Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.Br[C:37]1[S:38][CH:39]=[CH:40][N:41]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:37]3[S:38][CH:39]=[CH:40][N:41]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: Brc1nccs1
Reactant: CC1(C)OB(c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2nccs2)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 9.1, 50 mg, 0.101 mmol), 2-bromothiazole (24.9 mg, 0.152 mmol), PdCl2(dppf)-(CH2Cl2) (8.28 mg, 10.14 μmol), Na2CO3 (32.2 mg, 0.304 mmol), DME (522 μL) and water (92 μL) were added to a MW vial, which was sealed, evacuated/purged with argon, and RM was stirred at 90° C. for 16 h. The RM was diluted with THF (2 mL), treated with Si-Thiol (1.27 mmol/g, 39.9 mg, 0.051 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 40% for 0.2 min then 40% to 70% in 14 min) to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=2.51 min, m/z=451-452 [M+H]+, m/z=449-450 [M−H]; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.80 (m, 1H) 1.81-1.92 (m, 1H) 2.94 (d, J=11.74 Hz, 1H) 3.25-3.30 (m, 2H) 3.43-3.53 (m, 1H) 4.18-4.26 (m, 1H) 4.81-4.94 (m, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.83-7.88 (m, 2H) 7.89 (d, J=3.42 Hz, 1H) 7.94 (d, J=3.42 Hz, 1H) 8.19 (d, J=2.45 Hz, 1H) 8.82 (d, J=2.20 Hz, 1H) 10.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][O:22][CH2:23]OC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:21][O:22][CH3:23]
Reactant: Oc1ccc(F)cc1Br
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COCOc1ccc(F)cc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-4-fluoro-phenol (1 g, 5.23 mmol) in CH2Cl2 (120 mL) was added p-toluenesulphonic acid (0.07 g, mmol), dimethoxymethane (2.31 mL, 26.15 mmol) and the resulting mixture was heated under reflux for 16 h under a soxhlett apparatus charged with freshly dried molecular 4 Å sieves. The reaction was allowed to warm to room temperature and washed with 2M sodium hydroxide (100 mL) then dried (Na2SO4), filtered and the solvent was evaporated under vacuum to give title compound as an oil: 0.567 g, 46%. 1H-NMR (CDCl3, 300 MHz) δ7.31 (dd, 1H, J=2.9, 7.9 Hz, ArH), 7.13 (dd, 1H, J=4.9, 9.1 Hz, ArH), 6.98 (m, 1H, ArH), 5.21 (s, 2H, —OCH2O—), 3.54 (s, 3H, —OCH3)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Fe]>[Br:12][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1ccc(C(=O)O)c(F)c1
Agent: [Fe]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: Cc1cc(F)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2-Fluoro-4-methylbenzoic acid (244 mg) was added in portions to a mixture of bromine (1 ml) and iron powder (60 mg) and the reaction stirred in a sealed vial at room temperature for 25 minutes. The reaction was poured into aqueous sodium thiosulphate and extracted with ethyl acetate (x2). The combined extracts were washed with brine, dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was recrystallised from cyclohexane to give 5-bromo-2-fluoro-4-methylbenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C

Procedure:
A mixture of p-hydroxyacetophenone (15 g) and 1-bromo-3-chloropropane (12 mL) in acetone (200 mL) was treated with potassium carbonate (17 g). The mixture was stirred at reflux temperature for 18 hours. The reaction was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in ether, washed with water, dried over sodium sulfate, filtered and evaporated to yield the title compound (23 g).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2.[OH:15]S(O)(=O)=O.N([O-])=O.[Na+]>O>[OH:15][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cnc2cccc([N+](=O)[O-])c2c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc2ncc(O)cc12
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
3-Amino-5-nitroquinoline, as described above in Step C, (4.48 g, 23.68 mmol) was dissolved in H2SO4 (6N aqueous solution, 50 mL, 300 mmol) and cooled to approximately 5° C. A 0° C. solution of NaNO2 (1.63g, 23.68 mmol) in water (5 mL) was added dropwise to the amine solution. After 45 min at 5 to 10° C., the reaction was poured into refluxing 5% aqueous H2SO4 (300 mL). The resulting mixture was heated for 5 min, then cooled and extracted once with CH2Cl2. The aqueous layer was basified with solid NaHCO3 and extracted once with CH2Cl2. The aqueous layer was then neutralized with aqueous HCl and filtered. The filtered solid was dried in vacuo to yield the above-titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2.[H-].[Na+].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1F)[CH:27]=[O:28]>CN(C=O)C>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:13][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([CH3:20])[C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:27]=[O:28]
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3F)c(-c3ccccc3)c(C)cc2c1
Temperature: 0 °C
Yield: 34.6 %

Procedure:
Compound 7 (204 mg, 0.77 mmol, 1 equiv) was dissolved in DMF (5 mL) and cooled to 0° C. under N2. Sodium hydride, 60% dispersion (34 mg, 0.85 mmol, 1.1 equiv), followed by 3,4-difluorobenzaldehyde (170 μL, 1.54 mmol, 2 equiv) were added and the entire reaction mixture was heated to 70° C. for 2 days. The mixture was then partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chomatography (5% EtOAc in hexanes) to provide 24 (103 mg, 44%) as a clear oil. 1HNMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 7.77 (s, 1H), 7.63 (m, 1H), 7.58 (d, J=9.2 Hz, 1H), 7.47 (m, 1H), 7.38 (m, 1H), 7.31-7.17 (m, 5H), 7.12 (dd, J=2.3, 8.9 Hz, 1H), 6.58 (t, J=7.3, 8.9 Hz, 1H), 3.87 (s, 3H), 2.19 (s, 3H). MS m/z 463.3 (M−H)−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.[CH:21]1([CH2:25][NH:26][CH2:27][CH3:28])[CH2:24][CH2:23][CH2:22]1.O>CN(C)C=O.C(OCC)(=O)C>[CH:21]1([CH2:25][N:26]([CH2:27][CH3:28])[C:8]2[C:17]([CH:18]=[O:19])=[CH:16][C:15]3[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: CCNCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC1CCC1)c1nc2c(C)cccc2cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Potassium carbonate (0.62 g, 4.5 mmol) was added to a solution of 2-chloro-8-methyl-quinoline-3-carbaldehyde (0.45 g, 2.2 mmol) and cyclobutylmethyl-ethyl-amine (0.47 g, 4.1 mmol) in anhydrous dimethyl formamide (5 mL) under nitrogen. After stirring for 0.5 h at RT, the reaction mixture was heated for 20 h at 80-95° C. Thereafter, the reaction was cooled to RT, water (30 mL) and ethyl acetate (30 mL) were added, and the organic layer was separated from the aqueous mixture. The organic extract was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by chromatography using silica gel to afford the title compound as a pale yellow liquid (0.46 g, 75%).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O=C1[N:21](CCC(C)C)[C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[N:18]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)C(=O)C1=NNC1C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:1]12([C:11]([NH:21][C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=3[NH:18][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(Cn2c(=O)c(=NNc3ccccc3)c(=O)n(CCC(C)C)c3ccccc32)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccccc2NC(=O)C23CC4CC(CC(C4)C2)C3)cc1
Yield: 151.4 %

Procedure:
1-Adamantanecarbonyl chloride (1.91 g )) was dropped into a solution of intermediate 2 (1.83 g ) and triethylamine (1.45 ml) in dry THF (100 ml at 23°, under a nitrogen atmosphere. The mixture was stirred at reflux for 3 h, allowed to cool to 20°, then diluted with ethyl acetate (120 ml) washed with brine (150 ml), dried, and concentrated in vacuo. This material (3.21 g) was crystallised from DCM/CH to give the title compound as a white solid (2.3 g). T.l.c. CH-EA (8:2), Rf 0.34 IR:3393, 3304 (NH) cm-1.
Reaction SMILES: [CH:1]1([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(OO)(=[O:16])C.O>C(Cl)Cl>[CH:3]12[O:16][CH:4]1[CH2:5][CH2:6][CH:1]([C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2]2
Reactant: CCCCCC(=O)C1CC=CCC1
Reactant: CC(=O)OO
Solvent: O
Solvent: ClCCl
Product: CCCCCC(=O)C1CCC2OC2C1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 8.42 g (0.0668 mol) 1-(3-cyclohexen-1-yl)-1-hexanone, and 80 mL of methylene chloride. Peracetic acid (14.5 g, 35 wt. % in acetic acid; 0.0668 mol) in methylene chloride (60 mL) was added dropwise to above mixture over 20 min. in an ice bath. After the above mixture was reacted at room temperature overnight, 200 mL of water was added to above reaction mixture, the water layer was extracted with methylene chloride (2×100 mL), the organic layer was combined, and washed with saturated sodium carbonate solution (2×100 mL), then with water (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from (4-chloro-5-isobutylamino-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example C31) (1.93 g, 5.61 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a brown solid (1.30 g, 74%).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: OB(O)c1ccccc1F
Product: Oc1ccc2ncn(-c3ccccc3F)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-fluorophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=230.2 [M+H]+.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)C>C1COCC1.Cl.C(OCC)(=O)C.O>[OH:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]=[O:3])=[CH:6][CH:7]=1
Reactant: CCOC(OCC)c1ccc(CO)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CO)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
Alcohol 1 (10.09 g, 48 mmol) was dissolved in a mixture of THF (100 ml) and 2 M HCl (100 ml) and stirred for 1 hour. The solvent was evaporated and the residue obtained was dissolved in ethyl acetate (100 ml) and water (100 ml). The phases were separated and the organic phase was washed with water (100 ml), dried over magnesium sulphate, and evaporated to yield 2 as a white solid (6.54 g, 48 mmol, 100%). Rf=0.54 (ethyl acetate/chloroform, 1:1); νmax=3327, 1689, 1607, 1206, 1010, 823 cm−1; 1H NMR (250 MHz, CDCl3) δ=10.02 (s, 1H, CHO), 7.89 (d, 3J(H,H)=8.1 Hz, 2H, ArCH α to CHO), 7.54 (d, 3J(H,H)=8.1 Hz, 2H, ArCH α to CH2OH), 4.82 (d, 3J(H,H)=5.9 Hz, 2H, CH2OH), 1.94 (t, 3J(H,H)=5.9 Hz, 1H, CH2OH); 13C NMR (75 MHz, CDCl3) δ=192.0 (CHO), 147.7 (ArCCOH), 135.7 (ArCCHO), 130.0 (ArCH α to ArCCHO), 127.0 (ArCH α to ArCCH2OH), 64.6 (CH2OH); HRMS (ESI−): m/z calculated for C8H7O2 [M−H]−: 135.0446, found 135.0448; elemental analysis calcd (%) for C8H8O2 (136.15): C, 70.57; H, 5.92. found: C, 70.70; H, 6.00.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2[NH:12][CH2:11][CH2:10][N:9]=2)=[CH:5][CH:6]=1.[H-].[Na+].[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18]Cl>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][N:9]1[CH2:10][CH2:11][N:12]=[C:8]1[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: c1ccc(CC2=NCCN2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CN2CCN=C2Cc2ccccc2)c(Cl)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
Tolazoline (16 g, 0.1 mol) in dimethylformamide (40 ml) was added dropwise to a suspension of sodium hydride (80% dispersion in mineral oil, 3 g, 0.1 mol) in dimethylformamide (40 ml) under a nitrogen atmosphere. After stirring at 20° C. for 30 minutes and at 65° C. for an additional 30 minutes, a solution of 2,4-dichlorobenzyl chloride (19.5 g, 0.1 mol) in dimethylformamide was added dropwise to the reaction mixture over a period of 2.5 hours. The mixture was heated to 80°-90° C. for 5 hours, cooled and concentrated under reduced pressure. Water was added to the residue and the resulting mixture was extracted with ethyl acetate. The organic phase was separated, washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure yielding a residue which was chromatographed on silica gel eluting with ammonia/methanol/ethyl acetate (3:12:85) to yield as a colorless oil, 1-(2,4-dichlorophenylmethyl)-4,5-dihydro-2-phenylmethylimidazole (16 g). Treatment of the oil with ethereal hydrogen chloride yielded the hydrochloride salt of 1-(2,4-dichlorophenylmethyl)-4,5-dihydro-2-phenylmethyl imidazole m.p. 185°-189° C. (Found C, 56.75; H, 4.91; N, 7.71. C17H17Cl3N2.1/4H2O requires C, 56.70; H, 5.58; N, 7.77) having the formula ##STR22##
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH2:14]([O:21][CH2:22][C@@H:23]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[NH:24]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH2:14]([O:21][CH2:22][C@@H:23]1[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[N:24]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Reactant: COC(=O)c1ccc(Br)cc1OC
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2[C@H](COCc3ccccc3)CCS2(=O)=O)cc1OC
Yield: 93.8 %

Procedure:
To a mixture of methyl 4-bromo-2-methoxybenzoate (245 mg), (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (241 mg) described in Preparation Example 1, potassium carbonate (276 mg), potassium iodide (166 mg) and copper(I) iodide (95 mg) were added toluene (3 mL) and N,N′-dimethylethylenediamine (110 μL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (380 mg).
Reaction SMILES: [CH2:1]([C@@H:8]1[O:10][C@@H:9]1[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:14].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C=O)C.O.Cl>[CH2:1]([C@H:8]1[O:10][C@H:9]1[C:11]([OH:14])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@@H]1O[C@@H]1CO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC[C@H]1O[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 300 mg (1.16 mmole) (2R-cis)-3-heptyloxiranemethanol in 50 ml of DMF was added 2.62 g (6.97 mmole) of pyridinium dichromate. The reaction was allowed to stir overnight under argon. The mixture was then diluted with 150 ml H2O and 20 ml 0.1 M HCl and washed three times with 50 ml of Et2O. The combined Et2O layers are dried over MgSO4, filtered and evaporated to afford a white powder. This residue was crystallized from petroleum ether to afford 155 mg of white power, mp 53-5° C. 1H NMR (CDCl3) δ 3.60 (d, 1, J=5 Hz), 3.24 (dd, 1, J=5 12 Hz), 1.6-1.2 (m, 12), 0.88 (t, 3, J=7 Hz). Mass Spectra: M-45(--CO2H)(3.7)141.1, M(100)41.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[S:21](Cl)(=[O:23])=[O:22])([O-:11])=[O:10]>N1C=CC=CC=1>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[S:21]([O:8][N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])(=[O:23])=[O:22])([O-:11])=[O:10]
Reactant: [O-][n+]1ccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Product: O=c1ccccn1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 31 %

Procedure:
2-Hydroxypyridine-1-oxide (0.5 g, 4.5 mmol) was reacted with 2,4-dinitrobenzenesulfonyl chloride (1.32 g, 5.0 mmol) in 40 mL of pyridine to afford PZBG-1d in 31% yield (0.48 g, 1.4 mmol). 1H NMR (500 MHz, CDCl3) δ=8.96 (d, J=2.3 Hz, 1H), 8.42 (dd, J1=9.2 Hz, J2=2.3 Hz, 1H), 7.68 (dd, J1=6.9 Hz, J2=1.7 Hz, 1H), 7.50 (dt, J1=7.5 Hz, J2=2.3 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 6.82 (dd, J1=9.2 Hz, J2=1.8 Hz, 1H), 6.35 (dt, J1=6.9 Hz, J2=1.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ=157.0, 155.6, 140.5, 135.1, 129.6, 124.0, 122.9, 116.0, 106.6.
Reaction SMILES: [CH3:1][S:2][CH:3]([CH2:13][CH2:14][CH2:15][CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH-].[Na+].I([O-])(=O)(=O)=[O:26].[Na+]>O>[CH3:1][S:2]([CH:3]([CH2:13][CH2:14][CH2:15][CH:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:26]
Reactant: CCCCCC(O)CCCC(CCCCCCC(=O)O)SC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
8-Methylthio-12-hydroxyheptadecanoic acid (Ex. 1) (6.7 g., 0.0202 mole) is dissolved in a solution of sodium hydroxide (1.0 g., 0.025 mole) in water (80 ml.). Sodium metaperiodate (4.7 g., 0.022 mole) is added and the resulting mixture is stirred at room temperature overnight (17 hours). The solids present are then filtered off and the filtrate is acidified with dilute hydrochloric acid to liberate the oily acid product. The oil is taken up in ether, washed with water and dried over sodium sulfate. The ether is evaporated in vacuo to leave the crude 8-methylsulfinyl-12-hydroxy-heptadecanoic acid as a viscous yellowish oil weighing 5.8 g. Purification is effected by chromatography on a column containing 125 g. of silica gel using 4% methanol in chloroform as eluant. There is obtained 2.2 g. of pure 8-methylsulfinyl-12-hydroxyheptadecanoic acid, a colorless viscous oil with Rf 0.14 on silica gel thin layer chromatograms with chloroform-methanol-acetic acid 96:3:1 as eluant; pmr (CDCl3) δ 0.90 (3H, t); 2.50 (3H, s CH3SO); 3.64 (1H, m HCO).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].I[CH:15]([CH3:17])[CH3:16]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:15]([CH3:17])[CH3:16])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2,6-dichloro-9H-purine (a) (6.0 mmol) dissolved in anhydrous DMF (5.0 mL) was slowly added sodium hydride (7.8 mmol) with stirring at rt over 2 hr. 2-iodopropane was added and the mixture was stirred for 16 hr. The mixture was concentrated. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (20:1 to 3:1) to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.15 (s, 1H), 4.91 (m, 1H), 1.63 (d, 6H).
Reaction SMILES: OP([O-])(O)=O.[K+].OP([O-])([O-])=O.[K+].[K+].C[C@@H]([C@@H:21]1[C@@:25]2([CH3:43])[C@@H:26](O)[CH2:27][C@@H:28]3[C@@:33]4([CH3:39])[CH2:34][CH2:35][C@@H:36]([OH:38])[CH2:37][C@H:32]4[CH2:31][C@@H:30](O)[C@@:29]3(C)[C@@H:24]2[CH2:23][CH2:22]1)CCC([O-])=O.[Na+].CCC(CO[C:52]([C:65](N(CC[NH+](C)C)C)=O)([C:59]1C=CC=CC=1)[C:53]1C=[CH:57][CH:56]=[CH:55][CH:54]=1)CC.[Cl-].CC1N(C)N(C2C=CC=CC=2)C(=O)C=1N.C1(O)C=CC=CC=1>C(O)C.O>[CH3:59][CH:52]([CH2:53][CH2:54][CH2:55][C@H:56]([C@@H:24]1[C@:25]2([CH3:43])[C@H:21]([C@H:29]3[C@H:28]([CH2:27][CH2:26]2)[C@:33]2([CH3:39])[C:34]([CH2:35][C@H:36]([CH2:37][CH2:32]2)[OH:38])=[CH:31][CH2:30]3)[CH2:22][CH2:23]1)[CH3:57])[CH3:65]
Reactant: C[C@H](CCC(=O)[O-])[C@H]1CC[C@@H]2[C@]1(C)[C@@H](O)C[C@@H]1[C@@]3(C)CC[C@@H](O)C[C@H]3C[C@@H](O)[C@@]21C
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Solvent: O
Solvent: Oc1ccccc1
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
In a 250 ml flask, a reaction mixture (designated "mixture A") was prepared by adding to 90 ml of distilled water the following: 1.497 g (KH2PO4 ; 1.568 g K2HPO4 ; 0.431 g. sodium cholate; 1.05 ml of a 25% solution of an alkylphenoxypolyethoxy ethanol, commercially available from Rohm and Haas Co., Philadelphia, Pa., under the trade designation Triton X-100; 0.0169 g 4-aminoantipyrine (used as a chromogen); and 0.145 ml phenol (10 M). Sufficient distilled water was added to make a final volume of 100 ml.