Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:12]=2)[C:5]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[C:4]([C:26](=O)[CH3:27])[CH:3]=1.C([O-])(=O)C.[NH4+:33]>CO.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[CH:12]=2)[C:5]([C:18]2[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=2)=[C:4]([CH:26]([NH2:33])[CH3:27])[CH:3]=1
Reactant: [NH4+]
Reactant: CCOC(C)n1cc(-c2cc(Cl)cc(C(C)=O)c2-c2cc(F)cc(F)c2)cn1
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CC#N
Product: CCOC(C)n1cc(-c2cc(Cl)cc(C(C)N)c2-c2cc(F)cc(F)c2)cn1
Yield: 31.5 %

Procedure:
A solution of 1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluorobiphenyl-2-yl}ethanone (190 mg, 0.47 mmol), ammonium acetate (360 mg, 4.7 mmol) in methanol (2 mL) and acetonitrile (2 mL) was heated at 65° C. for 3 hours. The reaction mixture was quenched with acetic acid (˜100 uL) and poured into sodium bicarbonate (50 mL). This mixture was extracted with dichloromethane (3×60 mL) and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (60 mg, 32%). LCMS for C21H23ClF2N3O (M+H)+: m/z=406.1. Found: 406.1.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C1C(=O)N([Br:20])C(=O)C1.O>CN(C=O)C>[Br:20][C:9]1[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)c1cccc(C(=O)O)c1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.3 %

Procedure:
A solution of 3-(dimethylamino)benzoic acid (5.13 g, 31.0 mmol) in DMF (20 mL) was cooled to 5° C. To this cold solution was added NBS (6.23 g, 35.0 mmol) in several portions in order to keep the internal reaction temperature at 5° C. The reaction mixture was allowed to stir at this temperature for 15 min and then to warm to rt. The mixture was poured into water and extracted with EtOAc. The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered, and concentrated to give 2-bromo-5-(dimethylamino)benzoic acid (7.89 g, 93%) which was used without purification in the next step.
Reaction SMILES: P(=O)(O)(O)O.S(=O)(=O)(O)[OH:7].[C:11]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])(=[O:15])[CH2:12][CH:13]=[CH2:14]>O.ClCCCl.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:19][CH:18]([CH3:20])[CH2:17][O:16][C:11](=[O:15])[CH2:12][CH:13]1[O:7][CH2:14]1
Reactant: C=CCC(=O)OCC(C)C
Reactant: O=S(=O)(O)O
Agent: O=[W](=O)([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(C)COC(=O)CC1CO1
Temperature: 70 °C

Procedure:
Sodium tungstate dihydrate (0.852 g, 2.5 mmol), 85% phosphoric acid (0.850 ml, 5 mmol) 36.3% hydrogen peroxide (5.6 ml, 60 mmol) were dissolved in 20 ml of water and the pH was adjusted to 1.6 by 10% sulphuric acid. The solution was heated to 70° C., and under vigorous stirring a solution of 2-methylpropyl 3-butenoate (7.1 g, 50 mmol), trimethylcaprylammonium chloride (0.41 g) in 1,2-dichloroethane (15 ml) was added. After 6 hours the mixture was cooled, then the layers were separated. The aqueous phase was washed with 30 ml of dichloroethane. Organic layers were collected, washed with 2×40 ml of saturated solution or sodium sulphite, dried and distilled. The title compound was obtained as a colourless oil, b.p. 104°-108° 30 mmHg.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]([C@@H:36]2[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[N:37]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:33]([OH:35])=O)=[C:28]([F:50])[CH:27]=1.Cl.Cl.[CH3:53][C@H:54]1[C:62]2[C:61]([N:63]3[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]3)=[N:60][CH:59]=[N:58][C:57]=2[C@@H:56]([OH:69])[CH2:55]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([C@H:36]2[N:37]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[C:38]([CH3:41])([CH3:42])[CH2:39][CH2:40]2)[C:33]([N:66]2[CH2:67][CH2:68][N:63]([C:61]3[C:62]4[C@H:54]([CH3:53])[CH2:55][C@@H:56]([OH:69])[C:57]=4[N:58]=[CH:59][N:60]=3)[CH2:64][CH2:65]2)=[O:35])=[C:28]([F:50])[CH:27]=1
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@H](C(=O)O)c2ccc(Br)cc2F)CCC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.9 %

Procedure:
HATU (0.149 g, 0.391 mmol) was added to a solution of (R)-2-(4-bromo-2-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.168 g, 0.391 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.1 g, 0.326 mmol; see Example 3, Step 12), and N-ethyl-N-isopropylpropan-2-amine (0.171 mL, 0.977 mmol) in DCM (8 mL), and the reaction mixture was stirred overnight at room temperature. The reaction was then quenched with H2O. The reaction was washed with H2O (3×30 mL). The organic layer was dried with MgSO4, filtered and concentrated. Purification by flash chromatography yielded (S)-tert-butyl 5-((S)-1-(4-bromo-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.0334 g, 0.0517 mmol, 15.9% yield). LCMS (APCI+) 646.4, 648.5 m/z [M+H]+; Retention time=4.25 minutes.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C:10]3=[C:9]([C:23](OC)=[O:24])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:28][NH:29][O:30][CH3:31].C([Mg]Cl)(C)C>C1COCC1>[CH3:31][O:30][N:29]([CH3:28])[C:23]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:15][C:10]=12)=[O:24]
Reactant: CNOC
Reactant: COC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
Under a nitrogen atmosphere 7-tert-butyl 1-methyl 3-phenyl-5,6-dihydroimidazo[1,5-a]pyrazine-1,7(8H)-dicarboxylate (Intermediate 3A) (1.50 g, 4.20 mmol) was dissolved in THF (6 mL) and N,O-dimethyl-hydroxylamine hydrochloride (1.23 g, 12.59 mmol) was added. The resulting suspension was cooled to −20° C. and a solution of iPrMgCl (2M, 6.3 mL, 12.59 mmol) in THF was added dropwise over 10 min. The mixture was stirred for 20 min at −10° C. and then was quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, filtered and concentrated to provide Intermediate 26A as a white solid (1.35 g, 83%). 1H-NMR (400 MHz, CDCl3) δ: 1.52 (s, 9H), 3.63 (s, 3H), 3.80 (m, 2H), 3.90 (s, 3H), 4.12 (t, 2H), 5.02 (s, 2H), 7.46 (m, 3H), 7.65 (m, 2H); LCMS (+ESI) m/z 387.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([N:17]1[C:21]2[C:22](=[O:33])[N:23]([CH2:31][CH3:32])[C:24]3[N:25]([N:26]=[C:27]([CH2:29]Br)[N:28]=3)[C:20]=2[N:19]=[C:18]1[CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[CH2:10]([N:17]1[C:21]2[C:22](=[O:33])[N:23]([CH2:31][CH3:32])[C:24]3[N:25]([N:26]=[C:27]([CH2:29][O:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:28]=3)[C:20]=2[N:19]=[C:18]1[CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CBr)nc12
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(COc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
66 mg of sodium hydride (66% in mineral oil) are added to a solution of 0.16 g of phenol in 15 ml of dimethylformamide. After 30 minutes' stirring at ambient temperature, 0.68 g of 6-benzyl-2-bromomethyl-7-cyclopentyl-4-ethyl-imidazo[4,5-e]-s-triazolo[1,5-a]pyrimidin-5-one are added. The mixture is stirred at elevated temperature (about 100° C.) until the reaction is complete (about 8 hours). For working up, some water is added and then the solvent is distilled off in vacuo. The residue remaining is taken up in 20 ml of dichloromethane and 20 ml of water. After acidification with aqueous 1N HCl solution, the organic phase is separated off, washed with water and dried over magnesium sulphate. The solvent is distilled off and the residue remaining is recrystallised from diethyl ether. 0.6 g of the title compound remain, pure enough to be used in the subsequent reactions.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)([CH3:29])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([CH:27]([CH3:28])[CH3:29])=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, light yellow solid (42 mg, 36%), MS (ISP) m/z=473.4 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-isopropyl-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].S(=O)(=O)(O)O.[CH2:28]([C:30](=[CH2:33])[CH:31]=O)[CH3:29]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:6]([CH:31]=[C:30]([CH2:28][CH3:29])[CH:33]=[N:5]2)=[CH:7][CH:8]=1
Reactant: C=C(C=O)CC
Reactant: Nc1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: CCc1cnc2cc(Br)ccc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a well-stirred mixture consisting of 3-bromo-aniline (5.40 g, 31.4 mmol), sodium 3-nitro-benzene sulfonate (4.25 g, 18.9 mmol), 8.5 g (177 mmol) of concentrated sulfuric acid, and 3.2 ml of water heated to 100° C., 2-ethyl acrolein (5.0 ml, 51 mmol) was added. After maintaining the reaction temperature at 100° C. for 1 hour, the temperature was elevated to 110° C. An additional portion of 2-ethyl acrolein (1.0 ml, 10.2 mmol) was added, and the reaction was stirred at 110° C. for 1 hour. The reaction temperature was then elevated to 120° C. prior to addition of another 1.0 ml (10.2 mmol) portion of 2-ethyl acrolein. After heating the reaction at 120° C. for 1 hour, the temperature was increased to 130° C. prior to addition of 1.0 ml (10.2 mmol) of 2-ethyl acrolein. Finally, the reaction temperature was raised to 140° C. and maintained at that temperature for 2 hours after addition of a final portion (1.3 ml, 13.2 mol) of 2-ethyl acrolein. The cooled reaction was quenched with ice (50 g), and the pH of the resulting mixture was adjusted to by addition of 6 N aqueous sodium hydroxide. The mixture was then extracted with two 30 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo, affording an amber oil. Flash chromatography of the entire sample utilizing the Biotage Flash 401i™ silica gel flash chromatography module and manufacturer's prepacked silica gel cartridges described in Example 1, Step 4, and eluting with methylene chloride, afforded the title compound (1.46 g, 19.7% yield) as a viscous light amber syrup which solid on standing.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][N+:12]([O-])=O)=[CH:6][CH:5]=1.[H][H]>[Pd].C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CCN)cc1
Yield: 103.9 %

Procedure:
Palladium on carbon (10%, 50 mg) was added to a solution of 4-(2-nitrovinyl)benzoic acid methyl ester (228 mg) in 5 mL of ethyl alcohol and 2 mL of acetic acid. The reaction vessel was saturated with hydrogen and stirred under a 1 atm hydrogen atmosphere for 20 h. The vessel was saturated with nitrogen and filtered through celite. Evaporation of the solvents gave 205 mg of crude 4-(2-amino-ethyl)-benzoic acid methyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[CH:18][CH:19]=2)[C:10]([F:25])=[C:9]([CH3:26])[C:8]=1[F:27])#[N:2].CI.N1(C2CCCCCCCCCC2)CCCCCCCC[CH2:35]N1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([O:24][CH3:35])=[O:23])[CH:17]=[CH:18][CH:19]=2)[C:10]([F:25])=[C:9]([CH3:26])[C:8]=1[F:27])#[N:2]
Reactant: Cc1c(F)c(Oc2cccc(C#N)c2)nc(Oc2cccc(CCC(=O)O)c2)c1F
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Solvent: ClCCl
Solvent: CI
Product: COC(=O)CCc1cccc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Reaction time: 15 h

Procedure:
To 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionic acid (0.50 g, 1.2 mmol) in methylene chloride (20 mL) was added methyl iodide (0.26 g, 1.8 mmol) and diazabicycloundecane (2.8 g, 1.8 mmol). After stirring for 15 hours, the solution was concentrated in vacuo and chromatographed on silica gel with ethyl acetate/hexane (1/4) to give 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionic acid, methyl ester; NMR (CDCl3) 7.3 (m,5), 7.05 (d,1), 6.85 (m,2), 3.68 (s,3), 2.9 (t,2), 2.55 (t,2), 2.4 (s,3) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.CN1CCOCC1.ClC(OCC)=O.C(=[N:31][CH2:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)C1C=CC=CC=1>ClCCl>[NH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:10])[CH2:35][CH2:34]1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: NCC1CCN(C(=O)c2cccnc2Cl)CC1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A solution of 2-chloropyridine-3-carboxylic acid (4.09 g) and 1-methylmorpholine (2.7 ml) in dichloromethane (100 ml) was stirred at -5° C. under nitrogen and ethyl chloroformate (2.4 ml) was added dropwise. After 10 minutes a solution of N-benzylidene-1-(4-piperidyl)methylamine (5.0 g) in dichloromethane (25 ml) was added and stirring continued at -5° C. for 2 hours then at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue stirred with potassium hydrogen sulphate solution (1 M; 250 ml) for 5 hours. The mixture was filtered and the filtrate washed with dichloromethane (2×150 ml), basified with aqueous sodium hydroxide solution (5 M) and extracted with dichloromethane (3×150 ml). The combined extracts were dried over magnesium sulphate and the solvent was evaporated to give 4-(aminomethyl)-1-(2-chloro-3-pyridylcarbonyl)-piperidine (4.81 g) contaminated with some 1-methylmorpholine. This material was used in the next reaction without further purification.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:9]>[O-2].[Cr+3].[Cu+2]>[C:1]([NH2:8])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: O
Agent: [Cr+3]
Agent: [Cu+2]
Agent: [O-2]
Product: NC(=O)c1ccccc1
Yield: 20 %

Procedure:
Watanabe et al., in Bull. Chem. Soc. Japan, 39, 8 (1966) also show the use of a copper chromium oxide catalyst, Cu--CrO2, to convert benzonitrile to benazmide. Although the preparation is not disclosed, Watanabe's catalyst apparently was not prepared according to the present invention since benzonitrile in water reacted in the presence of the catalyst for 8 hours gave only a 20% yield of benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[C:34]([F:36])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:37])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:35]=[C:34]([F:36])[C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:37])[CH:3]=1
Reactant: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
A solution of 4-(4-bromo-2,6-difluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (578 mg, 1 mmol) in methylene chloride (10 ml) containing TFA (4 ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was suspended in water. The aqueous layer was adjusted to approximately pH10 and was extracted with methylene chloride. The organic layer was washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with ether and dried under vacuum to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (110 mg, 23%).
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:47])[NH:12][C:13]1([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[C:25]4[CH:30]=[CH:29][C:28](B5OC(C)(C)C(C)(C)O5)=[CH:27][N:26]4[C:40]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].[CH2:48]([O:55][C:56]1[C:61](Br)=[CH:60][CH:59]=[CH:58][N:57]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[C:6]([O:10][C:11](=[O:47])[NH:12][C:13]1([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]=[C:25]4[CH:30]=[CH:29][C:28]([C:61]5[C:56]([O:55][CH2:48][C:49]6[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=6)=[N:57][CH:58]=[CH:59][CH:60]=5)=[CH:27][N:26]4[C:40]=3[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH2:16]1)([CH3:8])([CH3:7])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(B5OC(C)(C)C(C)(C)O5)cn4c3-c3ccccc3)cc2)CCC1
Reactant: Brc1cccnc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(-c5cccnc5OCc5ccccc5)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 110 °C

Procedure:
To the crude DMF solution of the boronate from Step 1 was added 2-benzyloxy-3-bromopyridine (0.25 g), aqueous sodium carbonate solution (2M, 2.8 mL) and dioxane (4 mL) and the mixture placed under argon. [1,1-bis-(diphenylphosphino)-ferrocene]-dichloropalladium-dichlormethane-complex (0.070 mg) was added and the mixture heated at 110° C. under microwave irradiation for 30 minutes. On cooling the mixture was partitioned between DCM and water and extracted. The organic portion was washed with brine, dried and concentrated in vacuo. Purification was achieved by chromatography on silica gel to give the title compound (138 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][C:6](=[O:43])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:41]C)([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].C(N)(C)(C)C>>[CH3:44][Si:2]([CH3:1])([CH3:45])[CH2:3][CH2:4][O:5][C:6](=[O:43])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([OH:41])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(OC)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Solvent: CC(C)(C)N
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Temperature: 60 °C
Yield: 41.5 %

Procedure:
A mixture of 2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (184 mg, 0.270 mmol) in tert-butylamine (2.8 mL, 27 mmol) was heated at 60° C. for 24 hours. The solution was allowed to cool to room temperature and concentrated. The residue was purified by silica gel column chromatography using MeOH/CH2Cl2 (0-30%) to provide 75 mg of the product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 9H), 0.04 (s, 9H), 0.89 (appt t, 2H, J=9 Hz), 1.23 (appt t, 2H, J=9 Hz), 1.77 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s, 3H), 2.36 (d, 1H, J=22 Hz), 2.38 (d, 1H, J=22 Hz), 2.52 (septet, 1H, J=9 Hz), 3.39 (d, 2H, j=7 Hz), 3.51 (d, 3H, J=11 Hz), 4.01-4.08 (m, 2H), 4.30 (dd, 2H, J=8, 9 Hz), 5.11 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.56 (m, 2H), 8.49 (br s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 22.1 ppm; MS (m/z) 667.4 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:14]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-Methyl-3-nitrophenol (10.0 g) was mixed with iodoethane (10.5 mL), potassium carbonate (13.5 g) and DMF (130 mL), and the obtained mixture was stirred at 60° C. overnight. Water was added to the reaction mixture, and the mixture was extracted twice with diethyl ether. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (11.8 g).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[OH:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:19][CH2:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: OCc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(CO)cccc21
Yield: 77.8 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 173 mg of 4-(hydroxymethyl)indoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 288 mg of 2-{2-[4-(hydroxymethyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following: