Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]([F:28])([F:27])[CH:7]([O:14][C:15]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])C.O1CCOCC1.[OH-].[Na+].COS([O-])(=O)=O.[C:43]([C:47]1[CH:52]=[CH:51][C:50]([S+:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:49][CH:48]=1)([CH3:46])([CH3:45])[CH3:44]>C(Cl)Cl.O>[C:17]12([C:15]([O:14][CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:6]([F:27])([F:28])[C:4]([O-:5])=[O:3])=[O:16])[CH2:24][CH:23]3[CH2:25][CH:19]([CH2:20][CH:21]([CH2:22]3)[CH2:26]1)[CH2:18]2.[C:43]([C:47]1[CH:52]=[CH:51][C:50]([S+:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)=[CH:49][CH:48]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CCOC(=O)C(F)(F)C(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Agent: CC(C)(C)c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: COS(=O)(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)C(F)(F)C(=O)[O-])C12CC3CC(CC(C3)C1)C2
Reaction time: 0.5 h
Yield: 47 %

Procedure:
After stirring a mixed solution of 1-adamantane carboxylic acid 2-ethoxycarbonyl-2,2-difluoro-1-phenyl-ethyl ester (6.6 g) prepared in Synthesis Example 1-5, 1-4-dioxane (20 g) and 25% by mass of caustic soda (2.5 g) for 2 hours, water (30 g) was added to the reaction solution and washed with n-hexane to prepare an aqueous solution of sodium 3-(adamantane-1-carbonyloxy)-2,2-difluoro-3-phenyl propionate. An aqueous solution of 4-tert-butyl phenyldiphenylsulfonium methyl sulfate (95 g) and methylene chloride (100 g) were added to the product, stirred for 30 minutes, and then an organic layer was isolated and washed with water, and thereafter was concentrated under reduced pressure. Methylisobutyl ketone was added to the concentrated solution, and concentrated again. Diisopropyl ether was added to the concentrated solution for crystallization, and a solid obtained was dried under reduced pressure to obtain a target compound, or 4-tert-butylphenyldiphenyl sulfonium 3-(adamantane-1-carbonyloxy)-2,2-difluoro-3-phenyl propionate (5.4 g) as a white crystal (yield: 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20]C)=[O:19])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.CO.[OH-].[Li+].Cl>O>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([OH:20])=[O:19])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc3ccc(N)cc3c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc2ccc(C(=O)Nc3cccc(C(=O)O)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 51 mg (0.16 mmol) of compound 111 was added 1 mL of methanol. 1 mL of water, and 800 μL of 1N lithium hydroxide (aqueous). The reaction was allowed to stir for 16 hours at ambient temperature. The pH of the solution was lowered to 3 with 1N HCl (aqueous) and the volatiles removed in vacuo. The resulting solid was suspended in water and collected by vacuum filtration. This provided 16 mg of compound 115.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)[C:9]2[C:10]([CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C)n2)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(C)n2)cc1
Yield: 39.6 %

Procedure:
Using cyclohexyl[1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]methanol (0.68 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.55 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.44 g, 39%) was obtained as a white solid.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:54]=[CH:53][C:18]([CH2:19][O:20][CH2:21][C@H:22]([CH3:52])[C@H:23]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C@@H:24]([CH3:43])[CH2:25][C@@H:26]([CH3:42])[C:27](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:28])=[CH:17][CH:16]=1>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][CH2:21][C@H:22]([CH3:52])[C@H:23]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C@@H:24]([CH3:43])[CH2:25][C@@H:26]([CH3:42])[CH2:27][OH:28])=[CH:53][CH:54]=1
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C[C@@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C[C@@H](C)CO)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
n-BuLi (2.5 M in hexane, 17.6 mL, 44 mmol) was added to a solution of diisopropylamine (6.65 mL, 47.4 mmol) in THF (48 mL) stirred at −78° C. The solution was stirred at −78° C. for 5 min and warmed to 0° C. for 15 min. Borane-ammonia complex (90%, 1.55 g, 45.2 mmol) was added and the resulting mixture was stirred at 0° C. for 15 min, warmed to room temperature for 15 min and then cooled to 0° C. A solution of amide 26 (6.62 g, 11.3 mmol) in THF (35 mL) was added dropwise and the reaction was stirred at 0° C. for 1 h and then at room temperature for 2 h. The mixture was cooled to 0° C. and quenched carefully with saturated aqueous NH4Cl. The mixture was extracted with Et2O and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (step gradient of 4:1 to 7:3 hexane/EtOAc) to afford the alcohol 27 (4.57 g, 96%) as a colorless oil: IR (film) 3410, 1612, 1513, 1249, 1067, 1038 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 4.44 (d, J=11.7 Hz, 1H), 4.39 (d, J=11.7 Hz, 1H), 3.81 (s, 3H), 3.51 (m, 2H), 3.44 (dd, J=5.6, 3.4 Hz, 1H), 3.37 (dd, J=10.6, 6.5 Hz, 1H), 3.22 (dd, J=9.0, 7.0 Hz, 1H), 2.03-1.95 (m, 1H), 1.78-1.62 (m, 2H), 1.53 (br, 1H), 1.41 (ddd, J=13.5, 7.5, 5.8 Hz, 1H), 0.95 (d, J=6.9 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H), 0.88 (s, 9H), 0.87 (d, J=6.9 Hz, 3H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.2, 130.9, 129.4, 113.9, 77.5, 72.8, 67.7, 55.4, 38.3, 38.0, 33.6, 33.2, 26.3, 18.6, 18.0, 15.6, 15.5, −3.5, −3.8; [α]20D−6.3 (c 1.7, CHCl3).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cccn3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1]/[C:2](=[N:13]\[O:14][C:15]([C@H:17]([CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O)/[CH:3]1[CH2:8][CH2:7][N:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][CH2:4]1.N1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[CH:29]1([CH2:28][CH2:27][CH2:26][C@@H:17]([C:15]2[O:14][N:13]=[C:2]([CH:3]3[CH2:8][CH2:7][N:6]([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][CH2:4]3)[N:1]=2)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)C1CCN(S(C)(=O)=O)CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CCN(S(C)(=O)=O)CC2)no1
Yield: 36.2 %

Procedure:
A solution of tert-butyl(3R)-3-{[({(Z)-amino[1-(methylsulfonyl)-4-piperidinyl]methylidene}amino)oxy]carbonyl}-6-cyclohexylhexanoate (preparation 42) (1.50 g, 1.83 mmol) in toluene (100 ml) was treated with pyridine (90 μl, 1.83 mmol) and anhydrous ZnCl2 (150 mg, 1.83 mmol) and heated at reflux for 20 hours. The reaction mixture was diluted with EtOAc and washed with H2O, brine and H2O, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of cyclohexane:EtOAc (90:10) gradually changing to (50:50). The oil was recrystallised from pentane to afford the title compound as a white solid (320 mg, 36%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][S:19][CH2:20][C@@H:21]([OH:25])[C:22]([OH:24])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](OC(N1CCC(CCOC[C@@H](O)C(O)=O)CC1)=O)[C:27]1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][S:19][CH2:20][C@@H:21]([OH:25])[C:22]([O:24][CH2:26][CH3:27])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H](O)COCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)[C@H](O)CSCCC1CCN(C(=O)OCc2ccccc2)CC1
Product: CCOC(=O)[C@H](O)CSCCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
3.7 g of 3-[2-(1-benzyloxycarbonyl-4-piperidyl)ethylthio]-2(S)-hydroxypropionic acid, in place of 3-[2-(1-benzyloxycarbonyl-4-piperidyl)ethoxy]-2(R)-hydroxypropionic acid, is subjected to the same reaction and treatment procedures as in Reference Example 9 to give 2.0 g of oily ethyl 3-[2-(1-benzyloxycarbonyl-4-piperidyl)ethylthio]-2(S)-hydroxypropionate.
Reaction SMILES: [CH2:1]([C:3]1([CH2:9][OH:10])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)[CH3:2].[C:11](Cl)(=[O:15])/[CH:12]=[CH:13]/[CH3:14].[Na+].[Cl-]>C(Cl)(Cl)Cl>[C:11]([O:10][CH2:9][C:3]1([CH2:1][CH3:2])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)(=[O:15])/[CH:12]=[CH:13]/[CH3:14]
Reactant: CCC1(CO)COC(=O)N1
Reactant: C/C=C/C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C/C=C/C(=O)OCC1(CC)COC(=O)N1

Procedure:
3.1 grams (0.021 mole) 4-ethyl-4-hydroxymethyl-2-oxazolidinone, prepared identically to that discussed in example 1, 2.3 grams (0.022 mole) trans-crotonyl chloride, and 25 milliliters chloroform were mixed in a one-necked round-bottom flask. The procedure employed was identical to that discussed in example 1. 4.20 grams (98 % of the yield theoretically expected) of pure product was obtained as a clear oil. The product exhibited the following spectral data: 1H NMR (CDCl3) δ0.90(t, 3H J=1.8 Hz), 1.48-1.67(m, 2H), 1.83(d, 3H J=3.6 Hz), 3.97-4.19(m, 4H), 5.79(d, 1H J=3.6 Hz), 6.90-6.99(m, 2H); 13C NMR (CDCl3) δ7.3, 18.1, 28.3, 60.2, 66.7, 70.9, 121.7, 146.3, 159.6, 166.0; IR (NaCl) 3229, 3020, 2960, 1780 cm-1 ; MS m/z 213. This monomer can be chlorinated or brominated by the same procedure as in example 1.
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1)#[CH:2].[CH2:10]([O:12][C:13]([C:15]1[S:19][C:18](Br)=[C:17]([CH3:21])[CH:16]=1)=[O:14])[CH3:11].C(OC(C1SC(C#C[C@H]2COC(C)(C)O2)=CC=1)=O)C>>[CH2:10]([O:12][C:13]([C:15]1[S:19][C:18]([C:2]#[C:1][C@H:3]2[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]2)=[C:17]([CH3:21])[CH:16]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cc(C)c(Br)s1
Reactant: C#C[C@H]1COC(C)(C)O1
Agent: CCOC(=O)c1ccc(C#C[C@H]2COC(C)(C)O2)s1
Product: CCOC(=O)c1cc(C)c(C#C[C@H]2COC(C)(C)O2)s1
Yield: 67 %

Procedure:
Starting with 4(S)-Ethynyl-2,2-dimethyl-[1,3]dioxolane and 2-Bromo-3-methyl-thiophene-5-carboxylic acid ethyl ester, prepared according to M. Nemec, Collection Czechoslov. Chem. Commun., compound (31) was prepared in 67% yield according to the general procedure described for compound (1).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=O)[O:33]C(C)(C)C)[CH2:27][CH2:26]2)=[O:24])[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].Cl.O1[CH2:47][CH2:46]OCC1>C1COCC1>[C:32]([NH:31][CH:28]1[CH2:29][CH2:30][N:25]([C:23]([NH:22][CH2:21][CH2:20][C:7]2([C:5]([NH:4][CH2:3][C:2]([F:40])([F:39])[F:1])=[O:6])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[O:24])[CH2:26][CH2:27]1)(=[O:33])[C:47]1[CH:46]=[CH:9][CH:8]=[CH:7][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)NCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1
Reactant: C1COCCO1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NC1CCN(C(=O)NCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Example 487 compound (1.1 g, 1.97 mmol) in THF (4 mL) was added 4N HCl in dioxane (9 mL, 36.4 mmol). The reaction mixture was stirred at room temperature for 3 h and concentrated in vacuo and then from dioxane (3×10 mL) to give crude title compound (1.46 g) as a white foamy solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[N:30]1([C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][C:2]1[C:3]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:39][C:38]3[CH:37]=[N:36][C:35]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:42][CH:41]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: O=Cc1ccc(N2CCCC2)nc1
Reactant: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)N1CCN(Cc2ccc(N3CCCC3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a mixture of 11.9 mg of 7-methyl-8-(piperazin-1-ylcarbonyl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one, 15.9 mg of 6-(1-pyrrolidinyl)nicotinaldehyde, 0.3 mL of 1,2-dichloroethane, and 30 μL of acetic acid was added 19.1 mg of sodium triacetoxyborohydride, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution) to obtain 9.7 mg of 7-methyl-8-[(4-{[6-(pyrrolidin-1-yl)pyridin-3-yl]methyl}piperazin-1-yl)carbonyl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])=O.[NH4+]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(OC3CCCCC3)ccc2c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1ncc2cc(OC3CCCCC3)ccc2c1O
Yield: 72.3 %

Procedure:
To a mixture of 1-bromo-7-cyclohexyloxy-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (936 mg) in ethyl acetate (25 ml) was added 10% Pd/C (50% wet) (430 mg) and then ammonium formate (1.4 g). Resulting mixture was refluxed for 4 h. After cooling, reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography (3%-10% ethyl acetate in methylene chloride) to give the title compound (550 mg). MS-(+)-ion M+1=344.22.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][CH2:14][CH2:15][CH2:16][CH3:17].[Li+].[OH-]>C1COCC1.CO>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:18])=[O:2])=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=1
Reactant: CCCCNc1cc(F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCNc1cc(F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid methyl ester (145 mg, 0.58 mmol) in THF (4 mL) and MeOH (2 mL) was added 1 N LiOH (4 mL). The mixture was stirred for 2 hours at room temperature, concentrated under reduced pressure, and then acidified with 3 N HCl. The mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid (120 mg, 88%) after purification by crystallization form EtOAc and hexane. To a mixture of 3-(4-fluoro-2-butylamino-phenyl)-acrylic acid (52 mg, 0.22 mmol), (R)-[1-(3,5-difluoro-4-methanesulfonylaminophenyl)ethylamine hydrochloride (64 mg, 0.22 mmol) and N-methylmorpholine (36 μL, 0.33 mmol) in THF (5 mL) was added 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholirium chloride hydrate (DMTMM, 68 mg, 0.25 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, washed with 2 N HCl and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (4.5 mg, 4%) after trituration with ethyl ether. 2:1).
Reaction SMILES: O1CCC1.[CH:5]1([C:11]2([CH2:15][OH:16])[CH2:14][O:13][CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Br[CH:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)[CH2:19]Br>>[CH:5]1([C:11]23[CH2:12][O:13][C:25]([C:24]4[CH:28]=[CH:29][C:21]([C:18]#[CH:19])=[CH:22][CH:23]=4)([O:16][CH2:15]2)[O:26][CH2:14]3)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: OCC1(C2CCCCC2)COC1
Reactant: O=C(Cl)c1ccc(C(Br)CBr)cc1
Agent: C1COC1
Product: C#Cc1ccc(C23OCC(C4CCCCC4)(CO2)CO3)cc1

Procedure:
Utilizing Procedure 2, 4-cyclohexyl-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared from its respective oxetane. The 3-cyclohexyl-3-hydroxymethyloxetane was reacted with 4-(1,2-dibromoethyl)benzoyl chloride by the method of Procedure 2. The resulting product was characterized by NMR (300 MHz, CDCl3): δ 1.0-1.4 and 1.6-2.0 (11H, m, cyclohexyl CH2), 3.9-4.1 (2H, m, CH2Br), 4.4 (2H, s, CH2O), 4.55 (4H, d of d, CH2OCH2), 5.1 (1H, d of d, ArCHBr), 7.45 (2H, d, aromatic), 8.1 (2H, d, aromatic).
Reaction SMILES: ClC1C=C[C:5]([CH:8]2[CH2:13][CH:12](CN3C=NC=N3)[O:11][C:9]2=[O:10])=CC=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.C(OCC)(=O)C=C.[C-]#N.[Na+]>CN(C)C=O>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]([CH2:5][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:26])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1OC(Cn2cncn2)CC1c1ccc(Cl)cc1
Agent: C=CC(=O)OCC
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(=O)c1ccc(Cl)cc1
Yield: 83 %

Procedure:
This Example illustrates the preparation of -(4-chlorophenyl)-γ-(1,2,4-triazol-1-yl)methyl-γ-butyrolactone (A). ##STR45## Ethyl 3-(4-chlorobenzoyl)propanoate (25.0 g, 83%) was prepared from 4-chlorobenzaldehyde (23.4 g), ethyl acrylate (12.5 g) and sodium cyanide (4.0 g) in dimethylformamide (DMF: 300 ml) by the method described for the preparation of the corresponding methyl ester in Example 1.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23](Br)[N:22]=[N:21]4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.[CH2:29]([OH:32])[C:30]#[CH:31]>CN1CCCC1=O.C(N(CC)CC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu](I)I>[O:1]=[S:2]1(=[O:28])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[C:23]([C:31]#[C:30][CH2:29][OH:32])[N:22]=[N:21]4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1
Reactant: O=C1O[C@@H](Cn2cc(Br)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Reactant: C#CCO
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1O[C@@H](Cn2cc(C#CCO)nn2)CN1c1ccc(C2=CCS(=O)(=O)CC2)c(F)c1
Temperature: 90 °C
Yield: 12.1 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-[4-bromo-1,2,3-triazol-1-ylmethyl]oxazolidin-2-one (Example 36) (235 mg, 0.5 mmol), propargyl alcohol (42 mg, 0.75 mmol), tetrakis(triphenylphosphine)palladium (0) (29 mg, 5 mol %) and copper iodide (5 mg, 5 mol %) were mixed in N-methylpyrrolidone/triethylamine (5 ml, 5:1). The reaction mixture was flushed with nitrogen and heated to 90° C. for 48 hours. The reaction mixture was filtered and extracted with ethyl acetate/water, the organic phase was concentrated and purified by flash chromatography on silica gel with 5% of methanol in dichloromethane to give the title product (27 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[CH:34]=1)=[O:32])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-4-cyano-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J32) (318 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (400 mg, 73%).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:19])/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3]/[C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1]/[C:2](/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:19])/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:3]/[CH2:4][OH:5]
Reactant: CCOC(=O)/C=C(/C)CC/C=C(\C)CCC=C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C\CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1 g (0.0038 mol) of ethyl (2Z,6E)-3,7,11-trimethyl-2,6,10-dodecatrienoate in 8 ml of toluene is treated dropwise at -5° to -10° with 9.45 ml of a solution of diisobutylaluminium hydride in toluene (1.2 mol/l). The solution is stirred at the same temperature for 1 hour under argon. The reaction mixture is poured into an ice-water mixture and extracted with ether. After drying and removing the solvent the residue is chromatographed on silica gel with ether-hexane 1:1. There is obtained (2Z,6E)-3,7,11-trimethyl-2,6,10-dodecatrien-1-ol which has the following bands in the IR spectrum; 3326 cm-1, 1669 cm-1, 1446 cm-1, 1378 cm-1, 1000 cm-1.