triethylamine (0.6 mL). The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[[2-(dimethylamino)ethyl](methyl)amino]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (0.24 g, 55%) as a golden powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]([C:26]([S:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:7][P:8]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]([C:26]([S:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:45])=[O:27])[CH2:7][P:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:9])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CN(CP(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1)C(=O)SCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CN(CP(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1)C(=O)S(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl-N-[(benzylthio)carbonyl]-N-[bis(4-chlorophenoxy)phosphinylmethyl]-glycinate (3 g.; 0.0053 mol.) dissolved in 25 ml. of methylene chloride at 0° C. was added metachloroperbenzoic acid (1.1 g.; 0.0053 mol.). The reaction mixture was stirred for one hour at 0° C. The mixture was washed with 5% sodium hydroxide, dried and concentrated in vacuo to yield ethyl-N-[(benzylsulfinyl)carbonyl]-N-[bis(4-chlorophenoxy)phosphinylmethyl]-glycinate as a solid having a melting point of 121°-125° C. and the following analysis:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[C:15]([OH:17])=[O:16])[CH2:3][CH2:2]1.C[O-].[Na+].[CH3:21][O:22]C(OC)N(C)C>CO>[C:15]([C:11]1[N:10]([CH2:9][CH2:8][CH2:7][CH:4]2[CH2:5][CH2:6][N:1]([CH:21]=[O:22])[CH2:2][CH2:3]2)[CH:14]=[CH:13][N:12]=1)([OH:17])=[O:16]
Reactant: COC(OC)N(C)C
Reactant: O=C(O)c1nccn1CCCC1CCNCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=CN1CCC(CCCn2ccnc2C(=O)O)CC1
Temperature: 80 °C

Procedure:
A mixture of 1-[3-(4-piperidinyl)propyl]-1H-imidazole-2-carboxylic acid 1.75 molar hydrochloride 0.65 molar hydrate (1.3 g, 0.0047 M) and sodium methoxide (0.005 M) in methanol (23 ml) was added to dimethylformamide dimethylacetal (15 ml) and heated at 80° C. for 8 hrs. The reaction mixture was filtered and stripped to dryness to give 4-[3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidine carboxaldehyde. The solution of the above piperidine carboxaldehyde dimethylacetal in methanol (5 ml) was then added to a mixture of 6-aminopenicillanic acid (0.81 g, 0.0037 M) and diisopropylethylamine (0.4 ml) in chloroform (30 ml) at 0° C. The reaction was stirred at 0° C. 2 hrs and room temperature for 2 hrs. The solvent was removed and water (15 ml) was added. After being washed with ether, the aqueous solution, acidified to pH 3 to about 3.5, was purified on Sephadex LH 20 columns to give [2S-(2alpha,5alpha,6beta]-6-[[[1-(3-(2-carboxy-1H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrate (0.38 g, 17% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:10]=1[NH:11][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c(F)cccc1OCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CNc1c(F)cccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 2-benzyloxy-6-fluoroaniline (950 mg, 4.37 mmol), methyl bromoacetate (456 μL, 737 mg, 4.82 mmol), and potassium carbonate (1.21 g, 8.76 mmols) in DMF (10 mL) is heated at 60° C. for 18 h. The mixture is poured into ethyl acetate and extracted once with water and five times with brine. The organic layer is dried, filtered, and the solvent removed under reduced pressure to afford a crude oil that is chromatographed on an Isco Companion (80 g silica gel, 0-30% gradient of hexane/ethyl acetate) to afford methyl 2-(2-benzyloxy-6-fluoroanilino)-acetate as an oil. MS (M+1)+=290; NMR (CDCl3): δ 7.39 (m, 5H), 6.67 (m, 3H), 5.10 (s, 2H), 4.57 (br s, 1H), 4.11 (m, 2H), 3.72 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH:23]([Si:25]([O:30][CH3:31])([O:28][CH3:29])[O:26][CH3:27])=[CH2:24]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH3:27][O:26][Si:25]([O:30][CH3:31])([O:28][CH3:29])[CH:23]=[CH:24][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc(Br)cc1
Reactant: C=C[Si](OC)(OC)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CO[Si](C=Cc1ccc(OC(=O)OC(C)(C)C)cc1)(OC)OC

Procedure:
Into a mixture of 20 ml of triethylamine and 40 ml of acetonitrile, were dissolved 15.0 g (54.9 mmol) of 1-(t-butoxycarbonyloxy)-4-bromobenzene synthesized in the step (i) and 9.76 g (65.9 mmol) of vinyltrimethoxysilane, and the reaction system was substituted by argon by bubbling argon in thus obtained solution. In the reaction system, was added 246.5 mg (1.1 mmol) of palladium acetate as a catalyst, the mixture was refluxed for one night. After completion of the reaction, solvent was removed, and the obtained residue was extracted by hexane. Hexane was removed from the extraction to prepare 9.5 g of 1-(2-trimethoxysilylvinyl)-4-(t-butoxycarbonyloxy)benzene being the objective compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[F:23][C:24]([F:38])([F:37])[C:25]1[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:27][CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O>[Cl:16][C:12]1[CH:11]=[C:10]([C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:34]3[CH2:35][CH2:36][N:31]([C:26]4[C:25]([C:24]([F:38])([F:23])[F:37])=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:32][CH2:33]3)[N:3]=[C:4]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:5]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1c(Cl)nc(N2CCOCC2)nc1-c1cccc(Cl)c1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1c(-c2cccc(Cl)c2)nc(N2CCOCC2)nc1N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
Dissolve 4-chloro-6-(3-chlorophenyl)-2-morpholinopyrimidine-5-carbonitrile (33.5 mg, 0.1 mmoles) and 1-(3-(trifluoromethyl)-pyridin-2-yl)piperazine (23 mg, 0.1 mmoles) in CH3CN (1.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (28 mg, 0.2 mmoles) to this mixture and heat at 80° C. for 24 hours. Cool, dilute with water (5 mL), extract with EtOAc (3×2 mL) and dry over MgSO4. Filter, and concentrate under vacuum to afford crude product Purify by flash column chromatography using 30% EtOAc/hexane to afford the title product as white solid. NMR (DMSO-D6) δ 3.30 (4H, s), 3.62 (4H, m), 3.80 (4H, s), 3.93 (4H, s), 7.19 (1H, m), 7.51 (1H, m), 7.59 (1H, m), 7.76 (1H, m), 7.83 (1H, s), 8.07 (1H, d, J=2.0), 8.52 (1H, d, J=1.2). Mass spec m/z=530.12.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:4][C:3]=1[CH3:18].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[CH2:35]([C@@H:42]1[CH2:46][O:45][C:44](=[O:47])[NH:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([N:43]2[C@H:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:46][O:45][C:44]2=[O:47])=[O:15])=[CH:4][C:3]=1[CH3:18]
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: Cc1cc(COCCCCCC(=O)O)ccc1F
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(COCCCCCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)ccc1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a cooled (−10° C.) solution of 6-(4-fluoro-3-methylbenzyloxy)hexanoic acid (0.565 g, 2.222 mmol) in 15 mL of THF, were added stepwise triethylamine (0.80 mL, 5.713 mmol) and pivaloyl chloride (0.27 mL, 2.179 mmol). The reaction mixture was stirred at −10° C. for 1 h and then LiCl (0.092 g, 2.179 mmol) and (R)-4-benzyloxazolidin-2-one (0.375 g, 2.116 mmol) were added stepwise. After warmed slowly to room temperature with stirring overnight, the reaction mixture was diluted with ethyl acetate (80 mL) and washed with saturated NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.482 g, 52% yield). LC-MS: tR=11.2 min; m/z 414 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4][C:3]1=[N:10][OH:11].[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:14](F)=[O:15].C(N(CC)CC)C>O1CCOCC1>[CH3:12][N:13]([S:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:14]([O:11][N:10]=[C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[S:4]1)=[O:15]
Reactant: CN1C(=O)C(C)(C)SC1=NO
Reactant: CN(SSc1ccc(Cl)cc1)C(=O)F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(SSc1ccc(Cl)cc1)C(=O)ON=C1SC(C)(C)C(=O)N1C

Procedure:
2-[[O-[N-Methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was prepared according to the procedure described in Example I, by reacting 5.0 g (0.0287 m) of 3,5,5-trimethyl-2-oximinothiazolidin-4-one, 7.22 g (0.0287 m) of N-methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl fluoride and 2.9 g (0.0287 m) of triethylamine in 50 ml of dioxane. 2-[[O-[N-Methyl-N-(4-chlorophenylthiosulfenyl)carbamoyl]oximino]]-3,5,5-trimethylthiazolidin-4-one was crystallized from isopropyl ether to yield 5.9 g of a white solid, m.p. 74°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[C:13]([F:19])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][C:13]=2[F:19])=[C:4]([I:9])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: Oc1ccc(Cl)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(Cl)ccc1COc1ccc(Cl)cc1I

Procedure:
As for Reaction 1, using 84.87 g 4-chloro-2-iodophenol, 76 g 4-chloro-2-fluorobenzyl bromide and 92 g potassium carbonate in 900 ml acetone. Yield 129.36 g. Identical by TLC with product of Reaction 1.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
40% Methanolic Triton B (0.11 mL, 0.24 mM) was added to a solution of the 9-[(phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (70 mg, 0.22 mM) in 20 mL DMF at 0° C. After 15 minutes, methyl bromoacetate (70 mg, 0.44 mM) was added and the resultant mixture stirred at room temperature for 5 hours. The mixture was diluted with ethyl acetate, washed with 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was combined with the crude material derived from a similar run utilizing 45 mg (0.14 mM [0.36 mM total]) of 9-[(phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole. The combined residues were purified by column chromatography on silica gel (elution with ethyl acetate) to afford 76 mg (54%) of the {9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ 7.65 (d, 1H, J=8 Hz), 7.5 (br s, 1H), 7.4-7.15 (m, 9H), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1) 3367, 3200, 1760, 1643, 1579, 1496, 1452, 1427, 1216, 1157, 772, and 716. MS (FD) m/e 388.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[SH:11].[Cl:12][C:13]([CH2:15]Cl)=[CH2:14].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11][CH2:15][C:13]([Cl:12])=[CH2:14]
Reactant: C=C(Cl)CCl
Reactant: O=[N+]([O-])c1ccc(Cl)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(Cl)CSc1cc([N+](=O)[O-])ccc1Cl
Temperature: 80 °C
Yield: 89 %

Procedure:
A solution of 2-chloro-5-nitro-benzenethiol (1.0 g, 5.27 mmol, prepared in accordance with the procedure described by Still et al. Synth. Comm. 13, 1181 (1983)) in 15 mL DMF was treated with 2,3-dichloropropene (693 μL, 7.52 mmol) and K2CO3 (433 mg, 3.13 mmol). The mixture was heated at 80° C. for 2 h and then allowed to cool to rt. EtOAc (200 mL) and H2O (100 mL) were added. The organic phase was washed with H2O (2×250 mL), saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting with 20% EtOAc in hexanes to give compound 260A (1.09 g, 89%) as an orange oil.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25](OCC)=O)[CH:19]=1.N1C=CC=C(CC([O-])=O)C=1>C(O)C.O.C(O)(=O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1cccnc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: O=C([O-])Cc1cccnc1
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccnc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Sodium (0.11 g) was dissolved in ethanol and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.49 g, 2.21 mmol) was added, followed 10 minutes later by ethyl 3-pyridinylacetate (0.73 g) in ethanol (2 mL) . The reaction mixture was refluxed overnight, additional 3-pyridinylacetate (0.35 g) was added and the reaction mixture was again refluxed overnight. The reaction mixture was cooled to room temperature, the solvent was stripped and the residue was dissolved in water and treated with acetic acid (to pH of 7). The mixture was extracted with CHCl3 (3×50 mL), the organic layers were combined, dried over MgSO4 and stripped to a pale yellow oil. The oil was crystallized by the addition of ether and the product was collected by filtration and washed with ether to afford 0.4 g of 1-cyclopentyl-3-ethyl-6-[3-pyridinylmethyl]pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[C:17](O)(=[O:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
Three grams (0.014 mole) of the product of Example 3 [2-(hydroxymethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one] is refluxed with 250 ml of glacial acetic acid for 20 hours under nitrogen. The solution is cooled and stripped to a solid residue which is dissolved in a mixture of ethyl acetate-absolute ethanol. The volume of solution is reduced and the concentrated solution set aside at 5°. The precipitate is filtered off to give 3.5 g of product. Recrystallization from ethyl acetate-absolute ethanol gives 3.1 g of analytically pure title compound, m.p. 177°-179°.