Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=[N:22][CH2:21][CH2:20][O:16][N+:17]([O-:19])=[O:18])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: COC(=NC#N)c1ccoc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccoc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 8.2 %

Procedure:
Methyl N-cyano-3-furancarboximidate (0.5 g, 3.3 mmol) was dissolved in methanol (10 ml), and 2-nitroxyethylamine nitrate (0.84 g, 5.0 mmol) and sodium methoxide (0.27 g, 5.0 mmol) were added. The mixture was stirred at room temperature for 26 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was extracted with chloroform (60 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 20 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol diethyl ether to give the title compound (0.06 g, 0.27 mmol, yield: 8%) as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1(=O)CCCCC1>CN1CCCC1=O.[Cu]I>[CH2:9]=[CH:10][C:1]#[N:2].[CH2:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc2cnccc2c1
Agent: [Cu]I
Solvent: O=C1CCCCC1
Solvent: CN1CCCC1=O
Product: C=CC#N
Product: C=Cc1ccccc1
Yield: 10 %

Procedure:
A solution of 2.0 g. CuI, 1.4 g. isoquinoline (1:1 ratio), 50.0 g. N-methylpyrrolidone solvent, 46.6 g. cyclohexanone and 0.20 g. Lustran SAN 31-1,000 (10% on CuI) was prepared. The resulting coating solution was coated on 7 mil raw PET with number 10 Meyer rod and dried three minutes at 240° F. The coating had very good uniformity and clarity and was gold and blue iridescent and lustrous. The resistivity measured 13-20×107 Ω/sq. The solution after time showed some precipitation, which crystals were redissolved upon reheating.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:19])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([Cl:18])[N:6]=2.[O:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:18][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([CH2:2][N:29]3[CH2:30][CH2:31][CH:26]([N:23]4[CH2:24][CH2:25][O:20][CH2:21][CH2:22]4)[CH2:27][CH2:28]3)[N:4]2[CH3:19])=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: Cn1c(CBr)nc2c(N3CCOCC3)nc(Cl)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 4-(8-(bromomethyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine (935 mg, 2.7 mmol) in DCM (30 mL) was added 4-morpholino-piperidine (505 mg, 2.97 mmol) and DIEA (0.70 mL). The resulting mixture was stirred at room temperature for 18 hours. The mixture was then poured onto water and the layers were separated. The aqueous layer was extracted with three times with DCM. The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude product was then purified by flash chromatography (0-30% gradient MeOH in DCM) to give the title compound as a white solid (95%). LCMS: M+H+=436.2.
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]([CH3:5])[CH3:4].[CH3:7][C:8](=[CH:11][CH2:12][CH3:13])[CH:9]=[O:10]>CCOCC>[CH3:7][C:8]([CH:9]([OH:10])[CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:11][CH2:12][CH3:13]
Reactant: CCC=C(C)C=O
Reactant: CC(C)CBr
Agent: [Mg]
Solvent: CCOCC
Product: CCC=C(C)C(O)CC(C)C

Procedure:
A Grignard reagent, prepared by reacting 11.8 g (0.49 g atom) of magnesium in 50 ml of ether and 67.13 g (0.49 mol) of isobutyl bromide in 250 ml of ether, is reacted with 40.0 g (0.41 mol) of 2-methyl-2-pentenal in 100 ml of ether in a manner analogous to Example 5. Fractional distillation of the crude product (94 g) over a 20 cm Widmer column give 44.4 g (69.4%) of olfactorily good 4,7-dimethyl-3-octen-5-ol of boiling point 47°-48° C./0.04 mm Hg.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1

Procedure:
Ethyl bromoacetate is reacted with para-nitrophenol under standard conditions to afford ethyl 2-(4-nitrophenoxy)acetate, which is elaborated to ethyl 2-(4-hydrazinophenoxy)acetate using the reduction/oxidation sequence described for Example Y.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>O.C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: CCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.40 g), sodium hydrogen carbonate (2.00 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(2-methyl-6-oxo-1-phenyl-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.83 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.48 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.44 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.57 g, 41%).
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.[S:12]([O-])(=O)(=O)C.C(N(CC)CC)C.[C:24]([O:27][CH2:28]C)(=[O:26])C>C(Cl)Cl>[S:12]1[CH2:6][CH2:5][CH:4]=[C:3]([C:24]([O:27][CH3:28])=[O:26])[CH2:2]1
Reactant: CCOC(C)=O
Reactant: CS(=O)(=O)[O-]
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCCSC1
Temperature: 0 °C
Reaction time: 7.5 h
Yield: 63 %

Procedure:
To a solution of 4.93 gm (0.0279 mole) of methyl tetrahydro-2H-thiopyran-4-hydroxy-3-carboxylate from part B in anhydrous methylene chloride (25 mL) was added 6.77 mL (0.0837 mole) anhydrous pyridine. The solution was cooled to 0° C., upon which was added 3.25 mL (0.0420 mole) methanesulfonyl chloride, dropwise via syringe. The solution was allowed to warm to room temperature and stirred under N2 for 7.5 hrs. The reaction was then cooled to 0° C. and an additional 0.648 mL (0.00837 mole) of methanesulfonyl chloride was added. The solution was stirred at room temperature an additional 16 hrs. upon which ethyl acetate (125 mL) was added. The organic layer was washed with dilute HCl, saturated sodium bicarbonate, and saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a mixture of the cis and trans mesylate and unreacted methanesulfonyl chloride. The crude-mesylate mixture was dissolved in anhydrous methylene chloride (30 mL) upon which was added 12.68 mL (0.0911 mole) triethyl amine. The reaction was stirred under N2 for 7 hrs. upon which was added 8.5 mL (0.061 mole) triethyl amine and the solution stirred 17 more hrs. The organic layer was washed once with dilute acid and once with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on 300 gm silica gel with 4–25% ethyl acetate in hexane to give 2.76 gm (63%) of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate as a clear oil; mass spectrum m/z 159 (CI,M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([Cl:28])[C:3]=1[CH2:4][C:5]1[N:9]([CH3:10])[C:8]2[C:11]([C:15]([CH2:18][CH3:19])=[CH:16][CH3:17])=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=1.[C:29]([OH:32])(=[O:31])[CH3:30].C(=O)(O)[O-].[Na+].ClC1C=C(C(F)(F)F)C=C(Cl)C=1CC1N(C)C2C(C(CC)C(O)C)=CC=CC=2N=1>O1CCCC1>[C:29]([O:32][CH:16]([CH3:17])[CH:15]([C:11]1[C:8]2[N:9]([CH3:10])[C:5]([CH2:4][C:3]3[C:2]([Cl:1])=[CH:23][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:21][C:20]=3[Cl:28])=[N:6][C:7]=2[CH:14]=[CH:13][CH:12]=1)[CH2:18][CH3:19])(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: CC=C(CC)c1cccc2nc(Cc3c(Cl)cc(C(F)(F)F)cc3Cl)n(C)c12
Agent: CCC(c1cccc2nc(Cc3c(Cl)cc(C(F)(F)F)cc3Cl)n(C)c12)C(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(c1cccc2nc(Cc3c(Cl)cc(C(F)(F)F)cc3Cl)n(C)c12)C(C)OC(C)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 25 %

Procedure:
To a solution of 2-[2,6-dichloro-4-(trifluoromethyl)benzyl]-7-[1-ethylprop-1-en-1-yl]-1-methyl-1H-benzimidazole (60 mg, 0.141 mmol) in tetrahydrofuran (1.5 mL) was added a solution of borane-dimethyl sulfide complex in tetrahydrofuran (1.9 M, 1.5 mL, 2.81 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 15 hr, acetic acid (3.0 mL) was added thereto and the mixture was heated at 120° C. for 2 hr. After cooling, the mixture was poured into saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL, twice). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-50% ethyl acetate/n-hexane gradient mixture to give 2-{2-[2,6-dichloro-4-(trifluoromethyl)benzyl]-1-methyl-1H-benzimidazol-7-yl}-1-methylbutyl acetate (17 mg, 0.0349 mmol, 25%) and 3-{2-[2,6-dichloro-4-(trifluoromethyl)benzyl]-1-methyl-1H-benzimidazol-7-yl}pentan-2-ol (less polar diastereomer; 2.4 mg, 0.00539 mmol, 4%, more polar diastereomer; 2.5 mg, 0.00562 mmol, 4%).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:23][CH:22]=1>C(O)(=O)C>[CH3:11][C:10]1[N:20]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:26]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)C(CC(=O)c1ccccc1)c1ccccc1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)cc(-c2ccccc2)n1-c1ccc(CCCC(=O)O)cc1
Reaction time: 6 h

Procedure:
A soln of 1,3-diphenyl-pentane-1,4-dione (104 mg; 0.412 mmol) and 4-(4-amino-phenyl)-butyric acid (89 mg; 0.497 mmol) in acetic acid (2 mL) was heated at 120° C. After 6 h, the reaction was concentrated on a rotary evaporator. Ethyl acetate (5 mL) was added and this washed with H2O (1×2 mL) and satd NaCl (1×3 mL). The organic portion was dried (MgSO4) and filtered through silica with an EtOAc wash. Crude product was adsorbed onto silica (0.3 g) then purified by MPLC (12 g of silica using a 0→50% EtOAc in hexanes gradient). Pure product was obtained as a white solid (115 mg; 71%). 1H NMR (CDCl3) d 7.54-7.49 (m, 2H), 7.44-7.38 (m, 2H), 7.26-7.07 (m, 10H), 6.56 (s, 1H), 2.72 (t, J=7.6 Hz, 2H), 2.40 (t, J=7.4 Hz, 2H), 2.25 (s, 3H), 2.00 (m, 2H); LC-MS (ESI−) 394 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].Br[CH2:8][C:9]([OH:11])=[O:10].O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:5])([O:4][CH2:8][C:9]([OH:11])=[O:10])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)CBr
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OCC(=O)O
Temperature: 25 °C
Yield: 46.3 %

Procedure:
To a 3-neck 2-liter round-bottom flask equipped with a mechanical stirrer, reflux condenser and addition funnel was added potassium tert-butoxide (100.00 g, 0.891 moles) and 1500 ml of toluene under nitrogen. A solution of bromoacetic acid (61.90 g, 0.446 moles) in 100 ml of toluene was then added dropwise and the mixture then heated at reflux for 24 hours. After cooling the mixture to room temperature, water (100 ml) was added and the layers separated. The aqueous layer was washed with ether (2×50 ml) and then acidified to pH 1 with concentrated hydrochloric acid. The resulting mixture was extracted with ether (3×100 ml) and the combined extracts washed with saturated sodium chloride solution (1×75 ml), dried over magnesium sulfate and concentrated in vacuo to give 27.3 g of the product as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[C:3](=O)[CH2:4][Cl:5].C[O:9][C:10]([C:12]1[N:13]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][C:17]([Cl:22])=[CH:16][CH:15]=2)=O.C(=O)([O-])[O-].[K+].[K+]>ClC1C=C2C(=CC=1)N(C1C=CC(F)=CC=1)C=C2SCCN(C)CCN1CCNC1=O>[ClH:5].[CH3:1][N:2]([CH2:3][CH2:4][O:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:22])[CH:18]=2)[N:13]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[C:12]=1[CH2:10][OH:9])[CH3:7]
Reactant: CN(C)C(=O)CCl
Reactant: COC(=O)c1c(O)c2cc(Cl)ccc2n1-c1ccc(F)cc1
Agent: CN(CCSc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12)CCN1CCNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCOc1c(CO)n(-c2ccc(F)cc2)c2ccc(Cl)cc12
Product: Cl

Procedure:
A solution of N,N-dimethyl-2-chloroacetamide (28 g) in acetone (300 mL) was added dropwise during 1 hour to a mixture of 5-chloro-1-(4-fluorophenyl)-3-hydroxy-1H-indole-2-carboxylic acid methyl ester (64 g) (prepared according to the method of Unangst et al. J.Heterocyc.Chem. 1984, 21, 709-714 and 1987, 24, 811-815) and potassium carbonate (40 g) in acetone (500 mL) kept at reflux. The mixture was refluxed for another 3 hours and subsequently worked-up. The resulting crude acetamide derivative crystallized from cyclohexane. Yield 72 g. Mp: 124°-125° C. To a suspension of LiAlH4 pellets (10 g) in dry THF (200 mL) kept at gentle reflux was added dropwise a solution of the acetamide derivative (35 g) in dry THF (300 mL). After reflux for 2 hours the mixture was cooled on an ice bath and excess LiAlH4 was hydrolyzed by cautiously adding a mixture of 10% water in THF. Inorganic salts were filtered off and the solvent evaporated in vacuo leaving the title compound as a visceous oil. Yield: 19 g. The hydrochloric acid salt of the title compound 9 crystallized from acetone by addition of a solution of hydrogenchloride gas in diethyl ether.mp 185°-186° C.; 1H NMR (DMSO-d6) δ 2.90 (s, 6H), 3.60 (t, 2H), 4.40 (s, 2H), 4.45 (t, 2H), 7.05 (d, 1H), 7.10 (dd, 1H), 7.40 (t, 2H), 7.55 (dd, 2H), 7.85 (d, 1H). MS (m/z) 363 (MH+), 72 (100); Anal (C19H20ClFN2O2.HCl) C, H, N.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1.C(O[CH:23](OCC)[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29](F)=[N:30][CH:31]=1)C.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][C:29]4[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)=[CH:31][N:30]=4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(COc1ccc(F)nc1)OCC
Reactant: Cc1cnc(Nc2ncnc3ccc(O)cc23)cn1
Reactant: C1CCNC1
Product: Cc1cnc(Nc2ncnc3ccc(Oc4ccc(OCCN5CCCC5)cn4)cc23)cn1

Procedure:
The compound of Example 38 was obtained as follows: Using 4-[(5-methylpyrazin-2-yl)amino]quinazolin-6-ol, 5-(2,2-diethoxyethoxy)-2-fluoropyridine and pyrrolidine, and in the same manner as in Example 31 or according to a method similar to it or according to a combination thereof with an ordinary method, the entitled compound (11 mg) was obtained as a pale yellow solid.
Reaction SMILES: C([C@@H]1C(OC)=[N:8][C@@H:7]([C@@H:12]([O:23][CH3:24])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:6]([O:25][CH3:26])=N1)(C)C.Cl.C1C[O:31]CC1>CC#N>[NH2:8][C@@H:7]([C@@H:12]([O:23][CH3:24])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C:6]([O:25][CH3:26])=[O:31]
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1[C@@H](OC)c1ccc(C(F)(F)F)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H](N)[C@@H](OC)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-((S)-methoxy(4-(trifluoromethyl)phenyl)methyl)-2,5-dihydropyrazine (3.40 g, 9.1 mmol) in THF (25 mL) and CH3CN (50 mL) was added 0.25 N hydrochloric acid (73 mL, 18 mmol) at room temperature. The mixture was stirred overnight and the solvent was removed in vacuo. The residue was neutralized with saturated NaHCO3 and extracted with ether. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (30%-50% EtOAc-hexane) to provide the product as a colorless oil (1.1 g, 43%). LCMS (API-ES) m/z (%): 278 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[S:17]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(#N)C>[S:17]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[CH:18]1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Reactant: OB(O)c1ccsc1
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: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2ccncc2-c2ccsc2)CC1
Yield: 76 %

Procedure:
General procedure D was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (17 mg, 0.060 mmol), thiophene-3-boronic acid (9.2 mg, 0.072 mmol), tetrakis(triphenylphosphine)palladium(0) (3.5 mg, 5 mol %), 0.5 M sodium carbonate (0.17 mL, 0.084 mmol) and acetonitrile (1 mL) for 50 min. The crude product was purified by preparative tlc (CH2Cl2, MeOH, 10:1) to furnish the title compound as a white solid (13 mg, 76%), LC-MS (ESI, 3.5 min) Rt 1.12 min, m/z 288 (100%, [M+H]+); m/z (ESI) C15H18N3OS requires 288.1165 found [M+H]+ 288.1163.
Reaction SMILES: N1C=CC(CO[C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][C:15](=[CH:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:16]3=[O:19])=[CH:11][CH:10]=2)=CC=1.[H][H].[CH3:29][OH:30]>[Pd]>[CH3:9][C:10]1[C:11]([O:19][CH2:16][CH2:15][CH3:14])=[C:12]2[C:17](=[CH:18][C:29]=1[O:30][CH2:10][CH2:9][CH3:18])[C:16](=[O:19])[CH:15]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:14][CH2:13]2
Reactant: O=C1C(=Cc2cccnc2)CCc2ccc(OCc3ccncc3)cc21
Reactant: CO
Reactant: [H][H]
Agent: [Pd]
Product: CCCOc1cc2c(c(OCCC)c1C)CCC(Cc1cccnc1)C2=O

Procedure:
A mixture of Compound 25 (3.96 g, 10.8 mmol) and 10% palladium on carbon (600 mg) in abs. methanol (100 mL) was hydrogenated at 1 atm for 12 hr. The hydrogen was replaced with nitrogen, the reaction was filtered and concentrated in vacuo. Chromatography of the residue on silica gel (elution with 20% ethyl acetate:hexanes) provided 2.72 g of Compound 26.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:34])=O)(C)(C)C.[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[C:38]([CH3:43])[C:37]=1[CH:44]=[N:45][C:46]([O:48][Si](C)(C)C)=[CH2:47]>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:34])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])[CH2:47][C:46](=[O:48])[NH:45][CH:44]3[C:37]3[C:38]([CH3:43])=[CH:39][CH:40]=[C:41]([F:42])[C:36]=3[F:35])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1c(C)ccc(F)c1F)O[Si](C)(C)C
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2c(C)ccc(F)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 14.2 %

Procedure:
In a manner similar to the method described in Example 1e, E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 5.94 mmol) was reacted with 1-(2,3-difluoro-6-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (18 mmol) in toluene to give the title compound as a white solid (510 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([CH2:8][C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=[N:5][C:4]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:3]1[C:20]#[N:21].[CH2:22](N(CC)CC)[CH3:23].BrCC>CN(C=O)C.ClCCl>[CH2:22]([N:17]1[CH2:16][CH2:15][N:14]([C:4]2[N:5]=[C:6]([CH2:8][C:9]3[CH:13]=[CH:12][S:11][CH:10]=3)[NH:7][C:2](=[O:1])[C:3]=2[C:20]#[N:21])[CH2:19][CH2:18]1)[CH3:23]
Reactant: N#Cc1c(N2CCNCC2)nc(Cc2ccsc2)[nH]c1=O
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(Cc3ccsc3)[nH]c(=O)c2C#N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.17 mmol) of 6-oxo-4-(piperazin-1-yl)-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are dissolved together with 34 mg (0.33 mmol) of triethylamine in DMF and, after addition of 19.9 mg (0.18 mmol) of bromoethane, stirred at RT overnight. The mixture is then diluted with dichloromethane and washed with water. The organic phase is separated off and dried over sodium sulphate, and the residue is flash-chromatographed on silica gel (mobile phase: dichloromethane/methanol 100:1, 80:1, 60:1, 40:1). 38 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: S(O[CH2:6][C@@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)(=O)C.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[SH:33].[CH:34](N(C(C)C)CC)(C)C.[I-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[S:33][C:6]1[CH:7]=[CH:16][C:17]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:34]=1.[C:9]([NH:8][C@@H:7]([CH2:6][SH:33])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)Cc1ccccc1
Reactant: Sc1ccc2ccccc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CS)Cc1ccccc1
Product: c1ccc2cc(Sc3ccc4ccccc4c3)ccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-Boc-D-phenylalaninol mesylate (0.3 g, 0.9 mmol), dimethylformamide (10 mL), 2-napthalenethiol (0.22 g, 1.39 mmol), diisopropylethylamine (1.39 mmol) and sodium iodide (0.14 g, 0.93 mmol) was kept at 80 ° C. for 18 hr, cooled to room temperature and methylene chloride (25 ml) was added. This mixture was washed with water (2×10 mL), 1M sodium hydroxide (3×10 mL) and brine (2×15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate adsorbed onto silica gel and applied to a column prepacked with silica gel. The title compound (121 mg) was eluted with hexane:ethyl acetate (90:10, v:v) to afford a white solid.