Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:15](=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][C:12]1[O:13][C:14]2[C:15](=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[N:16]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(O)cccc2o1
Product: Oc1cccc2oc(CCC#Cc3ccccn3)nc12
Yield: 7364.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (203 mg, 1.29 mol) and 2-(but-3-ynyl)benzo[d]oxazol-4-ol (241 mg, 1.29 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) and SCX column (DCM/MeOH 100:0 to 94:6, DCM/MeOH/NH4OH 94:5:1 to 90:8:2) to yield 25 mg (95 mmol, 7%) of 2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazol-4-ol as an orange solid.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH2:22][C:23]1[C:32](Br)=[N:31][C:30]([Br:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[NH2:22][C:23]1[C:32]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:8][CH:9]=2)=[N:31][C:30]([Br:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: CC(C)OC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)OC(C)C)cc2)c1N
Temperature: 110 °C
Reaction time: 16 h
Yield: 43.2 %

Procedure:
A mixture of 4-isopropoxycarbonylphenylboronic acid (0.98 g, 4 7 mmol), sodium carbonate (1.02 g, 9.58 mmol), tetrakistriphenylphosphine palladium (0) (0.205 g, 0.177 mmol), and methyl 3-amino-2,6-dibromoisonicotinate (1.1 g, 3 6 mmol) in a vial was flushed with nitrogen. Toluene (12 mL) and methanol (4 mL) were added and the reaction stirred at 110° C. for 16 h. The reaction mixture was partitioned between EtOAc and sat. aq. sodium bicarbonate solution. The organic phase was washed with sat. aq. sodium bicarbonate solution, brine, and dried with sodium sulfate. Removal of the solvents followed by silica gel chromatography (step gradient elution with hexane containing 0 to 20% EtOAc afforded methyl 3-amino-6-bromo-2-(4-(isopropoxycarbonyl)phenyl)isonicotinate (1.04 g, 2.59 mmol, 73% yield). MS (ESI) m/z 393.00 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.14 (2H, d, J=8.24 Hz), 7.84 (1H, s), 7.69 (2H, d, J=8.24 Hz), 5.94 (2H, br. s.), 5.27 (1H, dt, J=12.51, 6.26 Hz), 3.93 (3H, s), 1.38 (6H, d, J=6.10 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[OH:9]O>C(O)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N+:3]=1[O-:9]
Reactant: Cc1cccc(Br)n1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(Br)[n+]1[O-]
Temperature: 90 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
2-Bromo-6-methylpyridine (36 g, 0.2 mol) was dissolved in acetic acid (700 ml), hydrogen peroxide (30%, 62 ml, 0.6 mol) was added and the mixture was stirred at 90° C. for 24 hours. After cooling to room temperature, the mixture was diluted with water (700 ml) and extracted with DCM (4×). The combined organic phases were washed with water, dried (sodium sulfate) and concentrated under reduced pressure to give 36 g of a red-brown liquid (0.19 mol, 94%) MS(APCI) m/z=188.0 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(C)=O)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.005 mL (0.068 mMol) acetyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: C(OC([N:8]([CH2:17]/[CH:18]=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH2:30][CH:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[O:28][N:27]=2)[CH:21]=1)[O:9]C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(Cl)Cl>[F:37][C:34]1[CH:33]=[CH:32][C:31]([CH:29]2[O:28][N:27]=[C:26]([C:22]3[CH:21]=[C:20](/[CH:19]=[CH:18]\[CH2:17][NH:8][OH:9])[CH:25]=[CH:24][CH:23]=3)[CH2:30]2)=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)ON(C/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: ONC/C=C\c1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a solution of the product of Step 4, above (16, 3.2 g, 6.2 mmol) in CH2Cl2 (30 ml) cooled to 0° C., was slowly added trimethylsilyl trifluoromethanesulfonate (2.5 ml, 13.4 mmol) under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and was stirred for 1.5 hours. The reaction mixture was poured carefully into ice cold water (30 ml), the organic layer was separated and the aqueous layer was extracted with CH2Cl2 (30 ml×3). The combined extracts were washed with aqueous NaHCO3 (50 ml) and brine (50 ml), then was dried (MgSO4) and solvent was removed under reduced pressure to afford the title compound (17, (1.8 g, 93% yield) as pale yellow solids.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]4[O:23][C:22]([SH:24])=[N:21][N:20]=4)[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.IC.[C:29](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][S:24][C:22]1[O:23][C:19]([C:16]2[CH:17]=[CH:18][C:13]3[O:12][CH:11]=[C:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:25])[F:26])[CH:5]=4)[C:14]=3[CH:15]=2)=[N:20][N:21]=1
Reactant: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(S)o4)cc23)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A suspension of the obtained 5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol, iodomethane (2.17 mL, 34.8 mmol) and potassium carbonate (3.61 g, 26.1 mmol) in N,N-dimethylformamide (70 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=4/1) and recrystallized from hexane/ethyl acetate to give the title compound (1.01 g, yield 15%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([C:18](=[O:33])[N:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH:11]([C:18](=[O:33])[N:19]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:42])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCCCCN(CCc1ccccc1)C(=O)C(CCC(=O)OC)CSc1ccc(Cl)c(Cl)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCN(CCc1ccccc1)C(=O)C(CCC(=O)OC)CS(=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Yield: 34.6 %

Procedure:
Into a solution of methyl 5-(3,4-dichlorophenylthio)-4-(N-pentyl-N-phenethylcarbamoyl)pentanoate (280 mg) in dry chloroform (10 ml) were added portions of m-chloroperbenzoic acid (70%, 140 mg) with stirring at -78° C. After stirring at -78° C. for 2 hours, sodium sulfite was added. The reaction mixture was washed with a saturated sodium bicarbonate solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica by eluting with dichloromethane/diethy ether/hexane (1:1:2) to give 100 mg of methyl 5-(3,4-dichlorophenylsulfinyl)-4-(N-pentyl-N-phenethylcarbamoyl)pentanoate (diastereomer A) in a early fraction and 110 mg of diastereomer B in a later fraction.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N+:3]=1[O-].[Cl:11]C(Cl)(Cl)C(Cl)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:11][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc[n+]([O-])c(C)c1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(CCl)c1C

Procedure:
A solution of 13.3 g of 2,3,4-trimethylpyridine N-oxide in 130 ml of abs. chloroform is boiled at reflux under argon and treated through the condenser with 33.2 ml of trichloroacetyl chloride. After 18 hours the reaction mixture is poured on to ice, whereupon 10% sodium bicarbonate solution is added, the mixture is extracted with methylene chloride and the methylene chloride solution is dried and concentrated. The thus-obtained crude product is chromatographed on silica gel (solvent: methylene chloride/ether [5:1]). The 2-chloromethyl-3,4-dimethylpyridine obtained is processed directly.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12]O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][Br:33])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Methyl 3-bromo-5-(hydroxymethyl)benzoate (2.0 g, 8.2 mmol) and triphenylphosphine (4.28 g, 16.3 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. N-Bromosuccinimide (3.05 g, 17.1 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (10% ethylacete/hexanes) gave 2.1 g (83%) as a light brown oil. 1H-NMR (CDCl3, 300 MHz) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.70 (s, 1H), 4.42 (s, 2H), 3.90 (s, 3H). Mass spec.: 308.93 (MH)+.
Reaction SMILES: C(O[C:5]1([CH3:14])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][C:12]#[CH:13])(=O)C.S(=O)(=O)(O)[OH:16]>>[OH:16][CH:9]1[CH2:8][C:7](=[O:10])[C:6]([CH2:11][C:12]#[CH:13])=[C:5]1[CH3:14]
Reactant: O=S(=O)(O)O
Reactant: C#CCC1C(=O)C=CC1(C)OC(C)=O
Product: C#CCC1=C(C)C(O)CC1=O
Reaction time: 1 h

Procedure:
In the same flask as in Example 1, 20% sulfuric acid (10 ml) was charged, and dl-3-acetoxy-2-propargyl-3-methyl-4-cyclopentenone (1.92 g) was dropwise added thereto in 1 hour while keeping the inner temperature at 0° C. After completion of the dropwise addition, the resultant mixture was stirred at the same temperature as above for 3 hours. The reaction mixture was subjected to post-treatment and purification as in Example 1 to give 1.38 g of 4-hydroxy-2-propargyl-3-methyl-2-cyclopentenone. Yield, 91%.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]=[O:9].[C:10]1([CH2:16][CH2:17][CH2:18][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]([OH:9])[CH2:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1ncc(Br)c1C=O
Reactant: Br[Mg]CCCc1ccccc1
Product: Cn1ncc(Br)c1C(O)CCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 4-bromo-2-methyl-2H-pyrazole-3-carbaldehyde and 3-phenyl-propyl magnesium bromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12](OCC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:6](=[O:11])[CH2:5]2
Reactant: CCOC(OCC)OCC
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCOC(OCC)N1C(=O)Cc2cc(Br)ccc21
Yield: 68 %

Procedure:
A mixture of 5-bromooxindole (6.36 g, 30 mmol), (prepared according to J. Am. Chem. Soc. 1975, 67, 1656), and triethyl orthoformate (100 ml) was heated and stirred at reflux for 8 hours. The volatiles were removed by evaporation and the residue purified by column flash chromatography using petroleum ether/ether (7/3) as eluent. Evaporation of the solvents lead to a crystalline material which was collected, washed with a minimum of petroleum ether and dried under vacuum to give 5-bromo-1-diethoxymethyloxindole (6.43 g, 68%).
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Br:24])[C:18](O)=[O:19])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][NH2:26]>>[CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Br:24])[C:18]([NH:26][CH3:25])=[O:19])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Reactant: CN
Product: CNC(=O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
3-[(N-Benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzoic acid and methylamine (2M in THF) were reacted as described in Example 5, Step 6 to provide 3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-N-methyl-benzamide.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[OH:5][CH:6]([CH2:15][CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.C(=O)(O)[O-].[Na+]>Cl.O>[CH2:15]([C:6]1[O:5][C:2](=[O:1])[NH:3][C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:16]
Reactant: N#C[O-]
Reactant: CCC(O)C(=O)c1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CCc1oc(=O)[nH]c1-c1ccccn1
Reaction time: 1 h

Procedure:
Potassium cyanate (35.4 g, 0.44 mol) was added to a solution of 2-hydroxy-1-(2-pyridyl)butan-1-one (31 g, 0.15 mol) in 250 ml of 2N HCl diluted with 300 ml of water. After 1 hour the acidity was adjusted (pH=1) with concentrated hydrochloric acid and then allowed to stir overnight. The mixture was made basic by addition of aqueous sodium bicarbonate. The resulting gummy precipitate was chromatographed on silica gel and recrystallized twice from 50% aqueous ethanol to give the title compound, m.p 196°-97° C. (dec.).
Reaction SMILES: [CH3:1][C:2](=[O:11])[CH2:3][CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9].CO.CCN(CC)CC>C(Cl)Cl>[OH:11][CH:2]([CH2:3][CH2:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:1]
Reactant: CCCCC(=O)CCC(C)=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)CCC(C)O
Yield: 65.2 %

Procedure:
A 100-ml stainless steel autoclave purged with nitrogen in advance was charged with 5 g (0.032 mol) of 2,5-nonanedione and 10 ml of methanol. A solution of 0.144 g (0.08 mmol) of Ru2Cl4 ((R)-T-BINAP)2 (NEt3) in 2 ml of methylene chloride was added thereto, thereby conducting reaction at a reaction temperature of 50° C. for 20 hours under a hydrogen pressure of 50 kg/cm2. After distilling off the solvent, the residue was purified by column chromatography on a silica gel using a developing solvent of hexane/ethyl acetate (4/1) to obtain 3.3 g of (-)-2-hydroxynonane-5-one (yield: 65.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ncc(F)cc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ncc(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
0.14 g of 5-(4-chlorophenyl)-4-(3,5-difluoro-2-pyridyl)-6-methyl-2H-pyridazin-3-one and 5 g of phosphorus oxychloride were mixed. The mixture was stirred for 1.5 hours on an oil bath of 120° C. The reaction mixture was allowed to cool to room temperature, the, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.14 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.08 g of 3-chloro-5-(4-chlorophenyl)-4-(3,5-difluoro-2-pyridyl)-6-methylpyridazine (hereinafter, described as compound (15) of the present invention.).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][CH:6]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[S:9](=[O:16])(=[O:15])[NH:8][CH2:7]1)[CH3:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[CH2:22]([O:21][C:19]([CH2:18][N:8]1[CH2:7][CH:6]([NH:5][CH2:3][CH3:4])[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[S:9]1(=[O:15])=[O:16])=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: CCNC1CNS(=O)(=O)c2sccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC1CN(CC(=O)OCC)S(=O)(=O)c2sccc21
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Under a nitrogen atmosphere, sodium hydride (0.44 g of 60% suspension in mineral oil, 0.011 mol) was washed free of mineral oil with petroleum ether. A solution of 3,4-dihydro-4-ethylamino-2H-thieno[3,2-e]-1,2-thiazine-1,1-dioxide (2.32 g, 0.01 mol) in dimethylformamide (10 ml) was added dropwise with stirring over 1/4 hr. Stirring was continued for another 1/2 hr in the cooling bath. Then ethyl bromoacetate (1.25 ml, 0.011 mol) was added and the mixture was stirred for 1/4 hr. with cooling and 1 3/4 hrs. at ambient temperature. The volatile components were removed under high vacuum. The oil-solid residue was extracted with ethyl acetate (2×25 ml). The combined extracts were washed with saturated NaCl, dried, filtered and concentrated in vacuo to a viscous yellow oil (2.75 g). Yield was 86%.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([OH:25])=[O:24].[CH2:27]([C:34]1[O:38][CH:37]=[C:36]([CH2:39]O)[CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:26])[C@H:19]([CH:20]=[C:21]=[CH2:22])[C@H:18]1[C:23]([O:25][CH2:39][C:36]1[CH:35]=[C:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:38][CH:37]=1)=[O:24]
Reactant: OCc1coc(Cc2ccccc2)c1
Reactant: C=C=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C=C[C@@H]1[C@@H](C(=O)OCc2coc(Cc3ccccc3)c2)C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43.3 %

Procedure:
1.22 g of dicyclohexylcarbodiimide and a few crystals of 4-dimethylamino-pyridine were added at 0° C. to a solution of 900 mg of (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)cyclopropane-carboxylic acid in 20 ml of methylene chloride and the mixture was stirred at 0° C. for 15 minutes. A solution of 1.23 g of 5-benzyl-3-furyl-methanol in 7 ml of methylene chloride was added to the mixture which was stirred at 20° C. for 24 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 3-7 petroleum ether (b.p.=35° to 70° C.)-benzene mixture and then a 7-3 petroleum ether (b.p.=35° to 70° C.)-benzene mixture yielded 825 mg of 5-benzyl-3-furyl-methyl (1R,trans) 2,2-dimethyl-3-(1,2-propadienyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =-24° (c= 0.6% in chloroform).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:44][N:45]([CH:47]=O)C>CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[N:45]1[C:44]2[C:9](=[CH:14][C:13]([C:2]3[N:3]=[C:4]4[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[NH:8][C:7]5[N:15]=[CH:16][CH:17]=[CH:18][C:6]=5[N:5]4[C:19]=3[C:20]3[CH:25]=[CH:24][C:23]([C:26]4([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)[CH:10]=[CH:4][CH:47]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc5ncccc5c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Yield: 98 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.090 mmol), 2-quinolin-6-ylboronic acid (31 mg, 0.18 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.09 mmol), and 2M Na2CO3 aq. (0.090 mL, 0.18 mmol) in DMF (2.5 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:4) to afford the desired product (53 mg, 98%) as a pale yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.85 (dd, J=4.0 Hz and 1.7 Hz, 1H), 8.22 (dd, J=8.0 Hz and 1.7 Hz, 1H), 8.19-8.14 (m, 1H), 8.08 (d, J=7.4 Hz, 1H), 8.03 (d, J=3.4 Hz, 1H), 7.94-7.92 (m, 1H), 7.87-7.79 (m, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.36-7.31 (m, 2H), 7.21-7.17 (m, 3H), 6.97 (d, J=7.4 Hz, 1H), 6.84 (d, J=7.4 Hz, 1H), 6.62 (dd, J=8.0 Hz and 4.6 Hz, 1H), 6.29 (s, 1H), 5.15 (br s, 1H), 2.58-2.53 (m, 2H), 2.50-2.40 (m, 2H), 2.20-2.12 (m, 1H), 1.95-1.87 (m, 1H), 1.40 (br s, 9H). LCMS: 607 [M+H].
Reaction SMILES: BrC1C=C(Cl)C=C(Cl)C=1.[Mg].[Cl:11][C:12]1[CH:13]=[C:14]([C:19](O[Mg]Br)([CH3:21])[CH3:20])[CH:15]=[C:16]([Cl:18])[CH:17]=1>CC(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[C:19]([CH3:21])=[CH2:20]
Reactant: CC(C)(O[Mg]Br)c1cc(Cl)cc(Cl)c1
Agent: Clc1cc(Cl)cc(Br)c1
Agent: [Mg]
Solvent: CC(C)=O
Product: C=C(C)c1cc(Cl)cc(Cl)c1

Procedure:
1-Bromo-3,5-dichlorobenzene is reacted with magnesium in a solvent and acetone is added to react it with the reaction product and a mineral acid is added to hydrolyze the resulting α-(3,5-dichlorophenyl) isopropoxymagnesium bromide and then, the product is dehydrated to obtain 3,5-dichloro-α-methylstyrene. 3,5-Dichloro-α-methylstyrene is useful intermediate for various agricultural chemicals, medicines and dyes and also useful monomer for rubbers, plastics and resins.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9]N1C(=O)CCC1=O>CN(C)C=O>[Br:1][C:2]1[C:7]([Cl:9])=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1cc(Br)ccn1
Solvent: CN(C)C=O
Product: Nc1cc(Br)c(Cl)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromopyridin-2-amine (500 mg, 2.89 mmol) in N,N-dimethylformamide (5 mL) was added N-chlorosuccinimide (463 mg, 3.47 mmol) and the mixture was stirred at room temperature for 12 hours. The mixture was filtered through diatomaceous earth and concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude title compound. Purification by column chromatography (silica gel, 30% ethyl acetate in hexane) afforded the title compound.