Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[Li+].[OH-].CO.Cl>O.CCOC(C)=O>[C:18]([O:17][C:15]([N:6]([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:5][C:4]([OH:22])=[O:3])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CN(CCc1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)CC(=O)O

Procedure:
A solution of the ester 14-1 (1.7 g, 5.5 mmol), 11.1 mL 1N LiOH and 11 mL MeOH was stirred at room temperature for 16 h. The mixture was poured into water/EtOAc and acidified with 1N HCl to pH≈3. After extraction with EtOAc (2×), the organic layers were washed with brine, dried (MgSO4) and evaporated to give 14-2 as a foam which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:9]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:10]=[CH:11][C@@H:12]([OH:29])[CH2:13][C@@H:14]([OH:28])[CH2:15][C:16]([NH:18][C@H:19]([C:24]([O:26]C)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:9]([C:30]2[N:34]([CH3:35])[N:33]=[N:32][N:31]=2)[CH:10]=[CH:11][C@@H:12]([OH:29])[CH2:13][C@@H:14]([OH:28])[CH2:15][C:16]([NH:18][C@H:19]([C:24]([OH:26])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)C[C@H](O)C[C@H](O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C[C@H](NC(=O)C[C@H](O)C[C@H](O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C)C(=O)O

Procedure:
When a solution of the compound from Example 147 in dioxane-water is treated at a temperature of about 0° C. with 1N NaOH and then acidified after workup, the title compound is thereby produced.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[CH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:28][CH2:29][C:30](Cl)=[O:31].O>ClCCl>[Cl:28][CH2:29][C:30]([NH:20][C:18]1[N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[N:16]2[N:17]=1)=[O:31]
Reactant: O=C(Cl)CCl
Reactant: Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)Nc1nc2cccc(-c3ccc4c(c3)OCCO4)n2n1
Reaction time: 8 h

Procedure:
To a solution of 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.4 g, 1.5 mmol) in dichloromethane (20 mL), triethylamine (0.62 mL, 4.47 mmol) and chloroacetyl chloride (0.142 mL, 1.8 mmol) were added successively. The mixture was then stirred overnight. Water was added and the mixture was extracted with dichloromethane, dried over magnesium sulphate and concentrated under reduced pressure. The crude was used without further purification. Yield: 0.52 g, 100%; LCMS Method: 2: 3.57 min, 345-347 [M+1].
Reaction SMILES: [F-].[K+].[CH2:3]([C:5]1[N:6]([CH:31]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]2)[N:7]=[C:8]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[C:16]([O:27][CH2:28][CH2:29][CH3:30])=[N:17][CH:18]=[C:19]([C:21]#[C:22][Si](C)(C)C)[CH:20]=3)=[N:10][C:9]=12)[CH3:4]>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([C:5]1[N:6]([CH:31]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:32]2)[N:7]=[C:8]2[C:13](=[O:14])[NH:12][C:11]([C:15]3[C:16]([O:27][CH2:28][CH2:29][CH3:30])=[N:17][CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=3)=[N:10][C:9]=12)[CH3:4]
Reactant: CCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(C3CN(C(=O)OC(C)(C)C)C3)nc2c(=O)[nH]1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C#Cc1cnc(OCCC)c(-c2nc3c(CC)n(C4CN(C(=O)OC(C)(C)C)C4)nc3c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium fluoride (0.38 mmol) was added to a stirred solution of the product of stage f) (0.19 mmol) in aqueous N,N-dimethylformamide (2 ml N,N-dimethylformamide/0.2 ml water) at 0° C. After 10 min the reaction was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water, 1 N hydrochloric acid (3 times) and brine. The organic layer was dried (MgSO4) and concentrated to give the title compound as a solid; 1H NMR (400MHz, CDCl3): δ=1.05 (t, 3H), 1.30 (t, 3H), 1.43 (s, 9H), 1.88-2.00 (m, 2H), 2H), 3.19 (s, 1H), 4.35 (app t, 2H), 4.52 (app t, 2H), 4.60-4.80 (br s, 2H), 5.22 (t, 1H), 8.39 (s, 1H), 8.80 (s, 1H), 10.75 (br s, 1H); LRMS (TSP—positive ion) 496 (MNH4+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[NH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:34]2[CH:38]=[CH:37][N:36]([CH2:39][CH2:40][NH2:41])[N:35]=2)[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32].C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:34]2[CH:38]=[CH:37][N:36]([CH2:39][CH2:40][NH:41][C:7]([C:5]3[CH:6]=[C:2]([CH3:1])[NH:3][N:4]=3)=[O:9])[N:35]=2)[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]
Reactant: COc1cc(-c2ccn(CCN)n2)ccc1[N+](=O)[O-]
Reactant: Cc1cc(C(=O)O)[nH]n1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-c2ccn(CCNC(=O)c3cc(C)[nH]n3)n2)ccc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
3-Methylpyrazole-5-carboxylic acid (70.0 mg, 0.555 mmol), HOBt (85 mg, 0.629 mmol) and PS-carbodiimide (672 mg) were weighed in a glass vial. DCM (4 ml) and DMF (0.4 ml) were added. The mixture was stirred for 10 minutes. 2-(3-(3-methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethanamine (97 mg, 0.370 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off. PS-Trisamine (616 mg, 1.849 mmol) was added to the filtrate. The mixture was stirred for 2 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 46 mg of the title compound. 1H-NMR (400 MHz; CDCl3): δ 2.35 (s, 3H), 3.92, (m, 2H), 4.05, (s, 3H), 4.40, (t, 2H), 6.57 (s, 1H), 6.61 (d, 1H), 7.31 (s, 1H), 7.40-7.43 (m, 1H), 7.47 (d, 1H), 7.62 (d, 1H), 7.96 (d, 1H), 9.94 (s, 1H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]([P:9]([O-:15])[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8]>>[CH2:7]([P:9]([CH2:1][CH:2]1[O:6][C:4](=[O:5])[CH2:3]1)(=[O:15])[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:8]
Reactant: CCCCOP([O-])CC
Reactant: C=C1CC(=O)O1
Product: CCCCOP(=O)(CC)CC1CC(=O)O1
Temperature: 85 °C

Procedure:
A solution of 0.98 parts of bis-(t-butylcyclohexyl)perdicarbonate in 12.6 parts of diketene was added dropwise over 1 hour to 90.2 parts of n-butyl ethylphosphonite which was vigorously stirred at 85° C. in a nitrogen atmosphere. After the addition the reaction mixture was passed down a wiped wall still at a temperature of 50° C. and a pressure of 0.13 mb to remove the excess phosphonite. The residue was distilled on the wiped wall still at a temperature of 75° C. and a pressure of 0.013 mb. The product n-butyl ethyl(2-oxo-4-oxetanylmethyl)phosphinate, was obtained as a colourless oil which the 31P NMR showed to be a nearly equal mixture of diastereoisomers having chemical shifts of δ-52.4 and δ-52.7 and which had the following elemental analysis by weight.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([C:17]([O:19][CH3:20])=[O:18])=[C:12]([CH2:14][O:15][CH3:16])[N:13]=1.[Cl:21]C1C=C(C(OCC)=O)NC=1C>CC#N>[CH3:20][O:19][C:17]([C:11]1[S:10][C:9]([Cl:21])=[N:13][C:12]=1[CH2:14][O:15][CH3:16])=[O:18]
Reactant: COCc1nc(N)sc1C(=O)OC
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COCc1nc(Cl)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl nitrite (2.2 ml, 18.6 mmol) and cuprous chloride (1.5 g) were suspended in anhydrous CH3CN (100 ml). Methyl 2-amino-4-(methoxymethyl)-1,3-thiazole-5-carboxylate (2.5 g) prepared as described in (Kennedy, Alan R. et al. Acta Crystallographica, Section C: Crystal Structure Communications (1999, C55 (7) 2) was added in one portion. The mixture was stirred at room temperature for 2 h and the temperature was raised to 70° C. for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was poured into 6 N HCl, extracted with EtOAc, dried with MgSO4 and concentrated to a black oil. Flash purification on silica gel with gradient elution (hexane to EtOAc) yielded product as a yellow liquid (0.82 g). NMR: 3.31 (s, 3H), 3.85 (s, 3H), 4.71 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(C)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CC(C)O)c1
Yield: 98.7 %

Procedure:
To a cold solution (5° C.) of 1-[3-(methyloxy)phenyl]-2-propanone (75 g, 0.457 mol) in MeOH (500 mL) was added NaBH4 (19 g, 0.502 mol) portion-wise over a period of 0.5 h. The resultant mixture was stirred at that temperature for 1 h. Reaction mixture was quenched with 1 N aqueous HCl (250 mL) and concentrated under reduced pressure to remove most of the methanol. The reaction mixture was extracted with EtOAc (3×150 mL). The combined organic layer was washed with water (1×100 mL), brine (1×100 mL), dried (Na2SO4) and concentrated under reduced pressure to afford the crude product. The reaction mixture was just passed through a pad of silica gel and washed with 1:1 hexanes:EtOAc to afford 75 g (99%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 7.24-7.20 (m, 1H), 6.80-6.75 (m, 3H), 4.02-3.97 (m, 1H), 3.79 (s, 3H), 2.78-2.63 (m, 2H), 1.25-1.19 (m, 3H).
Reaction SMILES: CON(C)[C:4]([CH:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[CH2:24]1[CH2:28][O:27][CH2:26][CH2:25]1>>[CH2:28]([O:27][CH2:26][C:4](=[O:5])[CH:6]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:24]1[CH:25]=[CH:8][CH:7]=[CH:6][CH:4]=1
Reactant: CON(C)C(=O)C(CCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCc1ccccc1)C(=O)COCc1ccccc1
Temperature: -60 °C

Procedure:
The mixture was cooled to −60° C. and stirred under nitrogen while a solution comprised of tert-butyl 1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarbamate (17 g, 52.73 mmol) in anhydrous THF was added via syringe and the mixture was stirred until the reaction was complete. The reaction was quenched slowly with ammonium chloride solution and the mixture was stirred for 15-30 minutes. The mixture was extracted with ethyl acetate (3×7 mL) and the combined extract was dried (Mg2SO4), filtered and concentrated. Product was purified from the residue by flash column chromatography using silica gel 60 to provide tert-butyl 3-benzyloxy-2-oxo-1-phenethylpropylcarbamate (17.15 g, 44.72 mmol). 1H NMR (CDCl3): δ 1.43 (s, 9H), δ 1.74-1.82 (m. 1H), δ 2.14-2.16 (m, 1H), δ 2.60-2.67 (m, 2H), δ 4.13-4.14 (d, 2H), δ 4.49-4.61 (m, 3H), δ 5.14-5.17 (d, 1H), δ 7.1-7.4(m, 10H).
Reaction SMILES: [F:1][CH:2]([F:21])[C@@:3]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])[CH2:4][CH:5]=[O:6].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:19][C:17]([S@@:15]([NH:14][C@:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])([CH2:4][C@@H:5]([OH:6])[C:23]([F:25])([F:24])[F:22])[CH:2]([F:1])[F:21])=[O:16])([CH3:18])[CH3:20]
Reactant: CC(C)(C)[S@](=O)N[C@@](CC=O)(c1ccccc1F)C(F)F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@](C[C@@H](O)C(F)(F)F)(c1ccccc1F)C(F)F
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
Intermediates XVII-1 and XVII-2: In a dry flask under an inert atmosphere a solution of (S)—N—((S)-1,1-difluoro-2-(2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (XVI-1) (1.45 g, 4.51 mmol) in THF (30 ml) was treated at 0° C. with (trifluoromethyl)trimethylsilane (1.28 g, 1.33 ml, 9.02 mmol) and dropwise with TBAF (1 M in THF, dried over molecular sieves 4 Å; 0.451 ml, 0.451 mmol). The slightly exothermic addition was completed within 3 min, thereafter the reaction mixture was stirred at 0° C. for 3 h, then left to warm to r.t. and stirred overnight. For the workup, the reaction mixture was quenched with a saturated solution of NH4Cl and extracted three times with AcOEt. The organic layers were washed with brine, dried over MgSO4 and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel (eluent: heptane/AcOEt; gradient: 0-90% AcOEt) to yield the (S)-2-methyl-N-((2S,4R)-1,1,5,5,5-pentafluoro-2-(2-fluorophenyl)-4-hydroxypentan-2-yl)propane-2-sulfinamide (XVII-1) (yellow oil, 377 mg as an approximately 7:3-mixture with its O-trimethylsilyl derivative) as the faster eluting epimer, the (S)-2-methyl-N-((2S,4S)-1,1,5,5,5-pentafluoro-2-(2-fluorophenyl)-4-hydroxypentan-2-yl)propane-2-sulfinamide (XVII-2) (yellow solid, 209 mg, 12% yield) as the second eluting epimer [MS: m/z=392.5 (M+H)+], and the starting aldehyde (yellow oil, crystallized on standing, 627 mg, 36% yield).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3([CH2:26][NH:27][CH2:28][CH3:29])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C>C1COCC1>[CH2:28]([N:27]([CH2:26][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:19][CH:18]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:1](=[O:3])[CH3:2])[CH3:29]
Reactant: CC(=O)Cl
Reactant: CCNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)C(C)=O
Reaction time: 2 h
Yield: 42.5 %

Procedure:
Acetyl chloride (14 μL, 0.20 mmol) was added dropwise to a solution of N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)ethanamine (70 mg, 0.20 mmol) and triethylamine (28 μL, 0.20 mmol) in THF (0.50 mL) at 0° C. and the reaction stirred for 2 hours. The reaction was quenched using NaHCO3 (10 mL), extracted with dichloromethane (3×10 mL) and the organic extracts dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on silica, eluting with DCM/MeOH/NH3 (95:5:0.5) to provide the title compound as a clear oil (33 mg, 42%). 1H NMR complicated by the presence of rotamers. 1H NMR (400 MHz, CDCl3) δ 7.20-7.12 (m, 2H), 6.92-6.86 (m, 2H), 4.06-4.00 (m, 2H), 3.88-3.76 (m, 2H), 2.56-2.48 (m, 2H), 3.42 (s, 2H), 2.66 (t, 2H), 2.58-2.52 (m, 4H), 2.48 (quartet, 2H), 2.08 (s, 3H), 2.06-1.92 (m, 6H), 1.84-1.76 (m, 4H), 0.98 (t, 0.6H) 0.86 (t, 2.4H). HRMS (ESI+) 389.2799 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:41][C:42]([OH:44])=[O:43])[CH2:12][C:13](=[O:40])[O:14][CH2:15][C:16](=[O:39])[C@@H:17]2[C@@:34]34[CH:35]([O:37][C@@H:32]([CH2:33]3)[C@H:31]3[C@@H:21]([CH2:22][CH2:23][C:24]5[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:38])[CH:25]=5)[C@@H:20]4[CH2:19][CH2:18]2)[OH:36])=[CH:7][CH:6]=1)(=O)C.C(N(CC)CC)C>CO>[C:42]([CH2:41][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1)[CH2:12][C:13](=[O:40])[O:14][CH2:15][C:16](=[O:39])[C@@H:17]1[C@@:34]23[CH:35]([O:37][C@@H:32]([CH2:33]2)[C@H:31]2[C@@H:21]([CH2:22][CH2:23][C:24]4[C@:29]2([CH3:30])[CH2:28][CH2:27][C:26](=[O:38])[CH:25]=4)[C@@H:20]3[CH2:19][CH2:18]1)[OH:36])([OH:44])=[O:43]
Reactant: CC(=O)Oc1ccc(C(CC(=O)O)CC(=O)OCC(=O)[C@H]2CC[C@H]3[C@@H]4CCC5=CC(=O)CC[C@]5(C)[C@H]4[C@@H]4C[C@]23C(O)O4)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H]2C[C@]3(C(O)O2)[C@@H](C(=O)COC(=O)CC(CC(=O)O)c2ccc(O)cc2)CC[C@@H]13
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A solution of 21-[3-(4-acetyloxyphenyl)-4-carboxy-1-oxobutoxy]-11β,18-epoxy-18-hydroxypregn-4-ene-3,20-dione (130 mg) in anhydrous methanol (15 ml) containing triethylamine (0.2 ml) is allowed to stand at room temperature for 24 hours. The methanol is then evaporated in vacuo, the residue is diluted with water (5.0 ml), acidified with 10% hydrochloric acid and extracted with ethyl acetate (three 5.0 ml portions). The ethyl acetate solution is washed with brine, dried over anhydrous magnesium sulfate, evaporated and the residue is subjected to preparative thin-layer chromatography on silica gel plates (using chloroform-methanol, 9:1 for development) to isolate 83 mg of the title compound, melting point 145°-152° C., with consistent spectral data.
Reaction SMILES: [O:1]=[C:2](C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]([O-])=O.C1(C2C(C=O)=C(C3C=CC(F)=CC=3)C3C(=CC=CC=3)N=2)CC1.CCCCCC.[CH2:55]([O:57][C:58](=[O:60])[CH3:59])[CH3:56]>C(#N)C>[CH2:55]([O:57][C:58](=[O:60])[CH2:59][C:2](=[O:1])[CH:3]=[CH2:4])[CH3:56]
Reactant: CCOC(C)=O
Reactant: O=C([O-])CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Solvent: CCCCCC
Solvent: CC#N
Product: C=CC(=O)CC(=O)OCC
Temperature: 25 °C

Procedure:
The ylide 3-oxo-4-(triphenylphosphoranylidene)butanoate (4.82 g, 12.36 mmol) is solved under argon atmosphere in 100 ml acetonitrile. Under vigorous stirring 2-cyclopropyl-4-(4-fluoro-phenyl)-quinoline-3-carbaldehyde (3 g, 10.3 mmol) is added in 5 portions and then heated to reflux. After 50 h the reaction is cooled to room temperature. The slight brown solvent is evaporated and the residue is dried under vacuum to obtain a brown waxy oil. Chromatography over silica gel with hexane:ethylacetate (4:1/v:v) give a yellow oil of 5-(2-cyclopropyl-4-fluoro-phenyl)-quinolin-3-yl)-3-oxo-pent-4-enoic acid ethyl ester. MS: 403.45
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]2[CH2:18][C@@H:17]3[O:19][C@:16]3([CH3:20])[C@@H:7]2[C@H:8]([O:11][C:12](=[O:15])[NH:13][CH3:14])[O:9][CH:10]=1)=[O:4]>CO.[OH-].[C+4].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][O:9][C@@H:8]([O:11][C:12](=[O:15])[NH:13][CH3:14])[C@H:7]2[C@@:16]3([CH3:20])[O:19][C@H:17]3[CH2:18][C@H:6]12)=[O:4]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: CNC(=O)O[C@@H]1OC[C@H](C(=O)OC)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Reaction time: 12 h
Yield: 74.5 %

Procedure:
500 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c] pyrane-4-carboxylic acid methylester descried in Example 3 were dissolved in methanol followed by the suspension of 50 mg of 20 % palladium-carbon hydroxide catalyst and stirring for 12 hours under hydrogen gas atmosphere at 1 atm. After filtering out the insoluble matter, the filtrate was concentrated. The residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ether eluate in the form of (1S,4R,4aS,6S,7R,7aR)-6,7-epoxy-7-methyl-1-(methylcarbamoyloxy)-1,3,4,4a,5,6,7,7a-octahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (375 mg, yield: 74%), and a colorless powder in the form of (1S,4S,4aS,6S,7R,7aR)-6,7-epoxy-7-methyl-1-(methylcarbamoyloxy)-1,3,4,4a,5,6,7,7a-octahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (68 mg, yield: 14%). The physicochemical properties of the former compound are described in Table 11, Compound No. 55, while those of the latter compound are described in Table 12, Compound No. 56.
Reaction SMILES: [C:1](O)(=O)C.CO.[P].C[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1>I>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([O:19][CH3:1])=[O:18])=[CH:12][CH:11]=1
Reactant: CC(=O)O
Reactant: COc1ccc(C(C)C(=O)O)cc1
Agent: I
Agent: [P]
Solvent: CO
Product: COC(=O)C(C)c1ccc(O)cc1

Procedure:
In a mixture of 12ml of hydroiodic acid, 90ml of acetic acid and 1g of phosphorus 10g of 2-(4-methoxyphenyl)propionic acid was refluxed for 3 hours and the reaction mixture was concentrated. 20ml of methanol and 2ml of sulfuric acid were added to the residue and the mixture was refluxed for one hour. After the methanol was concentrated, the water was added to the residue and extracted with ether. The extract was washed over magnesium sulfate and the ether was distilled off. The residue was distilled under reduced pressure to give the object compound having b.p. 150° - 153° C/6mm Hg in a yield of 6.7g (67%)
Reaction SMILES: [CH2:1]([O:3][C:4](/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]Br)=[CH:10][CH:9]=1)=[O:5])[CH3:2].[N:17]12[CH2:24][CH2:23][CH2:22][N:21]1[CH2:20][CH2:19][CH2:18]2>C(OCC)C>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:17]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1)=[O:5])[CH3:2]
Reactant: C1CN2CCCN2C1
Reactant: CCOC(=O)/C=C/c1ccc(CCBr)cc1
Solvent: CCOCC
Product: CCOC(=O)CCc1ccc(CCN2CCCNCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.2 %

Procedure:
To a solution of 2-[4-[(E)-2-ethoxycarbonylvinyl]phenyl]ethyl bromide (2.10 g) in diethyl ether (20 ml) was added 1,5-diazabicyclo[3,3,0]octane (0.89 g), and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. To a solution of the residue in ethanol (30 ml) was added a 10% palladium on activated carbon (0.44 g), and the mixture was stirred at room temperature for 5 hours under an atmosphere of hydrogen. The catalyst was removed by filtration through a celite column, and the filtrate was concentrated under reduced pressure. The residue was quenched with an aqueous 1N-NaOH solution (20 ml), and the mixture was extracted with methylene chloride (30 ml). The extract was dried over anhydrous MgSO4, and concentrated to dryness under reduced pressure to give 1-[2-[4-(2-ethoxycarbonylethyl)phenyl]ethyl]-1,5-diazacyclooctane (2.46 g) as a colorless oily liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.1 %

Procedure:
A mixture of 4′-hydroxy-3′-methylacetophenone (10.00 g; 66.6 mmol) and K2CO3 (13.80 g; 99.9 mmol) in acetone (100 mL) was stirred, at RT for 40 minutes. Subsequently, benzyl bromide (7.9 mL; 66.6 mmol) was added and the resulting mixture was heated under reflux for 2.5 h. After cooling to RT the mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with 5% aqueous ammonia, water, and brine, dried (MgSO4), filtered and concentrated in vacuo to afford 1-(4-benzyloxy-3-methylphenyl)-ethanone (15.86 g).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[CH3:16][O:17][C:18](=[O:28])[C:19]1[C:24]([Br:25])=[CH:23][C:22]([Br:26])=[CH:21][C:20]=1[NH2:27].CCCCCC>CCOC(C)=O>[CH3:16][O:17][C:18](=[O:28])[C:19]1[C:24]([Br:25])=[CH:23][C:22]([Br:26])=[CH:21][C:20]=1[NH:27][C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:11]
Reactant: CC(C(=O)O)c1ccccc1
Reactant: COC(=O)c1c(N)cc(Br)cc1Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(Br)cc(Br)cc1NC(=O)C(C)c1ccccc1
Yield: 91.9 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-phenyl-propionic acid (2.00 g, 13.3 mmol), SOCl2 (3.47 mL, 40.0 mmol), and 2-amino-4,6-dibromo-benzoic acid methyl ester (2.74 g, 8.88 mmol). After normal workup, the pure objective compound (3.60 g, 92%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=20:1): 1H NMR (200 MHz, CDCl3) δ 1.60 (d, J=7.3 Hz, 3H, CH3), 3.65-3.75 (m, 4H, CO2CH3 & CH) 7.24-7.44 (m, 5H, ArH), 7.48 (d, J=2.0 Hz, 1H, ArH), 8.55 (d, J=2.0 Hz, 1H, ArH), 8.68 (br s, 1H, NH).