Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([CH2:11]OS(C)(=O)=O)[CH:7]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C=O)C>[N:17]([CH2:11][C:8]1[CH:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:10][N:9]=1)=[N+:18]=[N-:19]
Reactant: CS(=O)(=O)OCc1cc(-c2ccco2)on1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(-c2ccco2)on1
Reaction time: 15 h
Yield: 86.8 %

Procedure:
To a solution of 2.21 g of methane sulfonic acid 5-furan-2-yl-isoxazol-3-ylmethyl ester in 45 mL of DMF was added 0.61 g of sodium azide. After stirring for 15 hrs, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride and distilled water, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1.50 g of 3-azidomethyl-5-furan-2-yl-isoxazole. This concentrate was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:14][N:15]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH3:24])[C@@H:9]([OH:13])[CH2:10][CH2:11][CH3:12])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:28]([O:27][C:25](=[O:26])[N:15]([CH2:14][C@H:8]([NH2:7])[C@@H:9]([OH:13])[CH2:10][CH2:11][CH3:12])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH3:24])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCC[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](O)[C@@H](N)CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
The compound (1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)-carbamic acid tert-butyl ester (580 mg, 1.2 mmol, see procedure 12a) was dissolved in CH2Cl2 (9 mL) and treated with TFA (3 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in benzene and concentrated in vacuo; this procedure was repeated to provide [(2S,3S)-2-amino-3-hydroxy-hexyl]-(2,4-dimethyl-benzyl)-carbamic acid benzyl ester. The amine was dissolved in 12 mL of 2:1 CH2Cl2/DMF. The resultant solution was charged sequentially with mono-benzyl malonate (232 mg, 1.2 mmol), N,N-diisopropylethylamine (1.05 mL, 6.0 mmol) and HATU (547 mg, 1.4 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide N-[(1S,2S)-(1-{([benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)]-malonamic acid benzyl ester (517 mg, 77% yield). MS found: (M+Na)+=583.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:17])=[C:7]([C:14](=[O:16])C)[CH:8]=2)[O:3]1.Cl[O-:20].[Na+].[OH-].[Na+]>O.O1CCOCC1>[CH3:18][C:2]1([CH3:1])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][C:6]([CH3:17])=[C:7]([C:14]([OH:16])=[O:20])[CH:8]=2)[O:3]1
Reactant: [O-]Cl
Reactant: CC(=O)c1cc2c(cc1C)OC(C)(C)CC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2c(cc1C(=O)O)C(C)(C)CC(C)(C)O2
Temperature: 45 °C
Reaction time: 48 h

Procedure:
A mixture of 950 mg (3.9 mmol) of 2,2,4,4,7-pentamethyl-6-acetylchroman (Compound 53), 100 ml of 10% sodium hypochlorite solution, 10 ml of a solution of 1.52 g (38 mmol) of sodium hydroxide in water and 10 ml of dioxane was heated at 45° C. for 72 hours. The mixture was cooled to room temperature and washed with 2×25 ml of ether. The aqueous layer was then treated with sodium metabisulphite until it was negative to the potassium iodide-starch test. The aqueous layer was acidified to pH=2 with dilute H2SO4 and the mixture was then stored in the refrigerator for 48 hours. The mixture was extracted with 3×25 ml of ether. The ether extracts were then combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solution was then filtered and the filtrate was concentrated in-vacuo to give the title compound as a white solid. PMR (CDCl3): & 1.34 (12H, s), 1.82 (2H, s), 2.53 (3H, s), 6.64 (1H, s), 8.03 (1 H, s).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]([CH3:9])=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[CH:18][C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:5]=1[CH3:9]
Reactant: COc1cc(Cl)c2c(c1)CCN2
Reactant: CCC(CC)n1c(C)c(Cl)nc(Cl)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)n1c(C)c(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
Part C: A solution 3,5-dichloro-1-(1-ethylpropyl)-6-methyl-2(1H)-pyrazinone from Part B (80 mg, 0.321 mmol) and 7-chloro-5-methoxyindoline (61.9 mg, 0.337 mmol) in THF (1.6 mL) was cooled to 0° C. and was treated with sodium hexamethyldisilazide (353 μL, 0.353 mmol, 1 M in THF). The reaction mixture was allowed to warm up to room temperature and was stirred overnight. The mixture was transferred to a separatory funnel containing saturated NaHCO3 and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% EtOAc in hexanes→40% EtOAc in hexanes) to provide the target compound (22 mg, 17% yield) as a brown oil: 1H NMR (CDCl3) δ 6.72 (s, 2 H), 4.27 (t, J=7.88 Hz, 2 H), 4.00-3.95 (m, 1 H), 3.77 (s, 3 H), 3.09 (t, J=7.8 Hz, 2H), 2.48-2.38 (m, 2 H), 2.42 (s, 3 H), 1.95-1.81 (m, 2 H), 0.87 (t, J=7.5 Hz, 6 H); HRMS (ESI) m/z 396.1259 [(M+H)+, calcd for C19H24N3O2Cl2 396.1246].
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[O:16][CH3:17].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl>[CH3:8][C:9]1[CH:14]=[C:13]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH:12]=[C:11]([CH3:15])[C:10]=1[O:16][CH3:17]
Reactant: COc1c(C)cccc1C
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1c(C)cc(C(=O)CCC(=O)O)cc1C
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Succinic anhydride (22.06 gm) was added to a mixture of 2,6-dimethylanisole (30 g) and anhydrous aluminium trichloride (59 g) in 1,2-dichloroethane (200 ml) at 0° C. The mixture was stirred for 0.5 hr at 0° C. and at room temperature for 4 hr. The mixture was poured onto ice-concentrated hydrochloric acid. After stirring vigorously for 5 min, the mixture was extracted with ethyl acetate. The dried (MgSO4) organic fraction was evaporated to give 4-(3,5-dimethyl-4-methoxyphenyl)-4-oxobutyric acid as white crystals, mp 108° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]5[O:28][N:27]=[C:26]([CH3:29])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[BrH:30].[OH-].[Na+]>>[BrH:30].[CH3:29][C:26]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]3[N:19]([C:15]([CH2:14][O:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[N:16][N:17]=3)[CH:20]=2)[O:28][N:27]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)no5)cn34)ccnc2c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(-c2ccc3nnc(COc4ccnc5cc(O)ccc45)n3c2)on1
Reaction time: 5 h

Procedure:
A 150 mL tube was charged with 7-methoxy-4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline (1.44 g, 3.72 mmol) and HBr (30.3 ml, 558 mmol), sealed, then placed in a 120° C. for 5 hours. The reaction mixture was slowly neutralized with 6N NaOH until a precipitate crashed out of solution (pH ˜5)—the solid was collected to give 4-((6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinolin-7-ol hydrobromide.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1CC[N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30]OCC4C=CC=CC=4)[C@@H:25]([OH:40])[C@H:24]3[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:15]=2)[CH2:10]1.Cl[C:58]1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.C(N)CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH2:9][CH2:10][NH:11][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[C@@H:23]2[CH2:27][C@H:26]([NH:28][C:29](=[O:39])[CH2:30][CH3:58])[C@@H:25]([OH:40])[C@H:24]2[OH:41])=[C:16]([NH:42][CH2:43][CH:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:15]=1
Reactant: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(NCCN)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate (Example 1 step 2) by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) and by replacing (3R)-3-aminopyrrolidine with ethylene diamine. (MH+ 545.4)
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7](=[O:14])[C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[C:30]1([Mg]Br)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:7](=[O:14])[C:8]([CH:12]([OH:13])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCCc1nc(C)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)c(C(O)c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Yield: 46 %

Procedure:
To a solution of 4′-[(2-butyl-5-formyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.66 g) in tetrahydrofuran (10 mL) was added phenylmagnesium bromide (1.0 mL, 1 M tetrahydrofuran solution) at −78° C., and the mixture was allowed to warm to 0° C. over 3 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (0.36 g, 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][C:3]=1[CH:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1.C([N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[C:23](F)[CH:24]=2)[C:19](=[O:28])[C:18]([C:29]([OH:31])=[O:30])=[CH:17]1)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][C:3]=1[CH:8]1[NH:9][CH2:10][CH2:11][N:12]([C:23]2[CH:24]=[C:25]3[C:20]([C:19](=[O:28])[C:18]([C:29]([OH:31])=[O:30])=[CH:17][NH:16]3)=[CH:21][C:22]=2[F:27])[CH2:13]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: Cc1cc(C)c(C2CNCCN2)o1
Solvent: c1ccncc1
Product: Cc1cc(C)c(C2CN(c3cc4[nH]cc(C(=O)O)c(=O)c4cc3F)CCN2)o1
Reaction time: 4 h
Yield: 21.9 %

Procedure:
The 1.4 g of 2-(3,5-dimethyl-2-furanyl)piperazine was dissolved in 5 ml of pyridine, 0.66 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid added and the mixture heated at 95°-100° C., under argon, :n a pressure bottle for 4 hours, then cooled. The solvent was removed in vacuo, the residue evaporated twice from toluene and the residue chromatographed, giving 700 mg of crude product. This product was recrystallized from methanol, giving 220 mg of the desired product, mp 230°-232° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:4][CH:3]=1.[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:22][CH:24]4[O:26][CH2:25]4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(OCC3CO3)cc2C1=O
Yield: 93 %

Procedure:
A mixture of 4(4-chlorophenyl)-7-hydroxy-2,2-dimethyl-1-tetralone (17.6 g), epichlorohydrin (30 ml) and potassium carbonate (6.0 g) was heated under reflux in acetone (30 ml) for 24 hr. The hot mixture was filtered and evaporation of the filtrate in vacuo gave 4-(4-chlorphenyl)-7-(2,3-epoxypropoxy)-2,2-dimethyl-1-tetralone as a light yellow gum (8.4 g, 93%).
Reaction SMILES: Cl.[C:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1)(=[O:4])[CH3:3].[BH4-].[Na+].Cl>CO>[OH:4][CH:2]([CH3:3])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:13])[CH2:8][CH2:7]1
Reactant: CC(=O)CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.76 Grams of 6-(4-acetylmethyl-1-piperazinylcarbonyl)-3,4-dihydrocarbostyril monohydrochloride was dissolved in 50 ml of methanol, under ice-cooled condition, 0.44 g of sodium borohydride (NaBH4) was added slowly and then stirred at a room temperature for 1 hour. After the reaction was completed, a concentrated hydrochloric acid was added to adjust the pH of the reaction mixture to about pH 1, then most portion of the solvent was removed by distillation under a reduced pressure and the residue was extracted with 1 N-NaOH-chloroform. The organic layer was washed with water and dried with anhydrous sodium sulfate, then the solvent was removed by distillation. The residue obtained was treated by means of a column chromatography and recrystallized from ethanol to obtain 2.26 g of 6-[4-(2-hydroxypropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless flake-like crystals. Melting point: 156°-157.5° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23]C(OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][C:43]#[C:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:42][C:43]#[C:44][C:45]([CH2:49][CH3:50])([OH:48])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(O)(C#CCBr)CC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(C#CCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)CC
Yield: 62.5 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (60.8 mg, 0.105 mmol), 6-bromo-3-ethyl-4-hexyn-3-ol (108 mg, 0.525 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=5:1, developed twice) to give the title compound as a colorless oil (38.4 mg, 63%).
Reaction SMILES: OC1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:3]1[NH:12]C(C)=O.[OH:16][CH:17]1O[C@H](C(=O)O)[C@@H](O)[C@H](O)[C@H]1O>>[CH2:3]([NH2:12])[CH:4]([OH:5])[CH:6]([OH:7])[CH:8]([OH:9])[CH:10]([OH:11])[CH2:17][OH:16]
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: O=C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O
Product: NCC(O)C(O)C(O)C(O)CO

Procedure:
1H NMR of IV, Na-salt (500 MHz, D2O, 2 mM NaHCO2, 30° C.): δ=5.473 (m, 2 —CH═CH— of DOPE), 5.328 (m, OCH2CHCH2O of DOPE), 4.574 and 4.473 (m, HA: H−1 of GlcNAc, H−1 of GlcA; CO—OCHCHCH2 of DOPE), 4.246 (dd, J=12.3 Hz, J=6.8 Hz, CO—OCHCHCH2 of DOPE), 4.027 (t, J=5.7 Hz, POCH2CH2N of DOPE), 3.95-3.34 (HA: H−2÷H-6 of GlcNAc, H−2÷H−5 of GlcA; POCH2CHCH2 of DOPE), 2.413 (m, 2 CH2COO of DOPE), 2.302 (m, 2 CH2CON), 2.049 (m, 2 CH2CH═CHCH2 of DOPE), 2.039 (m, NCOCH2 of GlcNAc), 1.630 (m, 2 CH2CH2CON and 2 CH2CH2COO of DOPE), 1.306 (m, —CH2— of DOPE), 0.892 (˜t, 2 CH2 of DOPE) ppm.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1([Mg]Br)[CH2:17][CH2:16]1>C1COCC1>[CH:15]1([C:12]2([OH:13])[N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:9](=[O:14])[CH2:10][CH2:11]2)[CH2:17][CH2:16]1
Reactant: Br[Mg]C1CC1
Reactant: O=C1CCC(=O)N1Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CCC(O)(C2CC2)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To 1-(phenylmethyl)-2,5-pyrrolidinedione (1 g, 5.29 mmol) in THF (50 mL) at −78° C. was added cyclopropylmagnesium bromide (42.3 mL, 21.1 mmol) dropwise. The reaction mixture was allowed to warm to 0° C. and stirred for an additional 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and transferred to a separatory funnel. EtOAc was added, and the organic phase was separated. The aqueous layer was further extracted with EtOAc, and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 80% EtOAc/hexanes) afforded the title compound (400 mg, 33%) as a yellow solid. LC-MS (ES) m/z=232 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][SH:8])=[CH:3][CH:2]=1.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](F)[N:13]=1>O1CCCC1>[CH2:7]([S:8][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[N:13]=1)[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: Fc1cccc(F)n1
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cccc(SCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of benzylthiol (5.4 g) in tetrahydrofuran (25 cm3) was added dropwise to a stirred suspension of sodium hydride (1.9 g of a 55% of a dispersion in oil) in tetrahydrofuran (350 cm3) under a nitrogen atmosphere. The mixture was stirred for 30 minutes and a solution of 2,6-difluoropyridine (5 g) in tetrahydrofuran (25 cm3) was added dropwise. The mixture was stirred for a further 3 hours and then carefully quenched with water. The products were extracted into diethyl ether and the combined ether extracts were washed with water and brine solution, then dried over anhydrous magnesium sulphate, filtered and concentrated by evaporation under reduced pressure. The residual dark liquid was purified by chromatography on a silica gel support, eluting with hexane containing 5% by volume ethyl acetate. Fractions containing 15-20 cm3 of eluent were collected separately during the elution, the product being collected in fractions 11 to 19. Evaporation of the eluent gave the title product (7.1 g) as a clear liquid.
Reaction SMILES: [CH2:1]([NH2:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][NH2:11].[S:13](Cl)([C:16]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:21]([N:22]([CH3:24])[CH3:23])[C:20]=2[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].O>C(#N)C>[NH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][CH2:1][NH:12][S:13]([C:16]1[C:28]2[C:20](=[C:21]([N:22]([CH3:24])[CH3:23])[CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: NCCCOCCOCCCN
Solvent: O
Solvent: CC#N
Product: CN(C)c1cccc2c(S(=O)(=O)NCCCOCCOCCCN)cccc12
Reaction time: 1.5 h
Yield: 60.7 %

Procedure:
4,7-Dioxadecane-1,10-diamine (32.6 g, 0.185 mole) in acetonitrile (100 mL) was chilled in an ice bath. To this was slowly added dropwise dansyl chloride (5 g, 0.0185 mole) dissolved in acetonitrile (60 mL) over a 20 min. period. Stirring in an ice bath was continued for 1.5 hr. The reaction mixture was poured into water (about 300 mL) and extracted with dichloromethane (2×100 mL). The combined extracts were washed with water and dried to give an oil. The oil was purified by column chromatography (silica gel eluting with acetonitrile containing increasing amounts of ethanol) to provide 4.6 g of N-(10-amino-4,7-dioxadecyl)-5-dimethylaminonaphthalene-1-sulfonamide as a viscous oil.
Reaction SMILES: CO[C:3]([C:5]#[C:6][C:7]([O:9]C)=[O:8])=[O:4].[OH:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][C:16]([CH3:25])([CH3:24])[O:17]2.[OH-].[Na+]>O1CCOCC1.O.OS(O)(=O)=O>[CH3:23][O:22][C:20]1[C:21]2[C:3](=[O:4])[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[O:11][C:12]=2[C:13]2[CH2:14][CH2:15][C:16]([CH3:25])([CH3:24])[O:17][C:18]=2[CH:19]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1cc(O)c2c(c1)OC(C)(C)CC2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(c3oc(C(=O)O)cc(=O)c13)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a solution of dimethylacetylenedicarboxylate (7.5 g) in dioxan (100 ml) containing `Triton 8` (10 drops) was added 5-hydroxy-7-methoxy-2,2-dimethylchroman (10.0 g) and the resulting mixture was warmed on a steam bath for 2 hours. A solution of sodium hydroxide (4.0 g) in water (20 ml) was added and heating was continued for 2 hours more. The organic solvent was removed and water (50 ml) was added to the residue and the mixture was acidified to give an oil which was extracted into ethylacetate. This solution was dried over MgSO4, filtered and the filtrate was evaporated to dryness. The oil so obtained was dissolved in concentrated H2SO4 (50 ml) and the solution was stirred at room temperature for 30 minutes, poured into ice and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), filtered and evaporated to dryness. The oil so produced was triturated with ethyl acetate, cooled to 0°, and the solid produced was filtered and dried. The solid was crystallised from ethanol to give 8,9-dihydro-5-methoxy-8,8-dimethyl-4-oxo-4H,10H-benzo[1,2-b: 3,4-b']dipyran-2-carboxylic acid as a white solid (3.4 g, 23%) mp 225°-6°.