Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:9][CH2:10][OH:11])[CH3:7])(=[O:4])=[O:3].C(OCC)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][S:2]([O:5][CH:6]([CH:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][CH:10]=[O:11])[CH3:7])(=[O:4])=[O:3]
Reactant: CC(OS(C)(=O)=O)C(CCO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)C(CC=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
1.2 g of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(H)-one (Dess-Martin Periodinane) was added to a solution of 490 mg of 5-hydroxy-3-phenylpentan-2-yl methanesulfonate in 5 mL of dichloromethane, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, ethyl acetate and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was successively washed with a sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (ethyl acetate/hexane=1/10 to 1/1), so as to obtain 414 mg of 5-oxo-3-phenylpentan-2-yl methanesulfonate in the form of a colorless oily product.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=2)[NH:18][CH:17]=1.[CH3:31]I>CN(C)C=O>[O:13]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:3])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=2)[NH:18][CH:17]=1
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1)S(C)(=O)=O
Reaction time: 1 h

Procedure:
Sodium hydride (80% in oil; 0.1 g) was added under nitrogen to a stirred solution of N-[[3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indol-5-yl]methyl]methanesulphonamide (1.2 g) in dry dimethylformamide (16 ml). After 1 h, methyl iodide (0.75 ml) was added.
Reaction SMILES: C(OC(=O)NCC1C=CC(CNC(C2C(Cl)=NC=CC=2)=O)=CC=1)(C)(C)C.[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33](O)[CH:32]=1)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O1CCOCC1>[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:28]
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)c2cccnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1
Temperature: 70 °C
Reaction time: 22 h
Yield: 0.1 %

Procedure:
(4-{[(2-Chloro-pyridine-3-carbonyl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (12.0 g, 32.2 mmol) (see Preparation 7), 3-hydroxy-benzoic acid ethyl ester (6.42 g, 38.6 mmol) and caesium carbonate (15.7 g, 48.3 mmol) were stirred in dioxan (180 ml) at 70° C. under an atmosphere of nitrogen for 18 hours. Starting material remained, so a further aliquot of 3-hydroxy-benzoic acid ethyl ester (6.42 g, 38.6 mmol) and caesium carbonate (15.7 g, 48.3 mmol) were added along with dioxan (420 ml) and N,N-dimethylformamide (40 ml) and the reaction stirred at 70° C. for a further 22 hours. The solvent was then removed under reduced pressure, the residue partitioned between ethyl acetate (200 ml) and water (200 ml), and the organic layer separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (3-fold 100 ml), the solvent removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with a solvent gradient of 0:100 changing to 50:50, by volume, ethyl acetate:hexane to give 3-{3-[4-tert-butoxycarbonylamino-methyl)-benzylcarbamoyl]-pyridin-2-yloxy}-benzoic acid ethyl ester (7.42 mg) as an off-white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[CH2:16]>COCCOC.O>[Br:8][C:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:15]=[CH2:16])[CH:22]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C=Cc1cccc(B(O)O)c1
Reactant: Brc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C=Cc1cccc(-c2cccc(Br)c2)c1
Temperature: 80 °C
Yield: 59.5 %

Procedure:
A solution of 1,3-dibromobenzene (5.3 mL, 43.9 mmol), potassium carbonate (14.0 g, 101 mmol) and 3-vinylphenylboronic acid (5 g, 33.8 mmol) in DME (100 mL) and water (20 mL) (in a pressure vessel) was sparged with nitrogen for 15 min. Pd(PPh3)3 (1.17 g, 1.014 mmol) was added and then the reaction was heated to 80° C. overnight. The reaction was cooled to r.t. and evaporated on the rotovap. The residue was diluted in EtOAc and washed with water then brine, dried over MgSO4, filtered and evaporated to give the crude material. The crude material was purified by flash chromatography on the Biotage (0-5% EtOAc:Hex) to give 3-bromo-3′-vinylbiphenyl (5.21 g, 20.10 mmol, 60% yield) as a clear liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.33 (d, J=10.79 Hz, 1H) 5.84 (dd, J=17.57, 0.75 Hz, 1H) 6.80 (dd, J=17.57, 10.79 Hz, 1H) 7.32 (t, J=7.78 Hz, 1H) 7.38-7.48 (m, 3H) 7.51 (dddd, J=13.24, 7.84, 1.76, 1.00 Hz, 2H) 7.56-7.61 (m, 1H) 7.76 (t, J=1.88 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][N+:6]#[C-:7])[CH3:2].[O:9]=[CH:10][C:11](=[CH2:13])C.[CH:14]1C=CC=CC=1>[Cu-]=O>[CH2:1]([O:3][C:4]([CH:5]1[CH:10]([CH2:11][CH:13]=[CH2:14])[O:9][CH:7]=[N:6]1)=[O:8])[CH3:2]
Reactant: C=C(C)C=O
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: c1ccccc1
Agent: O=[Cu-]
Product: C=CCC1OC=NC1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.6 g of red copper(1) oxide are introduced into 200 ml of benzene. A solution of 140 g of isocyanoacetic acid ethyl ester and 105 g of freshly distilled methacrolein in 200 ml of benzene is added dropwise to this suspension within a period of 10 minutes with vigorous stirring, during which time the reaction temperature is kept at between 30° and 32° by cooling with ice. When the addition is complete, the mixture is kept at 30°-32° until the exothermic reaction subsides, and is then stirred at room temperature for one hour. After excess copper(I) oxide has been filtered off, the filtrate is concentrated by evaporation in vacuo at 30°. 600 ml of ether are added to the residue, which is then filtered over Celite and concentrated to dryness by evaporation in vacuo. In this manner, 5-(2-propenyl)-2-oxazoline-4-carboxylic acid ethyl ester is obtained in the form of a colourless oil having a boiling point of 110°-130° (5.3 Pa).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]2)=[CH:6][CH:5]=1.[C:17](=O)([O-])[O-].[K+].[K+].COC(OC)N(C)C.[C:31]1(=[O:37])[NH:35][C:34](=[O:36])[CH:33]=[CH:32]1>O.C(O)(=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]3=[N:14][CH:17]=[C:33]4[C:34](=[O:36])[NH:35][C:31](=[O:37])[C:32]4=[C:12]3[CH:11]=[N:10]2)=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc(Cn2nccc2N)cc1
Agent: COC(OC)N(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)NC4=O)cc1
Temperature: 120 °C
Yield: 23 %

Procedure:
1-(4-methoxybenzyl)-1H-pyrazol-5-amine hydrochloride (2.0 g, 8.35 mmol) was free-based with 10% aqueous potassium carbonate (100 ml) and extracted with diethyl ether (100 ml). The organic layer was concentrated under reduced pressure to afford a yellow solid. N,N-dimethylformamide dimethylacetal (15 ml) was added and the mixture heated to 120° C. for 2.5 hours. The mixture was concentrated under reduced pressure which was then treated with maleimide (1.62 g, 16.7 mmol) and acetic acid (10 ml) and heated to 50° C. for 2 days. The mixture was poured into cold water (250 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-(4-methoxybenzyl)pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione as a pale yellow solid (593 mg, 23%). M.p.=196-197° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.55 (s, 1H), 9.02 (s, 1H), 8.50 (s, 1H), 7.24 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 5.70 (s, 2H), 3.68 (s, 3H); LCMS: 309 [M+H]. 1-(4-methoxybenzyl)-1H-pyrazol-5-amine hydrochloride was made according to the procedure described in Bioorganic and Medicinal Chemistry Letters, vol. 13, pp. 1133-6 (2003).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]([C:8]2[CH:9]([C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[NH:10][C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:7])[CH2:5][CH2:4]1.Br[CH2:35][C:36]1[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=1)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CCCCC.O1CCCC1>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[N:10]([CH2:35][C:36]3[CH:37]=[C:38]([CH:46]=[CH:47][CH:48]=3)[C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:16]=3)[C:13]([CH3:14])=[C:8]2[C:6]([CH:3]2[CH2:5][CH2:4]2)=[O:7])=[CH:33][CH:32]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)c1cccc(CBr)c1
Reactant: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1=C(C(=O)C2CC2)C(c2ccc(C#N)cc2)N(Cc2cccc(C(=O)OC(C)(C)C)c2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (12.1 mg, 0.31 mmol; 60% suspension in mineral oil) is washed with pentane (3×3 ml), then treated with a solution of 4-{5-(cyclopropylcarbonyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 22) (100 mg, 0.235 mmol) in tetrahydrofuran (5 ml). After 5 minutes, the reaction is treated with a solution of tert.-butyl 3-(bromomethyl)benzoate (77 mg, 0.28 mmol) in tetrahydrofuran (5 ml) and then stirred at room temperature overnight (16 h). The reaction mixture is quenched with water (50 ml) and extracted with ethyl acetate (3×150 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([CH2:13][CH2:14][C:15]([OH:17])=O)=[C:11]([CH3:18])[O:10][N:9]=1.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21]>ClCCl.CN(C)C=O>[NH3:9].[CH3:7][C:8]1[C:12]([CH2:13][CH2:14][C:15]([NH:21][NH:20][C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:17])=[C:11]([CH3:18])[O:10][N:9]=1
Reactant: Cc1noc(C)c1CCC(=O)O
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1noc(C)c1CCC(=O)NNC(=O)OC(C)(C)C
Product: N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (5.16 mL, 59.2 mmol) was added to a solution of β-(3,5-dimethyl-4-isoxazolyl)propionic acid (J. Org. Chem. 59(10); 1994; 2882) (2.5 g, 14.8 mmol) in dichloromethane (50 mL) and N,N-dimethylformamide (1 drop), and the solution was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure and the residue was azeotroped with dichloromethane (5×) to provide a brown liquid. This was dissolved in dichloromethane (25 mL), and tert-butyl carbazate (2.93 g, 22.2 mmol) was added portionwise. The mixture was diluted with further dichloromethane (23 mL) and the reaction was stirred for 18 hours at room temperature. The mixture was concentrated under reduced pressure, the residue was suspended in dichloromethane, the resulting precipitate was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0.5 to 90:10:1) to provide the title compound as an oil, 3.08 g.
Reaction SMILES: [O:1]=[C:2]1[CH:7](OS(C)(=O)=O)[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH:7]3[CH2:6][CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)OC1CCCNC1=O
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C(=O)C2CCN(C3CCCNC3=O)CC2)cc1
Temperature: 85 °C
Yield: 31.6 %

Procedure:
To a solution of methanesulfonic acid 2-oxo-piperidin-3-yl ester (250 mg, 1/294 mmol, 1.0 eq) and (4-methoxy-phenyl)-piperidin-4-yl-methanone (312 mg, 1.423 mmol, 1.1 eq) in acetonitrile (2.5 mL) was added diisopropylethylamine (351 mg, 0.475 mL, 2.1 eq) and the reaction was heated at 85° C. for 3 hours. The reaction was cooled to room temperature and the solvent evaporated in vacuo. The resulting oily residue was purified by silica gel column chromatography (MeOH/CH2Cl2) to give the title compound as a clear oil (142 mg, 0.449 mmol, 34.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (d, J=9.09 Hz, 2H) 7.39-7.43 (br. s, 1H) 7.04 (d, J=8.59 Hz, 2H) 3.84 (s, 3H) 3.23-3.33 (m, 2H) 2.97-3.14 (m, 4H) 2.74-2.85 (m, 2H) 1.75-1.91 (m, 2H) 1.57-1.75 (m, 4H) 1.47-1.54 (m, 2H). MS (m/z, MH+): 316.8
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[S:4]([C:7]1[C:15]2[O:14]C(C(C)(C)C)=[N:12][C:11]=2[CH:10]=[CH:9][C:8]=1[Cl:20])(=[O:6])=[O:5].S(=O)(=O)(O)O>O1CCOCC1.O>[NH2:12][C:11]1[C:15]([OH:14])=[C:7]([S:4]([N:3]([O:2][CH3:1])[CH3:21])(=[O:6])=[O:5])[C:8]([Cl:20])=[CH:9][CH:10]=1
Reactant: CON(C)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CON(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Temperature: 30 °C

Procedure:
2-tert-Butyl-6-chloro-benzooxazole-7-sulfonic acid methoxy-methyl-amide (4.8 g, 14.42 mmol) in dioxane (55 ml) and water (20 ml) was treated with concentrated sulphuric acid (20 ml) added dropwise over 30 minutes maintaining the temperature<30° C. The reaction mixture was heated at reflux for 2.5 h and then allowed to cool to RT. Dioxane was removed in vacuo and the resulting aqueous residue was basified with sat. NaHCO3 solution (250 ml) to pH12. The reaction mixture was extracted with EtOAc (3×200 ml) and the combined organic extracts were washed with water (3×100 ml) sat. brine (100 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a brown solid; [M+H]+ 266.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([OH:16])[CH2:9]1)C1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[OH-].[Na+]>CO.O.O1CCOCC1.[OH-].[OH-].[Pd+2]>[CH2:21]([O:20][C:18]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([OH:16])[CH2:9]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCC1CCN(Cc2ccccc2)CC1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC(CO)C(O)C1
Reaction time: 0.5 h

Procedure:
A solution of the 1-Benzyl-4-hydroxymethyl-piperidin-3-ol from Step 1 above (13.5 g) in methanol (450 mL) was hydrogenated at 50 psi over 20% palladium hydroxide on charcoal (10 g) for 48 h in three batches. The combined reaction mixtures were filtered and the filtrate evaporated to give an oil. This oil was dissolved in water (100 mL) and dioxane (100 mL), cooled to 5° C., and benzyl chloroformate (7.8 mL) was added slowly. 1M NaOH was added to maintain pH of 10–11. After 30 min, the cooling bath was removed and reaction mixture stirred for 30 min. The reaction mixture was concentrated to remove dioxane and the residue extracted with EtOAc (×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and solvent evaporated to give a mixture of cis and trans products. Purified by flash column chromatography (80% EtOAc hexane to 5% MeOH EtOAc) gave the upper Rf cis isomer and the lower Rf trans isomer.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:35])[NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[Li+].[OH-].O>CO.O1CCCC1>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([O:33][CH3:34])=[C:26]([S:23]([N:20]2[C:21]3[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:11]([C:8]4[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:36])=[O:2])=[CH:6][CH:7]=4)=[O:35])[CH:22]=3)[CH2:17][CH2:18][CH2:19]2)(=[O:25])=[O:24])[CH:31]=1
Reactant: COC(=O)Cc1ccc(C(=O)Nc2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCC3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc(NC(=O)c3ccc(CC(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
{4-[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylcarbamoyl]-phenyl}-acetic acid methyl ester (121.00 mg, 0.23 mmol) was dissolved in methanol/tetrahydrofuran 1:1 (1.40 mL) and treated at room temperature with a 1N solution of LiOH in water (0.70 mL, 0.70 mmol). The mixture was stirred at room temperature for 4 hours, then the organic solvents were evaporated and the residual aqueous phase acidified with HCl 1N (0.70 mL). The precipitated solid was filtered washing with ether, then purified by flash chromatography (dichloromethane/methanol gradient) to yield {4-[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylcarbamoyl]-phenyl}-acetic acid as an off-white solid, 69.00 mg (59%), MS (ISP): m/e=513.5 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[N:11][N:10]([CH3:13])[C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=1.[NH:23]1[CH:27]=[C:26]([C:28]#[N:29])[N:25]=[CH:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu-]=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[N:11][N:10]([CH3:13])[C:9]=1[CH2:14][O:15][C:16]1[N:17]=[CH:18][C:19]([N:23]2[CH:27]=[C:26]([C:28]#[N:29])[N:25]=[CH:24]2)=[CH:20][CH:21]=1
Reactant: Cn1nnc(-c2ccccc2F)c1COc1ccc(I)cn1
Reactant: N#Cc1c[nH]cn1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(-n2cnc(C#N)c2)cn1
Temperature: 90 °C
Yield: 39.3 %

Procedure:
The mixture of 2-[5-(2-Fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-5-iodo-pyridine (0.5 g, 1.22 mmol), 1H-imidazole-4-carbonitrile (0.170 g, 1.82 mmol), cesium carbonate (0.79 g, 2.43 mmol), copper(I)oxide (0.017 g, 0.122 mmol), ferric acetylacetonate (0.129 g, 0.365 mmol) in DMF (10 ml) was heated at 90° C. for 20 h. The reaction was monitored by TLC and UPLC. The reaction mixture was concentrated under reduced pressure, water was added and extracted with ethylacetate (3×50 ml). The organic layer was washed with brine (15 ml), dried over Na2SO4 and concentrated under reduced pressure to afford crude mass (500 mg, 109% mass balance). It was purified in grace column using 2% methanol in chloroform as an eluent to furnish desired 1-{6-[5-(2-Fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridin-3-yl}-1H-imidazole-4-carbonitrile (0.180 g, 39.38%) as off-white solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([CH:20]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[C:21](Cl)=[O:22])([CH3:19])[CH3:18].[C-:35]#[N:36].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCC>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]([O:12][C:21](=[O:22])[CH:20]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[CH:17]([CH3:19])[CH3:18])[C:35]#[N:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(OC(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C(C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1)c1ccc(OC(F)(F)F)cc1
Yield: 80 %

Procedure:
8.64 g (0.04 mol) of 3-phenoxy-4-fluoro-benzaldehyde and 11.22 g (0.04 mol) of α-isopropyl-4-trifluoromethoxy-phenyl-acetic acid chloride were together added dropwise to a mixture of 3 g of sodium cyanide, 4.7 ml of water, 200 ml of n-hexane and 1 g of tetrabutylammonium bromide at 20°-25° C., while stirring, and the mixture was then stirred at 20°-25° C. for 4 hours. 300 ml of toluene were then added to the reaction mixture and the mixture was extracted by shaking twice with 300 ml of water each time. The organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 15.6 g (80.1% of theory) of α-isopropyl-4-trifluoromethoxy-phenylacetic acid 3-phenoxy-4-fluoro-α-cyanobenzyl ester were obtained as a yellow oil with the refractive index nD29 : 1.5185.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22]([C:33]#[N:34])=[C:21](SC2C=CC=CC=2)[N:20]=1.Cl.C[O:44][CH2:45][CH2:46][O:47]C>O>[NH2:18][C:19]1[N:20]=[C:21]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[C:22]([C:33]#[N:34])=[C:23]([C:27]2[CH:28]=[CH:29][C:30]([O:44][CH2:45][CH2:46][OH:47])=[CH:31][CH:32]=2)[C:24]=1[C:25]#[N:26]
Reactant: COCCOC
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccccc1
Reactant: O=C(O)c1cccc(CO)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#Cc1c(N)nc(OCc2cccc(C(=O)O)c2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4.72 g (42.06 mmol) of potassium tert-butoxide were suspended in 25 ml of 1,2-dimethoxyethane. After addition of 1.73 g (10.51 mmol) of 3-(hydroxymethyl)benzenecarboxylic acid (Example 66A) and 1.72 g (5.26 mmol) of 2-amino-4-phenyl-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 36A), the mixture was stirred at 60° C. overnight. After cooling of the reaction mixture, 50 ml of water were added. With ice-cooling, the clear solution was acidified to pH 6-7 using conc. hydrochloric acid. The solution was evaporated. Purification was by column chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 1/1, finally acetonitrile/water 10/1).