Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:27](=[O:29])C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[Na+].BrBr>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:11][C:10]=1[C:27]([OH:29])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 78.8 %

Procedure:
1-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-ethanone [prepared as per WO 2004/072051] (2.02 g, 5.2 mmol) was dissolved in 1,4-dioxane (30 ml), a solution of sodium hydroxide (2.08 g, 52.0 mmol) in water (30 ml) was added and the mixture was stirred and treated dropwise with bromine (0.8 ml, 15.6 mmol). The resulting mixture was stirred at room temperature for 16 hours. The 1,4-dioxane was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 30% ethyl acetate in petroleum ether afforded 2,4-bis-benzyloxy-5-tert-butyl-benzoic acid (1.6 g, 79%) as a pale yellow oil. 1H NMR (DMSO-d6) 12.18 (1H, br s), 7.69 (1H, s), 7.52 (4H, t), 7.45-7.33 (6H, m), 6.93 (1H, s), 5.24 (2H, s), 5.23 (2H, s), 1.32 (9H, s). MS: [M+H]+ 391.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[Cl:12][CH2:13][CH2:14]Cl.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:12][CH2:13][CH2:14][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1
Reactant: ClCCCl
Reactant: Fc1ccc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(c1)c(I)nn2CCCl
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of 5-fluoro-3-iodo-indazole (3.0 g, 11.5 mmol) and 1,2-dichloroethane (5.7 g, 57.3 mmol) in ACN (50 mL) was added K2CO3 (3.2 g, 22.9 mmol) at rt. The reaction was stirred overnight at reflux. The reaction mixture was filtered and concentrated in vacuo. Purification by silica gel chromatography (30:1:5 hexanes/EtOAc/DCM) gave 2.5 g (67%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3): δ 3.97 (2H, t, J=6.0 Hz), 4.69 (2H, t, J=6.0 Hz), 7.13 (1H, dd, J=1.8, 7.8 Hz), 7.22-7.29 (1H, m), 7.42 (1H, dd, J=3.9, 9.3 Hz).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C>[Zn].O>[NH:10]([CH:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(NC2CCNCC2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
In a three neck round bottom flask equipped with mechanical stirrer and water condenser, 15.36 gm (0.10 moles) of 4-piperidone hydrochloride monohydrate and 20.95 gm (0.255 moles) of aniline was added. To this mixture, 26.14 gm (0.40 moles) of zinc and 120 gm (2.00 moles) of 90% acetic acid were added. The reaction mixture was stirred at room temperature for 12 hrs and at 50 to 70° C. for 12 hrs. Water was then added to the reaction mixture and filtered. Crushed ice was added to the filtrate and was neutralized with excess of aqueous sodium hydroxide solution. The crude 4-anilinopiperidine was obtained by filtration.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH:16]([CH3:20])[C:17]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18]
Reactant: CC(Cl)C(=O)Cl
Reactant: OCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Cl)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 90.4 %

Procedure:
Benzyl alcohol (242 mL, 253 g, 2.34 mol) and pyridine (204 mL, 204 g, 2.57 mol) were dissolved in methylene chloride (2.5 L) and cooled to 0° C. 2-Chloropropanoyl chloride (250 mL, 327 g, 2.57 mol) was added dropwise keeping the temperature between 0° C. and 5° C. After addition the mixture was allowed to warm to RT overnight. The mixture was washed with 20% aqueous citric acid (2.5 L), saturated aqueous NaHCO3 (2.5 L), brine (2.5 L), dried (MgSO4), filtered and concentrated in vacuo. The resulting brown liquid (450 g) was dissolved in a small amount of methylene chloride and filtered through a short path of silica gel. After concentration, the crude was purified via bulb-to-bulb distillation (2*10-2 mbar, 90-95° C.) affording the title compound as a pale yellow liquid (420 g, 90%). 1H-NMR: (CDCl3, 300 MHz): δ ppm 1.75 (d, 3H, CH3), 4.45 (q, 1H, CHCl), 5.25 (s, 2H, CH2Ar), 7.40 (m, 5H, ArH).
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[I:18])[C:9]2[C:8](=[O:19])[N:7]([CH3:20])[C:6](=[O:21])[N:5]([CH3:22])[C:4]=2[N:3]=1.[C:23]([O:27][C:28]([NH:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>CC(O)C>[C:23]([O:27][C:28](=[O:29])[NH:30][CH:31]1[CH2:35][CH2:34][N:33]([C:2]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[I:18])[C:9]3[C:8](=[O:19])[N:7]([CH3:20])[C:6](=[O:21])[N:5]([CH3:22])[C:4]=3[N:3]=2)[CH2:32]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2I)n(C)c1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(nc(N3CCC(NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2I)n(C)c1=O
Reaction time: 3 h

Procedure:
8-Chloro-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (5A) (100 mg, 0.23 mmol) and (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (216 mg, 1.16 mmol), and triethylamine (0.32 ml, 2.32 mmol) were dissolved in 20 ml of 2-propanol and the mixture was subjected to microwaves (method F, 130° C., 300 W) for three hours. The solvents were evaporated and the crude product was purified by preparative HPLC (method A1, Rt=12.99 min.). Evaporation of the solvent afforded compound (7A) as white crystals.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.CCOC(C)=O>C(Cl)Cl>[Br:20][C:13]1[CH:12]=[C:11]([C:8]([CH3:10])([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:18])[CH3:19])[CH:16]=[CH:15][C:14]=1[NH2:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 4-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-phenylamine (as prepared in the previous step, 1.41 g, 5.04 mmol) in 25 mL of DCM at 0° C. was slowly added N-bromosuccinimide (NBS) (898 mg, 5.04 mmol) in three portions over five minutes. After stirring at RT for 2 h, the mixture was treated with 50 mL of EtOAc and washed with H2O (2×30 mL) and brine H2O (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (DCM) to give 1.59 g (88%) of the title compound as a light yellow oil. Mass spectrum (ESI, m/z): Calcd. for C16H28BrNOSi, 358.1 (M+H). found 358.4.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[CH2:15]([C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=O)[CH3:16].C(O)C>C(O)(=O)C.O>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17](=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[CH2:15][CH3:16])[CH:20]=1
Reactant: CCC(=O)c1cccnc1
Reactant: NNC(=O)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCC(=NNC(=O)c1cccc(C(F)(F)F)c1)c1cccnc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A mixture of 10.21 gm (0.05 mole) of 3-trifluoromethylbenzoic acid hydrazide, 6.76 gm (0.05 mole) of ethyl-3-pyridyl ketone, 10 drops of glacial acetic acid and 100 ml of absolute ethanol was refluxed 15 hr. The reaction mixture was diluted with water to the cloud point and cooled at room temperature than chilled in the refrigerator. The solids that separated were collected, washed with Skellysolve B and dried to give 11.88 gm (74%) of product having a melting point of 119.4° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:17][C:16](=[O:18])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1ccccc1)C(=O)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
Sodium hydride (82 mg, 60% dispersion in mineral oil, weight percent) was suspended under a nitrogen atmosphere in DMF (5 mL). Compound A3 (0.5 g, 1.95 mmol) was added thereto and the reaction mixture was stirred for 10 min at RT. Benzyl bromide (235 μL, 1.97 mmol) was added thereto. The reaction mixture was stirred for 18 h at RT, combined with water and extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was dissolved in a mixture of ether and heptane. After removal of the ether, the desired product 3-benzyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A4) (0.54 g, 80% of theoretical) was obtained as a white solid by filtration.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31][C:32]1[N:37]=[C:36](Cl)[C:35]([Cl:39])=[CH:34][N:33]=1.[Cl:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[Cl:47].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOCC.CCO>[Cl:31][C:32]1[N:37]=[C:36]([C:44]2[CH:43]=[CH:42][C:41]([Cl:40])=[C:46]([Cl:47])[CH:45]=2)[C:35]([Cl:39])=[CH:34][N:33]=1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: Cc1ccccc1
Product: Clc1ncc(Cl)c(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 0.19 g (0.5 mmol) of bis(benzo-nitril) dichloro-palladium (II) and 0.2 g 1,4-bis(di-phenylphosphino)butane in 10 mL of toluene was heated at reflux with stirring for 1 h under nitrogen. The suspension was cooled to room temperature. One gram (6.6 mmol) of 3A, 1.57 g of 3,4-dichlorobenzene boronic acid (8.2 mmol), 2.5 mL EtOH and 5 mL of 1 M Na2CO3 were added and the mixture heated to reflux for 20 h. The reaction mixture was cooled and diluted with 100 mL Et2O. The suspension was filtered through a plug of silica gel and the cake washed with an additional 100 mL of Et2O. The ether was evaporated and the residue chromatographed over silica gel (10% EtOAc/hexane). A fraction containing 0.72 g (32%) of 2,5-dichloro-4-(3,4-dichlorophenyl)pyrimidine was isolated as a white solid. (m.p. 125-126° C.)
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:10][S:11]SC.O>O1CCCC1.C([Li])CCC>[CH3:10][S:11][C:3]1[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[CH:1][N:2]=1
Reactant: c1ccn2cncc2c1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc2ccccn12
Yield: 104.6 %

Procedure:
To a solution of 1.63 g of imidazo[1,5-a]pyridine in 20 ml of tetrahydrofuran, 11 ml of n-butyl lithium (1.6N-hexane solution) is added below 70° C. during 15 minutes under nitrogen gas atmosphere. After stirring the mixture for an hour at the same temperature, a solution of 1.7 g of dimethyldisulfide in 10 ml of tetrahydrofuran is dropwise added during 30 minutes and continued to stir for 30 minutes. The mixture added with water is extracted with ether. The extract is dried over anhydrous magnesium sulfate and distilled to remove ether. The residue is purified by silica gel chromatography (eluent: chlooform-ethylacetate) to give 2.37 g of the oily title compound.
Reaction SMILES: NC(C(O)=O)CCC[C:6]([NH:8][C:9]1([NH:29][CH:30]=[O:31])[C:27](=[O:28])[N:11]2[C:12]([C:24]([OH:26])=[O:25])=[C:13]([CH2:16][S:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][S:15][C@H:10]12)=[O:7].OO.[N-]=[N+]=[N-].[Na+].P([O-])([O-])([O-])=O>>[C:24]([CH2:12][CH2:13][CH2:14][C:6]([NH:8][C:9]1([NH:29][CH:30]=[O:31])[C:27](=[O:28])[N:11]2[C:12]([C:24]([OH:26])=[O:25])=[C:13]([CH2:16][S:17][C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[CH2:14][S:15][C@H:10]12)=[O:7])([OH:26])=[O:25]
Reactant: NC(CCCC(=O)NC1(NC=O)C(=O)N2C(C(=O)O)=C(CSc3ccncc3)CS[C@@H]21)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: OO
Agent: [N-]=[N+]=[N-]
Product: O=CNC1(NC(=O)CCCC(=O)O)C(=O)N2C(C(=O)O)=C(CSc3ccncc3)CS[C@@H]21

Procedure:
7-(5-Amino-5-carboxyvaleramido)-7-formylamino-3-(pyridin-4-yl)thiomethyl-3-cephem-4-carboxylic acid obtained in Example 2 was diluted to make a solution showing the inhibition zone diameter of 20 mm against Proteus sp. SS-12 by the paper disc method. The solution was adjusted to pH of 7.5. To 30 μl of the solution were added 12 μl of a 1% aqueous hydrogen peroxide solution, 12 μl of a 1% sodium azide aqueous solution and 18 μl of a solution obtained by diluting D-amino acid oxidase derived from Trigonopsis variabilis (IFO 0755, IFO 0671, cf. U.S. Pat. No. 4,242,449) with a 0.02M phosphate buffer solution (pH 7.0) in 40,000 units/ml. The thus obtained solution was reacted at 37° C. for 1 hour to give 7-(4-carboxybutyramido)-7-formylamino-3-(pyridin-4-yl)thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: O1CCCC1.COC(C)(C)C.[CH:12]1([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]3[C:29]([O:83][CH:84]([O:86][CH2:87][CH3:88])[CH3:85])([CH3:82])[CH2:30][CH2:31][CH:32]([O:74][Si](CC)(CC)CC)[CH2:33][C:34]([O:36][CH:37](/[C:42](/[CH3:73])=[CH:43]/[CH:44]=[CH:45]/[C:46]([CH3:72])([O:64][Si](CC)(CC)CC)[CH2:47][CH:48]4[O:63][CH:49]4[CH:50]([CH3:62])[CH:51]([O:54][Si](CC)(CC)CC)[CH2:52][CH3:53])[CH:38]([CH3:41])[CH:39]=[CH:40]3)=[O:35])=[O:26])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH:12]1([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH:28]3[C:29]([O:83][CH:84]([O:86][CH2:87][CH3:88])[CH3:85])([CH3:82])[CH2:30][CH2:31][CH:32]([OH:74])[CH2:33][C:34]([O:36][CH:37](/[C:42](/[CH3:73])=[CH:43]/[CH:44]=[CH:45]/[C:46]([OH:64])([CH3:72])[CH2:47][CH:48]4[O:63][CH:49]4[CH:50]([CH3:62])[CH:51]([OH:54])[CH2:52][CH3:53])[CH:38]([CH3:41])[CH:39]=[CH:40]3)=[O:35])=[O:26])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)O[Si](CC)(CC)CC)O[Si](CC)(CC)CC)C(C)C=CC1OC(=O)N1CCN(C2CCCCCC2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOC(C)OC1(C)CCC(O)CC(=O)OC(/C(C)=C/C=C/C(C)(O)CC2OC2C(C)C(O)CC)C(C)/C=C/C1OC(=O)N1CCN(C2CCCCCC2)CC1
Agent: CCOC(C)OC1(C)CCC(O[Si](CC)(CC)CC)CC(=O)OC(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)O[Si](CC)(CC)CC)O[Si](CC)(CC)CC)C(C)/C=C/C1OC(=O)N1CCN(C2CCCCCC2)CC1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(C)OC1(C)CCC(O)CC(=O)OC(/C(C)=C/C=C/C(C)(O)CC2OC2C(C)C(O)CC)C(C)C=CC1OC(=O)N1CCN(C2CCCCCC2)CC1
Reaction time: 22 h

Procedure:
Under a nitrogen atmosphere and warming to hold the outside temperature at 25° C., tetrahydrofuran (145 mL) was added to a t-butyl methyl ether solution of the (8E,12E,14E)-7-{(4-cycloheptylpiperazin-1-yl)carbonyl}oxy-6-(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-3,16,21-tris(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide obtained in Example 4, following which 93.8 mL (93.8 mmol) of a 1.0 M tetrahydrofuran solution of tetrabutylammonium fluoride was added dropwise over a period of 3 minutes. The reaction mixture was then stirred for 22 hours while being held at room temperature (25° C.). Water (145 mL) was added to this reaction mixture and the organic phase was separated, then washed with water (145 mL), yielding a t-butyl methyl ether/tetrahydrofuran solution of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([O:21]C1CCCCO1)/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1>C(O)(=O)C.O.C1COCC1>[CH3:1][CH:2]([CH2:28][C:29]#[C:30][CH3:31])[C@H:3]([OH:21])/[CH:4]=[CH:5]/[C@@H:6]1[C@@H:10]([CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:9](=[O:20])[CH2:8][CH2:7]1
Reactant: CC#CCC(C)[C@@H](/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC#CCC(C)[C@H](O)/C=C/[C@H]1CCC(=O)[C@@H]1C/C=C\CCCC(=O)O

Procedure:
410 mg. of (5Z,13E)-(15S,16RS)-16-methyl-9-oxo-15-(tetrahydropyran-2-yloxy)-5,13-prostadien-18-ynoic acid is agitated at 23° for 16 hours with 11 ml. of a mixture of glacial acetic acid/water/THF (65/35/10); the mixture is evaporated under vacuum, and the residue is purified by column chromatography on silica gel. With methylene chloride/5% methanol, 290 mg. of the title compound is obtained as a colorless oil.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC1C=C[C:7]([O:10]P(OCC)(OCC)=O)=[CH:6]C=1.[NH2:29][C@H:30]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:69]([NH2:71])=[O:70])[CH:66]([CH3:68])[CH3:67])=[O:63])[CH2:58][C:59](=[O:61])[NH2:60])=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:48])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=1.CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C>CN(C=O)C>[NH:29]([C:7]([CH3:6])=[O:10])[C@H:30]([C:47]([NH:49][C@H:50]([C:54]([NH:56][C@H:57]([C:62]([NH:64][C@H:65]([C:69]([NH2:71])=[O:70])[CH:66]([CH3:68])[CH3:67])=[O:63])[CH2:58][C:59](=[O:61])[NH2:60])=[O:55])[CH:51]([CH3:52])[CH3:53])=[O:48])[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][P:39]([O:44][CH2:45][CH3:46])([O:41][CH2:42][CH3:43])=[O:40])=[CH:36][CH:37]=1
Reactant: CCOP(=O)(OCC)Oc1ccc(C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(N)=O)C(C)C)C(C)C)cc1
Reactant: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(C)=O)C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(N)=O)C(C)C)C(C)C)cc1

Procedure:
The title compound was obtained by analogous manner as described in Example 18, but using BocTyr(PO3Et2)OH. The N-acetylation was performed by treatment of crude H—Tyr(PO3Et2)—Val—Asn—Val—NH2 with 1.5 equiv. of DIEA and 5 equiv. of acetic anhydride in DMF for 2 h at 25° C. The final compound was obtained with chromatographic purity (HPLC) of 90.0%. Amino acid ratios: Val 2 (2); Asx 1.17 (1); Tyr 0.87 (1). Peptide content: 83%. FAB mass spectroscopy; m/z 671 [M—H]+. (MW 670.1)
Reaction SMILES: [CH2:1]([O-:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li+].C(O)CCCCCCC.C([Li])CCC.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[N:27]=1.[Cl-].[Na+]>O1CCCC1.CCOCC>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:27]=1
Reactant: Fc1cccc(F)n1
Reactant: CCCCCCCC[O-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCCCCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCOc1cccc(F)n1

Procedure:
Lithium octanolate (previously prepared from 13.02 g (100.00 mmol) of 1-octanol and 69 ml (110.00 mmol) of a 1.6-molar n-butyllithium solution in 40 ml of tetrahydrofuran at 0° C.) and 11.51 g (100.00 mmol) of 2,6-difluoropyridine are refluxed in 40 ml of tetrahydrofuran for 7 hours. The mixture is then distributed between sodium chloride solution and ether, the ether phase is washed twice with sodium chloride, dried over sodium sulfate, filtered and freed from solvent. Purification of the residue by chromatography (silica gel, 9:1 hexane/ethyl acetate) gives 13.48 g (59.80 mmol) of 2-fluoro-6-octyloxypyridine. ##STR21##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([C:16]4[CH:15]=[N:14][C:10]5[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]6[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=6[C:28]([F:31])([F:30])[F:29])[C:9]=5[CH:17]=4)[CH:19]=3)=[O:22])[CH2:41][CH2:40]2)=[CH:37][CH:38]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.95 (M+H+); retention time=1.05 minutes.
Reaction SMILES: [CH:1]1([O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:20]1([N:26]2[C:30]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:20]1([N:26]2[C:30]3([CH2:31][CH2:32][N:33]([CH2:16][C:15]4[CH:18]=[CH:19][C:12]([O:11][CH:1]5[C:10]6[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=6)[CH2:4][CH2:3][CH2:2]5)=[CH:13][CH:14]=4)[CH2:34][CH2:35]3)[C:29](=[O:36])[NH:28][CH2:27]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(OC2CCCc3ccccc32)cc1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1ccc(OC3CCCc4ccccc43)cc1)CC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 4-(1,2,3,4-tetrahydro-1-naphthyloxy)benzaldehyde (264 mg, 1.05 mmol) and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (232 mg, 1.00 mmol) in 1,2-dichloroethane (15 mL) was added sodium triacetoxyborohydride (369 mg, 1.74 mmol). The resultant reaction mixture was stirred at room temperature under argon atmosphere for 20 h. The reaction mixture was quenched with 1 N aqueous NaHCO3 and extracted with CHCl3 (2×50 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (4% MeOH in CHCl3) to yield the title product as an off-white solid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]4[C:21]5[NH:22][CH:23]=[CH:24][C:20]=5[C:19]([O:25][CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[N:18][C:17]=34)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32](O)(=[O:36])[C@@H:33]([CH3:35])[OH:34].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[OH:34][C@H:33]([CH3:35])[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([O:25][C:19]2[C:20]3[CH:24]=[CH:23][NH:22][C:21]=3[N:16]3[N:15]=[CH:14][C:13]([C:10]4[CH:11]=[N:12][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)=[C:17]3[N:18]=2)[CH2:27][CH2:28]1)=[O:36]
Reactant: C[C@@H](O)C(=O)O
Reactant: c1ccc(-c2ccc(-c3cnn4c3nc(OC3CCNCC3)c3cc[nH]c34)cn2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)C(=O)N1CCC(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yloxy)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (Int-11e, 95.8 mg, 0.23 mmoL), D-(−)-lactic acid (25 mg, 0.28 mmoL), EDC (89 mg, 0.47 mmoL), HOBt (63 mg, 0.47 mmoL) and DIEA (244 uL, 1.46 mmoL) in DMF (4 mL) were stirred at room temperature for 2 hr. Purification with prep-LC provided (R)-2-hydroxy-1-(4-(3-(6-phenylpyridin-3-yl)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidin-5-yloxy)piperidin-1-yl)propan-1-one (35): LCMS tR=3.48 Min (10 min run, UV254nm). Mass calculated for, M+482.2, observed m/z 483.2 (M+H).