Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7](=[O:26])[CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[O:17][C:18]4[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C=O)C.C(OCC)(=O)C>[CH:35]1([CH2:34][O:25][C:23]2[CH:22]=[CH:21][C:19]3[N:20]=[C:16]([N:13]4[CH2:12][CH2:11][CH:10]([O:9][CH2:8][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:26])[CH2:15][CH2:14]4)[O:17][C:18]=3[CH:24]=2)[CH2:37][CH2:36]1
Reactant: O=C(COC1CCN(c2nc3ccc(O)cc3o2)CC1)N1CCOCC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{4-[2-(morpholin-4-yl)-2-oxoethoxy]piperidin-1-yl}-1,3-benzoxazol-6-ol (2.81 g) in DMF (26 mL) were added potassium carbonate (3.22 g) and (bromomethyl)cyclopropane (1.51 mL), and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (NH, hexane/ethyl acetate) to give the title compound (2.10 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([CH3:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([CH3:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCN=[N+]=[N-]
Temperature: 70 °C
Reaction time: 4 h
Yield: 105.7 %

Procedure:
A mixture of 3-(2-bromoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole (0.725 g; 1.87 mmol) and sodium azide (0.365 g; 5.62 mmol) in DMF (8 mL) was stirred at 70° C. for 4 hours and concentrated under reduced pressure. The residue was diluted in ethyl acetate, washed with brine, dried and concentrated under reduced pressure to afford 0.690 g (quantitative yield) of the title compound as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12]O)=[CH:8][CH:7]=1.P(Br)(Br)[Br:21]>CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][Br:21])=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Solvent: CCCCCC
Product: Fc1cc(F)cc(Oc2ccc(OCCBr)cc2)c1
Reaction time: 0.5 h

Procedure:
To a mixture of 2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (1.00 g, 3.76 mmol) and n-hexane (50 ml), phosphorus tribromide (0.71 g, 2.63 mmol) was gradually added with stirring under ice-cooling. After completion of the addition, the temperature was elevated to room temperature and stirred was continued at the same temperature for 30 minutes, followed by stirring under reflux for 1 hour. After allowed to cool, the upper n-hexane layer was collected by decantation, and the n-hexane layer was washed with water two times, an aqueous sodium carbonate solution three times and a saturated aqueous sodium chloride solution once in order and dried over anhydrous magnesium sulfate. Removal of the solventgave 2-[4-(3,5-difluorophenoxy)phenoxy]ethyl bromide (915 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11](OS(C(F)(F)F)(=O)=O)[C:5]=2[C:4](=[O:20])[O:3]1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[Cl-].[Li+].C(N(CC)CC)C>O1CCOCC1.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>[CH:22]([C:11]1[C:5]2[C:4](=[O:20])[O:3][C:2]([CH3:21])([CH3:1])[O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[CH2:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)OC(=O)c2c(cccc2OS(=O)(=O)C(F)(F)F)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=Cc1cccc2c1C(=O)OC(C)(C)O2
Temperature: 100 °C
Yield: 80.8 %

Procedure:
A mixture of 2,2-dimethyl-5-trifluoromethanesulfonyloxy-4H-1,3-benzodioxin4-one (9.90 g, 30.3 mmol), tributyl(vinyl)tin (10.10 g, 31.9 mmol), lithium chloride (8.70 g, 205 mmol), and triethylamine (5.0 mL, 36.0 mmol) in 1,4-dioxane (300 mL) was deoxygenated by bubbling nitrogen through the mixture for 1 h. To the mixture was added tetrakis(triphenylphosphine)palladium (3.40 g, 2.90 mmol) and the mixture was heated at 100° C. for 3 h. The mixture was allowed to cool to rt and was filtered. The filtrate was concentrated and purified by flash chromatography (1:12, EtOAc/hexanes) to provide 5-ethenyl-2,2-dimethyl-4H-1,3-benzodioxin-4-one (5.00 g, 81%) as a yellow oil: 1H NMR: (CDCl3) δ1.72 (s, 6H), 5.43 (dd, J=11.0, 1.3 Hz, 1), 5.72 (dd, J=17.5, 1.3 Hz, 1 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.73 (dd, J=17.5, 11.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=3[Cl:20])[N:10]=2)[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=3[Cl:20])[NH2:17])[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2cn3cc(Br)cnc3n2)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)c(-c2cn3cc(Br)cnc3n2)c1
Temperature: 75 °C
Reaction time: 12 h
Yield: 28.4 %

Procedure:
To a suspension of 6-bromo-2-(2-chloro-5-nitrophenyl)imidazo[1,2-a]pyrimidine (1-3) (10 g, 28.28 mmol, 1.00 equiv) in ethanol (100 ml) was added SnCl2.2H2O (12.7 g) and stirred for 12 h at 75° C. The solvent was removed under vacuum and the residue was diluted with water. The pH value of the mixture was adjusted to 8-9 with sodium bicarbonate (sat.). The solids were collected by filtration and applied onto a silica gel column with ethyl acetate/petroleum ether (2/1) to give 2.6 g (28%) of 3-[6-bromoimidazo[1,2-a]pyrimidin-2-yl]-4-chloroaniline (1-4) as a light yellow solid. 1H-NMR: (d6-DMSO, 400 MHz): 9.37 (d, J=2.4 Hz, 1H), 8.63 (d, J=2.4 Hz, 1H), 8.47 (s, 1H), 7.56 (d, J=2.8 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.59 (dd, J=8.4, 2.8 Hz, 1H), 5.44 (s, 2H). EI, m/z): MS (M+H)+=325
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][CH2:15][F:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[F:16][CH2:15][CH2:14][O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1
Reactant: FCCBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCF)cc1O
Temperature: 57.5 °C

Procedure:
A mixture of methyl 2,4-dihydroxybenzoate (5.04 g, 30 mmol), 1-bromo-2-fluoroethane (4.18 g, 2.46 mL, 33 mmol), potassium carbonate (4.55 g, 33 mmol) and potassium iodide (1 g) in DMF (20 mL) was heated overnight at 55-60° C. before it was poured into water (150 mL). The resulting white precipitate was filtered, redissolved in dichloromethane, dried (MgSO4), concentrated and diluted with hexane to afford the ether in two crops (1.30 g and 2.19 g). The first crop was characterized:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1.O.[NH2:31][NH2:32]>CN(C=O)C>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:32][N:31]=2)=[CH:22][CH:23]=1)#[N:28]
Reactant: NN
Reactant: N#Cc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 73 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-cyanophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (265 mg, 0.69 mmol, prepared in Synthetic Example 25) in DMF (7 ml) was added hydrazine monohydrate (80%, 82 μl, 2.05 mmol, 3.0 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-cyanobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (190 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH:13](O)=[O:14]>>[NH:10]1[CH:11]=[CH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH:13]=[O:14])=[CH:7][CH:6]=2)=[N:9]1
Reactant: Nc1ccc(-c2cc[nH]n2)cc1
Reactant: O=CO
Product: O=CNc1ccc(-c2cc[nH]n2)cc1

Procedure:
A solution of 3-(4-aminophenyl)-1-H-pyrazole (10 g) in formic acid (100 ml) was refluxed for 4 hours and evaporated to dryness. The residue was dissolved in water, and the solution was filtered through charcoal. The filtrate was made basic to give 9.5 g of N-[4-(pyrazol-3-yl)-phenyl]-formamide; M.p. 139°-141° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[C:13]1(C)C=CC=C[C:14]=1[ClH](C1C=CC=CC=1C)(C1C=CC=CC=1C)C(Cl)=O.C(N(CC)CC)C>C(#N)C.[Pd]>[CH:13]([C:2]1[N:3]=[N+:4]([O-:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)=[CH2:14]
Reactant: [O-][n+]1nc(Cl)nc2ccccc21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=Cc1nc2ccccc2[n+]([O-])n1

Procedure:
3-chloro-1,2,4-benzotriazine 1-oxide was treated with a slight excess of tri-N-butylvinyltin in a mixture of acetonitrile, tritoluyl phosgene and triethylamine, using palladium II catalysis (Pd II acetate) in a sealed tube at 100° C. for 48 hours. Removal of solvent and purification by column chromatography gave 3-vinyl-1,2,4-benzotriazine 1-oxide (33). Reduction with 9-borabicyclo [3.3.1] nonane (9-BBN) followed by oxidation with sodium hydroxide and hydrogen peroxide gave the title compound 3-(1-hydroxyethyl)-1,2,4-benzotriazine 1-oxide (34).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:20](/[CH:19]=[CH:18]/[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=3[F:15])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccccc3F)nc2n(CC)c1=O

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.70 g (13.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.49 g (15.0 mmol) of 2-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.81 g (yield of Compound 167 as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[BH4-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(C=O)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CO)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of 0.10 g (0.227 mmol) of the product of Example 335 in 5 mL of methanol and 2.0 mL of THF was added 8.6 mg of sodium borohydride. The reaction was stirred for 1 h at room temperature and then concentrated in vacuo. The residue was diluted with dichloromethane, washed with water, and the organics were then dried over Na2SO4, filtered and concentrated in vacuo. The resulting tan solid was washed with ether and dried in vacuo to give 0.086 g (86%) of the alcohol. Electrospray Mass Spec: 442.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:32]=1[C:33](Cl)=[O:34]>CC#N>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:33](=[O:34])[C:32]3[C:31]([Cl:30])=[CH:39][CH:38]=[CH:37][C:36]=3[Cl:40])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccc(C2CN(Cc3ccccc3)CCO2)cc1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a mixture of 4-(4-benzyl-morpholin-2-yl)-phenylamine (0.48 g; 1.8 mmol), and N-ethyldiisopropylamine (0.92 mL; 5.4 mmol) in CH3CN (10 mL) was added 2,6-dichlorobenzoyl chloride (0.31 mL; 2.2 mmol), at 0° C. The resulting mixture was allowed to warm to RT, stirred for 1 h, and partitioned between Et2O and 5% aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford N-[4-(4-benzyl-morpholin-2-yl)-phenyl]-2,6-dichloro-benzamide (0.61 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([OH:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][CH2:6][CH:7]([O:9][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: CC(O)COC(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(OC(C)COC(C)(C)C)ccnc2c1
Temperature: 37 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 1-tert-butoxypropan-2-ol (293 μl, 1937 μmol) in DMF (2.5 mL) under nitrogen was added NaH (93 mg, 3873 μmol) at 23° C. After 10 min, 4-chloro-7-methoxyquinoline (250 mg, 1291 μmol) was added. The mixture was heated to 37° C. for 18 h. The reaction was partioned between 5% NaHCO3 (10 mL) and CH2Cl2 (15%). The aqueous was extracted with CH2Cl2 (10 mL). The combined organics were dried with brine and MgSO4, concentrated under reduced pressure from toluene, and purified on silica (12 g) eluting with 0-30% of 5% (MeOH/CH2Cl2). MS (ESI pos. ion) m/z (MH+): 290. Calc'd exact mass for C17H23NO3: 291. 1H NMR (400 MHz, Chloroform-d) δ ppm 1.19 (s, 9H) 1.44 (d, J=6.26 Hz, 3H) 3.46-3.54 (m, 2H) 3.69 (dd, J=9.49, 5.77 Hz, 1H) 3.93 (s, 3H) 4.69-4.77 (m, 1H) 6.70 (d, J=5.28 Hz, 1H) 7.12 (dd, J=9.19, 2.54 Hz, 1H) 7.34 (d, J=2.54 Hz, 1H) 8.10 (d, J=9.19 Hz, 1H) 8.63 (d, J=5.48 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ ppm 17.15, 27.45, 50.29, 55.40, 65.09, 73.31, 74.06, 100.45, 106.89, 116.62, 118.04, 123.38, 151.26, 151.58, 160.89, 161.07
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[CH2:7]([Mg]Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.C(OCC)C>[CH2:7]([C:2]1[CH2:3][CH2:4][CH2:5][N:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: N#CCCCBr
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: c1ccc(CC2=NCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 132.6 %

Procedure:
To a solution of 4-bromobutyronitrile (2.0 g, 13.5 mmol) in toluene (70 ml) was added 1.0 M benzylmagnesium bromide (20.0 ml, 20.0 mmol) in diethyl ether (70 ml) and the mixture was stirred for 2 hours at room temperature. The mixture was partitioned between 0.1N hydrochloric acid and ethyl acetate, and the organic layer was washed with aqueous sodium hydrogen carbonate, dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford 5-benzyl-3,4-dihydro-2H-pyrrole (2.85 g). This compound was used without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1([CH2:17][OH:18])[CH2:16][O:15][CH2:14]1>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:18][CH2:17][C:13]2([CH3:12])[CH2:16][O:15][CH2:14]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(CO)COC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of p-toluenesulfonyl chloride (14.3 g, 75 mmol) in pyridine (60 mL) is slowly added 3-methyl-3-oxetanemethanol A3a (5.1 g, 50 mmol) over 10 min. The resulting suspension is stirred at rt for 1.5 h and poured into vigorously stirred ice water (300 mL). The slurry is stirred for 45 min. The solid is collected by filtration, washed with ice-cold H2O (100 mL), and dried under high vacuum to afford (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate A3b as a white powder. The compound is used in the next step without further purification. 1H-NMR (400 MHz, CDCl3) δ=7.83 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 4.39 (d, J=6.4 Hz, 2H), 4.36 (d, J=6.4 Hz, 2H), 4.13 (s, 2H), 2.49 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].F[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1>CN(C=O)C>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[CH3:15]
Reactant: Fc1ccnc(C(F)(F)F)c1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccc([N+](=O)[O-])cc1)c1ccnc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a solution of ethyl (4-nitrophenyl)acetate (760 mg, 3.6 mmol) in DMF (10 mL) was added 60% sodium hydride (145 mg, 3.6 mmol). The deep purple reaction mixture was stirred at rt for 30 min, then 4-fluoro-2-trifluoromethyl-pyridine (500 mg, 3.0 mmol) was added. After heating at 70° C. for 2 h, the mixture was poured onto ice water and extracted with ethyl acetate. The organic layers were washed with water and brine, then dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography, eluting with 10-30% ethyl acetate in hexanes, to give (4-nitro-phenyl)-(2-trifluoromethyl-pyridin-4-yl)-acetic acid ethyl ester as a viscous yellow oil (440 mg, 41%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[C:19]([F:25])[CH:18]=1)[C:6]([NH:8][NH:9]C(OC(C)(C)C)=O)=[O:7]>C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][CH:5]([C:17]1[CH:18]=[C:19]([F:25])[C:20]([F:24])=[C:21]([F:23])[CH:22]=1)[C:6]([NH:8][NH2:9])=[O:7]
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 221.1 %

Procedure:
A solution of 4 N hydrogen chloride in ethyl acetate (120 mL) was added to tert-butyl N′-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate (6.6 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (6.03 g). A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (565 mg) and triethylamine (1.0 mL) in ethanol (10 mL) was added to a solution of ethyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate dihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10 mL) at room temperature. The reaction solution was stirred at 80° C. for 25 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 150 mg of the racemic title compound. The racemic title compound (150 mg) was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the title optically active compound with a retention time of 13 minutes and positive optical rotation (54 mg) and the title optically active compound with a retention time of 34 minutes and negative optical rotation (51 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: N#Cc1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C#N)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-cyanopyridine.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCOCC1.O>[C:18]([O:22][C:23]([N:25]1[CH2:26][CH:27]=[C:28]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:29][CH2:30]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc([N+](=O)[O-])cnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
A mixture of 2-bromo-3-methyl-5-nitropyridine (10.0 g), cesium carbonate (42 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complex (1.88 g), and N-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (15 g) in 1,4-dioxane (150 ml) and water (50 ml) was stirred at 110° C. for 2.5 hours. To the reaction solution was added water, extracted with chloroform, the organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained solid was washed with a mixed solution of n-hexane and ethyl acetate to give 4-(3-methyl-5-nitropyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (13.25 g) as a red solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.C([O:17][B:18]([CH:24]=[CH2:25])OCCCC)CCC.Cl>C1COCC1.O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[CH:25]=[CH:24][BH:18][OH:17]
Reactant: Brc1cccnc1
Reactant: C=CB(OCCCC)OCCCC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OBC=Cc1ccccn1
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 3-bromopyridine (1.60 g, 10.0 mmol) in THF (15 mL) was added isopropylmagnesium chloride (2.0 M in THF) (5.0 mL, 10 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred for 1 h. To the mixture was added vinylboronic acid dibutyl ester (3.4 mL) drop wise, and the mixture was stirred at room temperature for 18 h. Water was added and the pH was adjusted to 7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (1.04 g, 78%).