Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:10]([CH3:15])=[N:11][NH:12][C:13]=1[NH2:14].[C:17]([C:19](=[C:25](OCC)[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]>C(O)C>[NH2:18][C:17]1[N:12]2[N:11]=[C:10]([CH3:15])[C:9]([C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:16])=[C:13]2[N:14]=[C:25]([CH3:26])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1N
Yield: 20.4 %

Procedure:
Concentrated dihydrochloric acid (0.1 mL) was added to a solution of 4-mesityl-3-methyl-1H-5-pyrazoleamine (2.5 g, 11.61 mmol) and ethyl 2-cyano-3-ethoxy-2-butenoate (2.13 g, 11.61 mmol) in ethanol (30 mL), followed by heating under reflux for 18 hours. The reaction mixture was evaporated as it was. Then, water was added and a 5N aqueous solution of sodium hydroxide was added under ice-cooling, to neutralize. Further, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane), to give the title compound (835 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.Cl.[CH2:15](O)[CH3:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:15][CH3:16])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(/C=C/C(=O)O)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)/C=C/c1cccc(OC)c1

Procedure:
To a solution of (2E)-3-(3-methoxyphenyl)acrylic acid (25 g) in ethanol (150 mL) was added conc HCl (25 mL) and the solution refluxed for 3 hours. The solvent was evaporated and residue dissolved in ethyl acetate. The organic phase was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to give ethyl (2E)-3-(3-methoxyphenyl)acrylate as yellow oil in quantitative yield. To a solution of isopropyl(triphenyl)phosphonium iodide (75 g, 0.173 mol) in dry THF (200 mL) at −78° C. was added butyl lithium (1.6M in Hexanes, 119 mL, 0.191 mol). The reaction was stirred for 1 hour at room temperature and then cooled to −78° C. To the solution was added ethyl (2E)-3-(3-methoxyphenyl)acrylate (2.91 g, 0.014 mol) in THF (200 mL). The solution was stirred at room temperature for few hours and then refluxed overnight. The reaction mixture was poured into 5% aqueous citric acid and extracted with ethyl acetate. The organic portion washed with saturated aqueous sodium bicarbonate, brine, dried over Na2SO4 and concentrated. The concentrated residue was chromatographed on silica gel using 5% ethyl acetate/hexane to afford viscous yellow oil. To the solution ethyl 3-(3-methoxyphenyl)-2,2-dimethylcyclopropanecarboxylate (15 g) in ethanol (60 mL) and water (20 mL) was added LiOH (12.74 g). The reaction mixture was heated for 3 hours at 50° C. and concentrated to remove ethanol. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to give 3-(3-methoxyphenyl)-2,2-dimethylcycloprop-anecarboxylic acid as yellow oil. 1H NMR (CDCl3) δ 7.15 (m, 1H), 6.74 (m, 3H), 3.8 (s, 3H), 2.67 (m, 1H), 2.05 (m, 1H), 1.38 (s, 3H), 1.06 (s, 3H). M−=219. Step 2. Synthesis of [3-(3-methoxyphenyl)-2,2-dimethylcyclopropyl]methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3=[CH:24][C:25]([CH2:26][OH:27])=[C:21]4[N:22]3[C:17](=[CH:18][CH:19]=[CH:20]4)[C:16]=2[CH2:28][CH3:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC(C)([O-])C.[K+].Cl.[CH3:39][N:40]([CH3:45])[CH2:41][CH2:42][CH2:43]Cl>CN(C)C=O.O.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3=[CH:24][C:25]([CH2:26][O:27][CH2:43][CH2:42][CH2:41][N:40]([CH3:45])[CH3:39])=[C:21]4[N:22]3[C:17](=[CH:18][CH:19]=[CH:20]4)[C:16]=2[CH2:28][CH3:29])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCCl
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(CO)c3cccc1n32
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(COCCCN(C)C)c3cccc1n32
Yield: 47.4 %

Procedure:
2-(4-Benzyloxyphenyl)-1-ethyl-4-hydroxymethylpyrrolo[2,1,5-cd]indolizine (1.0 g, 2.62 mmol) was dissolved in 100 ml of dry dimethylformamide under nitrogen atmosphere. Sodium hydride (60% in oil) (1.23 g, 30.8 mmol) and potassium-t-butoxide (0.03 g, 0.26 mmol) was added in portions and stirring was continued for ten minutes. 3-Dimethylamino-1-propylchloride hydrochloride (1.24 g, 7.84 mmol) was added, and the solution was stirred for twenty-four hours. Ethanol (20 ml) was added dropwise, and the reaction mixture was diluted with 250 ml of water. The organic material was extracted into ethyl acetate (2×100 ml), and the combined organic layers were dried over sodium hydrogen carbonate. The solvent was evaporated and the crude product was purified by column chromatography over silica gel 60, using 10% of methanol in dichloromethane as the eluent to afford 0.58 g (47%) of 2-(4-benzyloxyphenyl)-4-((3-dimethylaminopropoxy)methyl)-1-ethylpyrrolo[2,1,5-cd]indolizine as yellow crystals. M.p. 63-65° C. MS(SP): m/z 466 (M+). 1H-NMR (CDCl3, 300 MHz) δ: 1.47 (t, 3H); 1.82 (m, 2H); 2.23 (s, 6H); 2.39 (t, 2H); 3.24 (q, 2H); 3.61 (t, 2H); 5.01 (s, 2H); 5.17 (s, 2H); 7.15 (d, 2H); 7.32-7.52 (m, 5H); 7.53 (s, 1H); 7.64 (t, 1H); 7.73 (d, 2H); 7.91 (d, 1H); 7.99 (d, 1H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]([N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>CCOCC>[C:9]([O:8][C:6]([N:13]1[CH2:18][CH2:17][C:16]([CH2:1][CH2:2][CH2:3][CH3:4])([OH:19])[CH2:15][CH2:14]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [Li]CCCC
Solvent: CCOCC
Product: CCCCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of n-butyl lithium (16.06 mL, 40.2 mmol, 2.5 M in hexanes) at −78° C., was drop-wise added a solution of N-Boc-4-piperidone (4.0 g, 20.1 mmol) in ether (10 mL). The resulting solution was allowed to warm to room temperature and stirred for one additional hour. The solution was cooled to 0° C. before being quenched by the drop-wise addition of saturated aqueous ammonium chloride (30 mL), and extracted with ethyl acetate (2×30 mL). The combined organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude product as a yellow oil, which was then purified by silica chromatography on a Biotage (0-50% of EtOAc/Hexanes) to give the title compound as a colorless oil (1.66 g, still contaminated with the starting material ketone). This mixture was used in the next step without further purification.
Reaction SMILES: C([Li])CCC.[CH:6]([O:9][C:10](=[O:20])[NH:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)([CH3:8])[CH3:7].CN(C)CCN(C)C.[S:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1>C1COCC1>[F:18][C:16]1[CH:17]=[C:12]([NH:11][C:10](=[O:20])[O:9][CH:6]([CH3:8])[CH3:7])[CH:13]=[C:14]([F:19])[C:15]=1[C:32]1([OH:35])[CH2:33][CH2:34][S:29][CH2:30][CH2:31]1
Reactant: CC(C)OC(=O)Nc1cc(F)cc(F)c1
Reactant: O=C1CCSCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)OC(=O)Nc1cc(F)c(C2(O)CCSCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (2.5M in hexanes, 57.2 mL, 0.143 mol) was added dropwise with stirring at −78° C. to (3,5-difluoro-phenyl)-carbamic acid isopropyl ester (15.0 g, 0.07 mol) and N, N, N′, N′-tetramethylethylenediamine (21.04 mL, 0.139 mol) in THF (150 mL), and stirred for 20 min at this temperature. Tetrahydrothiopyran-4-one (8.50 g, 0.073 mol) dissolved in THF (10 mL) was then added dropwise at −78° C., stirred for 1 h, and then allowed to warm to room temperature. The reaction was stirred for another hour and then quenched with saturated aqueous ammonium chloride (100 mL). The reaction mixture was extracted with ethyl acetate, the extracts washed with brine, dried (MgSO4), and evaporated. The residue was purified by flash column chromatography (30% ethyl acetate/hexane) to give the title compound as white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:10][C:9]([CH3:11])=[CH:8][C:5]=2[NH:6][CH:7]=1)#[N:2].I[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[C:1]([C:3]1[C:4]2[S:10][C:9]([CH3:11])=[CH:8][C:5]=2[N:6]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:23][CH2:24][O:25][CH3:26])[CH:14]=2)[CH:7]=1)#[N:2]
Reactant: COCOc1cc(I)ccc1C(=O)OC
Reactant: Cc1cc2[nH]cc(C#N)c2s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COCOc1cc(-n2cc(C#N)c3sc(C)cc32)ccc1C(=O)OC
Temperature: 170 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a solution of 6-cyano-2-methyl-4H-thieno[3,2-b]pyrrole (0.37 g) in toluene (10 mL) were added methyl 4-iodo-2-(methoxymethoxy)benzoate (0.73 g), copper(I) iodide (43 mg), trans-N,N′-dimethylcyclohexanediamine (65 mg) and potassium carbonate (0.66 g), and the mixture was stirred at 170° C. for 20 minutes using microwave reactor. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=78/22−57/43) to give the title compound (0.63 g).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([NH:16]C(OC(C)(C)C)=O)[CH2:10]2)=[O:6])[CH2:2][CH3:3].[ClH:24].O1CCOCC1>C(O)(=O)C>[ClH:24].[CH2:1]([NH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([NH2:16])[CH2:10]2)=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCCNC(=O)c1ccc2c(c1)CC(N)C2

Procedure:
Using N-propyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (22 mg, 0.070 mmol), 4N hydrochloric acid-dioxane (2 ml) and acetic acid (6.0 ml), a similar procedure to Production Example 213 was carried out to obtain N-propyl-2-amino-5-indan carboxamide hydrochloride. Then using ethanol (1 ml), triethylamine (0.50 ml, 3.6 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (18 mg, 1.0 mmol), a similar procedure to b) in Production Example 208 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1 to 1:2) to obtain the title compound (12 mg, 0.033 mmol) having the following physical properties:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32]C3C4N=C(C5N(C(C)C)N=CN=5)SC=4CCOC=3C=2)C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:35]1[CH:36]=[CH:37][C:38]2[O:47][CH2:46][CH2:45][C:44]3[S:43][C:42]([C:48]4[N:49]([CH:53]([CH3:55])[CH3:54])[N:50]=[CH:51][N:52]=4)=[N:41][C:40]=3[C:39]=2[CH:56]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][CH:12]([C:35]2[CH:36]=[CH:37][C:38]3[O:47][CH2:46][CH2:45][C:44]4[S:43][C:42]([C:48]5[N:49]([CH:53]([CH3:54])[CH3:55])[N:50]=[CH:51][N:52]=5)=[N:41][C:40]=4[C:39]=3[CH:56]=2)[CH2:33][CH2:32]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(C(=O)OC(C)(C)C)C3)ccc1-2
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc1-2

Procedure:
The title compound was prepared by a similar procedure to 3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidine-1-carboxylic acid tert-butyl ester using 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 instead of 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene 27 and 4-piperidine-1-carboxylic acid tert-butyl ester zinc iodide instead of 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide. LCMS: RT=5.12 min, [M+H]+=496
Reaction SMILES: [N:1]1([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:14])[CH2:9][CH2:8]3)[CH2:4][CH2:3][CH2:2]1.CS(O)(=O)=O.[N-:20]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)Cl>[N:1]1([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:14])[NH:20][CH2:9][CH2:8]3)[CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2cc(N3CCC3)ccc21
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NCCc2cc(N3CCC3)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5-azetidin-1-yl-indan-1-one (1.9 g, 10.14 mmol) and methane sulfonic acid (10.8 ml) were added to CH2Cl2 (100 ml). The reaction mixture was cooled to 0° C. and sodium azide (1.32 g, 20.29 mmol) was carefully portion wise added over 30 min then reaction mixture was stirred at 0° C. for 2 hours. After the reaction was done, it was slowly added 20% NaOH aq. at 0° C.
Reaction SMILES: [CH:1]([NH2:3])=O.C([O:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][C:9]=1[NH2:15])C.C([O-])=O.[NH4+].O>C(OCC)(=O)C>[CH:12]1[CH:11]=[CH:10][C:9]2[N:15]=[CH:1][NH:3][C:7](=[O:6])[C:8]=2[CH:13]=1
Reactant: CCOC(=O)c1ccc(F)cc1N
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1[nH]cnc2ccccc12
Temperature: 140 °C

Procedure:
The intermediate 4-piperazinyl-7-(2-piperidylethoxy)quinazoline was prepared using the procedures as generally described in Scheme 1 as follows: Step A To the ethanol solution (15 mL) of 2-amino-4-fluorobenzoic acid (840 mg, 5.41 mmol) was added thionyl chloride (1.18 mL, 16.23 mmol) and the resulting suspension was refluxed overnight. The solvent was evaporated to the residue added EtOAc, washed with 10% NaOH solution, dried, filtered and evaporated to afford desired ethyl ester as a solid 981 mg, 82%). MS (ES) 184(M+H) Step B: To the formamide (6 mL) solution of ethyl-2-amino-4-fluorobenzoate (811 mg, 4.43 mmol) added ammonium formate (0.450 g, 7.14 mmol) and the reaction mixture was heated at 140° C. overnight. After cooling added water and ethyl acetate. The layers were separated, the EtOAc layer was dried, filtered and evaporated to give desired quinazolinone (1 g, quantitative). MS (ES) 165 (M+H) Step C: To the DMF solution (3 mL) of 1-piperidineethanol (0.689 mL, 5.18 mmol) at 0° C. added sodium hydride (0.518 g, 12.95 mmol) and the mixture was stirred for 30 min. To this cold solution added DMF solution (3 mL) of intermediate quinazolinone (0.284 g, 1.73 mmol, from Step B) and the mixture was heated at 75° C. overnight. The solvent was evaporated and the residue purified by RP-HPLC to afford desired product as a creamy solid (0.459 g, 97%) Step D: A mixture of 7-(2-piperidylethoxy)-4-quinazolinone (0.459 g, 1.68 mmol), from Step C) and POCl3 (5 mL) was heated at 75° C. overnight. After cooling excess POCl3 was removed by evaporation and the residue azeotroped with toluene to afford intermediate, 4-chloro-7-(2-piperidylethoxy)quinazoline (600 mg, 95%) Step E: To the isopropanol solution (10 mL) of 4-chloroquinazoline (0.615 g, 2.11 mmol, from Step D) added piperazine (0.727 g, 8.44 mmol) and heated the reaction for 4 h at 100° C. The solvent was evaporated and the residue purified by RP-HPLC to afford 4-piperazinyl-7-(2-piperidylethoxy)quinazoline as a white solid (0.630 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:10][C:11](N2[C@H](C3C=CC=CC=3)COC2=O)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.OO.[Li+].[OH-].S([O-])([O-])=[O:37].[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:10][C:11]([OH:12])=[O:37])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=S([O-])[O-]
Reactant: O=C(C[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1)N1C(=O)OC[C@H]1c1ccccc1
Agent: O=C([O-])O
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Reaction time: 0.75 h

Procedure:
A solution of (4R)-3-[(3S)-3-(3,5-difluorophenyl)-3-(4-fluorophenyl)propanoyl]-4-phenyl-1,3-oxazolidin-2-one (7.3 g, 17 mmol) in 90 mL of THF and 30 mL of water was cooled to 0° C. in an ice-water bath. To the solution was added hydrogen peroxide (7.0 mL of a 30% solution in water, 69 mmol) and LiOH (0.83 gg, 35 mmol). After 45 min, a solution of sodium sulfite (8.7 g, 69 mmol) in 30 mL of water was added, followed by 170 mL of a 0.5 M solution of aqueous NaHCO3 (86 mmol). The stirred mixture was warmed to ambient temperature and most of the THF was removed in vacuo. The aqueous mixture was extracted with two portions of CH2Cl2 to remove the chiral auxiliary. The aqueous phase was then acidified to pH 1 with the addition of 6 N HCl and extracted with two portions of EtOAc. The combined EtOAc layers were dried (MgSO4), filtered, and the solvent was removed in vacuo to give a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]3([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[O:15][CH:9]3[C:8]=2[CH:24]=1)([O-:3])=[O:2].[NH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]1=[O:31].O.C(OCC)(=O)C>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])([OH:15])[CH:9]([N:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]3=[O:31])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C2OC21CNC(=O)C(F)(F)F
Reactant: O=c1cccc[nH]1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)C1(O)CNC(=O)C(F)(F)F
Yield: 19.5 %

Procedure:
A mixture of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran (0.4 g, 1.16 mmol), 2(1H)-pyridinone (0.22 g, 2.32 mmol) and Triton B (0.05 ml) in dioxane (3 ml) was heated at reflux for nineteen hours. Water and ethyl acetate were added, and the organic phase separated and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/acetone (95/5), to give 0.1 g of 6-nitro-2,2-dimethyl-3-(trifluoroacetamido)methyl-3,4-dihydro-3-hydroxy-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 158° C.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Na+].[C:11]([O:15][C:16]([N:18]1[CH2:22][C:21](=O)[CH2:20][C@H:19]1[CH2:24][O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[CH2:22][C:21](=[CH2:1])[CH2:20][C@H:19]1[CH2:24][O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=C1C[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methytriphenylphosphonium bromide (38 g, 106 mmol) dissolved in 300 ml of toluene was cooled to 0° C., then added sodium hexamethyldisilazide (48.3 ml, 93.7 mmol) was added dropwise. After 2 hours at room temperature, The temperature was cooled to 0° C., a solution of (S)-2-(4-nitro-benzoyloxymethyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 56, 15.5 g, 42.6 mmol) in 300 ml of toluene was added. After 10 minutes 500 ml of water was slowly added, then reaction was allowed to reach room temperature. The organic solvent was washed with brine (500 ml), dried (Na2SO4) and evaporated to obtain crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 15/7 to 7/1). (S)-4-Methylene-2-(4-nitro-benzoyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was obtained as yellow solid (6.82 g, yield 46%).
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][C:21]([Cl:27])=[N:20]3)=[O:16])[C:9]=1[F:28])OC(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:21]1[CH:22]=[N:23][C:24]2[C:19]([N:20]=1)=[CH:18][C:17]([C:15]([C:10]1[C:11]([F:14])=[CH:12][CH:13]=[C:8]([OH:7])[C:9]=1[F:28])=[O:16])=[CH:26][CH:25]=2
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc2ncc(Cl)nc2c1)c1c(F)ccc(O)c1F
Yield: 62.1 %

Procedure:
A solution of tert-butyl (3-(3-chloroquinoxaline-6-carbonyl)-2,4-difluorophenyl) carbonate (42 mg, 0.1 mmol, 1.0 eq.) in TFA/DCM (1.5 mL/1.5 mL) was stirred at rt for 2 h, then concentrated. The residue was purified via flash column chromatography (PE/EA=4/1, v/v) to afford (3-chloroquinoxalin-6-yl)(2,6-difluoro-3-hydroxyphenyl)methanone as a yellow solid (19.9 mg) LRMS (M−H+) m/z calculated 319.0, found 318.9. 1H NMR (CDCl3, 400 MHz) δ 8.81 (s, 1 H), 8.31-8.34 (m, 2 H), 8.18-8.20 (d, 1 H), 7.08-7.14 (m, 1 H), 6.86-6.88 (m, 1 H), 5.43 (s, 1 H).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][OH:6])=[CH2:2].[OH-].[Na+].ClCO[SiH3].[C:13]([O:16][CH2:17][CH3:18])(=O)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:1]([O:3][CH2:4][CH2:5][O:6][CH2:18][CH:17]1[O:16][CH2:13]1)=[CH2:2]
Reactant: CCOC(C)=O
Reactant: C=COCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: C=COCCOCC1CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of hydoxyethyl vinyl ether (500 g) and tetra-n-butyl ammonium hydrogen sulfate (50 g), an aqueous solution of sodium hydroxide (340 g) dissolved in water ax (380 ml) was added over 30 minutes and then further stirred at room temperature for 1 hour. Further, chloromethyloxysilane (78.8 g) was added thereto and stirred at 60° C. for 2 hour. Then, ethyl acetate was added to the reaction mixture, followed by washing with water. The organic layer was extracted and dried with magnesium sulfate, and condensed at reduced pressure to distill off the solvents. The resulting liquid was purified by vacuum distillation, to obtain 530 g of the 2-glycidyloxyethyl vinyl ether (A-37) (boiling point 65° C., 532 Pa).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](=O)[CH3:12])[CH:9]=2)[CH:4]=[CH:3]1.O.NN.[OH-].[K+].O>C(O)COCCO>[CH2:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)[CH3:12]
Reactant: CC(=O)c1ccc2ccn(C)c2c1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCc1ccc2ccn(C)c2c1
Temperature: 62 °C
Yield: 96.3 %

Procedure:
A mixture of 0.226 g 1-(1-methyl-1H-indol-6-yl)-ethanone, 1.35 mL of 85% hydrazine hydrate, 0.88 g of potassium hydroxide in 15 mL of diethylene glycol was stirred at 62° C. over night. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated to give 0.200 g of 6-ethyl-1-methylindole as a colorless oil after chromatographic purification on a silica gel column.
Reaction SMILES: FC(F)C(O)=O.[F:7][CH:8]([F:19])[C:9]([NH:11][NH:12][C:13]1[CH:18]=[N:17][CH:16]=[CH:15][N:14]=1)=O.N>>[F:7][CH:8]([F:19])[C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[CH:18][C:13]2=[N:12][N:11]=1
Reactant: O=C(NNc1cnccn1)C(F)F
Agent: N
Agent: O=C(O)C(F)F
Product: FC(F)c1nnc2cnccn12
Temperature: 140 °C
Reaction time: 7 h
Yield: 27 %

Procedure:
2,2-Difluoro-N′-pyrazin-2-yl-acetohydrazide difluoroacetate 23b (2 g, 0.01 mol) was dissolved in 10 mL of polyphosphoric acid. After stirring at 140° C. for 7 hours, the reaction mixture was cooled to 50° C. and stirred for another 12 hours. The reaction mixture was poured into 50 mL of ice-water while hot, 30% aqueous ammonia was added dropwise until the pH of the reaction mixture was between 7 and 8, and the solution was extracted with ethyl acetate (30 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 30 mL of ethyl acetate and added with activated carbon. After stirring for 30 minutes, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine 23c (460 mg, yield 30%) as a yellow solid.