Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:24])[C:11]=2[C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[C:15]([O:17][CH3:18])=[O:16])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[OH:39]>CN1C(=O)CCC1>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[O:39][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:24])[C:11]=2[C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[C:15]([O:17][CH3:18])=[O:16])[N:7]=1
Reactant: COC(=O)c1ccc(OC)c(-c2c(=O)ccn3nc(Cl)ccc23)c1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(OC)c(-c2c(=O)ccn3nc(Oc4ccc(F)cc4F)ccc23)c1
Temperature: 80 °C

Procedure:
To a solution of methyl 3-(2-chloro-6-oxo-6H-pyrido[1,2-b]pyridazin-5-yl)-4-methoxybenzoate (1.05 g, 3.05 mmol) and Cs2CO3 (2.97 g, 9.15 mmol) dissolved in NMP (20 mL) was added 2,4 difluoro phenol (475 mg, 3.66 mmol). The mixture was heated to 80° C. for 1 hr until the reaction was complete via LCMS analysis. The reaction was poured into 500 mL of ice/H2O and the solid precipitate was collected. The crude residue was purified via silica gel chromatography (EtOAc/CH2Cl2, MeOH) to yield the title compound.
Reaction SMILES: [C:1](=[C:4]([OH:10])[C@H:5]([OH:9])[CH2:6][CH2:7]O)([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O.CCCCCC>C(Cl)Cl>[Br:30][CH2:7][CH2:6][C@@H:5]([OH:9])[C:4](=[C:1]([CH3:3])[CH3:2])[OH:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)=C(O)[C@H](O)CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)=C(O)[C@H](O)CCBr
Temperature: 0 °C
Yield: 46.8 %

Procedure:
(R)-Isopropylidenebutane-1,2,4-triol (0.3 g, 2.05 mmol) and triphenylphosphine (0.63 g, 2.4 mmol) were dissolved in methylene chloride (5 ml) and cooled to 0° C. and N-bromosuccinimide (0.38 g, 2.16 mmol) was added in small portions with stirring. After additional 1 h of stirring at 0° C. hexane (15 ml) was added and the resulting precipitate was removed by filtration and washed twice with hexane (2×5 ml). The combined hexane solution was passed through a short column of silica gel (5 g). Elution with hexane (15 ml) gave after evaporation and distillation the title compound as a colourless oil (0.2 g, 0.96 mmol, 47%): b.p. 74°-76° C. at 2.7 kPa (20 mm Hg), nD20 =1.4630. {α}D20 =+27.7° (c=20, CHCl3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@H:10]([CH3:24])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNCCN1C(=O)OCc1ccccc1

Procedure:
A solution of 4.3 g (R)-2-Methyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester in 20 ml dichloromethane was stirred in the presence of 10 ml TFA for 16 h. The solution was concentrated and the residue codistilled twice with toluene to give the crude hydrotrifluoroacetate. Yield: 6.1 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH:7]([N:25]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[C:13]1=[O:24])([CH3:4])([CH3:3])[CH3:2].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C(#N)C>[C:1]([O:5][C:6](=[O:39])[CH:7]([NH2:25])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[C:13]1=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(=O)n(CCCCC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)c(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cn1c(=O)n(CCCCC(N)C(=O)OC(C)(C)C)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
A solution of the title C compound, 2-(benzhydrylideneamino)-6-(1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazolin-3-yl)hexanoic acid t-butyl ester (2.15 g) in 80 mL of acetonitrile is treated with 8 mL of water and p-toluenesulfonic acid hydrate (0.800 g, 4.21 mmol), and the clear solution is stirred at 25° C. for 16 h. The solvent is evaporated under reduced pressure, and the residue is partioned between 150 mL of diethyl ether and 100 mL of 0.1 N aqueous HCl. The aqueous phase is added dropwise to 1 N aqueous NaOH (15 mL, 15.0 mmol) to precipitate an oily solid which is extracted into two 60 mL portions of methylene chloride. The organic extracts are combined, dried over anhydrous MgSO4, and concentrated. Chomatography on silica gel (eluant; ethyl acetate) affords 448 mg (30%) of 2-amino-6-(1-methyl-2,4-dioxo-1,4-di-hydro-2H-quinazolin-3-yl)hexanoic acid t-butyl ester as a colorless oil: NMR(CDCl3) 1.46 (s, 9H), 1.51-1.79 (m, 6H), 3.32 (dd, 1H, J=7.0, 5.4), 3.61 (s, 3H), 4.11 (t, 2H, J=7.4), 7.20 (d, 1H, J=8.3), 7.25-7.29 (m, 1H), 7.69 (td, 1H, J=8.6, 1.5), 8.23 (dd, 1H, J=7.9, 1.5); IR 1702, 1656; MS 362 (M++1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[F:14][C:15]([F:42])([F:41])[CH2:16][N:17](CC(F)(F)F)[C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([O-])=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1>>[F:42][C:15]([F:14])([F:41])[CH2:16][NH:17][C:18]1[CH:35]=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:30])=[CH:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1
Reactant: O=C([O-])c1ccc(-c2nc3cc(N(CC(F)(F)F)CC(F)(F)F)ccc3[nH]2)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(NCC(F)(F)F)ccc3[nH]2)cc1

Procedure:
Compound 455 was prepared from 4-morpholinoaniline and 4-(5-bis(2,2,2-trifluoroethyl)amino-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C26H24F3N5O2: 496.19; found: 496.02.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][CH2:23]Br>CN(C)C=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[O:9][CH2:23][CH2:22][N:11]3[C:10](=[N:14][CH:13]=[CH:12]3)[C:4]=2[CH:3]=1
Reactant: Oc1cc(F)c(Br)cc1-c1ncc[nH]1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cc2c(cc1Br)-c1nccn1CCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 224.7 %

Procedure:
Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of 4-bromo-5-fluoro-2-(1H-imidazol-2-yl)phenol (755 g, 2.94 mol, 1.00 equiv) in N,N-dimethylformamide (7.5 L), Cs2CO3 (3350 g, 10.28 mol, 3.50 equiv), followed by the addition of 1,2-dibromoethane (2208 g, 11.75 mol, 4.00 equiv). The resulting solution was stirred overnight at 80° C. To this was added 1,2-dibromoethane (200 g). The resulting solution was stirred at 80° C. for 5.5 h. This reaction was repeated for 2 times. The reaction mixture was cooled to room temperature and diluted with 20 L of ice/water. The solids were collected by filtration, washed with 2×4 L of water and dried to afford 1870 g (crude) of 9-Bromo-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a gray solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:25])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:23][CH:22]=1
Reactant: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)O)cc1
Yield: 98.1 %

Procedure:
To a solution of 4-(1-hydroxy-heptyl)-benzoic acid methyl ester (1800 mg, 7.2 mmol) in toluene (72 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 2725 mg, 10.8 mmol) at 0° C., followed by the additions of tributylphosphine (2.69 mL, 10.8 mmol) and 4-bromo-phenol (1503 mg, 8.64 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid methyl ester. 1900 mg of the ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 2 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (2 mL), and extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid (1800 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:6]=2[C:5]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH2:24]([O:26][C:27](=[O:32])[CH2:28][C:29](O)=[O:30])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:15]([N:12]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:3][NH:2][C:29](=[O:30])[CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:32])[C:5]([NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:6]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCOC(=O)CC(=O)O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)NCc1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), 3-(ethyloxy)-3-oxopropanoic acid (171 mg, 1.30 mmol), HBTU (535 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature over the weekend. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layer was dried over sodium sulfate, filtered, concentrated and purified with CombiFlash eluting with 90% ethyl acetate in hexane. The product fractions were combined and concentrated to give ethyl 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoate as an oil (270 mg, 55%). LC-MS m/z 418 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:14])[CH2:11][O:12][CH3:13])=[CH:6][C:5]=1[N+:16]([O-])=O)=[N+]=[N-]>CCO.[Pd]>[CH3:13][O:12][CH2:11][C:10]([C:7]1[CH:6]=[C:5]([NH2:16])[C:4]([NH2:1])=[CH:9][CH:8]=1)([CH3:15])[CH3:14]
Reactant: COCC(C)(C)c1ccc(N=[N+]=[N-])c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COCC(C)(C)c1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Azido-4-(1-methoxy-2-methylpropan-2-yl)-2-nitrobenzene (1.102 g, 3.52 mmol) was dissolved in EtOH (30 ml) and Pd/C (10% wt.) (0.110 g, 10% wt.) was added. The reaction was purged 3 times with N2 then 3 times with H2 and the reaction stirred at r.t. overnight. The mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% heptane to 100% EtOAc as eluent to give the product as a pale brown oil which solidified into a dark orange solid (0.481 g, 63%, 90% pure): MS (ESI+) for C11H18N2O m/z 195.1 [M+H]+; LC purity 87% (ret. time, 0.99 min); 1H NMR (500 MHz, CDCl3) δH 6.65 (dd, J=11.2, 1.9 Hz, 2H), 6.58 (d, J=7.9 Hz, 1H), 3.26 (s, 2H), 3.24 (s, 3H), 1.20 (s, 6H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1.[CH2:14]([O:19][C:20]1[C:25]([C:26]2[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=[C:28]([C:38]#[N:39])[CH:27]=2)=[CH:24][C:23]([C:40]#[N:41])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH3:18].O>CS(C)=O>[C:40]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:25]([C:26]2[C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=[C:28]([C:38](=[NH:39])[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=3)[CH:27]=2)[CH:24]=1)#[N:41]
Reactant: CCCCCOc1ccc(C#N)cc1-c1cc(C#N)ccc1OCCCCC
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCOc1ccc(C#N)cc1-c1cc(C(=N)Nc2cccc(C(F)(F)F)c2)ccc1OCCCCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A slurry of sodium hydride (50% in oil, 1.76 g), m-aminobenzotrifluoride (5.91 g) and 6,6'-dipentyloxy[1,1'-biphenyl]-3,3'-dicarbonitrile (6.9 g; additional material is added to the batch of part (A) in 50 ml of anhydrous dimethylsulfoxide is stirred at room temperature for 3 days. The reaction mixture is poured into water and the resultant precipitate collected by filtration. The dried material is chromatographed on 1 liter of silica gel eluting with (1) dichloromethane and (2) 1% methanol/dichloromethane to yield 5'-cyano-2',6-bis(pentyloxy)-N-[3-(trifluoromethyl)phenyl][1,1'-biphenyl]-3-carboximidamide (melting point 74°-75° C after 2 recrystallizations from cyclohexane). The column is next eluted with 2% methanol/dichloromethane to yield 1.3 g of the desired product. Two recrystallizations of this material from 1% hydrochloric acid/methanol yields 900 mg of the title compound, melting point 207°-210° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH:9]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14][C:13]=2[C:12]([OH:22])=[CH:11][CH:10]=1>CC(C)=O>[CH3:1][O:22][C:12]1[C:13]2[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[C:17]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Oc1cccc2c1oc1ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cccc2c1oc1ccccc12
Reaction time: 18 h
Yield: 100 %

Procedure:
Potassium carbonate (1.4 g, 10.11 mmol) and methyl iodide (0.42 mL, 6.74 mmol) were added to a solution of dibenzofuran-4-ol (1.24 g, 6.74 mmol) in acetone (65 mL). The reaction was heated at reflux and stirred for 18 h. Upon cooling, the reaction mixture was successively washed with 1 M sodium hydroxide, water and brine. The organic layer was dried on magnesium sulfate, filtered and then concentrated to give the product (1.33 g, 6.74 mmol, 100%) as a white needle that was used without further purification: Rf=0.37 (AcOEt-EP 1:19); mp: 49-50° C.; λmax (EtOH)/nm 279; IR (cm−1) 3054, 2839, 1900, 1633, 1496, 1451, 1423, 1330, 1309, 1267, 1188, 1089, 931, 893, 782, 737; 1H NMR, (300 MHz, CDCl3) δ 4.03 (3H, s, OCH3), 6.94 (1H, d, JH2-H3=8 Hz, H-3), 7.26 (1H, t, J=8 Hz), 7.36 (1H, t, J=7 Hz), 7.48 (1H, t, J=7 Hz), 7.54 (1H, d, J=7 Hz), 7.69 (1H, d, J=8 Hz), 7.94 (1H, d, J=8 Hz); 13C NMR, (75 MHz, CDCl3) δ 56.11 (OCH3), 109.31, 111.96, 112.82, 120.85, 122.86, 123.46, 124.43 (Cq), 125.72 (Cq), 127.21, 145.20 (Cq), 145.63 (Cq), 156.04 (Cq); MS (EI) m/z 199.1 M+; HRMS calcd for C13H10O2 [M+H]+ 199.0754, found 199.0754.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6](/[CH:10]=[CH:11]/[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[C:5]([CH3:25])[CH:4]=1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([CH3:25])[C:6](/[CH:10]=[CH:11]/[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]2)=[C:7]([CH3:9])[CH:8]=1)=[O:27]
Reactant: Cc1cc(C#N)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C(N)=O)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 738 %

Procedure:
To a suspension of 133 mg of tert-butyl 4-[(E)-2-(4-cyano-2,6-dimethylphenyl)vinyl]piperidine-1-carboxylate in 5 ml of acetone and 2 ml of water, 146 mg of hydrogen peroxide-urea complex and 7 mg of potassium carbonate were added, followed by stirring overnight. Then, 221 mg of hydrogen peroxide-urea complex was added and the mixture was stirred overnight, and 293 mg of hydrogen peroxide-urea complex was further added, followed by stirring for 4 days. An aqueous solution of sodium sulfate was added to the reaction mixture and extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform-methanol) to give 134 mg of tert-butyl 4-{(E)-2-[4-(aminocarbonyl)-2,6-dimethylphenyl]vinyl}piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([F:15])[CH:8]=1)(=[O:6])[CH3:5]>C1COCC1>[F:15][C:9]1[CH:8]=[C:7]([C:4]([OH:6])([CH3:1])[CH3:5])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: CC(=O)c1ccc(C#N)c(F)c1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C#N)c(F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 4.7 g (0.019 mol) anhydrous CeCl3 in 30 mL anhydrous THF at 0° C. was added 6 mL of 3.0M CH3MgCl dropwise. Stirred at 0° C. for 45 minutes. Next a solution of 2.5 g (0.015 mol) 4-Acetyl-2-fluoro-benzonitrile in 200 mL anhydrous THF was added dropwise at 0° C. Stirred at 0° C. for 1 hour, then quenched with 2N acetic acid added dropwise. The mixture was poured into 200 mL water and acidified to pH 2 with 2N acetic acid. The aqueous layer was extracted with ethyl acetate (2×200 mL). The ethyl acetate extracts were combined, washed with water (2×40 mL), brine (1×40 mL), dried over MgSO4 and concentrated to give an oil, which was then chromatographed on silica gel eluted with 50% ethyl acetate/50% hexanes to give 1.95 g of an amber oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=1>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]([O:12][CH2:19][C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)=[O:11]
Reactant: O=C(O)CCOC1CCCCO1
Reactant: BrCc1ccccc1
Solvent: ClCCl
Product: O=C(CCOC1CCCCO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of 3-(tetrahydro-2H-pyran-2-yloxy) propanoic acid (1 g, 5.7 mmol) and TEA (0.863 g, 8.55 mmol, Shantou Xilong chemical factory) in 50 mL of CH2Cl2 was added BnBr (0.98 g, 5.7 mmol, Aldrich) via a syringe at 0° C. After stirring at rt overnight, the reaction mixture was quenched with 20 mL of water, and was extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (20:1 (v/v) petroleum ether/EtOAc) to give the title compound as colorless oil (270 mg, 18.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[C:20](Cl)(Cl)=[O:21]>C1(C)C=CC=CC=1>[Cl:13][C:12]1[C:7]([O:6][C:5]2[CH:18]=[CH:19][C:2]([N:1]=[C:20]=[O:21])=[CH:3][CH:4]=2)=[N:8][CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
A mixture of 2-(4-aminophenoxy)-3-chloro-5-trifluoromethylpyridine (0.45 g) and a solution of phosgene in toluene (50 ml of a 12% solution) was heated at the reflux temperature for 6 hours. Evaporation of the volatile portion under reduced pressure yielded 3-chloro-5-trifluoromethyl-2-(4-isocyanatophenoxy)pyridine as a residual pale brown oil (0.5 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:1][C:2]([C:5]1[N:6]=[C:7]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)[O:8][CH:9]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1coc(Cn2ncc(N)n2)n1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C(C)(F)F)co3)n2)c1

Procedure:
Following general procedure A, starting from 2-[4-(1,1-difluoro-ethyl)-oxazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCN4CCOCC4)c(F)cc(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 22 h
Yield: 87.1 %

Procedure:
607 mg (1.16 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.00 mL (11.6 mmol) of morpholine was added and the mixture was stirred at 50° C. for 22 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 523 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-morpholinopropylamino)-4H-1-benzopyran-4-one (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:16]1[CH:17]=[N+:18]([O-:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:16]2[CH:17]=[N+:18]([O-:25])[CH:19]=[CH:20][C:21]=2[N+:22]([O-:24])=[O:23])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)ccc1Oc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 5-bromosalicylate (5.78 g, 25.00 mmol) in 30 mL of dry THF was added slowly sodium hydride (0.600 g, 25.00 mmol, 60 wt %) and the solution was stirred at rt for 15 minutes. The solvent was evaporated and the residue was dissolved in 10 mL of dry DMF. To this was added 3-bromo-4-nitropyridine 1-oxide (4.38 g, 20.00 mmol) and the reaction mixture was stirred at 50° C. for 4 h and 40° C. overnight. Water was added and the resulting solid was washed with water, filtered and dried under vacuum. Purification of the crude residue by column chromatography (CH2Cl2 to CH2Cl2/EA=10:1 to 5:1 to 3:1 to 1:1 to pure EA) gave 3-(4-bromo-2-(methoxycarbonyl)phenoxy)-4-nitropyridine 1-oxide as a yellow solid.