Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].S(Cl)([Cl:12])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH3:8])/[CH:3]=[CH:4]/[C:5]([Cl:12])=[O:6]
Reactant: CC(C)(C)/C=C/C(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)(C)/C=C/C(=O)Cl

Procedure:
To a solution of (E)-4,4-dimethyl-2-pentenoic acid (Gream, G. E.; Serelis, A. K. Aust. J. Chem. 1978, 31, 863) (200 mg, 1.6 mmol) in benzene (10 ml) was added thionyl chloride (0.5 ml) and the mixture was heated to reflux for 60 min. Volatiles were removed by evaporation to give crude (E)-4,4-dimethyl-2-pentenoyl chloride. Free base of the titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine (150 mg, 0.81 mmol) and (E)-4,4-dimethyl-2-pentenoyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base was dissolved with a 10% methanol solution of hydrogen chloride (5 ml). Concentration and recrystallization from ethyl acetate yielded the titled compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]2[CH:7]=[CH:8][C@H:9]([OH:10])[C@@H:4]2[O:3]1.N1C=CC=CC=1.Cl[C:19]([O:21][CH3:22])=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:19](=[O:20])([O:21][CH3:22])[O:10][C@@H:9]1[C@H:4]2[C@H:5]([O:6][C:2]([CH3:11])([CH3:1])[O:3]2)[CH:7]=[CH:8]1
Reactant: CC1(C)O[C@H]2[C@@H](O)C=C[C@H]2O1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)O[C@H]1C=C[C@H]2OC(C)(C)O[C@@H]12
Temperature: 0 °C

Procedure:
(3aS,4S,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (2-1) (9.76 g, 62.5 mmol, 1.0 equiv) was dissolved in DCM (200 mL). Pyridine (7.58 mL, 94.0 mmol, 1.5 equiv) was added and the mixture stirred at 0° C. After 1 hour DMAP (3.05 g, 25.0 mmol, 0.4 equiv) was added followed by methyl chloroformate (19.4 mL, 250 mmol, 4 equiv). The resulting mixture was stirred overnight, and the temperature was allowed to slowly increase to room temperature. The reaction was partitioned between DCM and water, and the organic layer was separated and washed with water, dried (MgSO4), and concentrated to yield desired (3aR,4S,6aR)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methyl carbonate (2-2) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 6.10 (d, J=5.9 Hz, 1H); 5.91 (d, J=5.9 Hz, 1H); 5.30 (d, J=5.4 Hz, 1H); 5.03 (d, J=5.7 Hz, 1H); 4.92 (t, J=5.5 Hz, 1H); 3.83 (s, 3H); 1.40 (s, 3H); 1.38 (s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11].C1COCC1.[CH3:17][C:18]1[C:19]([N:23]=[C:24]=[S:25])=[CH:20][S:21][CH:22]=1>C(N(CC)CC)C>[NH2:3][C:4]1[C:8]([NH:9][C:24]([NH:23][C:19]2[C:18]([CH3:17])=[CH:22][S:21][CH:20]=2)=[S:25])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11]
Reactant: Cc1sc(C)c(N)c1N
Reactant: Cc1cscc1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cscc1NC(=S)Nc1c(C)sc(C)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1 g of 3,4-diamino-2,5-dimethylthiophene dihydrochloride, 60 ml of anhydrous THF and 1.05 g of triethylamine was stirred at room temperature for 30 minutes and then admixed with 0.902 g of 4-methyl-3-thienyl isothiocyanate. After the mixture had been heated to 35–40° C. for 15 minutes, it was stirred for approx. 18 hours, the solvent was distilled off and the residue was admixed with water and extracted repeatedly with ethyl acetate. After the solvent of the combined organic phases had been distilled off, the residue was purified by column chromatography on silica gel using a solvent mixture of equal parts of toluene and ethyl acetate. After the solvent had been distilled off under reduced pressure, a semicrystalline oil was obtained and was used without further purification.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:10]=[C:9]([N+]([O-])=O)[CH:8]=[C:7](Cl)[C:5]=1N.F[C:16]1[C:23]([C:24]#N)=[C:22](F)[C:21](F)=C(F)C=1C#N.O.[CH3:30][N:31]([CH:33]=O)[CH3:32]>>[CH3:30][N:31]1[CH2:33][CH:16]=[C:23](/[CH:22]=[CH:21]/[C:4]2[C:5]3[C:7](=[CH:10][CH:4]=[CH:5][CH:7]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:24][CH2:32]1.[ClH:3]
Reactant: N#Cc1c(F)c(F)c(F)c(C#N)c1F
Reactant: Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CC=C(/C=C/c2cccc3ccccc23)CC1
Product: Cl

Procedure:
3.12 g (0.078 mol) of sodium hydroxide was added to a solution of 8.07 g (0.039 mol) of 2,6-dichloro-4-nitroaniline in 60 mL of DMF, followed by addition of 7.80 g (0.039 mol) of 2,4,5,6-tetrafluoroisophthalonitrile under stirring, the mixture was stirred for 5 h after addition at room temperature. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was poured into water and extracted with ethyl acetate, the organic phase was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column (ethyl acetate/petroleum ether (boiling point range 60-90° C.)=1:5, as an eluent) to give 8.08 g of compound B-115 as yellowish solid, m.p. 164-166° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1.Cl[CH2:31][CH2:32][C:33]1[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:31][CH2:32][C:33]4[O:37][N:36]=[C:35]([CH:38]([CH3:40])[CH3:39])[N:34]=4)[CH2:18][CH2:17]3)=[CH:11][C:10]=2[CH3:22])=[N:6][CH:7]=1
Reactant: CC(C)c1noc(CCCl)n1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCc5nc(C(C)C)no5)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (14 mg, 0.033 mmol), 5-(2-chloroethyl)-3-isopropyl-1,2,4-oxadiazole (9 mg, 0.053 mmol) and DIEA (29 uL, 0.17 mmol) in NMP (1 mL) was stirred at 50° C. for 3 days. The crude reaction mixture was purified by RP-HPLC to give 5-Chloro-N2-(4-(1-(2-(3-isopropyl-1,2,4-oxadiazol-5-yl)ethyl)piperidin-4-yl)-2,5-dimethylphenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as a white solid; ESMS m/z 550.3 (M+H+).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:14].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>CCOCC>[C:22]([O:1][CH:2]([O:13][C:12]1[CH:7]=[C:8]([CH3:14])[CH:9]=[CH:10][CH:11]=1)[C:3]([Cl:6])([Cl:5])[Cl:4])(=[O:24])[CH3:23]
Reactant: Cc1cccc(O)c1
Reactant: CC(=O)Cl
Reactant: O=CC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC(Oc1cccc(C)c1)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of anhydrous chloral (37.0 g) in dry ether (125 ml) was added meta-cresol (27.0 g) and the mixture was stirred at the ambient temperature for 20 minutes, after which it was cooled to 10° C and a solution of triethylamine (25.25 g) in dry ether (100 ml) was slowly added. Acetyl chloride (20.0 g) was then carefully added to the stirred mixture and stirring was continued for 1 hour. The insoluble material was removed by filtration and the filtrate dried over anhydrous magnesium sulphate. After removal of the ether by evaporation under reduced pressure the residual oil was distilled under high vacuum and the fraction boiling at 132°-135°/0.5 mm Hg collected. Infra-red and nuclear magnetic spectroscopic analysis indicated that this was 1(3-tolyloxy)-2,2,2-trichloroethyl acetate.
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[CH:27]1[CH2:36][C:35](=[O:37])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[CH:27]1[CH2:36][CH:35]([OH:37])[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([OH:38])[CH:33]=2)[O:28]1
Reactant: O=C1CC(c2c(F)cccc2F)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1c(F)cccc1F)O2

Procedure:
2-(2,6-Difluorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 4.45 g of 2-(2,6-difluorophenyl)-6-hydroxychroman-4one. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 7.48 (m, 1H), 7.17-7.13 (m, 2H), 6.90 (d, 1H, J 2.9 Hz), 6.55-6.54 (m, 2H), 5.46 (dd, 1H, J 12.2, 1.8 Hz), 4.87 (m, 1H), 2.37 (m, 1H), 2.23 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3]I.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1.O>CN(C)C=O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:3])=[CH:10][CH:11]=1
Reactant: CI
Reactant: OCCCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 88 %

Procedure:
Sodium hydride (purity: 55%, 434 mg) and methyl iodide (0.62 mL) were added to a solution of 4-(4-bromophenyl)butan-1-ol obtained in Reference Example 5-21(1) in N,N-dimethylformamide (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 7.5 hours. Water was added to the reaction solution, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→20:1→10:1) to give the title compound (1.06 g, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1)([O-:3])=[O:2].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N1C=CC=CC=1>O>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]3[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:13][N:12]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 5-(3-nitrophenoxy)pyridin-2-amine (2.70 g, 11.7 mmol), p-toluenesulfonyl chloride (2.67 g, 14.0 mmol) and pyridine (20 mL) was stirred at 80° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give 4-methyl-N-[5-(3-nitrophenoxy)pyridin-2-yl]benzenesulfonamide (4.15 g, 92%) as a white solid. A mixture of 4-methyl-N-[5-(3-nitrophenoxy)pyridin-2-yl]benzenesulfonamide (4.15 g, 10.7 mmol) thus-obtained, N,N-diisopropylethylamine (2.44 mL, 14.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr, iodoacetamide (2.59 g, 14.0 mmol) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (5.28 g, 99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][N:19]=[C:20]=[O:21].O1CCCC1>CN(C)C=O>[CH3:18][NH:19][C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21]
Reactant: CN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Reaction time: 3.5 h
Yield: 23 %

Procedure:
A solution of 0.15 gm (0.65 mMol) 5-amino-3-(1-methyl-piperidin-4yl)pyrrolo[3,2-b]pyridine and 0.046 mL (0.78 mMol) methyl isocyanate in 6 mL 5:1 tetrahydrofuran: dimethylformamide was stirred at room temperature for 5 hours. At this point an additional 0.020 mL methyl isocyanate were added and stirring continued for another 3.5 hours. The reaction mixture was then concentrated under reduced pressure. The residue was partitioned between 3:1 chloroform:isopropanol and 1N sodium hydroxide. The phases were separated and the aqueous phase extracted well with 3:1 chloroform:isopropanol. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (2mm silica gel plate), eluting with dichloromethane containing from 20-40% methanol and 1% ammonium hydroxide. Fractions shown to contain produce were combined and concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide 0.043 gm (34%) of the title compound. m.p.=228.8-230.4° C. MS(m/e): 288(M+1) Calculated for C15H21N5O: Theory: C, 62.70; H, 7.37; N, 24.37. Found: C, 62.49; H, 7.29; N, 24.40.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12][CH3:13].[CH:14]1([C:17]2[CH:21]=[C:20]([OH:22])[N:19]([CH3:23])[N:18]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:31](=O)([O-])[O-:32].[K+].[K+]>O1CCOCC1>[CH:14]1([C:17]2[C:21]([C:31](=[O:32])[C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=3[S:12][CH3:13])=[C:20]([OH:22])[N:19]([CH3:23])[N:18]=2)[CH2:16][CH2:15]1
Reactant: Cn1nc(C2CC2)cc1O
Reactant: O=C([O-])[O-]
Reactant: CSc1cc(C(F)(F)F)ccc1I
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CSc1cc(C(F)(F)F)ccc1C(=O)c1c(C2CC2)nn(C)c1O
Yield: 89.3 %

Procedure:
Into a 200 ml autoclave, 1.59 g of 4-iodo-3-methylthiobenzotrifluoride prepared in accordance with the following Preparation Example 10, 1.38 g of 3-cyclopropyl-5-hydroxy-1-methylpyrazole (after-mentioned Intermediate No. 1a-1), 0.5 g of triethylamine, 3.1 g of potassium carbonate, 0.22 g of palladium (II) bis-triphenylphosphine) dichloride and 40 ml of dioxane were put and sealed, and the interior of the autoclave was flushed with carbon monoxide (pressure: 65 kg/cm2), followed by a reaction at 140° C. for 8 hours. After completion of the reaction, the solvent was distilled off, and the residue was dissolved in water, and then insoluble matters were filtered off. The filtrate was washed with dichloromethane. The washed product was acidified (pH=1) with concentrated hydrochloric acid and extracted with dichloromethane. The obtained extract solution was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 1.59 g of 3-cyclopropyl-1-methyl-4-(2-methylthio-4-trifluoromethylbenzoyl)-5-hydroxypyrazole (after-mentioned Compound No. a-82) as a reddish brown solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:22]N1C(=O)CCC1=O>C(#N)C>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH2:12][CH3:13])[C:9]2[CH:14]=[C:15]([Br:22])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCC1CN(C(=O)C(F)(F)F)CCc2cc(OC)c(Br)cc21
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A solution of N-trifluoroacetyl-1-ethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.710 g, 2.36 mmol) in acetonitrile (20 mL) was treated with N-bromosuccinimide (0.504 g, 2.83 mmol), and stirred overnight at 20 C. The product mixture was concentrated, diluted with EtOAc (100 mL), washed with water (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.561 g of a clear oil. MS calculated for C15H17BrF3NO2+H: 380, observed: 380.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1)[CH3:2].Br[CH2:10]/[CH:11]=[CH:12]/[CH2:13]Br>C(#N)C>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:10]/[CH:11]=[CH:12]/[CH2:13][N:5]2[CH2:6][CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4]2)[CH2:4]1)[CH3:2].[NH3:3]
Reactant: BrC/C=C/CBr
Reactant: CCN1CCCNC1
Solvent: CC#N
Product: CCN1CCCN(C/C=C/CN2CCCN(CC)C2)C1
Product: N
Temperature: 80 °C

Procedure:
A mixture of 1.07 g (9.37 mmol) of 1-ethyl-hexahydro-pyrimidine (Chem. Pharm. Bull. 28, 3310 (1980)), 0.5 g (2.34 mmol) of trans-1,4-dibromo-2-butene and 10 ml of acetonitrile is heated for 16 h at 80° C., with stirring and under a nitrogen atmosphere, and is then concentrated by evaporation in vacuo. The residue is partitioned between 2N sodium hydroxide solution and methylene chloride, and the methylene chloride phase is washed with brine, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue is purified by means of flash chromatography over silica gel having a particle size of 0.04-0.063 mm, using methylene chloride-methanol (9:1) and methylene chloridemethanol-concentrated ammonia (90:10:0.5), yielding the title compound in the form of an oil, Rf value=0.63 (silica gel/methylene chloride:methanol:concentrated ammonia (40:10:1)).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])[CH:7]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][C:17]=1[CH3:31]>>[ClH:15].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][N:9]3[CH:13]=[CH:12][N:11]=[C:10]3[CH3:14])[CH:7]=2)=[CH:18][C:17]=1[CH3:31]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Cl
Reactant: Cc1nccn1Cc1cncc(Br)c1
Product: Cc1cc(-c2cncc(Cn3ccnc3C)c2)ccc1Cl
Product: Cl

Procedure:
The title compound, MS: m/e=298.3 (M+H+) was obtained as a white solid (73% yield) by the reaction of 3-bromo-5-(2-methyl-imidazol-1-yl-methyl)-pyridine with 2-(4-chloro-3-methyl-phenyl)-4,4,5,5-tetramethyl[1,3,2]-dioxaborolane.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:6]=[CH:7][C:8](O)=[N:9][CH:10]=1)([CH3:3])[CH3:2].P(Br)(Br)([Br:14])=O>CN(C=O)C>[Br:14][C:8]1[CH:7]=[CH:6][C:5]([S:4][CH:1]([CH3:3])[CH3:2])=[CH:10][N:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)Sc1ccc(O)nc1
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(Br)nc1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 62.9 %

Procedure:
DMF (5 mL) was added slowly to a stirred mixture of 5-isopropylsulfanylpyridin-2-ol (765.8 mg, 4.525 mmol) and POBr3 (5.189 g, 18.10 mmol) at ambient temperature. After 10 minutes, the reaction mixture was warmed to 95° C. for 1 hour. The reaction mixture was cooled to ambient temperature and quenched by the slow addition of ice. The aqueous layer was extracted with EtOAc (×3) and the combined organics washed with saturated aqueous NaHCO3 (×3), brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 80 g column, eluting with 0 to 20% EtOAc/Petroleum Ether, loaded in DCM) to give the sub-title product as an off-white solid (661 mg, 63% Yield, 65% purity). 1H NMR (400.0 MHz, DMSO) δ 1.24 (d, J=6.8 Hz, 6H), 3.58 (sept, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.78 (dd, J=2.6, 8.4 Hz, 1H) and 8.37 (d, J=2.5 Hz, 1H) ppm; MS (ES+) 231.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.COC([CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:24][O:23][C:21]([CH:18]1[N:19]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:20][CH2:15][N:16]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17]1)=[O:22]
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Chloro phenyl boronic acid (2.0 equiv, 3.68 mmol) and piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.0 equiv, 1.84 mmol) were dissolved in dichloromethane followed by the addition of copper acetate (1.0 equiv), 4 Å molecular sieves and pyridine (2.0 equiv). The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (20%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][C:29]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][OH:36])([CH3:32])[C:30]#[CH:31]>>[CH3:32][C:29]([N:33]([CH2:37][CH3:38])[CH2:34][CH2:35][OH:36])([CH3:28])[C:30]#[C:31][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:26])([F:1])[F:27])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)C(F)(F)F
Reactant: C#CC(C)(C)N(CC)CCO
Product: CCN(CCO)C(C)(C)C#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 14.1, Trifluoro-methanesulfonic acid 3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl ester and 2-[(1,1-Dimethyl-prop-2-ynyl)-ethyl-amino]-ethanol were converted to yield 2-((1,1-Dimethyl-3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl)-ethyl-amino)-ethanol as off-white foam, MS: 433 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[N:6][CH:7]=1.[CH3:16][Mg]Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH3:16])=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(F)cn1
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[(1E)-(5-fluoropyridin-2-yl)methylene]-2-methylpropane-2-sulfinamide (52.12 g, 228 mmol) in dichloromethane (1000 mL) at −78° C. was added methylmagnesium bromide (3.0 M in THF; 198 mL, 594 mmol). The mixture was allowed to warm to ambient temperature. After 30 min, the mixture was cooled down to −78° C. and was quenched with saturated aqueous ammonium chloride (100 mL). The mixture was allowed to warm to ambient temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% ethyl acetate) gave the title compound. MS 245 (M+1).