Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([C:18]([OH:23])=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:24][CH3:25])[C:15]=2[CH3:26])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[I:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47]I.Cl>O1CCCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[N:22]3[C:17]([C:18]([O:23][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][I:27])=[CH:19][CH:20]=[CH:21]3)=[C:16]([O:24][CH3:25])[C:15]=2[CH3:26])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: ICCOCCOCCOCCOCCOCCOCCI
Reactant: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(O)cccn23)ccc1N
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)c2c(C)c(OC)c3c(OCCOCCOCCOCCOCCOCCOCCI)cccn23)ccc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
12 ml (6.0 mmol) of potassium hexamethyldisilylamide (0.5 M solution in toluene) at −20° C. under nitrogen is added, dropwise, to the solution of 2.0 g (5.64 mmol) of methyl 2-amino-5-[(8-hydroxy-1-methoxy-2-methyl-indolizin-3-yl)carbonyl]benzoate (described in stage F of Example 1) in 56 ml of tetrahydrofuran. The formation of a red precipitate is observed. The mixture is allowed to return to ambient temperature and 18.5 g (33.9 mmol) of 1,20-diiodo-3,6,9,12,15,18-hexaoxaicosane are added (Example R1). The solution is stirred at ambient temperature for 18 hours. The reaction medium is poured into a solution of hydrochloric acid (1 M) and the mixture is extracted with an ethyl acetate/tetrahydrofuran mixture. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue obtained is purified by flash chromatography on silica gel (gradient of dichloromethane/methanol: 100/0 to 90/10). 2.3 g (53%) of a yellow oil are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[F:12][CH2:13][C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17].[NH2:21][C:22]([CH3:30])=[CH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25]>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]1[C:23]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[C:22]([CH3:30])[NH:21][C:14]([CH2:13][F:12])=[C:15]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: CC(N)=CC(=O)OC(C)C
Reactant: O=Cc1c(F)ccc(Cl)c1Cl
Reactant: COC(=O)CC(=O)CF
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC(C)C)C1c1c(F)ccc(Cl)c1Cl
Reaction time: 2.5 h
Yield: 33.8 %

Procedure:
2,3-Dichloro-6-fluorobenzaldehyde (1.44 g, 7.5 mmoles), methyl 4-fluoro-3-oxobutanoate (1.0 g, 7.5 mmoles) and 1-methylethyl 3-amino-2-butenoate (1.06 g, 7.5 mmoles) were heated at 90° under nitrogen with stirring for 2.5 hours. The cooled reaction mixture was chromatographed on silica eluting with ethyl acetate/methylene chloride mixtures. The title compound (1.1 g) was obtained by crystallisation from a petroleum ether (60°-80°)/2-propanol mixture mp 129°-31°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[S:8][CH2:7]1)=[O:5])[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.ClC1C=CC=CC=1C(Cl)=O>>[CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[S:8][CH:7]1[C:19](=[O:21])[CH3:20])=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([CH:6]1[CH:14]2[C:9]3([CH:18]=[CH:17][CH:16]=[CH:15][C:10]3=[N:11][CH2:12][CH2:13]2)[S:8][CH:7]1[C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1CSC23C=CC=CC2=NCCC13
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: O=C(Cl)c1ccccc1Cl
Product: CCOC(=O)C1C(C(=O)c2ccc(OC)cc2)SC23C=CC=CC2=NCCC13
Product: CCOC(=O)C1C(C(C)=O)SC23C=CC=CC2=NCCC13

Procedure:
2-Acetyl-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester and 2-(4-methoxybenzoyl)-1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester were synthesized using 1,2,3,4-tetrahydro-benzo[b]thieno[2,3-c]pyridine-3-carboxylic acid ethyl ester as the starting material by following the same procedure as in Example 5 except that 324 mg of acetic anhydride or 510 mg of 4-methoxybenzoyl chloride, respectively, in place of 614 mg of 2-chlorobenzoyl chloride in Example 5.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:27][CH3:28])[C:25](=[O:26])[N:12]2[C:13]([C:22]([OH:24])=[O:23])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:15][S:16][C@H:11]12)=[O:8].CC(OCC1CS[C@@H]2[C@H](NC(CC3SC=CC=3)=O)C(=O)N2C=1C(O)=O)=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1([O:27][CH3:28])[C:25](=[O:26])[N:12]2[CH:13]([C:22]([OH:24])=[O:23])[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)C(COC(C)=O)=CS[C@@H]21
Yield: 68.2 %

Procedure:
To a cooled (0°), stirred solution of 7.75 g. of 7-(2-thienylacetamido)-7-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid [prepared from cephalothin in accordance with procedures described by G. A. Koppel and R. E. Koehler, J. Amer. Chem. Soc., 95, 2403 (1973)] in 46 ml. of dry pyridine was added 5.02 ml. of acetic anhydride. The reaction mixture was allowed to stir with cooling for 2 hours, after which time the mixture was evaporated in vacuo to near dryness. The residue was dissolved in ethyl acetate, and the resulting solution was extracted 3 times with aqueous sodium bicarbonate. The aqueous extracts were combined, layered with ethyl acetate, and acidified with cold 1N.HCl. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided 5.29 g. (68.2 percent) of the title product as a brown froth. Thin layer chromatography of the methyl ester derived from diazomethane exhibited a single spot. For identification purposes a small portion of the product acid was also converted to the corresponding benzhydryl ester using diphenyldiazomethane. Chromatography on a small silica gel column provided pure benzhydryl 7-(2-thienylacetamido)-7-methoxy-3-acetoxymethyl-2-cephem-4-carboxylate: ir (CHCl3) 1780 cm-1 (β-lactam); nmr (CDCl3) δ1.92 (s, 3, OAc), 3.42 (s, 3, OCH3), 3.85 (s, 2, side chain CH2), 4.55 (s, 2, --CH2OAc), 5.01 (m, 1, C4 --H), 5.35 (s, 1, C6 --H) and 6.35 (m, 6, CH2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:13]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1Br
Yield: 93.9 %

Procedure:
2-Bromo-4-nitrophenol (2.5 g; Desc. 9), 2-iodopropane (2.2 g) and potassium carbonate (5 g) were refluxed in acetone (30 ml) for 18 hours. The reaction mixture was then evaporated to dryness, and taken up in ethyl acetate/water. The organic layer was washed (water, brine), dried (MgSO4) and evaporated in vacuo. Chromatography on silica eluting with 10% ethyl acetate/hexane gave the title compound (2.8 g, 94%). 1H NMR (250 MHz, CDCl3) δ 8.46 (1H, s), 8.20 (1H, m), 6.93 (1H, m), 4.75 (1H, m), 1.42 (6H, d, J=7.5 Hz).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].O.C(O)C>C1(C)C=CC=CC=1.O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(-c2nc3ccccn3c2Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2nc3ccccn3c2-c2ccc(F)cc2)cc1
Temperature: 90 °C

Procedure:
0.46 g (1.5 mM) 4-(3-bromoimidazo[1,2-a]pyridin-2-yl)benzaldehyde (prepared as described by Sundberg et al.; J. Heterocyclic Chem., 25, 129, 1988) is dissolved in 5 mL of toluene. To this mixture is added 4-fluorphenyl boronic acid (1.5 eq) followed by tetrakis triphenylphosphine palladium (0) 10% by wt, K2CO3 (3 eq) and ethanol water mixture (4 mL). The reaction mixture is heated at 90° C. for 4-6 h. The reaction is cooled to room temperature and 20 mL of water is added and the reaction mixture is extracted with ethyl acetate. The organic layer is dried and concentrated. The crude is purified by flash column chromatography to obtain the desired compound.
Reaction SMILES: [CH2:1]([C:14]([OH:16])=[O:15])[CH:2]([C:11]([OH:13])=[O:12])[CH:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5]([OH:7])=[O:6].[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOCC1>>[CH2:28]([O:6][C:5]([CH2:4][CH:3]([C:8]([OH:10])=[O:9])[CH:2]([C:11]([OH:13])=[O:12])[CH2:1][C:14]([OH:16])=[O:15])=[O:7])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)CC(C(=O)O)C(CC(=O)O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CCCCCCCCCCCCOC(=O)CC(C(=O)O)C(CC(=O)O)C(=O)O

Procedure:
A blend of 1,2,3,4-butane tetracarboxylic acid (28.5 g., 0.121 mole), dodecyl alcohol (21.8 grams, 0.118 mole), p-toluenesulfonic acid (0.1 gram, 0.6 mole) and 300 ml. (3.4 moles) of dioxane was placed in a Soxhlet apparatus containing 4A molecular sieve. The mixture was brought to reflux with the vapor condensate passing through the molecular sieve to remove water formed during the reaction. After 48 hours reflux, the dioxane solution was removed and stripped of solvent under reduced pressure (20 mm.). The residue (50 grams) showed the presence of both carboxylic acid and ester groups in the infrared.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:4]=1O)[CH3:2].[C:11]1([CH2:17][C:18]([OH:20])=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)(Cl)Cl.CN([CH:30]=[O:31])C>>[CH2:1]([C:3]1[CH:4]=[C:6]2[C:7](=[CH:8][C:9]=1[OH:10])[O:20][CH:18]=[C:17]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:30]2=[O:31])[CH3:2]
Reactant: O=C(O)Cc1ccccc1
Reactant: CN(C)C=O
Reactant: CCc1c(O)cccc1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCc1cc2c(=O)c(-c3ccccc3)coc2cc1O
Yield: 87.7 %

Procedure:
This compounds was synthesised in the same manner as described above. Ethyl resorcinol (0.83 g, 6 mmol), phenylacetic acid (0.82 g, 6 mmol), BF3Et2O (3.88 ml, 31.5 mmol), PCl5 (1.88 g, 9 mmol), DMF (4.6 ml and 10 ml). The precipitate formed was filtered and re-crystallized from methanol to give 6-Ethyl-7-hydroxy-3-phenyl-chromen-4-one as a pale brown solid (1.4 g, 87.7%); Rf 0.4 cf SM 0.5 ethyl acetate/hexane (40/60).
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[Si](C)(C)C.[Br:29]Br>CN(C=O)C>[Br:29][CH:9]([CH2:8][CH:5]1[CH2:4][CH2:3][C:2]([F:16])([F:1])[CH2:7][CH2:6]1)[C:10](=[O:15])[C:11]([F:13])([F:14])[F:12]
Reactant: O=C(CCC1CCC(F)(F)CC1)C(F)(F)F
Reactant: BrBr
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C(Br)CC1CCC(F)(F)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
4-(4,4-Difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (100 mg, 0.410 mmol) obtained in step 1 was dissolved in DMF (1.0 mL). Under ice-cooled condition, triethylamine (0.110 mL, 0.788 mmol) and chlorotrimethylsilane (0.0570 mL, 0.450 mmol) were added, and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was extracted with hexane after adding saturated sodium hydrogen carbonate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was dissolved in dichloromethane (1.0 mL). Under ice-cooled condition, bromine (73.0 mg, 0.456 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL) after adding a saturated sodium hydrogen carbonate aqueous solution and sodium thiosulfate aqueous solution. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give 3-bromo-4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (73.8 mg, yield 56%).
Reaction SMILES: [N:1]1([C:7]([C@@H:9]2[CH2:14][C@H:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH2:12][N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:42][CH2:43][CH3:44]>CC(N(C)C)=O.O>[N:1]1([C:7]([C@@H:9]2[CH2:14][C@H:13]([N:15]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])[CH2:42][CH2:43][CH3:44])[CH2:12][N:11]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])C[C@@H](C(=O)N2CCOCC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCN([C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 4 h

Procedure:
tert-Butyl (3R,5S)-3-(morpholin-4-ylcarbonyl)-5-{[(2-nitrophenyl)sulfonyl]amino}piperidine-1-carboxylate (4.68 g) was dissolved in DMA (20 ml), cesium carbonate (9.18 g) and 1-iodopropane (1.83 ml) were added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7-10:0) was concentrated under reduced pressure to give the object product (4.02 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[C:10]2=[N:11][C:12]([NH2:20])=[N:13][C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[C:9]2[CH:8]=[N:7]1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30].O.[N:34]1C=CC=CC=1>>[NH2:20][C:12]1[N:11]=[C:10]2[N:6]([CH2:5][C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[CH:28][S:24][C:25]=4[S:29]([NH2:34])(=[O:31])=[O:30])[CH:23]=[CH:22][CH:21]=3)[N:7]=[CH:8][C:9]2=[C:14]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:13]=1
Reactant: Nc1cccc(Cn2ncc3c(-c4ccco4)nc(N)nc32)c1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: c1ccncc1
Solvent: O
Product: Nc1nc(-c2ccco2)c2cnn(Cc3cccc(-c4ccsc4S(N)(=O)=O)c3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
A solution of 1-(3-aminobenzyl)-4-(2-furyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (153 mg, 0.5 mmol) in pyridine (2 mL) was treated with 2-thiophenesulphonyl chloride (91 mg, 0.5 mmol), stirred at room temperature for 16 h, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (MeOH:DCM, 1:99) to give the title compound (49 mg, 22%) as a cream solid.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[C:19]([OH:21])[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:17][C:16]=2[CH2:29][CH3:30])=[CH:8][CH:7]=[CH:6][C:5]=1[S:31]([C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=[O:36])=[O:32])[CH2:2][CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:47]>C(Cl)Cl>[OH2:10].[CH2:1]([C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[C:19]([OH:21])[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:17][C:16]=2[CH2:29][CH3:30])=[CH:8][CH:7]=[CH:6][C:5]=1[S:31]([C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([OH:37])=[O:36])(=[O:47])=[O:32])[CH2:2][CH3:3]
Reactant: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1S(=O)c1ccccc1C(=O)O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)cccc1S(=O)(=O)c1ccccc1C(=O)O
Product: O
Temperature: 4 °C
Reaction time: 18 h
Yield: 113.4 %

Procedure:
To a solution of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenylsulfinyl]benzoic acid (150 mg, 0.260 mmol) in methylene chloride (3.0 mL) at 0° C. was added a solution of 85% m-chloroperoxybenzoic acid (53 mg) in methylene chloride (1 mL). After 1 hour the mixture was warmed to 4° C. and stirred for 18 hours. The mixture was concentrated in vacuo; purification of the residue via silica gel chromatography (90% chloroform/9.5% methanol/0.5% acetic acid) provided 90 mg (58%) of the title product as a white solid: mp 80°-90° C.; NMR (DMSO-d6) 7.88 (m, 2H), 7.55-7.78 (m, 3H), 7.50 (m, 2H), 7.33 (m, 2H), 7.04 (m, 2H), 6.95 (s, 1H), 6.51 (s, 1H), 4.19 (t, J=4.8 Hz, 2H), 4.05 (t, J=5.8 Hz, 2H), 2.69 (m, 2H), 2.44 (q, J=5.8 Hz, 2H), 2.19 (m, 2H), 0.90-1.10 (m, 5H), 0.71 (t, J=4.5 Hz, 3H); MS-FD m/e 595 (p+2, 30), 594 (p+1, 40), 593 (p, 100); IR (CHCl3, cm-1)2966, 1730, 1603, 1497, 1299, 1146. Analysis for C33H3307FS.H2O: Calc: C, 64.90; H, 5.78; Found: C, 64.89; H, 5.67.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.[N+:52]([O-])([OH:54])=[O:53]>C(#N)C>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[C:5]([N+:52]([O-:54])=[O:53])=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(C)c([N+](=O)[O-])c2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 70 °C
Yield: 32.7 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.14 mmol) in acetonitrile (1 mL) was added zirconyl(IV) nitrate hydrate (36 mg, 0.16 mmol). The reaction mixture was heated to 70° C. for 1 h. After cooled to room temperature, the reaction mixture was filtered through a micro filter and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative TLC (silica gel, 96:4 chloroform/methanol) and semi-preparative HPLC to afford (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-4-nitro-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (34 mg, 33%) as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.23 (s, 1H), 12.27 (br s, 1H), 8.19 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 5.89 (s, 1H), 5.31 (s, 1H), 5.19 (s, 1H), 4.69 (d, J=8.5 Hz, 1H), 4.61 (s, 1H), 3.91 (s, 3H), 3.79 (s, 3H), 3.76-3.65 (m, 2H), 3.61 (s, 3H), 3.49 (dd, J=19.5, 6.5 Hz, 1H), 3.40 (s, 3H), 3.39-3.35 (m, 1H), 3.28 (d, J=19.5 Hz, 1H), 3.13 (t, J=9.5 Hz, 1H), 2.47 (d, J=4.5 Hz, 1H), 2.40 (s, 3H), 1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 743 (M+H); HPLC 98.0% (AUC), tR 13.79 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[N:22]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:8].[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[N:22]=1)[CH2:6][C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:8])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N(CCCN)CC(=O)NCCc2ccc3c(c2)OCO3)nc(-n2ccnc2)n1
Solvent: c1ccncc1
Product: CC(=O)NCCCN(CC(=O)NCCc1ccc2c(c1)OCO2)c1cc(C)nc(-n2ccnc2)n1
Reaction time: 16 h
Yield: 41.7 %

Procedure:
To 2-[(3-aminopropyl)[2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide (0.3 g, 0.7 mmol) (a compound of formula (Yc6)) dissolved in pyridine (5 mL) was added acetic anhydride (0.10 mL, 1.0 mmol). After stirring for 16 hours, the reaction was partitioned with ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (Na2SO4), and the solvent was removed in vacuo. Chromatography on silica with CH2Cl2 gave 0.14 g of 2-[[3-(acetylamino)propyl][2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl]amino]-N-[2-(1,3-benzodioxol-5-yl)ethyl]acetamide, a compound of formula (Yc7); NMR (DMSO-d6) 8.4 (s, 1), 8.05 (t, 2), 7.85 (t, 1), 7.8 (s, 1), 7.05 (s, 1), 6.7 (m, 2), 6.6 (m, 1), 6.2 (s, 1), 5.9 (s, 2), 4.1 (m, 2), 3-3.6 (m, 6), 2.6 (m, 2), 2.3 (m, 3), 1.8 (s, 3), 1.65 (m, 2) ppm.
Reaction SMILES: [O:1]=[C:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[C:3](=[O:5])[CH3:4].S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)Cl>[Cl:15][CH2:4][C:3](=[O:5])[C:2]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)C(=O)N1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(CCl)C(=O)N1CCCCC1
Reaction time: 0.21 h

Procedure:
To a hot (50°) solution of the product of step B in 20 ml chloroform, 2.61 g (1.55 ml) of sulfuryl chloride is added dropwise (using a syringe) with vigorous stirring over a period of from 10 to 15 minutes. The mixture is stirred for about 7 hours at 50°. The mixture is then quenched by pouring into water. The resulting mixture is then extracted with methylene chloride. The combined extracts are washed with 10% aq. sodium bicarbonate solution then brine, dried over anh. sodium sulfate, then concentrated (under vacuum) to obtain an oily residue. The oil is distilled under vacuum (0.01 mm Hg) at 100° (constant boiling point) to obtain an oil which is re-distilled (at 0.001 mm Hg) at 90° C. for 1/2 hr. to obtain refined title product.