Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([Cl:18])[C:11]([CH2:14][N+:15]([O-:17])=[O:16])=[N:12][CH:13]=1.Cl[CH2:20][NH:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30].Cl>CN(C)C=O>[Br:7][C:8]1[CH:9]=[C:10]([Cl:18])[C:11]([CH:14]([N+:15]([O-:17])=[O:16])[CH2:20][NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])=[N:12][CH:13]=1
Reactant: O=C(NCCl)c1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])Cc1ncc(Br)cc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCC(c1ncc(Br)cc1Cl)[N+](=O)[O-])c1ccccc1C(F)(F)F
Temperature: 0 °C
Yield: 67 %

Procedure:
To 4.2 g of potassium tert-butoxide in 72 ml of N,N-dimethylformamide, 7.8 g of 5-bromo-3-chloro-2-(nitromethyl)pyridine was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at the same temperature for another 1 hour. Then, to the reaction mixture, 4.7 g of the N-chloromethyl-2-(trifluoromethyl)benzamide prepared in Step 2 in Synthetic Example 19 in 30 ml of N,N-dimethylformamide was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 2 hours. After completion of the reaction, the reaction mixture was carefully poured into 100 ml of ice-water, acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (100 ml×2) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 6.0 g of the desired product as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1.O>[NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([C:32]1[CH:33]=[CH:34][C:35]([OH:36])=[C:30]([Cl:29])[CH:31]=1)[N:5]=2
Reactant: OB(O)c1ccc(O)c(Cl)c1
Reactant: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(Cl)nc21
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(-c3ccc(O)c(Cl)c3)nc21
Temperature: 85 °C
Yield: 110 %

Procedure:
In a round bottom flask 0.3 g (0.71 mmol) 2-amino-7-chloro-1-ethyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-[1,8]naphthyridin-4-one, 0.185 g (1.07 mmol) 3-chloro-4-hydroxy-phenylboronic acid, 0.098 g (0.11 mmol) tris-(dibenzylidenacetone)dipalladium (0), 0.030 mg (0.0.11 mmol) tricyclohexyl phosphine, 0.303 g of potassium phosphate tribasic, and 8 mL of dioxane/water (50/50) (degassed) were stirred and heated at 85° C. for 8 h. The solvents were evaporated and the residue was purified by column chromatography (DCM/MeOH: 9/1) to yield 0.4 g of a brown solid. This solid was engaged without further purification in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)O1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:8][C:7]1[C:2]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:19]=2)=[CH:3][C:4]([NH2:9])=[CH:5][N:6]=1
Reactant: CC1(C)OB(c2ccnc(N3CCOCC3)c2)OC1(C)C
Reactant: Cc1ncc(N)cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ncc(N)cc1-c1ccnc(N2CCOCC2)c1
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-6-methylpyridin-3-amine (1.0 equiv.) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (1.7 equiv.) in DME and 2M sodium carbonate (4:1, 0.14 M) was added PdCl2(dppf)-DCM adduct (0.1 equiv.) in a microwave vial equipped with a stir bar. The reaction was heated to 110° C. for 15 min in the microwave. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography over silica gel (DCM with a 0-20% methanol gradient). The pure fractions were concentrated in vacuo to afford 2-methyl-2′-morpholino-[3,4′-bipyridin]-5-amine in quantitative yield. LCMS (m/z) (M+H)=271.1, Rt=0.26 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)=[O:23])[CH3:20].C(OCC)(=O)C>CCCCCC>[CH2:19]([O:21][C:22](=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([N:14]2[C:13]([C:12]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][O:10][C:11]=3[CH3:18])=[CH:17][N:16]=[CH:15]2)[CH:29]=1)[CH3:20]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1c[nH]cn1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-n2cncc2-c2c(-c3cccc(F)c3)noc2C)c1
Yield: 32 %

Procedure:
As described for Example 3, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (2.43 g, 10 mmol) was converted, using of 3-ethoxycarbonylphenylboronic acid instead of 4-fluorophenylboronic acid, through chromatography (SiO2, ethyl acetate: hexane=20:10) to the title compound (1.26 mg, 32%) which was obtained as a light yellow solid. MS: m/e=392.1 [M+H]+.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[N:19][N:18]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(Cl)Cl>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[N:19][N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Clc1nncc2ccccc12
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(c3nncc4ccccc34)CC2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 15.9 %

Procedure:
A mixture of 5.11 g (15 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 2.48 g (15 mmol) of 1-chlorophthalazine, 2.08 g (15 mmol) of powdered K2CO3 and 55 ml of absolute DMF was warmed to 85° C., and 346 mg of powdered K2CO3 were added at 85° C. with stirring in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (a total of 1.038 g, 7.51 mmol of K2CO3), and the mixture was stirred for a further 2 hours at 90° C. and 3 hours at 105° C. The DMF was then removed by distillation in vacuo, the residue was taken up in CH2Cl2 /water, the phases were separated after through mixing, and the aqueous solution was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The residue remaining (4.75 g) was chromatographed on a silica gel S/CH2Cl2 column (diameter 2.6 cm, height 43 cm) by elution with CH2Cl2 /C2H5OH mixtures with increasing C2H5OH content (1-10% by volume). The fractions in which, according to TLC, the required compound was concentrated were combined and evaporated. The crystalline residue produced (2.04 g) was boiled briefly with 15 ml of CH2Cl2, cooled in an ice bath, and filtered off under suction. 0.73 g of pure 1-(4-hydroxyphenyl)-4-(1-phthalazinyl)piperazine, melting point 244°-45° C., were thus obtained. The mother liquor was again purified by chromatography in analogous fashion to the first column chromatography on a silica gel/CH2Cl2 column (diameter 2.0 cm, height 22 cm). The concentrated product produced from this procedure was, like the first part, boiled briefly with 7 ml of CH2Cl2 and filtered off under suction when cool. A further 0.28 g of pure compound, melting point 244°-45° C., was obtained from this procedure. The total yield was 1.01 g=22% of theory;
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]O)=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:31])CC>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][F:31])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CCO)c(C(F)(F)F)c1)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(CCF)c(C(F)(F)F)c1)OCc1ccccc1
Reaction time: 3 h
Yield: 45.1 %

Procedure:
[4-(2-Hydroxyethyl)-3-(trifluoromethyl)phenyl]carbamic acid benzyl ester (428 mg, 1.26 mmol) was dissolved in DCM (4 mL), and DAST (339 mL, 2.10 mmol) was added thereto. The resulting mixture was stirred for about 3 hours. The reaction solution was quenched with a saturated sodium bicarbonate solution, and then DCM (20 mL) was added thereto. The organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=5:1) to give [4-(2-fluoroethyl)-3-(trifluoromethyl)phenyl]carbamic acid benzyl ester (194 mg, 45%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14](=[O:25])[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].[F:27][C:28]([Si](C)(C)C)([F:30])[F:29].C(=O)([O-])[O-].[Cs+].[Cs+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.O>[Br:1][C:2]1[C:11]([NH:12][C:13](=[O:26])[C:14]([OH:25])([C:28]([F:30])([F:29])[F:27])[CH2:15][C:16]([CH3:17])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:24])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(CC(=O)C(=O)Nc1ccc2c(c1Br)COC2=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CC(O)(C(=O)Nc1ccc2c(c1Br)COC2=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
350 mg of 4-bromo-5-(4-methyl-2-oxo-4-phenyl-valeroyl-amino)-phthalide is dissolved under argon in 15 ml of dimethylformamide and mixed with 0.77 ml of trifluoromethyl-trimethylsilane and 350 mg of cesium carbonate while being cooled with ice. After 3 hours of stirring at room tempera-ture, 5 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran and some drops of water are added and stirred for one hour at room temperature. After 100 ml of water is added, it is extracted with ethyl acetate, the organic phase is dried (Na2SO4) and concentrated by evaporation. 250 mg of 4-bromo-5-(2-hydroxy-4-methyl-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide, melting point 187-194° C., is obtained.
Reaction SMILES: Br[CH:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][C:10]([CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])([C:13]#[N:14])[C:11]#[N:12])=[CH:7][CH:6]=1)[CH2:3][Br:4].CC(C)([O-])C.[K+].O>CN(C)C=O>[Br:4][CH:3]=[CH:2][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]([CH2:15][CH2:16][C:17]([F:18])([F:19])[F:20])([C:13]#[N:14])[C:11]#[N:12])=[CH:21][CH:22]=1
Reactant: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C(Br)CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C=CBr)cc1
Yield: 41 %

Procedure:
First, 0.2 g of (2-(4-(1,2-dibromoethyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (43)) was dissolved in 5 ml of N,N-dimethylformamide, to which 0.1 g of potassium t-butoxide was added, while stirring under ice cooling. After stirring for 5 hours at room temperature, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was successively washed with water, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.05 g of 2-(4-(2-bromovinyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (58)).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccnc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cccnc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 78.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 3-(chloromethyl)pyridine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(3-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.68 g) was obtained.
Reaction SMILES: [CH3:1][S:2]([CH:5]=[CH2:6])(=[O:4])=[O:3].[Cl:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][NH:13][CH2:12][CH2:11][C:10]=2[N:9]=1>CCO>[Cl:7][C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][N:13]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: Clc1ccc2c(n1)CCNC2
Reactant: C=CS(C)(=O)=O
Solvent: CCO
Product: CS(=O)(=O)CCN1CCc2nc(Cl)ccc2C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Methylsulfonylethene (commercially available from Sigma-Aldrich, St. Louis, Mo.) (142 mg, 1.33 mmol) was added dropwise to a solution of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine (150 mg, 0.89 mmol, commercially available from D-L Chiral Chemicals, ST-0143) in EtOH (10 mL). The reaction mixture was stirred at 60° C. for 2 hours, and then concentrated and purified by flash chromatography on silica gel eluting with 0% to 5% MeOH in DCM to give 2-chloro-6-(2-(methylsulfonyl)ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (220 mg, 90% yield). 1H NMR (400 MHz, CD3OD) δ ppm 2.91-3.11 (9H, m) 3.43 (2H, t, J=6.65 Hz) 3.73-3.77 (2H, m) 7.26 (1H, d, J=8.22 Hz) 7.56 (1H, d, J=8.02 Hz) ppm; LC/MS m/z: 275 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.[CH3:13]/[CH:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Li]CCCC>>[C:4]1([N:7]2[CH2:8][CH2:9][N:10]([CH:14]([CH3:13])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:12]2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: C/C=C/c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [Li]CCCC
Product: CC(Cc1ccccc1)N1CCN(c2ccccc2)CC1

Procedure:
According to GP, 2.22 mmol (=0.36 g=0.34 ml) of phenylpiperazine and 2.22 mmol (=0.26 g=0.29 ml) of β-trans-methylstyrene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (3:1) gives the product 1-phenyl-4-(1-methyl-2-phenylethyl)piperazine as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][N:24]([CH3:36])[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[Br:35])[NH2:31]>>[CH3:23][N:24]([CH3:36])[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:31][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[N:12]=[C:11]([CH3:13])[O:10][N:9]=4)=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH:32]=[CH:33][C:34]=1[Br:35]
Reactant: CN(C)CCOc1cc(N)ccc1Br
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)no1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(Br)c(OCCN(C)C)c4)cc3)c(C)c2)no1

Procedure:
The title compound was prepared from 2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxylic acid (EP 0533268A1) and 3-(2-dimethylaminoethoxy)-4-bromoaniline (D60) using a similar procedure to Example 1 (64%). Mp 138°-140° C.
Reaction SMILES: ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC(C)C)=CC=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]2[CH2:65]CC[CH2:62]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[N:39]([C:40]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)=[O:41])[C:38]([C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][C:50]=3[O:57][CH2:58][CH3:59])=[N:37][CH:36]2[CH2:60][CH:61]([CH3:62])[CH3:65])=[CH:31][CH:30]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Agent: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(CC(C)C)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1

Procedure:
[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-isobutyl-4,5-dihydro-1H-imidazole (Example 10) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 513.2632, calculated for C28H38N4O3Cl [(M+H)+]513.2627.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9](=[O:20])[NH:8][C:7]1=[O:21].O>C1COCC1>[O:21]=[C:7]1[NH:8][C:9](=[O:20])[C:10]([C:12]2[C:13]([C:18]#[N:19])=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][N:6]1[CH2:5][CH2:4][CH:3]=[O:2]
Reactant: COC(CCn1cc(-c2cccnc2C#N)c(=O)[nH]c1=O)OC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ncccc1-c1cn(CCC=O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
3-[1-(3,3-Dimethoxy-propyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-pyridine-2-carbonitrile (Prep104, 210 mg, 0.66 mmol) was dissolved in THF (5 ml) and 2N HClaq (1 ml) was added. The solution was stirred at room temperature for 2 hours. The reaction mixture was neutralized with TEA. Water was added (1 ml) and the product extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 130 mg of a yellow oil (73% yield)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:33]=[CH:32][C:23](/[CH:24]=[CH:25]/[C:26]3O[C:28]([CH3:31])=[N:29][N:30]=3)=[CH:22][CH:21]=2)=[C:4]([CH3:34])[CH:3]=1.FC(F)(F)C([O-])=O.[NH4+:42]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:33]=[CH:32][C:23](/[CH:24]=[CH:25]/[C:26]3[NH:42][C:28]([CH3:31])=[N:29][N:30]=3)=[CH:22][CH:21]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/c4nnc(C)o4)cc3)c(-c3ccc(F)cc3C)sc2c1
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc2c(Oc3ccc(/C=C/c4nnc(C)[nH]4)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 180 °C
Yield: 65.3 %

Procedure:
To a microwave vial, (E)-2-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-1,3,4-oxadiazole (23 mg, 0.049 mmol) and ammonium trifluoroacetate (128 mg, 0.973 mmol) were suspended in toluene (2 mL). The reaction was heated for 18 h at 180° C. under microwave irradiation. The reaction mixture was concentrated and the crude product was purified by reverse phase HPLC (neutral condition, 0.1% TFA in 20-100% CH3CN/H2O) to afford (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-5-methyl-4H-1,2,4-triazole (15 mg, 0.032 mmol, 65% yield) as a white solid. LC/MS (m/z, MH+): 472.1.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1.[CH2:12]([O:14][C:15](=[O:23])[CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:13].N1C=CC=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=2)[C:20]=1[CH3:21])=[O:23])[CH3:13]
Reactant: COc1cccc(NN)c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2cccc(OC)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-methoxyphenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a Solution of 50% pyridine in ethanol. The resulting solid was determined to be the named product by 1H-NMR (CDCl3, ppm): 1.38 t (3H); 2.50 s (3H); 2.52 s (3H); 3.84 s (3H); 4.32 q (2H); 6.96 m (3H); 7.3 st (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:17]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([C:18]([CH3:20])([CH3:21])[CH3:19])[N:17]=1)=[O:9]
Reactant: CC(C)(C)C(=O)c1sc(N)nc1C(C)(C)C
Reactant: O=C(O)c1cc(Cl)ccc1O
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: CC(C)(C)C(=O)c1sc(NC(=O)c2cc(Cl)ccc2O)nc1C(C)(C)C
Temperature: 25 °C
Yield: 48.5 %

Procedure:
A mixture of 5-chlorosalicylic acid (143.6 mg, 0.83 mmol), 2-amino-4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]thiazole (200.0 mg, 0.83 mmol), phosphorus trichloride (40 μL, 0.46 mmol) and chlorobenzene (4 mL) was refluxed for 3 hours. After the reaction mixture was cooled to room temperature, the residue obtained by concentration of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the title compound(159.1 mg, 48.4%) as a white powder.
Reaction SMILES: [CH3:1][S:2][CH:3]([S:6][CH3:7])[S:4][CH3:5].C([Li])CCC.[F:13][C:14]([F:41])([F:40])[C:15]1[CH:39]=[CH:38][C:18]([O:19][CH2:20][C:21]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([C:30]4[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=4[CH:32]=[O:33])=[CH:29][C:23]=3[N:22]=2)=[CH:17][CH:16]=1>C1COCC1>[CH3:1][S:2][C:3]([S:6][CH3:7])([S:4][CH3:5])[CH:32]([C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[C:28]1[CH:27]=[CH:26][C:24]2[NH:25][C:21]([CH2:20][O:19][C:18]3[CH:38]=[CH:39][C:15]([C:14]([F:41])([F:40])[F:13])=[CH:16][CH:17]=3)=[N:22][C:23]=2[CH:29]=1)[OH:33]
Reactant: CSC(SC)SC
Reactant: O=Cc1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSC(SC)(SC)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 0.5 h
Yield: 219.7 %

Procedure:
To a solution of tris(methylthio)methane (0.640 g, 4.15 mmol) in THF (12 mL) at −78° C. was added n-butyllithium (1.6 mL, 4.15 mmol). After stirring for 30 min, 2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-benzaldehyde (0.274 g, 0.691 mmol, Example 9, Step A) in THF (2 mL) was carefully added to the reaction mixture at −78° C. After 20 min, the reaction was quenched by addition of methanol. The reaction mixture was purified by chromatography (silica, hexanes: EtOAc, 2:1) to afford the title compound as a yellow oil (0.836 g, 94%).