Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][NH:11][C:12]2[C:16]([C:17](O)=[O:18])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B.O1CCCC1.CO>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][NH:11][C:12]2[C:16]([CH2:17][OH:18])=[CH:15][NH:14][N:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CNc2n[nH]cc2C(=O)O)cc1OC1CCCC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CNc2n[nH]cc2CO)cc1OC1CCCC1
Temperature: -15 °C
Reaction time: 72 h
Yield: 86.6 %

Procedure:
Pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-pyrazolecarboxylic acid (compound 3) (1.32 g, 4.0 mmol) was dissolved in 50 ml of THF and cooled to -15° C. under nitrogen. Borane-tetrahydrofuran (30 ml of 1 M solution, 30 mmol) was added over 30 minutes and the resulting solution was stirred for 72 hours at room temperature. Methanol (30 ml) was added to the reaction and the solvent was evaporated under reduced pressure. The residue was treated with 160 ml of methanol and evaporated again. The crude product was treated with 30 ml of 10% aqueous ammonia and some brine and then extracted with three 50 ml portions of ethyl acetate. Evaporation of the solvent afforded 1.1 g of crude 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole which was purified by flash chromatography on 30 g of flash chromatography silica gel. Elution with ethyl acetate/hexane (1:4) afforded a small amount of material which was discarded. Elution with 60 ml of 1:1 ethyl acetate/hexane gave 600 mg of 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole which was recrystallized from 2 ml of toluene to give 500 mg of pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-hydroxymethylpyrazole (compound 4) mp 129-130° C.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1>[F:1][C:2]1([F:9])[CH2:7][CH2:6][C:5](=[CH:15][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(F)(F)CC1
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCC(F)(F)CC1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 4,4-difluorocyclohexan-1-one (1.0 g, 7.46 mmol, 1.00 equiv) and (carbethoxymethylene)triphenylphosphorane (3.9 g, 24.05 mmol, 1.50 equiv) in THF (20 mL) was stirred under argon overnight at 65° C. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and the crude residue was purified using flash column chromatography (silica gel, EtOAc/petroleum ether (1:10)) to yield 1.5 g (97%) of a colorless oil. 1H-NMR (400 MHz, CDCl3): δ ppm 5.75 (s, 1H), 4.18 (m, 2H), 3.06 (t, J=6.8 Hz, 2H), 2.34 (t, J=6.8 Hz, 2H), 2.11-1.99 (m, 4H), 1.33-1.26 (m, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(O[C@H:16]1[C@H:21]([O:22][Si](C(C)(C)C)(C)C)[CH2:20][C:19]([C:30]([O:32][CH3:33])=[O:31])=[CH:18][C@@H:17]1[CH2:34][CH:35]=[CH2:36])(=O)C1C=CC=CC=1.CS(Cl)(=O)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.ClCCl.C1COCC1.C(OCC)(=O)C>[CH2:34]([C@@H:17]1[C@H:16]2[C@H:21]([O:22]2)[CH2:20][C:19]([C:30]([O:32][CH3:33])=[O:31])=[CH:18]1)[CH:35]=[CH2:36]
Reactant: C=CC[C@H]1C=C(C(=O)OC)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1OC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: C=CC[C@H]1C=C(C(=O)OC)C[C@H]2O[C@@H]12

Procedure:
Potassium carbonate can be added to a room temperature solution of Example 18E in methanol and stirred over night. The reaction mixture can then be filtered, concentrated, and purified to yield the first intermediate compound. Methanesulfonyl chloride can then be added to a 0° C. solution of the first intermediate in dichloromethane. After stirring for up to 12 hours, the reaction mixture can then be washed with saturated NaHCO3, dilute citric acid solution, water, and brine, dried (MgSO4), filtered and concentrated. The concentrate can then be purified to afford the second intermediate. Tetrabutylammonium fluoride can then be added to a room temperature solution of the second intermediate in THF. After stirring for up to 12 hours, the reaction mixture can be diluted with ethyl acetate, washed with water, and brine, dried (MgSO4), filtered and concentrated and purified to afford the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COCCOCCOc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOCCOc1cc2ncnc(Cl)c2cc1OC
Yield: 87 %

Procedure:
A solution of 6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)-3,4-dihydroquinazolin-4-one (930 mg, 3.16 mmol) in thionyl chloride (15 ml) and DMF (150 μl) was heated at 60° C. for 1.5 hours. The mixture was allowed to cool and the volatiles were removed by evaporation and by azeotroping with toluene. The residue was dissolved in methylene chloride and 5% aqueous sodium hydrogen carbonate solution was added until the aqueous layer was at pH8. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with ethyl acetate to give 4-chloro-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline (863 mg, 87%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.C1(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[C:1]([N:31]=[N+:32]=[N-:33])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
There are added to a suspension of 12.3 g of nicotinic acid in 100 ml of dimethylformamide 14.2 ml of triethylamine and then, after cooling to 0° C., 22 ml of diphenylphosphoryl azide in 50 ml of dimethylformamide. After stirring for 2 hours, the reaction mixture is poured onto ice. After extraction with ether, the organic phase is washed with a NaHCO3 solution, dried, and then concentrated to yield 9.68 g of the expected product.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([CH2:14][C:15]([OH:17])=O)=[CH:4]1)[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[C:5]([CH2:14][C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[CH:4]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCn1cc(CC(=O)O)c2c(O)cc(F)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(CC(=O)N2CCOCC2)c2c(O)cc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of compounds 11-3 (119 mg, 0.5 mmol) in DMF (2 mL) was added morpholine (66 uL, 0.75 mmol), triethylamine (0.24 mL, 1.75 mmol) and BOP (265 mg, 0.6 mmol). The reaction mixture was stirred at room temperature overnight. The solution was diluted with water and extracted with EtOAc. Combined organic layers were washed with 1N HCl, water, brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, ethyl acetate:hexanes: 25:75 to 100%) gave pure 11-4 (140 mg, 91%) as a white foam.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH2:8][O:9][C:10]1(O)[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][CH:11]1[C:12](OC)=[O:13])=[O:7])[CH3:4].Cl.[Cl-].[Li+]>CN(C)C=O>[N+:20]([C:19]1[C:10]2[O:9][CH:8]([C:6]([O:5][CH2:3][CH3:4])=[O:7])[C:12](=[O:13])[C:11]=2[CH:16]=[CH:17][CH:18]=1)([O-:22])=[O:21]
Reactant: CCOC(=O)COC1(O)C([N+](=O)[O-])=CC=CC1C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1Oc2c(cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.80 g, 0.020 mole) is placed in a flask, and the mineral oil is removed from it with two heptane washes. The sodium hydride is then suspended in 30 mL of N,N-dimethylformamide, and the suspension is cooled to 0°-10° C. To this suspension is added in a dropwise manner a solution of 4.53 g (0.016 mole) of methyl 2-ethoxycarbonylmethoxy-3-nitrosalicylate in 10 mL of N,N-dimethylformamide. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature at which it is stirred for approximately 16 hours. At the conclusion of this period, the reaction mixture is cooled and acidified with concentrated hydrochloric acid. Then 200 mL of a 10% aqueous solution of lithium chloride is added to the reaction mixture, and the resulting mixture is extracted three times with ethyl acetate. The combined extracts are washed with 100 mL of the 10% aqueous solution of lithium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure, leaving a residue which is then passed through a column of silica gel, eluting with ethyl acetate. The product-containing fractions are combined, and the solvent is evaporated under reduced pressure, leaving ethyl 2,3-dihydro-7-nitrobenzofuran-3-on-2-ylcarboxylate as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([C@@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1)[CH2:33][C:34]#[CH:35].CN(C=O)C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:35]#[C:34][CH2:33][CH2:32][C@@H:36]4[CH2:40][O:39][C:38](=[O:41])[NH:37]4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#CCC[C@@H]1COC(=O)N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#CCC[C@@H]3COC(=O)N3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added (4R)-4-(3-butynyl)-1,3-oxazolidin-2-one (83.4 mg). Anhydrous DMF (20 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), 2% MeOH in CH2Cl2 (1L), and 2.5% MeOH in CH2Cl2 (3L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 95.6 mg (31%) of the desired product as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4](C(OCC)=O)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37].CO>CN(C=O)C>[CH3:39][N:38]([CH3:40])[C:36](=[O:37])[CH2:35][O:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[NH:4][N:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCOC(=O)n1[nH]c(=O)c2cnc(NC(=O)N[C@H](C)c3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)Nc1cc2[nH]nc(OCC(=O)N(C)C)c2cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-Ethyl 3-oxo-6-(3-(1-phenylethyl)ureido)-2,3-dihydro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate (29 mg, 0.079 mmol), potassium carbonate (32.6 mg, 0.236 mmol), and 2-chloro-N,N-dimethylacetamide (8.8 μL, 0.087 mmol) were stirred in DMF (1 mL) at room temperature for 24 h. MeOH (0.5 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The insoluble inorganics were removed by filtration and the reaction mixture was purified via mass triggered, reverse phase prep-HPLC. Fractions containing pure product were concentrated in vacuo and the residue dissolved in MeOH. The MeOH solution was passed through a PS—HCO3 cartridge and the filtrate concentrated in vacuo to give (R)—N,N-dimethyl-2-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yloxy)acetamide. MS ESI calc'd. For C19H22N6O3 [M+1]+ 383. found 383. 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 8.94 (s, 1H), 8.58 (s, 1H), 7.77 (br s, 1H), 7.49 (s, 1H), 7.34-7.31 (m, 4H), 7.25-7.20 (m, 1H), 5.04 (s, 2H), 4.89-4.83 (m, 1H), 2.98 (s, 3H), 2.82 (s, 3H), 1.39 (d, J=7.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:14])[CH3:13]>CC(C)=O>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:14][CH2:12][CH3:13])[N:3]=1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CCN
Solvent: CC(C)=O
Product: CCNc1nc(Cl)c(C#N)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 12.9 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 150 ml of acetone was cooled to -10°, and 7.7 grams of an aqueous 70% ethylamine solution was added dropwise during 2 hours. The temperature of the reaction mixture was maintained at -10° throughout the addition. Following complete addition, the reaction mixture was allowed to warm to room temperature, where it stood for 16 hours. Then most of the acetone was removed by evaporation under reduced pressure. The residue was extracted with a mixture of water and diethyl ether. The ether layer was separated and dried over magnesium sulfate. The dried ether layer was filtered, and the ether was removed under reduced pressure. The residue was recrystallized from a mixture of methylcyclohexane and benzene, then from carbon tetrachloride, to give 4.2 grams of 4,6-dichloro-2- ethylamino-5-pyrimidinecarbonitrile; mp, 145°-150°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][C:5]([C:8]#[C:9][Si](C)(C)C)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][C:5]([C:8]#[CH:9])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1ccc(N)c(C#N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N)c(C#N)n1

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 9, using 1.3 grams (0.006 mole) of 3-amino-2-cyano-6-(trimethylsilylethynyl)pyridine and 0.9 gram (0.006 mole) of potassium carbonate in 50 mL of methanol, yielding 3-amino-2-cyano-6-ethynylpyridine. This reaction is repeated several times.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([S:8][C@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[N:15]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([O:34]CC)=[O:33].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[C:6]([S:8][C@H:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[N:15]=2)[CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[O:30][CH2:31][C:32]([OH:34])=[O:33]
Reactant: CCCC[C@H](Sc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC[C@H](Sc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
To a solution of ethyl ({2-methyl-4-[((1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)thio]phenyl}oxy)acetate (34 mg, 0.07 mmol) in THF (1 mL) and MeOH (1 mL) was added aqueous NaOH (2M, 1 mL) and the resulting mixture agitated for 1.5 hours at rt. The mixture was then reduced under vacuum, acidified with aqueous HCl (2M) and extracted with DCM (2 mL) and reduced to afford the title compound as a colourless oil (31 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[C:16]([C:19]([O:21]CC)=[O:20])[NH:17][N:18]=3)[CH:9]=2)[CH:7]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][C:26]([F:34])([F:35])[C:27]([F:33])([F:32])[C:28]([F:30])([F:31])[F:29])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[C:16]([C:19]([OH:21])=[O:20])[NH:17][N:18]=3)[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc(-c2cccc(-c3cc(F)ccc3OCC(F)(F)C(F)(F)C(F)(F)F)c2)n[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc(-c2cccc(-c3cc(F)ccc3OCC(F)(F)C(F)(F)C(F)(F)F)c2)n[nH]1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 0.1 g (0.196 mmol) of ethyl 5-[5′-fluoro-2′-(2,2,3,3,4,4,4-heptafluorobutyloxy)biphenyl-3-yl]2H-1,2,4-triazole-3-carboxylate (prepared according to procedures described in Reference Example 3, Step B) in 1.4 mL of methanol was added 0.59 mL (0.59 mmol) of a 1N aqueous solution of NaOH and the reaction mixture was stirred at rt for 23 hr. The pH of the reaction mixture was adjusted to pH=4-5 with 1N HCl solution and the mixture was extracted with EtOAc. The organic fractions were dried (Na2SO4), filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, CH2Cl2:acetone 9:1, then CH3OH: CH2Cl2 1 to 10% linear gradient) to give the title compound.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.[F:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[NH:20][NH2:21].C(Cl)Cl.Cl>CCO>[NH2:10][C:9]1[N:20]([C:13]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=2[F:11])[N:21]=[C:4]([CH3:5])[C:6]=1[C:7]#[N:8]
Reactant: COc1ccc(NN)c(F)c1
Reactant: CCOC(C)=C(C#N)C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-n2nc(C)c(C#N)c2N)c(F)c1
Temperature: 105 °C
Yield: 84.5 %

Procedure:
To a stirred solution of 2-(1-ethoxyethylidene)malononitrile (167 mg, 1.23 mmol) was added (2-fluoro-4-methoxyphenyl) hydrazine (220 mg, 1.41 mmol) in EtOH (3 mL). The solution was heated to 105° C. in the microwave for 30 min. CH2Cl2 and 1 M HCl was added and separated, the organic extract was washed with aqueous NaHCO3. The solution was dried using a phase separator and concentrated under reduced pressure to give 5-amino-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (256 mg, 85%), which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][O:1][C:2]2[CH:33]=[CH:32][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][N:8]3[CH2:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:4][C:3]=2[O:34][CH3:35])[CH2:38][CH2:37]1
Reactant: BrCC1CC1
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Product: COc1cc2c(cc1OC)C(Cc1ccc(OCC3CC3)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with cyclopropyl-methyl bromide
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(O)[CH2:10][N:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[N:7]1)=[O:5])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(O)CN(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2Cl)=N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Yield: 69.7 %

Procedure:
A mixture of 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester I-7b (45 g, 108.8 mmol) and p-toluenesulfonic acid monohydrate (2.1 g, 10.8 mmol) in toluene (540 ml) was heated to reflux overnight. The reaction mixture was cooled and the solvent removed in vacuo. The crude residue was taken up in methylene chloride and washed with water, aqueous sodium bicarbonate, and brine. After drying over anhydrous magnesium sulfate and concentrating, the residue was purified by plug filtration on 600 g silica gel using ethyl acetate/hexanes (20:80) to give pure 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester I-7c (30 g, 69.7%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([S:16](Cl)(=[O:18])=[O:17])[C:9]=2[CH3:20])[CH2:5][C:4](=[O:21])[C:3]=1[C:22](=[O:25])[CH2:23][CH3:24].Cl.[NH3:27]>>[OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([S:16](=[O:18])(=[O:17])[NH2:27])[C:9]=2[CH3:20])[CH2:5][C:4](=[O:21])[C:3]=1[C:22](=[O:25])[CH2:23][CH3:24]
Reactant: N
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(S(=O)(=O)Cl)c2C)CC1=O
Agent: Cl
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(S(N)(=O)=O)c2C)CC1=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of 3-hydroxy-5-(2,4,6-trimethyl-3-chlorosulphonylphenyl)-2-propionylcyclohex-2-en-1-one (1.3 g) and aqueous ammonia (50 ml, 25%) was stirred at 20° C. for 1 hour. The mixture was acidified with dilute hydrochloric acid and the product was extracted into dichloromethane (2×100 ml). The organic layer was dried over anhydrous sodium sulphate and the solvent was removed by evaporation under reduced pressure using a rotary evaporator to give 3-hydroxy-5-(2,4,6-trimethyl-3-sulfamoylphenyl)-2-propionylcyclohex-2-en-1-one (1.1 g, 81%) as a pale brown foam. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.17 (3H, t): 2.42 (3H, s); 2.63 (3H, s); 2.72 (3H, s); 2.8-4.0 (7H, m); 4.98 (2H, s); 6.96 (1H, s); 18.27 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[N:18]1([C:22]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[N:18]1([C:22]([C:24]2[N:25]=[CH:26][C:27]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([OH:7])=[O:6])=[CH:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Temperature: 160 °C
Yield: 58 %

Procedure:
Methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (875 mg, 3.68 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (1.06 g, 4.41 mmol), caesium carbonate (3.59 g, 11.03 mmol), and bromotris(triphenylphosphine)copper (0.69 g, 0.735 mmol) were added together in DMA (16 mL) and heated in a microwave reactor at 160° C. for 9 hours. The mixture was taken up in water (25 mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was acidified with 1N hydrochloric acid (30 mL) and extracted with ethyl acetate (5×30 mL). The combined organic extract was washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and evaporated to give a brown solid which was triturated with diethyl ether to give the desired compound as a beige solid (820 mg).