Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:22])[C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.C(N(CC)CC)C.C1C[O:33][CH2:32]C1>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:22])[C:7]=1[C:8]1[CH:13]=[C:12]2[NH:14][C:32](=[O:33])[NH:15][C:11]2=[N:10][C:9]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C1CCOC1
Reactant: Nc1cc(-c2c(F)cncc2F)c(-c2cccnc2)nc1N
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(-c3c(F)cncc3F)c(-c3cccnc3)nc2[nH]1
Reaction time: 72 h
Yield: 59 %

Procedure:
A solution of 3″,5″-difluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 14, 0.045 g, 0.15 mmol), N,N′-carbonyldiimidazole (0.1 g, 0.6 mmol) and triethylamine (0.084 mL, 0.6 mmol) in THF (1.5 mL) was heated at 80° C. in a sealed tube. After 72 hours, the mixture was cooled and the solid was separated, washed with THF and dried to give the title compound (0.029 g, 59% of yield).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5](OB(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O.CC(C1C=CC=C(C(C)C)C=1N1C(=[Pd])N(C2C(C(C)C)=CC=CC=2C(C)C)C=C1)C.CC(C1C=CC=C(C(C)C)C=1N1C(=[Pd])N(C2C(C(C)C)=CC=CC=2C(C)C)C=C1)C.C1C=C2C(C(C=CC2=O)=O)=CC=1.C1C=C2C(C(C=CC2=O)=O)=CC=1>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=C(Br)C(F)(F)F
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd]
Agent: O=C([O-])[O-]
Agent: O=C1C=CC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 60 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a stirred solution of 3,5-bis(trifluoromethyl)phenyl boric acid (20.0 g) in tetrahydrofuran (100 mL) and water (40 mL) was added 2-bromo-3,3,3-trifluoropropene (20.2 g) and potassium carbonate (30.0 g), followed by the addition of 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) dimer (0.023 g). The reaction mixture was stirred at 60° C. for 3 hours under nitrogen atmosphere and then cooled to room temperature. The resulting mixture was poured into ice-water (100 mL) and extracted with ethyl acetate (100 mL×2). The organic extracts were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with hexane to afford the title compound as orange oil (21.9 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C1CNCCN1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)N1CCNCC1
Yield: 13 %

Procedure:
20 g of anhydrous piperazine was dissolved in 1,000 ml of tetrahydrofuran and then 33.6 g of stearoyl chloride was added dropwise thereto under stirring and under cooling with ice. The mixture was stirred under cooling with ice for 1 h and tetrahydrofuran was distilled off under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue. After extraction with 200 ml of chloroform three times, the extract was washed with a saturated aqueous solution of common salt and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=9/1) to obtain 5.1 g of the intended product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1.[Na].[CH2:18]([OH:20])[CH3:19]>>[Cl:1][C:2]1[N:7]=[C:6]([O:20][CH2:18][CH3:19])[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(Cc2cnc(Cl)nc2Cl)cn1
Reactant: CCO
Agent: [Na]
Product: CCOc1nc(Cl)ncc1Cc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a stirred solution of 8.1 g (32 mmol) of 2,4-dichloro-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine prepared as in Example 1 in 200 ml of ethanol at 10° was added dropwise over 1 hour a solution of 0.8 g (35 mg-atom) of sodium metal in 100 ml of ethanol. The resulting mixture was stirred for 18 hours at room temperature, concentrated, and the resulting oil dissolved in 100 ml of ethyl acetate. The resulting solution was washed with water, dried over sodium sulfate, filtered and concentrated to give 7.6 g (0.0288 mmol, 90%) of 2-chloro-4-ethoxy-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine; MS(FD)m/e 263 parent ion.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:23](O)=[O:24]>>[OH:10][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[CH:23]=[O:24]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1cccc(O)c1
Agent: C1N2CN3CN1CN(C2)C3
Product: CC(C)c1ccc(C=O)c(O)c1
Temperature: 60 °C

Procedure:
To 100 mL of trifluoroacetic acid were added 25.39 g of 3-isopropylphenol and 26.14 g of hexamethylenetetramine. After being stirred at 60° C. for an hour, the reaction mixture was concentrated under reduced pressure. To the residue was added diluted hydrochloric acid, and the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium bicarbonate solution, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 6.69 g of 2-hydroxy-4-isopropylbenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[NH:5][C:4](=[O:10])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:37]2[CH2:39][C@@H:38]2[CH2:40]O)=[N:35][CH:36]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[N:5]=[C:4]([O:10][CH2:40][C@H:38]2[CH2:39][C@@H:37]2[C:34]2[CH:33]=[CH:32][C:31]([CH3:30])=[CH:36][N:35]=2)[CH:3]=1
Reactant: Cn1[nH]c(=O)cc(Br)c1=O
Reactant: Cc1ccc([C@H]2C[C@@H]2CO)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(Br)c(=O)n(C)n2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-1-methyl-1,2-dihydropyridazine-3,6-dione (100 mg, 0.49 mmol) in THF (3 mL) at 0° C. was added triphenyl phosphorous (257 mg, 0.98 mmol) and ((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methanol (4) (80 mg, 0.49 mmol) followed by dropwise addition of DIAD (198 mg, 0.98 mmol). The reaction mixture was warmed to ambient temperature. After stirred for 1 h, the mixture was concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EA (1/2) to give the title compound as oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]#[CH:27].O>CS(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:27][C:26]#[CH:25])=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Clc1nc(NCc2ccccc2)c2[nH]cnc2n1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C#CCn1cnc2c(NCc3ccccc3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A solution of 2-chloro-6-benzylaminopurine (1.1 g, 3.8 mmol), in DMSO (5 mL) was cooled to 0° C., potassium carbonate (0.79 g, 5.7 mmol) and propargyl bromide (0.45 g, 3.8 mmol) was added to the contents, and stirred for 1 h at 0° C. Water (20 mL) was then added to the reaction mixture, and the resulting yellow precipitate was filtered and washed with excess water (50 mL). Compound 5 (1.1 g, 80%) was obtained as an off-white solid upon successive recrystallization from dichloromethane and ethyl acetate: mp 180° C.; EI/MS (m/z (relative %)): 297 (63, M+.), 298 (15), 299 (23), 258 (46), 91(100); 1H NMR (400 MHz, DMSO) δ 8.23 (s, 1H), 7.21-7.38 (m, 5H), 5.03 (bs, 2H), 4.62 (d, J=6 Hz, 2H), 3.51 (s, 1H). 13C NMR (100 MHz, DMSO) δ 155.6 (s), 154.0 (s), 150.3 (s), 140.7 (d, 1JC—H=214 Hz) 139.9 (s), 128.9 (d, 1JC—H=159 Hz), 127.9 (d, 1JC—H=157 Hz), 126.8 (d, 1JC—H=158 Hz), 118.1 (s), 78.5 (t, 2JC—H=9 Hz) 76.7 (dt, 1JC—H=252 Hz, 3JC—H=4 Hz), 43.8 (t, 1JC—H=126 Hz), 33.3 (t, 1JC—H=139 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C
Reactant: c1cn[nH]c1
Product: Cc1sc2nc(-n3cccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CI.[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][C:9]=1[OH:10].[C:16](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:16]
Reactant: COC(=O)Cc1ccc(O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.4 %

Procedure:
Methyl iodide (2.05 mL, 4.68 g, 33 mmol) was added to a mixture of methyl 3-bromo-4-hydroxyphenylethanoate (Description 73, 7.35 g, 30 mmol) and potassium carbonate (8.29 g, 60 mmol) in dimethylformamide (30 mL) and the mixture was stirred at room temperature for 16 h. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with aqueous sodium hydroxide (1M, 2×100 mL), water (2×100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (7.65 g, 100%). 1H NMR (360 MHz, CDCl3) δ7.47 (1 H, d, J 2.1 Hz), 7.18 (1 H, dd, J 8.4, 2.1 Hz), 6.85 (1 H, d, J 8.4 Hz), 3.88 (3 H, s), 3.70 (3 H, s), and 3.49 (2 H, s).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:11][S:12]([C:8]1[CH:9]=[N:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1cccnc1O
Product: O=C(O)c1cc(S(=O)(=O)Cl)cnc1O
Temperature: 160 °C
Yield: 44 %

Procedure:
2-Hydroxynicotinic acid (10.0 g, 71.8 mmol) was dissolved in 25 ml of chlorosulfonic acid and heated to 160° C. overnight. After cooling the reaction was slowly poured into ice and stirred in an ice bath until a white precipitate formed. The solid was filtered off and dried under vacuum to afford 7.55 g of 5-(chlorosulfonyl)-2-hydroxynicotinic acid (44% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.9 (dd, J=2.5, 0.7 Hz, 1H) 8.4 (dd, J=2.6, 0.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][CH:10]([C:16](=O)[CH3:17])[C:11](OCC)=[O:12]>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:16]([CH3:17])[C:10]([CH3:9])=[C:11]2[OH:12]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)C(C)=O
Product: Cc1nc2ccc(Cl)cc2c(O)c1C

Procedure:
Prepared according to procedure R using 4-chloroaniline (2 g, 15.68 mmol) and ethyl 2-methyl-3-oxobutanoate (4.53 mL, 31.36 mol) to give 6-chloro-2,3-dimethylquinolin-4-ol as a white solid: Mass Spectrum (ESI) m/e=208.0 (M+1).
Reaction SMILES: C([Li])(C)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1.[N:14]1([C:19]2([C:23]#[N:24])[CH2:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)(O)[O-].[Na+].[BH4-].[Na+]>C(OCC)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:23]([NH2:24])[C:19]2([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:20][CH2:21][CH2:22]2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(I)cc1
Reactant: N#CC1(N2CCCC2)CCC1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: NC(c1ccc(F)cc1)C1(N2CCCC2)CCC1
Temperature: -75 °C
Reaction time: 0.75 h
Yield: 86.8 %

Procedure:
tert-Butyllithium (1.6M in pentane, 65 mL, 104 mmol) was added during 30 min at −75° C. to −60° C. to a solution of 4-fluoroiodobenzene (13 g, 59 mmol) in 40 mL diethylether. The reaction mixture was stirred at −75° C. for 45 min. 1-Pyrrolidin-1-yl-cyclobutanecarbonitrile (intermediate F) (5 g, 29 mmol) in 5 mL diethylether was added slowly. The reaction mixture was allowed to slowly warm up and was poured into cold saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The residue was dissolved in 100 mL methanol and sodiumborohydride (2.3 g, 59 mmol) was added portion-wise at 0° C. The reaction mixture was stirred at room temperature for 2 hours and quenched by addition of water. The solvent was evaporated off. The residue was taken up in water and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on amine silica gel with dichloromethane yielded the title compound as a yellow oil (6.25 g, 85%), MS: m/e=249.2 [(M+H)+].
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:7]=[C:8]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[I-].[Na+]>CS(C)=O>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:7][C:6]=1[CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: COc1ccc(Oc2ccccc2Cl)cc1CCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2ccccc2Cl)cc1CC#N
Reaction time: 0.67 h
Yield: 57.2 %

Procedure:
Powdered potassium cyanide (2.05 g) was added to a solution of 2-chlorophenyl 3-chloromethyl-4-methoxyphenyl ether (8.5 g) and sodium iodide (4.7 g) in dimethyl sulfoxide (50 ml) at room temperature and stirred at the same temperature for an hour and then at 70° C. for 40 minutes. The reaction mixture was treated in a similar manner to that of Example 3-(7) to give oily 2-[2-methoxy-5-(2-chlorophenoxy)phenyl]acetonitrile (4.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]3[CH:29]=[CH:28][C:20]4[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=4[CH:18]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:32](=O)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH2:32]([N:16]([CH2:15][C:14]1[CH:30]=[CH:31][C:11]([C:10]#[C:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)[C:17]1[CH:29]=[CH:28][C:20]2[O:21][C:22]([CH3:27])([CH3:26])[O:23][C:24](=[O:25])[C:19]=2[CH:18]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: COc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(OC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Temperature: 70 °C
Yield: 103.5 %

Procedure:
To a solution of 6-({4-[(4-methoxyphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (416 mg; 1.01 mmol) in anhydrous DCE (15 mL) were added hexanal (Aldrich, 181 μl; 1.51 mmol), sodium triacetoxyborohydride (426 mg, 2.01 mmol) and acetic acid (115 μl). The resulting mixture was heated at 70° C. under nitrogen atmosphere for 24 h and poured into a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM (twice) and combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and concentrated. Purification by flash chromatography on silica gel (EtOAc/c-Hex 5:95 then 10:90) gave 520 mg of the title compound (quantitative). HPLC, Rt : 5.82 min (purity: 99.9%). LC/MS, M+(ESI): 498.7. 1H NMR (CDCl3) δ: 7.43 (d, J=8.9 Hz, 4H), 7.21 (s, 1H), 7.16 (d, J=8.1 Hz, 2H), 6.74-6.86 (m, 4H), 4.48 (s, 2H), 3.80 (s, 3H), 3.34 (t, J=7.8 Hz, 2H), 1.68 (s, 6H), 1.61 (m, 2H), 1.27 (s, 6H), 0.86 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[NH:24][C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.[C:34](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:34])[C:23]2=[O:33])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To a mixture of 0.10 g of methyl [3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate, 1 ml of acetonitrile, and 31 mg of potassium carbonate was added 32 mg of methyl iodide, and the mixture was stirred at room temperature for 1.5 hours. Then, 64 mg of methyl iodide was added, and the mixture was stirred at 50° C. for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 97 mg of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6).
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([NH:12][NH2:13])[N:7]=1.[C:14](#[N:18])/[CH:15]=[CH:16]/[CH3:17]>C1C=CC=CC=1>[NH2:18][C:14]1[CH2:15][CH:16]([CH3:17])[N:12]([C:8]2[CH:9]=[N:10][CH:11]=[C:6]([Cl:5])[N:7]=2)[N:13]=1
Reactant: C/C=C/C#N
Reactant: NNc1cncc(Cl)n1
Agent: [Na]
Solvent: CCO
Solvent: c1ccccc1
Product: CC1CC(N)=NN1c1cncc(Cl)n1

Procedure:
A 0.30 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 6.72 g. of 2-chloro-6-hydrazinopyrazine (prepared as described above) is added and after 5 minutes, 4.6 g. of distilled crotononitrile is added. The reaction mixture is refluxed for 6 hours. The solvent is removed in vacuo and water is added to the residue to separate a gum. The gum is dissolved in dichloromethane, dried over magnesium sulfate and filtered. The filtrate is evaporated to give a gum. The gum is treated with benzene to separate yellow crystals. The crystals are collected, dried and recrystallized from acetone-hexane to give 1.4 g of the desired product as yellow crystals, m.p. 147°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1F)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[S-:19][CH2:20][CH3:21].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[S:19][CH2:20][CH3:21])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC[S-]
Reactant: O=[N+]([O-])c1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1c(Cl)cc2c([nH]c3cnccc32)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 81.2 %

Procedure:
A 25 ml round-bottom flask with a magnetic stirrer was charged with 6-chloro-7-fluoro-8-nitro-9H-β-carboline (102 mg, 0.38 mmol) in 5 ml of anhydrous DMF. To the resulting orange mixture at RT was slowly added sodium thioethoxide (80% pure, 69.7 mg, 0.66 mmol) in powder form. The reaction mixture was stirred at RT for 45 minutes, then added drop-wise to a 5:1 mixture of H2O/saturated sodium bicarbonate (˜30 ml). The resulting precipitated solid was collected by suction filtration, washed with 1:1 hexanes/diethyl ether (2×20 ml), and air-dried to afford 95.0 mg of 6-chloro-7-ethylsulfanyl-8-nitro-9H-β-carboline as an orange solid (79%).
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[S:8][C:4]=2[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:16](Cl)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>ClCCl>[C:16]([C:2]1[S:1][C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[S:8][C:4]=2[CH:3]=1)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: c1cc2c(s1)sc1ccsc12
Reactant: CCCCCCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCC(=O)c1cc2sc3sccc3c2s1
Yield: 62.8 %

Procedure:
Dithienothiophene 2 (R1=R2=R3=R4=H) (765 mg, 3.90 mmol) was dissolved in dry dichloromethane (35 cm3) and the solution was ice-cooled before AlCl3 (790 mg, 5.92 mmol) was added in one portion yielding a dark mixture. A solution of octanoyl chloride (1.00 g, 6.02 mmol) in dichloromethane (20 cm3) was added dropwise over a 20 minute period and the mixture was then allowed to stand at room temperature For a further thirty minutes. It was hen added to ice and the mixture was acidified with dilute hydrochloric acid (100 cm3). Additional dichloromethane (100 cm3) was added and the layers separated. The organic layer was washed with water, dried over MgSO4 and concentrated. Column Chromatography (hexane—30% dichloromethane/hexane) afforded 790 mg (63%) of the title compound. An analytical sample may be prepared by recrystallisation from a mixture of dichloromethane and methanol. Rf 0.31 (1:1 dichloromethane/hexane); m.p. 130-131° C.; 1H (250 MHz, CDCl1) δ0.89 (3H, t, J6.5, CH2CH3); 1.25 (8H, br s, CH2CH2CH2); 1.78 (2H, m, CH2CH2CO); 2.93 (2H, t, J7.5, CH2CO); 7.32 (1H, d, J5.0, Dt-H); 7.52 (1H, d, J5.0, Dt-H); 7.91 (1H, s, Dt-H); 13C (100 MHz, CDCl3) δ14.1; 22.6; 25.0; 29.1; 29.3; 30.9; 31.7; 39.0; 120.9; 125.5; 129.0; 141.4; 144.4; 144.9; 193.7; v (cm−1, KBr) 600, 702, 1191, 1364, 1466, 1493, 1644 (C=O), 2925; Calc. for C16H18S3O C: 59.6; H: 5.6; Found: C: 59.2; H: 5.6.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][NH:29][CH2:28]2>>[F:35][C:24]([F:23])([F:34])[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:28]2
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCN3Cc4ccc(C(F)(F)F)cc4C3)cn2)c1
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 5-trifluoromethylisoindoline according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.12 (2H, t, J=6.0 Hz), 4.10 (4H, s), 4.21 (2H, t, J=5.9 Hz), 7.45 (1H, d, J=8.0 Hz), 7.55 (2H, d, J=8.8 Hz), 7.60 (1H, s), 7.81 (1H, s), 7.86 (1H, s), 8.26 (1H, s), 8.56 (1H, m). [M+H] Calc'd for C20H17F3N4O2, 403. Found, 403.