Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[K+].[K+].[Si:35]([O:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47]Br)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C)C=O>[Si:35]([O:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 20 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole (164 mg) and potassium carbonate (115 mg) in N,N-dimethylformamide (5 mL) was added 3-tert-butyldimethylsilyloxymethylbenzyl bromide (197 mg) at room temperature, and the mixture was stirred for 20 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1–5/1) to give 4-[2-(3-tert-butyldimethylsilyloxymethylbenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole. To a solution of the obtained 4-[2-(3-tert-butyldimethylsilyloxymethylbenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole in tetrahydrofuran (2 mL) was added tetra-(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 0.065 mL) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (22 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([CH2:29][CH:30]=C)[C:13]([N:15]([CH2:25][CH2:26][O:27][CH3:28])[C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:17]=C)=[O:14].CS(C)=O>C1(C)C=CC=CC=1.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH3:28][O:27][CH2:26][CH2:25][N:15]1[C@H:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:30][CH2:29][CH:12]([N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[C:13]1=[O:14]
Reactant: C=CCC(C(=O)N(CCOC)[C@@H](C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COCCN1C(=O)C(N2C(=O)c3ccccc3C2=O)CC=C[C@H]1c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-(2-methoxyethyl)-N-[(1S)-1-phenylprop-2-en-1-yl]pent-4-enamide (6b) (524 mg) dissolved in Toluene (50 mL) at 80° C. under N2 was added Grubbs catalyst (2nd generation) (53 mg) and the reaction mixture was stirred at 80° C. for 1 h, then cooled to RT. DMSO (0.2 mL) was added to the reaction and the mixture stirred for 1 h, then concentrated. The crude product was directly purified via flash chromatography (gradient—5%, 10%, 20%, 30% EtOAc/hexanes) to give a diastereomeric mixture (1:1) of the title compound. (426 mg, 87%).
Reaction SMILES: [F:1][CH2:2][CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)[CH2:4][F:5].[H-].[Na+].F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].O>O1CCCC1>[F:5][CH2:4][CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=2[N+:27]([O-:29])=[O:28])[CH2:8][CH2:7]1)[CH2:2][F:1]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: OCC1CCN(C(CF)CF)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(OCC2CCN(C(CF)CF)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1-(1,3-difluoropropan-2-yl)piperidin-4-yl)methanol (0.068 g) in tetrahydrofuran (1 mL) was added sodium hydride (0.056 g) and the reaction stirred for 30 minutes at room temperature. 4-Fluoro-3-nitrobenzenesulfonamide (0.077 g) was added in one portion and stirring was continued for 1 hour. The reaction was poured into water (20 mL) and extracted with dichloromethane. The pH of the aqueous layer was adjusted to pH ˜8 and it was extracted with dichloromethane (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl-].[O:12]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[CH:22]=[N+:23]([CH3:25])[CH3:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[CH3:24][N:23]([CH3:25])[CH:22]([C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[NH:6][CH:5]=1)[C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=1
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Reactant: Cc1cccc2[nH]ccc12
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: Cc1cccc2[nH]cc(C(c3cccc(Oc4ccccc4)c3)N(C)C)c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-methyl-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=O.CC(C)([O-])C.[K+].[C:26]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:27][CH2:28][C:29]([O-:31])=[O:30].Cl>C(O)(C)(C)C.O>[CH2:34]([O:33][C:26]([C:27](=[C:5]([C:4]1[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=1)[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH2:28][C:29]([OH:31])=[O:30])=[O:32])[CH3:35]
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cccc(F)c2)cc1
Reactant: CCOC(=O)CCC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C(CC(=O)O)=C(c1ccc(S(C)(=O)=O)cc1)c1cccc(F)c1
Yield: 75.6 %

Procedure:
35.5 g (0.1275 mol) of 3-fluoro-4'-methanesulfonylbenzophenone, prepared in Example 10, are added in portions to a solution of 15.7 g (0.140 mol) of potassium t-butoxide in 100 ml of t-butanol. The mixture is stirred and 32 ml (0.191 mol) of ethyl succinate are added dropwise at a rapid rate. The mixture is subsequently refluxed for 30 minutes and cooled, water and 1N hydrochloric acid are added to bring the pH to 1 and the mixture is then extracted with t-butyl methyl ether. The organic phase is treated with 2% sodium hydroxide solution and the mixture is decanted. The aqueous phase is acidified with 1N hydrochloric acid and then extracted with t-butyl methyl ether. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 39.2 g of 3-ethoxycarbonyl-4-(3-fluorophenyl)-4-(4-methanesulfonylphenyl)-3-butenoic acid in the form of a thick oil, which is used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C=O)C>[N:19]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[N+:20]=[N-:21]
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(N=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 48 h
Yield: 98.1 %

Procedure:
A mixture of the title compound of Example 2 (57.1 g, 205 mmol) and NaN3 (39.9 g, 614 mmol, 3.0 eq) in DMF (200 mL) was heated and stirred at 70° C. for 48 h when TLC (solvent system C) indicated the reaction to be complete. The reaction mixture was cooled to rt and poured into cold water (200 mL). The aqueous mixture was extracted with Et2O (500 mL) and the organic extract was back-washed with water (2×100 mL), dried (Na2SO4) and the solvent was evaporated in vacuo to afford the product (45.5 g, 98%) as a colorless oil: 1H-NMR (CDCl3) ∂3.66-3.80 (m, 1H), 3.57 (m, 1H), 3.46 (m, Japp=4.0 Hz, 1H), 3.12 (m, 2H), 1.90-2.05 (m, 2H), 1.69-1.83 (m, 2H), 1.47 (s, 9H). No attempt was made to further purify or characterize this compound.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:28][C:29]1[CH:30]=[C:31]([CH:35]([N:39]2[CH:43]=[C:42]([C:44]3[C:45]4[CH:52]=[CH:51][N:50]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:46]=4[N:47]=[CH:48][N:49]=3)[CH:41]=[N:40]2)[CH2:36][CH:37]=O)[CH:32]=[CH:33][CH:34]=1>C1COCC1>[Br:28][C:29]1[CH:30]=[C:31]([CH:35]([N:39]2[CH:43]=[C:42]([C:44]3[C:45]4[CH:52]=[CH:51][N:50]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:58])[CH3:59])[C:46]=4[N:47]=[CH:48][N:49]=3)[CH:41]=[N:40]2)[CH2:36][CH:37]=[CH2:1])[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)[O-]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC=O)c4cccc(Br)c4)c3)ncnc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCC(c1cccc(Br)c1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Potassium tert-butoxide in THF (1M, 200 μL) was added to a solution of methyltriphenylphosphonium iodide (80 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) at 0° C. The reaction was stirred at room temperature for 1 h and then cooled to −78° C. The 3-(3-bromophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanal (90 mg, 0.0002 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was allowed to warm to room temperature gradually. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel eluting with EtOAc:Hexane, (1:1) to give 4-{1-[1-(3-bromophenyl)but-3-en-1-yl]-1H-pyrazol-4-yl}-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (35 mg, 40%) as an oil. m/z=524, 526 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([NH:8][C@:9]([C:31]2[CH:39]=[CH:38][C:34]([C:35](F)=[O:36])=[CH:33][CH:32]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:42]([F:45])([F:44])[F:43].[NH3:46]>C(#N)C>[C:35]([C:34]1[CH:33]=[CH:32][C:31]([C@@:9]([NH:8][C:6](=[O:7])[C:5]2[CH:40]=[CH:41][C:2]([F:1])=[C:3]([C:42]([F:43])([F:45])[F:44])[CH:4]=2)([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])[CH:20]=[C:19]([F:30])[CH:18]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:39][CH:38]=1)(=[O:36])[NH2:46]
Reactant: N
Reactant: O=C(F)c1ccc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1
Solvent: CC#N
Product: NC(=O)c1ccc([C@@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(OC(F)(F)C(F)F)c2)cc1
Reaction time: 24 h
Yield: 67.7 %

Procedure:
To a suspension of (R)-4-(1-(4-fluoro-3-(trifluoromethyl)benzamido)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)benzoyl fluoride (20 mg, 0.03 mmol) in acetonitrile (1 mL) was added ammonia (7 M in methanol, 20 μL, 0.14 mmol). The reaction mixture was stirred for 24 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (4 g silica gel; 0-100% ethyl acetate, hexane gradient over 14 min., 18 mL/min) to provide (R)—N-(1-(4-carbamoylphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (Example 320, 13 mg, 65% yield). LCMS: RT=1.81 min [M+H] 631 (Chromolith Performance 18e 4.6×100 mm column, 50-90% methanol, water with 0.1% trifluoroacetic acid gradient over 2 min, 5 mL/min). 1H NMR (400 MHz, CDCl3) ppm 7.86 (1H, d, J=4.83 Hz), 7.77 (1H, dt, J=8.35, 2.20 Hz), 7.71 (2H, d, J=8.35 Hz), 7.14-7.25 (3H, m), 7.08 (3H, t, J=7.47 Hz), 6.85-6.90 (3H, m), 6.71 (1H, s), 6.63 (2H, d, J=7.03 Hz), 6.05 (1H, s), 5.88 (1H, tt, JHH=2.75 Hz, JHF=53 Hz), 5.70 (1H, s), 3.86 (2H, dd, J=37.4, 13.2 Hz).
Reaction SMILES: Br.C(OC([NH:12][CH:13]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[S:15][CH2:14]1)=O)C1C=CC=CC=1.CCOCC>C(O)(=O)C>[NH2:12][CH:13]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[S:15][CH2:14]1
Reactant: O=C(NC1CSc2ccccc2NC1=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC1CSc2ccccc2NC1=O
Temperature: 25 °C

Procedure:
14 ml of a 25% solution of hydrogen bromide in acetic acid was added to 3.0 g of 3-benzyloxycarbonylamino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and the resulting mixture was stirred at room temperature for an hour. After the addition of ether, the precipitated crystals were separated by filtration to obtain 2.45 g of the hydrobroxide of the desired compound, or 3-amino-2,3-dihydro-1,5-benzothiazepin-4(5H)-one. Its melting point was 290° C. or above.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]1([C:27]2[N:28]=[CH:29][NH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:30]4[CH:31]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:28]=[CH:29]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(-n3cnc(-c4ccccc4)c3)c(F)cc2c1=O
Yield: 56.5 %

Procedure:
A mixture of 2.8 g (10 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 4.3 g (30 mmol) of 4-phenylimidazole, 20 ml of triethylamine and 100 ml of DMSO is refluxed for 3 hours. It is allowed to cool, poured into a water/ice mixture and adjusted to pH 5 to give a precipitate, which is filtered off and washed with water. The solid is dried under vacuum to give 2.3 g of 1-cyclopropyl-6,8-difluoro-7-(4-phenylimidazol-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid melting at 286°-288° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[CH:11][N:10]([CH3:24])[C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncn(C)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10.0 g. 4,5-bis(4-methoxyphenyl)imidazole in 100 ml of dimethylformamide was treated with 2.4 g of a 50% sodium hydride dispersion and then 8.0 g of methyl iodide was added dropwise. Stirring at room temperature was continued overnight and the reaction mixture was poured onto ice water. The product was collected by filtration and recrystallization from hot 1-chlorobutane gave 7.0 g of 4,5-bis(4-methoxyphenyl)-1-methyl-1H-imidazole, m.p. 121.5°-122°.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][N:9]=1)=[O:7])(C)(C)C.COC1C=CC=C(OC)C=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[C:15]([C:11]1[CH:12]=[C:13]([CH3:14])[C:8]([C:6]([OH:7])=[O:5])=[N:9][CH:10]=1)#[N:16]
Reactant: Cc1cc(C#N)cnc1C(=O)OC(C)(C)C
Agent: COc1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cnc1C(=O)O
Reaction time: 6.5 h

Procedure:
To a solution of 8.50 g (38.9 mmol) 5-cyano-3-methyl-pyridine-2-carboxylic acid tert-butyl ester in 51 ml (389 mmol) 1,3-dimethoxybenzene were added 85 ml TFA and stirred for 6.5 h. The reaction mixture was diluted with toluene and evaporated. The residue was taken up in toluene and evaporated (2×). The product was crystallized from TBME/hexanes to give the title compound as a white powder. HPLC: RtH1=2.314 min; ESIMS [M+Na]+=163; 1H-NMR (360 MHz, CDCl3): δ 8.77 (s, 1H), 8.07 (s, 1H), 2.87 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.S(=O)(O)[O-].[Na+].C(Cl)[Cl:33]>>[Cl:33][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]=1[O:12][CH3:13]
Reactant: COC(=O)c1nc(Cl)ccc1OC
Reactant: ClCCl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1nc(Cl)cc(Cl)c1OC
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
Methyl 6-chloro-3-methoxypicolinate (prepared as in Van Heertum, J. C. et al. U.S. Pat. No. 5,571,775 A, Nov. 5, 1996; 4.0 g, 20 mmol) was dissolved in dry CH2Cl2 (20 mL), treated with urea hydrogen peroxide complex (4.0 g, 43 mmol), cooled to 0-5° C., stirred and treated in portions with trifluoroacetic anhydride (5.6 mL, 40 mmol). The mixture was allowed to warm to 20° C. and stirred for 20 h. An additional portion of the urea hydrogen peroxide complex (2.0 g) and trifluoroacetic anhydride (2.8 mL) were added and stirring was continued for 4 h. The mixture was stirred with 10% sodium bisulfite (NaHSO3) solution until negative to starch-iodide paper. The organic phase was washed with H2O (10 mL), dried (Na2SO4) and evaporated. This material was dissolved in phosphorus oxychloride (POCl3; 30 mL) and heated at 70° C. for 2 h and then at reflux for 3 h to produce a 1:1 mixture of the isomeric 4,5- and 4,6-dichloropicolinates. After cooling, the volatiles were removed under vacuum, the residue was combined with ice and the product was taken up in EtOAc. This solution was washed with H2O, dried (Na2SO4) and evaporated. The crude mixture was purified by reverse-phase high performance liquid chromatography (RP-HPLC; eluting with 60% acetonitrile (CH3CN)—H2O) to provide the title compound (1.1 g, 23%): 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); EIMS m/z 235.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1>>[N:11]1([CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][NH:34][CH:35]=3)=[CH:3][CH:4]=2)[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Brc1ccc(C(CCn2ccnc2)Oc2ccccc2)cc1
Product: c1ccc(OC(CCn2ccnc2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
1-[3-(4-Bromo-phenyl)-3-phenoxy-propyl]-1H-imidazole was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1 to give the title compound. LC/MS: (PS-A2) Rt 2.05 [M+H]+ 345.30. 1H NMR (Me-d3-OD) δ 2.30-2.55 (2H, m), 4.25-4.45 (2H, m), 5.10-5.15 (1H, m), 6.80-6.90 (3H, m), 7.10 (1H, s), 7.15-7.20 (2H, t), 7.25 (1H, s), 7.35-7.40 (2H, d), 7.55-7.60 (2H, d), 7.85 (1H, s), 7.95 (2H, s).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:31][O:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:37][CH:36]=1)=[O:34]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(C2=COCCN2C(=O)OC(C)(C)C)cc1
Temperature: 65 °C
Yield: 50.3 %

Procedure:
Tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate (20 g, 46.1 mmol) and (4-methoxycarbonylphenyl)boronic acid (9.0 g, 49.8 mmol) were dissolved in acetonitrile (300 ml). A solution of potassium phosphate (19.6 g, 92.3 mmol) in water (75 ml) was added, followed by bis(tri-tert-butylphosphine)palladium (0) (2.36 g, 4.61 mmol). Nitrogen was bubbled through the stirred mixture for 40 minutes, then the mixture was heated to 65° C. for 2 hours. The mixture was cooled and diluted with ethyl acetate (1 L) and water (200 ml). The organic phase was separated and washed with sat NaHCO3 (3×200 ml), then brine (200 ml), dried (MgSO4), filtered and partially concentrated to 50 ml. Solid material was removed by filtration (700 mg). The filtrate was concentrated to a brown solid. The crude was purified on silica gel, eluting with 0-10% ethyl acetate/petrol. This gave the title compound as a white solid (7.4 g, 50%); 1H-NMR (CDCl3) 1.13 (9H, s), 3.80 (2H, t), 3.93 (3H, s), 4.20 (2H, t), 6.36 (1H, s), 7.31 (2H, d), 7.98 (2H, d); 13C-NMR (CDCl3) 27.7, 41.5, 52.0, 66.8, 124.5, 129.6, 133.7; MS ES(+) 264.1 (M+-tBu); Anal. Calcd for C12H21NO5: C, 63.94; H, 6.63; N, 4.38. Found: C, 63.83; H, 6.53; N, 2.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:27]([O:29][C:30](=[O:35])[CH:31](Br)[CH2:32][CH3:33])[CH3:28].C([O-])([O-])=O.[Na+].[Na+].O>CN1CCCC1=O>[CH2:32]([CH:31]([N:23]1[C:22](=[O:26])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)[CH:25]=[N:24]1)[C:30]([O:29][CH2:27][CH3:28])=[O:35])[CH3:33]
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C(CC)n1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Temperature: 75 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
A mixture of 2,4-dihydro4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.05 mol), 2-bromo-butanoic acid ethyl ester (0.055 mol) and Na2CO3 (0.15 mol) in 1-methyl-2-pyrrolidinone (250 m1) was stirred at 75° C. over 2-Bromobutanoic acid ethyl ester (0.015 mol) was added again. The mixture was stirred at 75° C. for 6 hours, at room temperature for 48 hours, poured out into H2O and stirred for 30 minutes. The precipitate was filtered off and dissolved in CH2Cl2. The solution was filtered. The filtrate was dried, filtered and the solvent was evaporated. The residue was triturated in diisopropylether and ethylacetate, filtered off and dried, yielding 10 g (43%) of (±)-ethyl α-ethyl-4,5-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl ]phenyl]-5-oxo- 1H-1,2,4-triazol-1-acetate (interm. 1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:25][CH:26]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:25]3[CH:26]=[C:21]([OH:20])[CH:22]=[CH:23][CH:24]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Oc1cccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-hydroxyphenylboronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.