Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH3:18].[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([Cl:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[N:25]=[C:24]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]3)=[CH:4][C:3]=2[O:17][CH3:18])[C:23]([Cl:27])=[CH:22][N:21]=1
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1nc(Cl)ncc1Cl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone (150 mg) prepared in Preparation Example 1, 2,4,5-trichloropyrimidine (120 mg) and potassium carbonate (120 mg) were dissolved in dimethylformamide (2 ml), and stirred at 80° C. overnight. The dimethylformamide of the mixture was removed under reduced pressure and added with water to form a solid. The solid was filtered to obtain a target compound.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7]C2C=NC(C)=NC=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[CH3:31][C:32]1[N:37]=[C:36](C=O)[CH:35]=[CH:34][N:33]=1>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:34]2[CH:35]=[CH:36][N:37]=[C:32]([CH3:31])[N:33]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: Cc1nccc(C=O)n1
Product: Cc1nccc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)n1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 2-methylpyrimidine-4-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.59 (d, J=5.0 Hz, 1H), 8.03 (s, 1H), 7.20 (d, J=5.0 Hz, 1H), 4.84-4.76 (m, 1H), 4.13-4.08 (m, 2H), 3.97-3.93 (m, 1H), 3.70-3.67 (m, 1H), 3.61-3.53 (m, 2H), 3.40 (t, J=8.3 Hz, 1H), 3.14 (d, J=9.5 Hz, 1H), 2.88 (m, 1H), 2.72 (s, 3H), 2.69-2.63 (m, 1H), 2.47-2.27 (m, 3H), 2.10-2.08 (m, 1H), 1.91-1.83 (m, 2H), 1.21 (d, J=7.1 Hz, 3H). MS: (M+H m/z 410.2).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)(C)C.O>[CH3:11][N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:23][CH2:22][N:21]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[CH2:20][CH2:19]2)[CH2:16][CH2:17]1
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCC(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)CC1

Procedure:
4-Fluoronitrobenzene (3 g, 21.3 mmol), 1-(1-methylpiperidin-4-yl)piperazine (3.9 g, 21.2 mmol) and triethylamine (3.30 mL, 23.7 mmol) are stirred in anhydrous isopropanol (10 mL) for 10 min at 160° C. in the microwave. The reaction mixture is diluted with water (10 mL), the precipitate is filtered off washed with 50% water in isopropanol and dried in vacuo at 45° C. Yield: 5.14 g
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[C@@H:10]([CH3:16])[NH:11][O:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Br:25][CH2:26][C:27](Br)=[O:28]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:17])[C@@H:10]([CH3:16])[N:11]([C:27](=[O:28])[CH2:26][Br:25])[O:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Br)CBr
Reactant: C=CCON[C@H](C)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCON(C(=O)CBr)[C@H](C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a solution of (R)-N-allyloxyalanine benzyl ester (2a) (2.59 g, 11 mmol) and Et3N (1.11 g, 11 mmol) in dry CH2Cl2 (30 mL), a solution of bromoacetyl bromide (2.22 g, 11 mmol) in dry CH2Cl2 (20 mL) was added dropwise with cooling (−25˜−30° C.) and stirring. The reaction mixture was stirred for 1 h at 0˜+5° C. and allowed to warm up to RT. After dilution with CH2Cl2 (ca. 30 mL), the mixture was washed with water (2×30 mL), 1N HCl (30 mL), sat. aq. NaHCO3 (30 mL), and dried over MgSO4. Removal of the solvent afforded 3.90 g (99%) of the product 3 as a yellowish oil. 1H NMR (100 MHz) in CDCl3 (J, Hz): δ 1.60 (3H, d, 3J=7.3, MeCH), 4.08 (2H, CH2Br), 4.49 (2H, dt, 3J=6.1, 4J=0.9, OCH2CH═CH2), 4.98 (1H, q, MeCH, 3J=7.3), 5.16-5.48 (2H, m, CH═CH2), 5.20 (2H, CH2Ph), 5.76-6.15 (1H, m, 3J=6.1, 3Jcis=10.0, 3Jtrans=17.3, CH═CH2), 7.29-7.41 (5H, m, Ph). IR (film), cm−1: 1746, 1678, 1455, 1214. MS (CI, isobutane), m/Z: 357 (M++1), 356 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Cl)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Cl)c(CBr)c1
Temperature: 25 °C

Procedure:
To a solution of the 1-chloro-4-methoxy-2-methylbenzene (2.0 g, 12.77 mmol) in anhydrous carbon tetrachloride (50 mL), NBS (2.29 g, 12.98 mmol) and benzoyl peroxide (0.154 g, 0.64 mmol) was added. The reaction mixture was heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to provide crude 2-(bromomethyl)-1-chloro-4-methoxybenzene, which was used for the next step without any further purification; 1H NMR (400 MHz, DMSO-d6): δ 3.74 (s, 3H), 4.66 (s, 2H), 7.01 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 7.38 (d, J=8.9 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C=O)C>[CH3:14][N:15]([CH3:17])[CH:16]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8](=[O:11])[CH2:9][CH3:10]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)Cc1ccccc1
Solvent: CN(C)C=O
Product: CCC(=O)C(=CN(C)C)c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution of 1-phenylbutan-2-one (5.00 g, 33.7 mmol) in DMF (80.0 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (6.03 g, 50.6 mmol). The resulting mixture was stirred at 90° C. for 16 h. Upon completion, the reaction mixture was quenched with water (40.0 mL), extracted with EtOAc (4×50.0 mL), and washed with brine. The combined organics were dried over MgSO4, filtered, and concentrated to give a brown oil. This brown oil was purified by flash chromatography to give the title compound as a yellow oil (3.32 g). 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.32 Hz, 3H), 2.19 (q, J=7.49 Hz, 2H), 2.67 (s, 6H), 7.14-7.41 (m, 5H), 7.61 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:14][C:15]#[CH:16])[C:4](=[O:17])[C:3]=1[CH3:18].[CH3:19][S-:20].[Na+]>CO>[CH3:18][C:3]1[C:4](=[O:17])[N:5]([CH2:14][C:15]#[CH:16])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:7][C:2]=1[S:20][CH3:19]
Reactant: C[S-]
Reactant: C#CCn1c(-c2ccccc2)nc(Cl)c(C)c1=O
Agent: [Na+]
Solvent: CO
Product: C#CCn1c(-c2ccccc2)nc(SC)c(C)c1=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 2.5 g (9.67 mmol) of 6-chloro-5-methyl-2-phenyl-3-propargyl-4(3H)-pyrimidinone in 100 mL of methanol, was added 0.8 g (11.4 mmol) sodium thiomethoxide and the reaction was stirred at room temperature for 4 days. The methanol was evaporated and the residue was dissolved in 100 mL of ethyl acetate, then washed three times with 50 mL of 1M sodium hydroxide followed by one time with 50 mL of brine. The organic layer was dried over MgSO4 and concentrated to yield 2.6 g crude product. Flash column chromatography on silica gel (100% methylene chloride) afforded 5-methyl-2-phenyl-3-propargyl-6-thiomethyl-4(3H)-pyrimidinone (Compound 26) as a white solid. 1H-NMR (CDCl3) δ2.1 (3H, s); 2.35 (1H, t); 2.5 (3H, s); 4.55 (2H, d); 7.5 (3H, m); 7.7 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH3:27])[C:9]([CH2:18][CH:19]([OH:26])[CH2:20][C:21]([O:23]CC)=[O:22])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].CO>O1CCCC1>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH3:27])[C:9]([CH2:18][CH:19]([OH:26])[CH2:20][C:21]([OH:23])=[O:22])=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(O)Cc1c(C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn2c(Cl)ccc2c(-c2ccc(F)cc2)c1CC(O)CC(=O)O
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoate (52 mg) in tetrahydrofuran (1 ml) was added 1N sodium hydroxide (0.27 ml), followed by methanol (1 ml). After standing at 20° C. overnight, the mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to give 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoic acid (45 mg) as an yellow oil.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=2)=[O:4])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CSc1ccc(C(=O)C(C)(C)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(C(=O)C(C)(C)OC(=O)Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of 72 mg (0.34 mmol) 2-hydroxy-4'-(methylthio)isobutyrophenone in 1.7 mL of CH2Cl2 were added 0.2 mL of pyridine and 140 mg (0.81 mmol) of 4-fluorophenylacetyl chloride. The mixture was stirred at room temperature overnight and then quenched with NH4OAc buffer. The product was extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography eluting with 8:1 hexane/EtOAc to give 95 mg of the title product.
Reaction SMILES: [Li]CCCC.N1CCC[C@H]1C(O)=O.[CH3:14][C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1>CCOCC>[C:21]1([CH:15]([C:16]2[CH2:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C1=CC=CC1)c1ccccc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
n-BuLi (15 mL, 1.6M in hexanes, 24 mmol) was added dropwise to 1.4 g (12 mmol) of L-proline in 40 mL of ether. The resulting suspension was allowed to stir at room temperature over night. The reaction mixture was cooled to -78° C. and 2.0 g (12 mmol) of 6-methyl-6-phenylfulvene added dropwise. The reaction mixture was stirred at -78° C. for eight hours. The reaction mixture was allowed to warm to room temperature and the organic and aqueous layers were separated. The organic layer was dried over MgSO4 and the solvent removed under vacuum to give 2.05 g (100% yield) of (1-phenylethyl)cyclopentadiene as a yellow oil. The product was found to have a specific rotation of 4°(12% ee) .
Reaction SMILES: C[Li].[CH3:3]N(C)CCN(C)C.[CH3:11][C:12](=[CH2:21])[CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]([OH:20])=[O:19].CO>C(OCC)C.CCCCCC>[CH3:3][C:16]([CH2:15][CH2:14][CH2:13][C:12]([CH3:11])=[CH2:21])=[CH:17][C:18]([OH:20])=[O:19]
Reactant: CN(C)CCN(C)C
Reactant: C=C(C)CCCC#CC(=O)O
Agent: [Li]C
Solvent: CO
Solvent: CCCCCC
Solvent: CCOCC
Product: C=C(C)CCCC(C)=CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 11.0 mmol of cuprous iodide in 30 ml of dry diethyl ether at -40° under nitrogen is added 10.6 mmol of methyllithium in hexane, followed immediately by 13.0 mmol of tetramethylethylenediamine (TMEDA). After stirring for 30 min, the suspension is cooled to about -50°, and 10 mmol of the methyl ester of 7-methyl-7-octen-2-ynoic acid in 1 ml ether is added dropwise. The temperature is maintained at -45° to -50° for 20 min and then 2 ml of methanol is added dropwise to quench the reaction, followed by 1 ml sat. (NH4)2SO4. The suspension is allowed to warm to RT, after which the solid is filtered off and washed with ether. The combined organic layers are washed with sat. (NH4)2SO4, 5% HCl, sat. NaHCO3 and brine, then dried over CaSO4. The solvent is removed by distillation, yielding the Z methyl ester of 3,7-dimethyl-2,7-octadienoic acid.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=2[O:22][CH3:23])=[CH:9][CH:8]=1)C.CC(C[AlH]CC(C)C)C>>[CH:19]([C:17]1[CH:16]=[CH:15][C:14]([O:22][CH3:23])=[C:13]([C:10]2[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[CH2:4][OH:3])=[CH:8][CH:9]=2)[CH:18]=1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)/C=C/c1ccc(-c2cc(C(C)C)ccc2OC)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: COc1ccc(C(C)C)cc1-c1ccc(/C=C/CO)cc1

Procedure:
(E)-3-(5′-Isopropyl-2′-methoxy-biphenyl-4-yl)-acrylic acid ethyl ester was reduced by DIBAL-H by a procedure analogous to that described in example 52b to give (E)-3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-prop-2-en-1-ol.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[C:11]([F:39])[CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][CH:66]=1>ClCCCl>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=4[F:39])[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:66][CH:67]=1)#[N:70]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Yield: 51.2 %

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 71 (0.4 g, 0.67 mmol), was reacted with diisopropylethylamine (0.69 g, 5.4 mmol), diphenylphosphinic chloride (0.63 g, 2.7 mmol) in 1,2-dichloroethane at room temperature, then reacted with 4-aminobenzonitrile (Aldrich) (0.24 g, 2.1 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white solid (Yield 0.2 g, 51%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>C(N(CC)CC)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][O:23][C:19](=[O:22])[CH:20]=[CH:21][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:7][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Oc1ccc(-c2cc3cc(O)cc(Br)c3o2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 15.6 %

Procedure:
To a solution of 7-bromo-2-(4-hydroxy-phenyl)-benzofuran-5-ol 58 (1.0 g, 3.3 mmol) in triethylamine (10 mL) and acetonitrile (10 mL) was added methyl acrylate (0.44 mL, 4.9 mmol) and tri-(o-toly) phosphine (0.2 g, 0.66 mmol). This mixture was purged with nitrogen for 10 minutes. Then palladium (II) acetate (0.037 g, 0.17 mmol) was added and the reaction was heated at reflux for 4 hours. To the cooled reaction was added 2N HCl and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and the solvent removed in vacuo. The residue was purified via flash chromatography on silica gel, eluting with 22-50% ethyl acetate in hexane to give 0.16 g of 59: Mp=231-234° C.; 1H NMR (DMSO-d6) δ 9.93 (s, 1 H), 9.44 (s, 1 H), 7.80 (d, 1H, J=16.1 Hz), 7.72 (d, 2 H, J=8.6 Hz), 7.13 (s, 1 H), 7.02 (d, 1H, J=2.3 Hz), 6.98 (d, 1 H, J=2.3 Hz), 6.93 (d, 1 H, J=16.2 Hz), 6.92 (d, 2 H, J=8.6 Hz) 3.79 (s, 3 H); MS 311 (M+H)+
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]12[CH2:14][CH:11]([NH:12][CH2:13]1)[CH2:10][N:9]2[C:15]1[N:20]=[C:19]([NH2:21])[N:18]2[N:22]=[C:23]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[N:24]=[C:17]2[CH:16]=1.Cl[CH2:31][C:32]1[C:33]([CH3:38])=[N:34][O:35][C:36]=1[CH3:37].CCN(CC)CC>CC#N>[CH3:38][C:33]1[C:32]([CH2:31][N:12]2[CH2:13][CH:8]3[CH2:14][CH:11]2[CH2:10][N:9]3[C:15]2[N:20]=[C:19]([NH2:21])[N:18]3[N:22]=[C:23]([C:25]4[O:26][CH:27]=[CH:28][CH:29]=4)[N:24]=[C:17]3[CH:16]=2)=[C:36]([CH3:37])[O:35][N:34]=1
Reactant: Cc1noc(C)c1CCl
Reactant: Nc1nc(N2CC3CC2CN3)cc2nc(-c3ccco3)nn12
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1CN1CC2CC1CN2c1cc2nc(-c3ccco3)nn2c(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The TFA salt of 7-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-furan-2-yl-[1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine (0.3 mmol; see Example 18 above) was dissolved in 3 mL of CH3CN along with 0.3 mmol of 4-chloromethyl-3,5-dimethyl-isoxazole (Aldrich-Sigma, St. Louis, Mo.) and 0.5 mmol of Et3N. The reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and purified by preparative HPLC to afford the title compound. 1H NMR (400 Hz, DMSO-d6) δ 7.80 (d, J=1.0 Hz, 1H), 7.00 (d, J=3.6 Hz, 1H), 6.60 (dd, J=3.6, 1.0 Hz, 1H), 5.7 (s, 1H), 4.80 (brs, 2H), 2.4-3.6 (m, 14H). MS m/z: 407 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
To a solution of 3-bromo-4-hydroxybenzaldehyde (5 g, 25 mmol, 1 eq, Aldrich, Milwaukee, Wis., USA) in DMF (200 mL) was added solid cesium carbonate (16.25 g, 50 mmol, 2 eq) followed by dropwise addition of t-butyl 2-bromoacetate (4.4 mL, 30 mmol, 1.2 eq, Aldrich, Milwaukee, Wis., USA). After stirring at room temperature for 18 h, the DMF was removed in vacuo and the resultant residue was extracted between EtOAc (50 mL) and brine (50 mL). The separated organic layer was dried (Na2SO4), and concentrated in vacuo to give 7.74 g (98.4%) of t-butyl 2-(2-bromo-4-formylphenoxy)acetate (1). 1HNMR (CDCl3, 300 MHz): δ 9.83 (s, 1H), 8.08 (d, 1H), 7.76 (dd, 1H), 6.83 (d, 1H), 4.67 (s, 1H).1.44 (s, 9H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=1.[CH3:16]O>>[CH3:16][O:14][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:6])[N:12]=1)=[O:15]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)n1
Yield: 46 %

Procedure:
Concentrated sulfuric acid (5 mL) was added cautiously with stirring to a suspension of 6-methyl-pyridine-2-carboxylic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.; 7.00 g, 51 mmol) in methanol (approximately 250 mL). The mixture was heated at reflux overnight (with a calcium chloride drying tube) and then the solution was concentrated almost to dryness. A little water was added and then aqueous sodium bicarbonate was added to bring the pH to 8. The solution was extracted with ethyl acetate (2×100 mL) and the extracts were washed with brine, then dried (magnesium sulfate), filtered, and evaporated to give 6-methyl-pyridine -2-carboxylic acid methyl ester (3.53 g, 46%) as a pale yellow oil. Mass spectrum m/z 152.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCl.[C-:12]#[N:13].[Na+].[Cl-].[OH-].[Na+].Cl>C(Cl)(Cl)(Cl)Cl.O>[N:8](=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]#[N:13])[OH:9]
Reactant: ON=Cc1ccccc1
Reactant: [C-]#N
Agent: Cl
Agent: ClCl
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(=NO)c1ccccc1
Temperature: 25 °C

Procedure:
To 9.07 g (75 mmol) of benzaldoxime in 25 ml of carbon tetrachloride is added dropwise, at 5°, a solution of 45 ml of carbon tetrachloride saturated with 5.6 g (79 mmol) of chlorine gas. The mixture is stirred for 1 hourin an ice bath and then excess chlorine is removed by vacuum. A saturated solution of 7.35 g (150 mmol) of sodium cyanide in water is added dropwise, at 0°, to the thus-prepared phenhydroxamoyl chloride (I; R is phenyl, X is chloro). The mixture is stirred for 2 hours as it is allowed to warm to RT. An excess of aqueous sodium hydroxide is added to dissolve the product into the aqueous solution and then the carbon tetrachloride layer is discarded. The aqueous layer is acidified (HCl) and filtered, and the resulting solid is washed with water and dried to give α-oximinophenylacetonitrile, m.p.=120°-125° (II, R is phenyl).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:10]=[CH:23][CH:24]=[O:25])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cccc(-c2ncccn2)c1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1cccc(-c2ncccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 12) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[CH:31]=[CH:32][C:33]([OH:38])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([Br:29])[CH:31]=[CH:32][C:33]=3[OH:38])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Oc1ccc(Br)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-bromo-2-hydroxy-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 560.9.