Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](I)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:18]([OH:26])(=[S:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C(NC(C)C)(C)C>C1(C)C=CC=CC=1.CCOC(C)=O.[I+].[Cu+]>[C:18](=[O:26])([S:25][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC(=S)c1ccccc1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Agent: [Cu+]
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: [I+]
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: O=C(Sc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Temperature: 25 °C
Yield: 19.6 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-iodo-1H-indazole (103e, 0.224 g, 0.66 mmol), thiobenzoic acid (0.093 ml, 0.79 mmol), 3,4,7,8-tetramethyl-1,10-phenantroline (0.031 g, 0.13 mmol) and N,N-diisopropylamine (0.220 ml, 1.32 mmol) in toluene (2.5 ml) was added copper(I) iodine (2.245 μl, 0.07 mmol). The resulting mixture was stirred at 110 C O/N. The reaction mixture was cooled to r.t. diluted with EtOAc and washed with water. The organic phase was the dried the solvent evaporated and then purified on HPLC. The relevant fractions were collected freezdried to give 45 mg of product (20% yield) which was analysed by LC/MS.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].F[C:9](F)(F)[C:10]([OH:12])=[O:11].Br.[NH2:16][CH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:23]([OH:24])=[C:21]([OH:22])[CH:20]=1.[OH2:27]>>[C:10]([OH:12])(=[O:11])[C:9]([OH:6])=[O:27].[C:1]([OH:6])(=[O:22])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:1]([OH:6])(=[O:11])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:16][CH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:23]([OH:24])=[C:21]([OH:22])[CH:20]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O
Reactant: CC(C)(C)C(=O)Cl
Agent: Br
Agent: NCCc1ccc(O)c(O)c1
Product: CC(C)(C)C(=O)O
Product: O=C(O)C(=O)O
Reaction time: 2 h

Procedure:
To a stirred mixture of 28.1 g of pivaloyl chloride and 150 mL of trifluoroacetic acid, 18.01 g of dopamine hydrobromide were added. The mixture was stirred for 2 hours, then 14 mL of water were added and the mixture was concentrated in vacuo. The residual oil was dissolved in chloroform and washed with cold 10% KHCO3 solution until CO2 evolution ceased. The layers were separated and washed with water and the chloroform layer was dried over MgSO4, filtered and evaporated to dryness. The residue was taken up in 100 mL of ethyl acetate and 7 g of oxalic acid were added together with 100 mL of ethyl acetate. The resultant solution was filtered to remove insoluble materials and 1.6 g oxalic acid in 25 mL of ethyl acetate were added. The mixture was concentrated in vacuo and cooled. The crystals which formed were isolated by filtration, giving 13 g of the title compound. Cooling of the mother liquor afforded a second crop of crystals (5.9 g). The product had the formula: ##STR138##
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@H:64]1[C@@H:67]([CH2:68][N:69]2[C:73]([CH3:74])=[N:72][N:71]=[N:70]2)[NH:66][C:65]1=[O:75]>C(Cl)Cl.CN(C=O)C>[C:25]([O:24][C:22]([NH:21][C:18]1[S:19][CH:20]=[C:16](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:13]([NH:63][C@@H:64]2[C:65](=[O:75])[NH:66][C@@H:67]2[CH2:68][N:69]2[C:73]([CH3:74])=[N:72][N:71]=[N:70]2)=[O:14])[N:17]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nnnn1C[C@H]1NC(=O)[C@H]1N
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnnn1C[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
Prepared in an analogous manner to example 4, step 3 using (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (130 mg, 0.302 mmol), DIPEA (158 μL, 0.906 mmol) and HATU (115 mg, 0.302 mmol) in DCM:DMF (2:1, 3.0 mL) at 0° C. followed by a solution of (3S,4R)-3-amino-4-((5-methyl-1H-tetrazol-1-yl)methyl)azetidin-2-one (55 mg, 0.30 mmol) in DCM:DMF (2:1, 3.0 mL). After stirring at rt for 1 h it was concentrated in vacuo, dissolved in EtOAc, washed with water then brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM), affording the title compound (133 mg, 74%) as a solid. LCMS: Rt=0.92 min, m/z=594.2 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]2[C@@H:7]([CH3:11])[CH2:8][C@H:9](O)[C@@H:4]2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[C:38]2[N:39]=[CH:40][NH:41][C:37]=2[C:36]([F:42])=[CH:35][N:34]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:32][C:33]1[C:38]2[N:39]=[CH:40][N:41]([C@H:9]3[C@H:4]4[C@H:5]([O:6][C:2]([CH3:12])([CH3:1])[O:3]4)[C@@H:7]([CH3:11])[CH2:8]3)[C:37]=2[C:36]([F:42])=[CH:35][N:34]=1.[F:32][C:33]1[C:38]2[N:39]([C@H:9]3[C@H:4]4[C@H:5]([O:6][C:2]([CH3:12])([CH3:1])[O:3]4)[C@@H:7]([CH3:11])[CH2:8]3)[CH:40]=[N:41][C:37]=2[C:36]([F:42])=[CH:35][N:34]=1
Reactant: C[C@H]1C[C@H](O)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: Fc1ncc(F)c2[nH]cnc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](n2cnc3c(F)cnc(F)c32)[C@@H]2OC(C)(C)O[C@@H]21
Product: C[C@H]1C[C@@H](n2cnc3c(F)ncc(F)c32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 0 °C
Reaction time: 14 h

Procedure:
(3aS,4S,6S,6aR)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (6-2) (400 mg, 2.3 mmol, 1 equiv) was dissolved in THF (25 mL). Triphenylphosphine (914 mg, 3.5 mmol, 1.5 equiv) was added followed by 4,7-difluoro-1H-imidazo[4,5-c]pyridine (1-4) (396 mg, 2.6 mmol, 1.1 equiv). The mixture was cooled to 0° C. and DIAD (0.72 mL, 3.7 mmol, 1.6 equiv) was added dropwise. The resulting mixture was stirred at ambient temperature for 14 hours and then heated to 50° C. for an additional 72 hours. The solvent was removed at reduced pressure and the yellow residue was purified via flash chromatography (40 g SiO2, 15-100% EtOAc in hexanes) to yield 4,7-difluoro-1-((3aS,4R,6S,6aR)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-1H-imidazo[4,5-c]pyridine (6-3) and 4,7-difluoro-3-((3aS,4R,6S,6aR)-2,2,6-trimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-3H-imidazo[4,5-c]pyridine (6-4) as a 1:1 regioisomeric mixture. 1H NMR (6-3) (500 MHz, CDCl3): δ 8.02 (s, 1 H); 7.84 (t, J=4.5 Hz, 1H); 4.80-4.91 (m, 2H); 4.41 (q, J=6.5 Hz, 1H); 2.53 (sextuplet, J=6.5 Hz, 1H); 2.29 (septuplet, J=6.0 Hz, 1H); 2.00 (m, 1H); 1.57 (s, 3H); 1.31 (s, 3H); 1.25 (d, J=6.5 Hz, 3H). LRMS m/z (M+H) 309.9 found, 310.1 required. 1H NMR (6-4) (500 MHz, CDCl3): δ 8.10 (s, 1H); 7.81 (t, J=5.0 Hz, 1H); 4.80-4.91 (m, 2H); 4.41 (q, J=6.5 Hz, 1H); 2.53 (sextuplet, J=6.5 Hz, 1H); 2.29 (septuplet, J=6.0 Hz, 1H); 2.00 (m, 1H); 1.57 (s, 3H); 1.31 (s, 3H); 1.25 (d, J=6.5 Hz, 3H). LRMS m/z (M+H) 309.9 found, 310.1 required.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].C(N(CC)CC)C.[NH2:23][C:24]1[CH:56]=[CH:55][C:27]2[NH:28][C:29]([C:34]3[C:35](=[O:54])[N:36]([CH2:46][C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)[C@@H:37]4[C@H:42]([C:43]=3[OH:44])[C@@H:41]3[CH2:45][C@H:38]4[CH2:39][CH2:40]3)=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1>ClCCl>[F:53][C:50]1[CH:49]=[CH:48][C:47]([CH2:46][N:36]2[C:35](=[O:54])[C:34]([C:29]3[NH:28][C:27]4[CH:55]=[CH:56][C:24]([NH:23][S:10]([NH:13][C:14](=[O:15])[O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)(=[O:12])=[O:11])=[CH:25][C:26]=4[S:31](=[O:32])(=[O:33])[N:30]=3)=[C:43]([OH:44])[C@H:42]3[C@@H:37]2[C@H:38]2[CH2:45][C@@H:41]3[CH2:40][CH2:39]2)=[CH:52][CH:51]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Reactant: OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Benzyl alcohol (35 μL, 0.338 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0° C. Chlorosulfonyl isocyanate (29.4 μL, 0.338 mmol) was added and the mixture was stirred at 0° C. for 2.5 h. Triethylamine (47 μL, 0.34 mmol) followed by a solution of (1R,2S,7R,8S)-5-(7-amino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 30, 81.4 mg, 0.169 mmol) in dichloromethane (2 mL) were added at 0° C. and the mixture was stirred at 25° C. for 17 h. The mixture was extracted with water (2×2 mL) and saturated aqueous brine solution (2 mL). The organic layer was concentrated in vacuo and further dried for 16 h under high vacuum to afford the crude product, benzyl [N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-sulfamoyl]carbamate, which was used in the next step without any further purification. LC-MS (ESI) calcd for C32H30FN5O8S2 695.15, found 696.6 [M+H+].
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][C@H:9]([OH:12])[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([Si:5]([CH3:13])([CH3:14])[O:6][CH2:7][CH2:8][C@H:9]([OH:12])[CH2:10][O:11][S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](O)CO
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.4 %

Procedure:
To a solution of (2S)-4-(tert-butyl-dimethyl-silanyloxy)-butane-1,2-diol (23.9 g, 108 mmol; second eluting compound in Preparation C, step C.i) and DMAP (2.65 g, 0.2 eq) in DCM (80 mL) cooled to 0° C. were added TEA (43.8 mL, 2.9 eq.) and a solution of TsCl (20.7 g, 1.1 eq.) in DCM (15 mL). The mixture was stirred at rt for 5 h, poured on sat. aq. NaHCO3 and extracted with DCM. The org. layer was dried over MgSO4 and concentrated. The residue was purified by CC (Hept/EA 2:1) to afford the title intermediate as a colourless oil (31.3 g, 77% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[C:12](Cl)[N:11]=[C:10](Cl)[CH:9]=1.[C:16](=[O:19])([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:7][C:8]1[CH:13]=[C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:11]=[C:10]([N:1]2[CH2:6][CH2:16][O:19][CH2:3][CH2:2]2)[CH:9]=1
Reactant: C1COCCN1
Reactant: O=C([O-])[O-]
Reactant: Clc1cc(Br)cc(Cl)n1
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cc(N2CCOCC2)nc(N2CCOCC2)c1
Temperature: 100 °C

Procedure:
To a solution of Morpholine (5.0 equiv.) and 4-bromo-2,6-dichloropyridine (1.0 equiv.) in DMF (0.275 M) was added cesium carbonate (2.0 equiv.). The mixture was heated at 100° C. for 45 hours. LCMS analysis indicated formation of several products including the desired (M+H=288, Rt=0.87 min). The reaction mixture was then concentrated in vacuo to yield a glassy foam. Water was then added, and the mixture was extracted with ethyl acetate, and the combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was chromatographed via ISCO to provide 4,4′-(4-bromopyridine-2,6-diyl)dimorpholine (44%, 80% purity by LC) as a white crystalline solid. LCMS (m/z) (M+H)=288.0, Rt=0.87 min
Reaction SMILES: [S:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.O=[CH:22][C:23]([OH:25])=[O:24]>C(#N)C>[S:1]1[C:5]([CH:22]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:23]([OH:25])=[O:24])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: O=CC(=O)O
Reactant: Nc1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(O)C(Nc1ccccc1)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of benzo[b]thiophen-2-ylboronic acid (500 mg, 2.81 mmol), aniline (240 μl, 2.81 mmol), and 2-oxoacetic acid hydrate (259 mg, 2.81 mmol) in acetonitrile (20 ml) was stirred at room temperature for three days. The solvent was evaporated to dryness and the crude was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([SH:20])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1.[H-].[Na+].[C:24](Cl)(=[O:26])[CH3:25].C(O)C>O1CCCC1>[Cl:1][C:2]1([C:5]([OH:21])([CH2:14][N:15]2[C:19]([S:20][C:24](=[O:26])[CH3:25])=[N:18][CH:17]=[N:16]2)[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: OC(Cc1ccccc1Cl)(Cn1ncnc1S)C1(Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)Sc1ncnn1CC(O)(Cc1ccccc1Cl)C1(Cl)CC1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
At room temperature, a mixture of 1.72 g (5 mmol) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-mercapto-1,2,4-triazol-1-yl)-propan-2-ol in 20 ml of absolute tetrahydrofuran is admixed with stirring with 0.24 g (6 mmol) of sodium hydride (60% strength in paraffin oil) and stirred for 30 minutes, 0.72 ml (10 mmol) of acetyl chloride are then added and the reaction mixture is stirred at room temperature for a further 4 hours. The reaction mixture is then admixed with 1 ml of ethanol and concentrated under reduced pressure. The residue that remains is extracted repeatedly with dichloromethane. The combined organic phases are concentrated under reduced pressure. In this manner, 1.8 g (94% of theory) of 2-(1-chloro-cyclopropyl)-1-(2-chlorophenyl)-3-(5-acetylmercapto-1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of an oil.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:8])[C:4](=[O:7])[C:5]=1[OH:6].[CH2:9](O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21](S(O)(=O)=O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:9]([O:7][C:4]1[C:5](=[O:6])[C:2](=[O:1])[C:3]=1[O:8][CH2:28][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1c(O)c(O)c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1c(OCc2ccccc2)c(OCc2ccccc2)c1=O
Yield: 566.3 %

Procedure:
3,4-Dihydroxy-3-cyclobutene-1,2-dione (2.0 g, 17 mmol), benzyl alcohol (5.0 mL, 5.2 g, 48 mmol), and p-toluenesulfonic acid monohydrate (170 mg, 0.9 mmol) were slurried in toluene (20 mL), and heated under reflux with a Dean-Stark trap for 3 days. The insoluble material was filtered off, and the filtrate was diluted with ether (100 mL), washed with 2× with saturated aqueous NaHCO3 solution and brine, dried over Na2 SO4, filtered and concentrated to a crude residue. The crude product was purified by chromatography eluting with 4:1 hexane-EtOAc to give the title compound (1.5 g, 29%) as an oil which slowly solidified on standing. MS (FAB+) m/e 312 (M+NH3 +H)+.
Reaction SMILES: O=[C:2]([CH3:6])[CH2:3][CH2:4][OH:5].[CH2:7]([C:9]([CH2:11]C)=O)[CH3:8].[C:13]1([CH:20]=[CH:19][C:17]([OH:18])=[CH:16][CH:15]=1)O.C[O-].[Na+]>CO>[CH3:13][C:3]1[C:4](=[O:5])[CH:7]([CH3:8])[CH2:9][CH2:11][C:2]=1[CH3:6].[CH3:7][CH:13]1[CH2:20][CH2:19][C:17](=[O:18])[CH:16]=[C:15]1[CH2:2][CH3:3]
Reactant: Oc1ccc(O)cc1
Reactant: CCC(=O)CC
Reactant: CC(=O)CCO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(C)C(=O)C(C)CC1
Product: CCC1=CC(=O)CCC1C

Procedure:
A mixture of 88 g of 3-ketobutan-1-ol, 150 g of diethyl ketone and 0.1 g of hydroquinone is dripped in the course of two hours into a mixture of 250 g of diethyl ketone and 10 g of a 30% by weight solution of sodium methylate in methanol which is boiling under reflux. The reaction mixture is then heated under reflux for another two hours. 37 g of water is removed from the reaction mixture by entrainment during the reaction. The whole is processed as described in Example 8. 73 g of 2,3,6-trimethyl-2-cyclohexen-1-one and 10 g of 4-methyl-3-ethyl-2-cyclohexen-1-one are obtained. The total yield of cyclohexenone is 60% with reference to 3-ketobutan-1-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:18]([O-])=[CH:17][C:16]=2[N:15]=[C:14]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:28].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]([NH2:28])[C:16]=2[N:15]=[C:14]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: Cc1nc2c[n+]([O-])c3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
0.124 g (0.335 mmol) of 1-[4-(tert-Butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline-5-oxide was dissolved in 3 ml of methylene chloride. Two ml of concentrated aqueous ammonia (29%) and a solution of 70 mg (0.368 mg) of p-toluenesulfonyl chloride in 1 ml of methylene chloride were added thereto under ice-cooling and the mixture was stirred for 30 minutes, then stirred at room temperature for 3 hours. After brine was added, the reaction mixture was extracted with chloroform and dried (Na2SO4). The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1 to 20:1 (v/v)) to obtain 0.114 g (0.309 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-2-methyl-1H-imidazo[4,5-c]quinoline-4-amine shown below as a pale brown solid. ##STR60## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3460, 3370, 3100, 1710, 1640, 1540, 1380, 1260, 1170, 750.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(O)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:12]([O:18][C:16](=[O:17])[CH2:15][CH2:14][Br:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCBr
Solvent: c1ccccc1
Solvent: O
Solvent: OCc1ccccc1
Product: O=C(CCBr)OCc1ccccc1
Yield: 56 %

Procedure:
A spatula tip full of p-toluenesulfonic acid monohydrate was added to a solution of 3-bromopropionic acid (20.49 g, 0.134 mol) and benzyl alcohol (15 mL, ~15.7 g, 0.145 mol) in benzene (150 mL). A Dean-Stark trap was fitted to the reaction vessel and the solution was held at reflux with overnight stirring. After 16 hr at reflux, the reaction was cooled, washed with saturated sodium bicarbonate, dried (Na2SO4), and concentrated to an oil (28.78 g). Fractional distillation at reduced pressure (0.18 torr) gave the desired product as a colorless liquid (18.49 g, 56%) boiling in the range 99°-109° C.
Reaction SMILES: [I-].[CH3:2][S+](C)C.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([CH3:25])([CH3:24])[C:16](=[O:23])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.O>CS(C)=O.O1CCCC1>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([C:16]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:2][O:23]1)([CH3:25])[CH3:24]
Reactant: C[S+](C)C
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C(=O)Cn1cncn1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Reaction time: 6 h
Yield: 73.6 %

Procedure:
15.7 g (71.2 mmol) of trimethylsulphonium iodide are dissolved in 16 g of dimethyl sulphoxide under an atmosphere of nitrogen. 9.4 g (71.2 mmol) of potassium tert.-butylate are added at room temperature, with cooling. The mixture is allowed to stir for 6 hours and then a solution of 20 g (64.1 mmol) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butanone in 30 ml of tetrahydrofuran is added. The reaction mixture is allowed to stir at room temperature for 15 hours and under reflux for 4 hours, then cooled and poured into water. The mixture is extracted with methylene chloride, and the organic phase is dried over sodium sulphate and evaporated in vacuo. 15.4 g (73.7% of theory) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-ylmethyl)oxirane of refractive index nD20 =1.5539 are obtained. ##STR95##
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29](O)=[O:30])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH2:43][CH:44]1[CH2:46][CH2:45]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCCCCC>CN(C)C=O.C(OCC)(=O)C>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH2:43][CH:44]1[CH2:45][CH2:46]1)[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:30])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.8 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) (350 mg, 0.79 mmol) in dimethylformamide (7.5 mL) were added [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amine (8i) (274 mg, 1.19 mmol) N,N-diisopropylethylamine (0.4 mL), 2.39 mmol) and HATU (364 mg, 0.96 mmol). The reaction mixture was stirred at room temperature for 1 h while silica thin layer chromatography was performed (ethyl acetate:hexane=1:1/UV/SiO2, Rf=0.5). The reaction mixture was diluted with ethyl acetate (60 mL), washed with brine (3×30 mL) and dried and concentrated in vacuo to get a crude mass of 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (329) (600 mg) which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C)[CH:17]=[O:18]>C(N(CC)CC)C>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:6][CH:7]=1)=[C:17]=[O:18]
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C=Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reaction time: 0.5 h

Procedure:
5-(4-Aminophenyl)pyrazin-2(1H)-one (1 g) was dissolved in dimethylformamide (20 ml) and triethylamine (1.0 ml). The dark solution was filtered through diatomaceous earth, and then added dropwise to an ice-cooled solution of N,N'-carbonyldiimidazole (3.0 g) in dimethylformamide (20 ml) over 11/2 hours. The mixture was stirred for a further 30 minutes, to form 5-[4-(isocyanato)phenyl]-2(1H)-pyrazinone.