Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([Cl:9])=[CH:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[CH3:11][O-:12].[Na+]>C1COCC1>[Cl:9][C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[C:6]([O:12][CH3:11])[CH:7]=1
Reactant: C[O-]
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cnc(C#N)c(Cl)c1
Reaction time: 3 h

Procedure:
The product from Example 27A (0.865 g, 5.0 mmol) was dissolved in THF (10 mL) and 0.27 g NaOMe was added. After 3 h and 25° C., the reaction was quenched in 5% aq. NaHCO3 solution and extracted with diethyl ether. The organic phase was dried, evaporated, and the residue purified by column chromatography, eluting with 70:30 hexanes:ethyl acetate to yield 0.27 g (32%, second eluting component) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.95 (s, 3H), 7.29 (d, 1H), 8.28 (d, 1H).
Reaction SMILES: [CH2:1]([CH:5]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH:3]=[CH2:4].[OH-].[K+].CO.S(Cl)([Cl:29])=O>>[CH2:1]([CH:5]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([Cl:29])=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: O=S(Cl)Cl
Reactant: C=CCCC(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCCC(Oc1ccc(C(=O)Cl)cc1)C1CCCCC1

Procedure:
65 g (0.2 mol) of the above tosyl ester were added to a solution of 36.5 g (0.24 mol) of potassium tert-butoxide dissolved in tert-butanol, and the mixture was warmed to reflux with stirring and stirred under reflux for 8.5 hours. After cooling, the mixture was hydrolyzed and extracted with methyl tert-butyl ether, and the organic phase was washed (twice with water), dried and evaporated. The residue was again partitioned between 2 N NaOH and methyl tert-butyl ether, and the purification procedure was repeated, giving 37 g (60%) of methyl 4-(but-3-enylcyclohexylmethoxy)benzoate. This ester was hydrolyzed in a conventional manner using KOH/methanol to give the free acid, which was reacted with thionyl chloride to give 4-(but-3-enylcyclohexylmethoxy)benzoyl chloride. 18 g (0.06 mol) of this acid chloride and 10.0 g (0.063 mol) of commercial 1,4-butanediol monomethacrylate (Polysciences, D-69208 Eppelheim) were dissolved in 15 ml of toluene, and a solution of 6.1 g (0.067 mol) of triethylamine dissolved in 40 ml of toluene was added dropwise over the course of 5 minutes. The mixture was stirred at 50° C. for 30 minutes, warmed to 80° C., and stirred at this temperature for a further 2 hours. The mixture was then cooled, and the precipitated amine hydrochloride was filtered off, washed with 0.5 N hydrochloric acid and then with water, dried and evaporated. The residue was purified on a silica gel column. The target product had an m.p. of 22-25° C.
Reaction SMILES: [N:1]1[C:6]([CH:7]=O)=[CH:5][CH:4]=[CH:3][C:2]=1[CH:9]=O.[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:13]=1[NH2:14]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:13]=1[N:14]=[CH:9][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:7]=[N:14][C:13]2[C:12]([Cl:11])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[N:1]=1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=Cc1cccc(C=O)n1
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1N=Cc1cccc(C=Nc2c(Cl)cccc2Cl)n1

Procedure:
2,6-Pyridinedicarboxaldehyde (1 g, 7.4 mmol) and 2,6-dichloroaniline (2.6 g, 16.0 mmol) were dissolved in 100 ml of toluene. To this solution 4 Å molecular sieves were added. After standing for 2 days, with addition of more 4 Å molecular sieves the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. Yield 1.4 g (45%) of 6. 1H-NMR (CDCl3) δ 8.53 (s, 2H, HC═N), 8.45 (d, 2H, Py-Hm), 8.02 (t, 1H, Py-Hp), 7.36 (d, 4H, ArH), 7.03 (t, 2H, ArH).
Reaction SMILES: [C-]#N.[K+].[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[CH2:13]([OH:15])[CH3:14]>O>[OH:15][CH:13]([C:14]1[CH:11]=[CH:12][C:5]([F:4])=[CH:6][CH:7]=1)[C:9]([C:8]1[CH:11]=[CH:12][C:5]([F:4])=[CH:6][CH:7]=1)=[O:10]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCO
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: O=C(c1ccc(F)cc1)C(O)c1ccc(F)cc1
Reaction time: 72 h

Procedure:
A mixture of potassium cyanide (2.0 g, 31 mmol), 4-fluorobenzaldehyde, 96% ethanol (30 ml) and water (30 ml) was heated at reflux for 0.5 h and then kept at 5° C. for 72 h. The precipitated compound was collected and recrystallised from ethanol/water to give 20 g of 2-hydroxy-1,2-bis(4-fluorophenyl)ethanone.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][C:9](O)=[O:10])[CH:2]=[CH2:3].S(Cl)(Cl)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>C1C=CC=CC=1>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[CH:7]=[CH:8][C:9]([N:23]=[N+:24]=[N-:25])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=CC(=O)O)ccc1OC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: C=CCc1cc(C=CC(=O)N=[N+]=[N-])ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
22.2 g (0.09 mol) of 3-allyl-4-acetoxy-cinnamic acid are suspended in 100 ml of benzene and 13.2 ml (0.18 mol) of thionyl chloride are added. The reaction mixture is heated to the boil for half an hour under a reflux condenser and thereafter the solvent and excess thionyl chloride are removed by distillation under reduced pressure. The residual crude 3-allyl-4-acetoxy-cinnamic acid chloride is dissolved in 100 ml of absolute 1,2-dimethoxyethane, 17.5 g (0.27 mol) of sodium azide are added and the mixture is subsequently stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated under reduced pressure at 30°C. Hereupon, colourless crystals separate out. The crystallisation is completed by adding ether. 3-Allyl-4-acetoxy-cinnamic acid azide of melting point 87°-89°C (decomposition) is obtained.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 72 h
Yield: 40.8 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and morpholine (33 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (23 mg, yield 41%).
Reaction SMILES: C(O[C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)(C)(C)C.[Li]C(C)(C)C.[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([N:25]1[C:26](=[O:27])[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([Cl:14])[CH:10]=2)[NH:7][C:6]1=[O:15])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Reactant: CC(C)(C)N=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)n1c(=O)[nH]c2ccc(Cl)cc2c1=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To a room temperature solution of 4-chloro-phenylamine (5.0 g, 39.19 mmol) was added di-tert-butyl dicarbonate (9.41 g, 43.11 mmol) portion-wise. The solution was heated to reflux, stirred for 2 hrs, cooled, concentrated, and dissolved in diethylether. The solution was washed with water, sodium bicarbonate and brine, dried over MgSO4, filtered, and concentrated to provide (4-chloro-phenyl)-carbamic acid tert-butyl ester (8.5 g) as a white solid, which was used with no further purification. To a −78° C. solution of (4-chloro-phenyl)-carbamic acid t-butyl ester (5.046, 23.30 mmol) in THF (232 mL) was added 32.9 mL of t-BuLi (1.7 M in pentane, 55.92 mmol) via cannula. The solution was stirred 10 min, warmed to −20° C. and stirred 2 hours further. To the −20° C. red solution was added t-butyl isocyanate (3.33 mL, 29.13 mmol). The solution was stirred at −20° C. for 1 hr, warmed to room temperature, stirred 2 hrs, then heated to reflux and stirred for 12 hrs. The reaction was cooled to room temperature, concentrated and dissolved in diethylether. The solution was washed with water, sodium bicarbonate and brine, dried over MgSO4, filtered, and concentrated to provide 5.87 g of white solid (100%). 1H NMR (300 MHz, CDCl3) δ ppm 1.76 (s, 9H), 6.91 (d, J=8.6 Hz, 1H), 7.48 (dd, J=2.2, 8.5 Hz, 1H), 7.97 (d, J=2.3 Hz, 1H), 9.22 (br s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[S:18][C:19]([CH2:22]O)=[CH:20][CH:21]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([N:27](CC)[CH2:28][CH3:29])[CH3:26].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[S:18][C:19]([CH2:22][N:27]3[CH2:28][CH2:29][CH2:26][CH2:25]3)=[CH:20][CH:21]=2)[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CO)s1
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CN2CCCC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 200 mg (0.59 mmol) 4-benzyloxy-1-[2-(5-hydroxymethyl-thiophen-2-yl)-ethyl]-1H-pyridin-2-one (preparation 11d) in 8.0 mL DCM is added 245 μL (1.76 mmol) triethylamine and subsequently 91 μL (1.17 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT and 98 μL (1.17 mmol) pyrrolidine is added. The mixture is stirred overnight at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:25])[C:9]([C:23]#[N:24])=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([NH:7][C:8](=[O:25])[C:9]([C:23]#[N:24])=[CH:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[NH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(=Cc1c[nH]c2ccc([N+](=O)[O-])cc12)C(=O)Nc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: N#CC(=Cc1c[nH]c2ccc(N)cc12)C(=O)Nc1ccccc1
Yield: 80 %

Procedure:
To a solution of N-phenyl β-(5-nitro-3-indolyl)-α-cyanoacrylamide (3.324 g, 0.010 mol) in anhydrous ethanol (200 ml) was added palladium on charcoal (0.200 g) and the mixture was hydrogenated at room temperature and atmospheric pressure until 3 equivalent of hydrogen has been taken up. The hydrogen uptake was graphed as function of time. The catalyst was filtered and the solution concentrated under vacuum until crystallization began. The mixture was cooled to 0°-5° C., filtered, the residue washed with ice-cooled ethanol and dried under vacuum. Thus almost pure title compound was obtained in about 80% yield (2.416 g). An analytical pure sample was obtained by crystallization from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH:11](Cl)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:32]3[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=3[NH:30][C:29]2=[O:38])[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH:11]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[C:32]5[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=5[NH:30][C:29]4=[O:38])[CH2:26][CH2:27]3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2(c3ccc(F)cc3)C=CC(Cl)CC2)cc1
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(C2C=CC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1
Reaction time: 3 h

Procedure:
A mixture of 6.1 g of 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene (m.p. 39°-42° C), 5.0 g of 1-(4-piperidyl)-5-chloro-2-benzimidazolinone, 2.8 g of potassium carbonate, 3.3 g of potassium iodide and 50 ml of dimethylformamide is stirred at 65°-70° C for 3 hours. The reaction mixture is poured into water, and the precipitated powder is collected by filtration, dried and dissolved in a mixture of chloroform and methanol (9:1). The solvent is then removed, and the precipitate is collected by filtration and purified in the same manner to give 1-[1-(4,4-bis(p-fluorophenyl)-2-cyclohexenyl)-4-piperidyl]-5-chloro-2-benzimidazolinone as white crystalline powder, melting at 153°-157° C. This white crystalline powder, when recrystallized from a mixture of ethanol and methanol (7:3), turns into white crystals showing a melting point of 217°-219° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>N1C=CC=CC=1>[CH3:1][N:2]1[C:6]([NH:7][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(N)n(C)n1
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)C(C)(C)C)n(C)n1
Temperature: 23 °C
Reaction time: 3.5 h
Yield: 96 %

Procedure:
To 15.0 g (131 mmol) N-(2,5-dimethyl-2H-pyrazol-3-yl)-amine in 150 mL pyridine at 0° C. was added 19.3 mL (18.9 g, 158 mmol) of pivaloyl chloride. After stirring at 23° C. for 3.5 hours, the reaction solvent was evaporated, and the residue was evaporated with 2×200 mL toluene. The remaining solid was dissolved in 500 mL EtOAc/200 mL H2O and extracted. The aqueous layer was extracted with 2×100 mL EtOAc, and the combined organics were washed with 1×200 mL brine, dried over MgSO4, filtered and evaporated to an orange solid. Recrystallization from hot hexanes/EtOAc gave 24.45 g (125 mmol, a 96% yield) of the title compound as an off-white, crystalline solid: mp: 86-88° C.; 1H NMR (300 MHz, CDCl3): δ 1.32 (s, 9H), 2.22 (s, 3H), 3.63 (s, 3H), 5.98 (s, 1H), 7.12 (brs, 1H); IR (KBr, cm−1): 3316s, 3274s, 2967m, 2935m, 1673s, 1655m, 1570s, 1514m, 1492m, 1457m; MS (ES) m/z (relative intensity): (196, M+, 100). Anal. Calcd. for C10H17N3O: C, 61.51; H, 8.77; N, 21.52. Found: C, 61.33; H, 8.80; N, 21.23.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[CH:12]=[CH:11]1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)(=O)C(Cl)=O.ClCCl>[Br:1][C:2]1[S:3][C:4]([C:7]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:10][CH:11]=2)=[O:9])=[CH:5][N:6]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: c1cnc2[nH]ccc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1cnc(Br)s1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.9 %

Procedure:
A suspension of 2-Bromo-thiazole-5-carboxylic acid (98, 0.5 g, 0.002 mol) in oxalyl chloride (3 mL) was stirred at room temperature until it turned into a clear solution. Solvent was removed and the residue was dried over vacuum. A light yellow solid was obtained and was dissolved in dichloromethane (10 mL) and slowly added to a solution of 1H-Pyrrolo[2,3-b]pyridine (1, 0.34 g, 0.0029 mol) in dichloromethane (30 mL) at −10° C. To the mixture was then added aluminum trichloride (2.6 g, 0.019 mol) in one portion with vigorous stirring. The reaction was held at −10° C. for 30 minutes, then allowed to warm to room temperature. The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with ice-water and acidified with hydrochloric acid (10%) to pH 4. The solution was then extracted with dichloromethane. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (99, 12 mg, 2%). MS (ESI) [M−H+]=369.09.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C@H:3]1[C:15]([OH:17])=[O:16].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.O[C@@H:41]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:45]=1)[C:42]#[N:43]>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])=[O:14])[C@H:3]1[C:15]([O:17][C@H:41]([C:42]#[N:43])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:45]=1)=[O:16]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.5 %

Procedure:
1.3 g of (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2, 2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylic acid, 0.1 ml of pyridine and 15 ml of methylene chloride were mixed with agitation and then 1.05 g of dicyclohexylcarbodiimide were added thereto. A solution of 1.35 g of (S)α-hydroxy-3-phenoxy-benzene-acetonitrile in 5 ml of methylene chloride were then added to the mixture which was stirred for 5 hours at ambient temperature and then was filtered. The filter was rinsed with methylene chloride and 2N hydrochloric acid was added to the filtrate. The decanted organic phase was washed with water, dried and evaporated to dryness. The oil residue was chromatographed over silica gel and was eluted with 95-5 cyclohexane-ethyl acetate mixture to obtain 1.33 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-(2,2,2-trifluoroethoxy)-3-oxo-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+42°±2° (c=0.7% in benzene).
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[CH:29][N:28]=[N:27][C:26]=2[NH:38][NH2:39])=[CH:21][CH:20]=1>O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:30]2[CH:29]=[N:28][N:27]3[C:3](=[O:4])[NH:39][N:38]=[C:26]3[C:25]=2[C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=2)=[CH:32][CH:33]=1
Reactant: C1CCOC1
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a THF (20 mL) solution of carbonyldiimidazole (CDI), (1.7 g, 10.5 mmol) was added 1-(4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine (0.7 g, 2.1 mmol). The resultant brown solution was stirred at RT for 15 min. After this time, the reaction solution was poured into water (50 mL). The resultant pale colored solid was collected by filtration. Water was used to rinse the solid thoroughly to afford 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (0.75 g, 100%). MS (M+H)=357; 1H NMR (DMSO-d6, 500 MHz): δ 12.86 (1H, s), 8.37 (1H, s), 7.42-7.48 (4H, m), 7.35 (2H, d, J=10.0 Hz), 7.27 (2H, d, J=10.0 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)([C:18]([O:20]CC)=[O:19])[C:13]([O:15]CC)=[O:14].[Li+].[OH-]>CO.CO.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1)([C:13]([OH:15])=[O:14])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(Cc1ccc2ccccc2n1)(OC1CCCCO1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1ccc2ccccc2n1)(OC1CCCCO1)C(=O)O
Reaction time: 12 h
Yield: 90.7 %

Procedure:
A solution of ethyl 3-(quinolin-2-yl)-2-(2-tetrahydropyranyloxy)-2-ethoxycarbonyl-propanoate (0.5 g) in 5 ml of methanol is hydrolysed by treatment with a LiOH in MeOH-H2O solution. After 12 h at r.t., the solvent is evaporated off under vacuum and the residue is partitioned between AcOEt and an excess of a monobasic potassium phosphate saturated solution. The organic phase is separated, dried, evaporated to dryness to obtain 0.39 g of 3-(quinolin-2-yl)-2-(2-tetrahydropyranyloxy)-2-carboxy-propanoic acid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@@H:22]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:24]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:23]1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][Si:63]([C:76]([CH3:79])([CH3:78])[CH3:77])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH3:21])=[CH:17][CH:18]=2)=[CH:7][C:6]=1[C@@H:22]1[O:27][C@H:26]([CH2:28][O:29][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][Si:63]([C:76]([CH3:77])([CH3:79])[CH3:78])([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C@@H:25]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:24]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:23]1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](OCCCCCBr)(c1ccccc1)c1ccccc1
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCCCCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To a solution of ((2R,3R,4R,5S,6S)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol (16, 1.1 g, 1.51 mmol) in N,N-dimethylformamide (25 mL) was added sodium hydride (60% dispersion in mineral oil, 120.4 mg, 3.01 mmol) at 0° C., and the reaction mixture was stirred at ambient temperature for 0.5 h. After 1 h at room temperature, the reaction mixture was re-cooled to 0° C. and (5-Bromopentyloxy)(tert-butyl)diphenylsilane (27, 980 mg, 2.42 mmol) was added dropwise, and the mixture was stirred with gradual warming to ambient temperature over 5 h. After re-cooling to 0° C., the reaction mixture was quenched by addition of water (25 mL). The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude residue was purified on a Biotage® purification apparatus (silica gel, 5 to 20% tetrahydrofuran in hexanes gradient) to yield the title compound (28, 664 mg, 0.63 mmol, 42%) as yellowish oil.