Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[N:27]1([C@H:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:34]3[CH2:35][CH2:36][CH2:37][C@H:32]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:33]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C1CNC[C@@H](N2CCCC2)C1
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@H](N4CCCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-3-(pyrrolidin-1-yl)piperidine dihydrochloride. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.42-1.55 (m, 1 H) 1.61 (d, J=9.76 Hz, 1 H) 1.77 (br. s., 5 H) 2.06 (d, J=8.79 Hz, 1 H) 2.42 (s, 3 H) 2.77 (br. s., 2H) 2.87-3.09 (m, 2 H) 3.12-3.24 (m, 2 H) 3.33 (br. s., 1 H) 3.47-3.92 (m, 1 H) 3.93-4.48 (m, 1 H) 7.53 (dd, J=8.30, 1.95 Hz, 1 H) 7.58 (s, 1 H) 7.90-7.95 (m, 2 H) 8.08 (d, J=7.81 Hz, 1 H) 8.46-8.51 (m, 2 H); ESI-MS m/z [M+H]+ 457.3.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].C(N(CC)CC)C>ClCCl>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl isonipecotate (27.6 g, 175 mmol) in dichloromethane (50 ml) was added dropwise over 10 minutes to a solution of 3-chlorobenzoyl chloride (20 ml, 160 mmol) and triethylamine (28 ml, 200 mmol) in dichloromethane (500 ml) cooled to between 10 and 15° C. The reaction was then stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue was diluted with ether, the solution washed with 1N hydrochloric acid, sodium carbonate solution (×3) and brine. It was then dried over MgSO4 and evaporated under reduced pressure, to give the title compound as a solid, 44.49.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[N:5]\[O:6][CH3:7].[CH3:23][NH2:24]>>[CH3:23][NH:24][C:3](=[O:2])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[N:5]\[O:6][CH3:7]
Reactant: CN
Reactant: CO/N=C(\C(=O)OC)c1ccccc1Oc1cccc(C)c1
Product: CNC(=O)/C(=N\OC)c1ccccc1Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To Product (A') (286 mg), i.e. methyl-(Z)-2-[2-(3-tolyloxy)phenyl]-2-methoxyiminoacetate, 30% methanolic methylamine (197 mg) was added, followed by stirring at room temperature for 12 hours. Excess amine and methanol were removed from the mixture, which was subjected to silica gel column chromatography with a mixture of hexane and ethyl acetate to give 201 mg of (Z)-N-methyl2-[2-(3-tolyloxy)phenyl]-2-methoxyiminoacetamide (Compound No. 5).
Reaction SMILES: N1[C:5]2C=CC=[CH:9][C:4]=2N=N1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.FC(F)(F)[C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:21][N:22]([CH2:29][C:30]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:31]=1C=O)[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1>C(O)C>[F:48][C:45]([F:47])([F:46])[C:43]1[CH:42]=[C:20]([CH:19]=[C:18]([C:38]([F:41])([F:40])[F:39])[CH:44]=1)[CH2:21][N:22]([CH2:29][C:30]1[CH:37]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:35]=[CH:34][C:31]=1[CH:5]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:4][CH3:9])[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: C1COCCN1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C=O)n1
Solvent: CCO
Product: CCC(c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of benzotriazole (25.6 mg, 0.215 mmoles) in ethanol (2 mL) was added morpholine (18.7 mg, 0.215 mmoles) and the reaction mixture was stirred for 10 minutes at room temperature. A solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde (100 mg, 0.195 mmoles) in ethanol (2 mL) was added and the reaction mixture was further stirred for 16 hours. MS indicated formation of the imine intermediate MH+=581.4. The ethanol was evaporated and the residue was dissolved in toluene (3 mL). Ethyl magnesium bromide (0.19 mL, 0.586 mmoles of a 3M solution in ether) was added and the reaction mixture was heated at 50° C. for 2 h. LC-MS indicated formation of the desired product. The reaction mixture was diluted with ethyl acetate then washed with saturated aqueous NH4Cl solution followed by 1N NaOH solution. The organic layer was concentrated. The residue was purified by flash chromatography (silica gel, 40 g) (eluted over a gradient 5-30-50% ethyl acetate and hexane) to give the title compound as clear oil, 91 mg (76%). 1H NMR (CDCl3) δ 7.79 (1H, s), 7.65 (2H,s), 7.46(2H,m), 7.25(1H, s), 4.85(2H,m), 4.68(2H,s), 4.20(3H,s), 3.60(2H,m), 3.55(2H,m), 2.98(1H,m), 2.50(2H,m), 2.25(2H,m), 1.80(2H,m), 0.85(3H, t). MS (ES+) Calc: 610.5, Found: 611.2 (M+1).
Reaction SMILES: [H][H].Cl[C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[C:6]([CH3:13])[N:5]=1.C(N(CC)CC)C>[Pd].C(O)C>[CH3:13][C:6]1[N:5]=[CH:4][CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A hydrogen filled balloon was attached to a flask containing 2-chloro-6-methylpyridine-4-carboxylic acid (2 g, 12.0 mmol), palladium 10 wt. % on activated carbon (0.5 g), triethyl amine (4.8 ml) and ethanol (24 ml) and then stirred overnight at room temperature. The reaction mixture was filtered through celite, washed with methanol and concentrated. The residue was titurated with dichloromethane and then filtered to afford 6-methylpyridine-4-carboxylic acid as a white solid; 1.05 g (66%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:17]=[CH:16][C:14](N)=[CH:13][CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.OS(O)(=O)=O.N([O-])=O.[Na+].[I-:27].[Na+]>COCCOC.O.CCOC(C)=O>[I:27][C:14]1[CH:16]=[CH:17][C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(Oc2ccc3c(c2)OCO3)cc1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Ic1ccc(Oc2ccc3c(c2)OCO3)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
In a 300 mL round bottom flask, 5.28 g (22.96 mmol) 4-(benzo[d][1,3]dioxol-5-yloxy)aniline was dissolved in 40 mL DME and cooled to 0° C. in a brine/ice bath. Using a dropping funnel, 10 equivalents aqueous H2SO4 (10N aqueous) were slowly added to the DME solution, immediately creating a salt suspension. The suspension was stirred at 0° C. for 10 minutes. Then, a solution of 1.5 equivalents sodium nitrite (2.38 g, 34.45 mmol) in 20 mL water was dropped slowly into the suspension while keeping the temperature below 5° C. After adding the sodium nitrite, the mixture was stirred at 0° C. for 30 minutes. Then, a 30 mL aqueous solution of sodium iodide (10.32 g, 68.88 mmol) was dropped slowly into the mixture. LC/MS showed the reaction was complete. The mixture was diluted with 400 mL EtOAc and washed with 700 mL water and then 700 mL 1M sodium bisulfite. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was then chromatographed by combiflash using a 330 gram silica column and a gradient of EtOAc (15% max) in hexane to provide 6 g of 5-(4-iodophenoxy)benzo[d][1,3]dioxole (77%, light brown oil). m/z 340, 1H NMR (CHCl3): 7.61-7.54 (m, 2H), 6.79-6.68 (m, 3H), 6.58-6.53 (m, 1H), 6.51-6.45 (m, 1H), 6.00-5.96 (s, 2H).
Reaction SMILES: Br[CH:2]([C:22]1[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=1)[C:3]([C:5]1[CH:21]=[CH:20][C:8]2[N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:13])[N:11]([CH3:12])[C:7]=2[CH:6]=1)=O.CON(C)C(C1C=CC2[N:38](C3C=CC=CC=3)[C:39](=O)[NH:40]C=2C=1)=O.O.C(N)=O>[OH-].[NH4+]>[CH3:12][N:11]1[C:7]2[CH:6]=[C:5]([C:3]3[N:38]=[CH:39][NH:40][C:2]=3[C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[CH:21]=[CH:20][C:8]=2[N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:13]
Reactant: Cc1cccc(C(Br)C(=O)c2ccc3c(c2)n(C)c(=O)n3-c2ccccc2)c1
Reactant: CON(C)C(=O)c1ccc2c(c1)[nH]c(=O)n2-c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: NC=O
Solvent: O
Product: Cc1cccc(-c2[nH]cnc2-c2ccc3c(c2)n(C)c(=O)n3-c2ccccc2)c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
5-(Bromo-m-tolyl-acetyl)-3-methyl-1-phenyl-1,3-dihydro-benzoimidazol-2-one (prepared from 2-oxo-1-phenyl-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide as described in the general procedure, 0.26 gm, 0.60 mmol) was added to 5 mL of 8% water/formamide and the mixture was heated to 140° C. for 14 hours. The reaction mixture was then cooled to room temperature and diluted with 20 mL of ammonium hydroxide with rapid stirring. After stirring for ½ hour, the solid precipitate was filtered and purified by column chromatography (0.5% methanol in ethyl acetate) to afford 75 mg of the title compound. MS (M+1)=381.2
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:12]=[C:13](I)[C:8]2=[CH:7][N:6]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[C:31]([CH3:38])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:12]=[C:13]([C:32]3[CH:33]=[CH:34][C:29]([OH:28])=[CH:30][C:31]=3[CH3:38])[C:8]2=[CH:7][N:6]=1
Reactant: Cc1cc(O)ccc1B(O)O
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cnc(Oc3ccc(F)cc3F)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(O)ccc1-c1nn(COCC[Si](C)(C)C)c2nc(Oc3ccc(F)cc3F)ncc12
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
6-(2,4-Difluoro-phenoxy)-3-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidine from Example 11 (0.5 g, 0.99 mmol) was dissolved in 10 mL of dry dioxane, and the reaction mixture was degassed by treatment with vacuum and flushed with argon. Tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.1 mmol) was added, and the reaction mixture was stirred for 10 minutes. A solution of 4-hydroxy-2-methylphenyl boronic acid (0.311 g, 2.0 mmol) in 3 mL EtOH was added, and the reaction mixture was degassed, purged with argon, and stirred for 10 minutes. AA solution of potassium carbonate (0.411 g, 3.0 mmol) in 1 mL water was then added, and the reaction mixture was again degassed and flushed with argon. The reaction mixture was heated to 90° C. with stirring for 16 hours under argon. The reaction mixture was cooled, filtered, and the filtrate was partitioned between water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure. The resulting residue was subject to flash chromatography (hexanes/EtOAc 1:0 to 2:1) to yield 0.308 g (0.64 mmol, 64%) of 4-[6-(2,4-difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-3-methyl-phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:3]=1[CH2:4][N:5]1[C:9](CC#N)=[C:8]([Cl:13])[N:7]=[C:6]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[C:28]([OH:31])(=[O:30])[CH3:29].O>C(O)C>[Cl:1][C:2]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([CH2:29][C:28]([OH:31])=[O:30])=[C:8]([Cl:13])[N:7]=[C:6]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#CCc1c(Cl)nc(-c2ccccc2)n1Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1cc([N+](=O)[O-])ccc1Cl

Procedure:
1.9 g of 1-(2-chloro-5-nitrobenzyl)-4-chloro-5-cyanomethyl-2-phenylimidazole was boiled in a mixed solution of 12 ml of concentrated hydrochloric acid and 12 ml of glacial acetic acid for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, and 50 ml of water was added to the residue, resulting in the formation of a colorless powder. The residue was dissolved in 30 ml of heated ethanol, and 30 ml of water was added. Upon cooling, there was obtained 1.7 g of 1-(2-chloro-5-nitrobenzyl)-4-chloro-2-phenylimidazole-5-acetic acid as colorless, prism-formed crystals. m.p. 200°-205° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH:4]=[CH2:5].Cl[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].O>C1(C)C=CC=CC=1.C(O)C>[C@@H:4]1([C:3]([O:7][CH2:8][CH3:9])=[O:6])[CH2:5][C@@H:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CCl
Reactant: C=CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H]1C[C@H]1C(=O)OCC
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a stirred suspension of 32.8 g (818.8 mmol) of 60% sodium hydride mineral oil dispersion in 200 mL of toluene under nitrogen, was added between 10 to 20 mL of a blend of ethyl acrylate (81.2 g, 810.7 mmol) and ethyl chloroacetate (99.4 g, 810.7 mmol) followed by several drops of ethanol. After an induction period of about 1 h, steady gas and heat evolution began with the reaction mixture temperature reaching 35° C. The remaining mixed ester reagent was carefully added dropwise with ice-bath cooling so as to maintain a reaction temperature of 30°-80° C. After the addition was complete (4 h), the mixture was cooled to room temperature and carefully poured into water (300 mL). The organic layer was separated and dried (MgSO4) and evaporated to a dry residue. The dry residue was chromatographed on silica gel using 10% ethyl acetate in hexane as the eluant. The fractions containing the desired compound were combined and evaporated to dryness under reduced pressure to give 53.0 g of the title compound of Step A as a clear oil (35% yield). IR (neat, cm-1): 1728.9 (C=O);
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH3:20]>O1CCCC1.CN(C)C=O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:20])=[O:13])=[CH:5][CH:4]=1
Reactant: N
Reactant: CSc1ccc(C=CC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CSc1ccc(C=CC(N)=O)cc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a suspension of 5.00 g (25.7 mmol) 3-(4-methylsulfanyl-phenyl)-acrylic acid in 30.0 ml tetrahydrofuran and 0.3 ml N,N-dimethyl formamide a solution of 4.90 ml (38.6 mmol) oxalyl chloride in 5.0 ml tetrahydrofuran was added dropwise at 0° C. within 20 min. Stirring was continued at 0-5° C. for 30 min. and 3 h at room temperature thereafter. The resulting solution was cooled to 0-5° C. again and then added within 15 min. to 100 ml of a 25% aqueous ammonia solution. After evaporation of the organic solvent, 200 ml water were added and the solution cooled. The precipitated amide was collected, washed with water and n-heptane and dried at 40° C. in vacuo. Yield 4.46 g (90%) 3-(4-methylsulfanyl-phenyl)-acrylamide as an off-white solid melting at 193° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)=[C:24]([C:25]([N:14]2[CH2:13][CH:12]3[CH:16]([CH2:17][N:10]([C:4]4[N:5]=[C:6]([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[N:3]=4)[CH2:11]3)[CH2:15]2)=[O:26])[CH:28]=1
Reactant: COc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Cc1nc(N2CC3CNCC3C2)nc(C)c1C
Product: COc1ccc(-n2nccn2)c(C(=O)N2CC3CN(c4nc(C)c(C)c(C)n4)CC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 42 and 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C23H27N7O2, 433.22; m/z found 434.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.84 (d, J=9.0, 1H), 7.69 (s, 2H), 7.01 (dd, J=9.0, 2.8, 1H), 6.91 (d, J=2.8, 1H), 3.91-3.74 (m, 5H), 3.70-3.58 (m, 2H), 3.55 (dd, J=11.4, 5.2, 1H), 3.47-3.28 (m, 2H), 3.04-2.82 (m, 3H), 2.41-2.25 (m, 5H), 2.13-2.01 (m, 4H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[Cl:34])=[CH:19][C:15]=1[C:16](Cl)=[O:17].O>CN(C)C=O>[CH3:12][S:13][C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:25]=2[Cl:34])=[CH:19][C:15]=1[C:16]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CSc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-methylthio-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-methylthio-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl]phthalimide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][CH:11]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Br>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:34][C:35]2[CH:42]=[CH:41][CH:40]=[C:37]([CH3:38])[CH:36]=2)([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:22][CH2:23]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (-78° C.) solution of benzyl N-tert-butoxycarbonyl-isonipecotate (8.02 g, 25.11 mmol) in anhydrous THF (80 mL), a solution of sodium bis(trimethysilyl)amide (35 mL, 35 mmol; 1M) in THF was added over a period of 10 min. The resulting orange solution was stirred at -78° C. for 1 h. and then treated dropwise with 3-methylbenzyl bromide (4.1 mL, 30.6 mmol). The reaction mixture was allowed to warm to room temp., and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with ethyl acetate. The organic extracts were combined, washed with brine, and concentrated under vacuum. The residual oil was subjected to column chromatography on silica eluting with 20% ethyl acetate in hexane. Collection and concentration of appropriate fractions provided the title product.
Reaction SMILES: [C:1]1([C@@H:7]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C(OCC)(=O)C>O1CCCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]([CH3:12])([CH3:13])[O:10][C:9]1=[O:14])=[O:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)N1C(=O)OC(C)(C)[C@H]1c1ccccc1
Reaction time: 3 h
Yield: 57.4 %

Procedure:
Reaction of the auxiliary (15) (0.155 g, 0.81 mmol) in solution in tetrahydrofuran at -78° C. with butyllithium (1.0M, 0.819 ml, 0.821 mmol) and pivaloyl chloride (0.110 ml, 0.89 mmol) for 30 minutes and then at room temperature for 3 hours with work-up and flash column chromatography using 20% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (22) as an oil (0.128 g, 57%); νmax (CHCl3) 1687 and 1775 cm-3 ; [α]D25 (c 0.4 in CHCl3)=-60.3; (Found: C, 69.94; H, 7.84; N, 4.93. C16H21 NO3 requires C, 69.80; H, 7.69; N, 5.09%); δH (CDCl3 ; 300 MHz) 0.98 (3H, s, C(CH3)2), 1.39 (9H, s, C(CH3)3), 1.60 (3H, s, C(CH3)2), 5.11 (1H, s, CHPh), 7.14-7.37 (5H, m, ArCH; δC (125 MHz; CDCl3) 23.66 (CH3), 26.20 (CH3), 28.68 (CH3), 41.63 (C), 69.03 (CH), 81.80 (C), 126.10 (ArCH), 128.44 (ArCH), 128.85 (ArCH), 136.80 (C), 153.50 (CO), 178.00 (CO); m/z (CI+, NH3) 276 (M+ +1).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[NH:6][C:7](=O)[NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C:13]([O-:16])([O-])=O.[K+].[K+].[CH3:19]I>CN(C=O)C.O>[CH3:19][N:6]1[C:5]2[S:12][C:2]([CH3:1])=[CH:3][C:4]=2[C:9](=[O:10])[N:8]([CH3:7])[C:13]1=[O:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(=O)[nH]c(=O)[nH]c2s1
Reactant: CI
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(=O)n(C)c(=O)n(C)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Step 3 intermediate (13.5 g, 74.17 mmol) in dry DMF (148 ml) was added anhydrous K2CO3 (51.25 g, 370.85 mmol) and the mixture was stirred at room temperature for 1 h. Methyl iodide (34.74 g, 244.78 mmol) was added slowly with stirring and further stirred at room temperature for 24 h. The reaction mixture was diluted with water and the solid precipitated out was filtered, washed with water and dried to give 12.6 gm of the product as a brown solid; 1H NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H), 3.22 (s, 3H), 3.42 (s, 3H), 6.90 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.[Cu][C:22]#[N:23].C(OCC)(=O)C.N>CN1CCCC1=O>[CH2:8]([C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:22]#[N:23])[N:7]=1)[CH2:9][CH3:10]
Reactant: N#C[Cu]
Reactant: CCCc1cc(-c2cccc(C(F)(F)F)c2)nc(Cl)n1
Agent: N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)n1
Temperature: 200 °C
Yield: 8.5 %

Procedure:
To a solution of 2-chloro-4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine (50 mg) in 1-methyl-2-pyrrolidinone (2 mL), was added copper(I) cyanide (60 mg). The suspension was heated in the microwave at 200° C. for 20 min, than poured into a mixture of ethyl acetate (10 mL) and ammonia solution (5 mL). The organic layer was separated, washed with water (10 mL), dried over sodium sulphate and evaporated at reduced pressure. Preparative HPLC afforded the title compound 4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a brown gum (4.1 mg).