Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH2:12])[CH2:7][CH2:6]1)=[O:4].[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:14]>CN(C)C=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[O:14])[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)C1CCC(CN)CC1
Solvent: CN(C)C=O
Product: COC(=O)C1CCC(CNC(=O)n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.7 %

Procedure:
To a mixture of 4-aminomethyl-cyclohexanecarboxylic acid methyl ester (1.008 g, 4.758 mmol, Astatech,) in N,N-dimethyl formamide (20.0 mL) was added TEA (617 mg, 6.098 mmol) and 1,1′-carbonyldiimidazole (810.3 mg, 4.997 mmol, Aldrich,). After it was stirred at rt for 21 hrs under an argon atmosphere, the solvent was removed and the reaction mixture was extracted with EtOAc, and washed with water (2×), and saturated NaCl. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give 4-{[(imidazole-1-carbonyl)-amino]-methyl}cyclohexanecarboxylic acid methyl ester (1.184 g, 4.46 mmol, 93%) which was used without further purification.
Reaction SMILES: CO[CH:3](OC)[CH:4]([C:17]#[N:18])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([Cl:14])=[C:8]([O:15][CH3:16])[CH:7]=1.[NH2:21][C:22]([NH2:24])=[NH:23]>>[NH2:23][C:22]1[N:24]=[C:17]([NH2:18])[C:4]([CH2:5][C:6]2[CH:7]=[C:8]([O:15][CH3:16])[C:9]([Cl:14])=[C:10]([O:12][CH3:13])[CH:11]=2)=[CH:3][N:21]=1
Reactant: COc1cc(CC(C#N)C(OC)OC)cc(OC)c1Cl
Reactant: N=C(N)N
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1Cl

Procedure:
21 G. of 4-chloro-3,5-dimethoxy-α-cyano-hydrocinnamaldehyde dimethyl acetal were heated to reflux for 1.5 hours with 140 ml. of a 1N methanolic guanidine solution. The solvent was then removed by distillation on an oil bath at 160° C. and the residue heated for 15-20 minutes at this temperature until completely solidified to a crystalline mass. The mass was slurried with 80-100 ml. of water and removed by filtration under suction, whereby there was obtained 2,4-diamino-5-(4-chloro-3,5-dimethoxybenzyl)-pyrimidine of melting point 218° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:36](=[O:39])[CH:37]=[CH2:38])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
4-(4-Amino-benzenesulfonyl)-piperazine-1-carboxylic acid benzyl ester (0.25 g, 0.67 mmol) was dissolved in THF (10 ml). To this was added diisopropylethylamine (0.33 ml, 1.9 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.06 ml, 0.74 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 20% heptane, 80% ethyl acetate) to give the title compound (57 mg, 20% yield) as a white powder.
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]23[CH2:32][CH:27]4[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]4)[CH2:24]2)[CH2:30]3)[CH:16]=1)[C:3]#[C:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.C1COCC1.[OH-].[Li+].Cl>O>[O:1]=[C:2]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([C:23]23[CH2:24][CH:25]4[CH2:31][CH:29]([CH2:28][CH:27]([CH2:26]4)[CH2:32]2)[CH2:30]3)[CH:16]=1)[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:13][CH:14]=1
Reactant: COC(=O)c1ccc(C#CC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)C#Cc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
962 mg (2.2 mmol) of the above methyl ester (b) and 10 ml of THF were introduced into a round-bottomed flask and 283 mg (6.7 mmol) of lithium hydroxide were added. The reaction medium was heated at reflux for 5 hours and was then poured into water and acidified to pH 1 with concentrated hydrochloric acid. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The solid obtained was triturated from hexane, filtered off and dried. 600 mg (85%) of the expected acid, having a melting point of 232°-4° C., were recovered.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([C:12](=[O:14])[CH3:13])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:15][CH:2]([CH3:4])[CH3:3])=[C:10]([C:12](=[O:14])[CH3:13])[CH:11]=1
Reactant: CC(C)I
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)ccc1OC(C)C
Temperature: 80 °C
Yield: 93.3 %

Procedure:
Add 2-iodopropane (63.3 mL, 633 mmol) dropwise to a suspension of 1-(5-chloro-2-hydroxyphenyl)ethanone (90.0 g, 528 mmol) and potassium carbonate (109.46 g, 792 mmol) in DMF (1000 mL) at room temperature under nitrogen and heat the mixture at 80° C. for 22 hours. Cool and filter the mixture and remove the solvent reduced pressure. Dilute the residue with ethyl acetate (1 L), wash with water (300 mL) and brine (200 mL), dry over sodium sulfate, and remove the solvent under reduced pressure to afford 1-(5-chloro-2-isopropoxyphenyl)ethanone (104.78 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH3:15])([CH3:14])[C:7](=O)[CH2:6][CH2:5]2.[NH:17]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23])N>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:8]([CH3:15])([CH3:14])[C:7]3[NH:17][C:19]4[C:26]([C:6]=3[CH2:5][C:4]=2[CH:3]=1)=[CH:25][CH:24]=[C:21]([C:22]#[N:23])[CH:20]=4
Reactant: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Reactant: N#Cc1cccc(NN)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Br)Cc1c([nH]c3cc(C#N)ccc13)C2(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
6-Bromo-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound E1, 7.89 g, 27.85 mmol) and 3-hydrazino-benzonitrile (4.45 g, 1.2 eq.) were dissolved in TFA (250 mL), and stirred at 100° C. for 2 hr. TFA was removed under reduced pressure and the residues were added with saturated aqueous solution of NaHCO3 (500 mL), followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were added with ethyl acetate. After stirring at room temperature, the precipitated solid was separated by filtration (Compound E2-2). The filtrate was concentrated under reduced pressure to obtain the title compound as a mixture with E2-2 (yellowish white powder, 2.65 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:19]4[C:20]([C:25]5[N:29](C6CCCCO6)[N:28]=[CH:27][CH:26]=5)=[N:21][CH:22]=[CH:23][CH:24]=4)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1.Cl.[OH-].[Na+]>C1COCC1.O>[NH:29]1[C:25]([C:20]2[C:19]([C:17]([N:15]3[CH2:16][CH:11]4[CH:12]([CH2:13][N:9]([C:4]5[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=5)[CH2:10]4)[CH2:14]3)=[O:18])=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:26][CH:27]=[N:28]1
Reactant: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccnc4-c4ccnn4C4CCCCO4)CC3C2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccnc4-c4ccn[nH]4)CC3C2)n1
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methanone (Example 236) (210 mg, 0.43 mmol) in THF (10 mL) and H2O (1 mL) was added 4 N aq. HCl (1 mL). The reaction was let stir for 2 hours, neutralized with 3 N aq. NaOH, and extracted with DCM (3×20 mL). The organics were combined, dried with Na2SO4, and concentrated. Purification (FCC) (MeOH(NH3)/DCM) gave the title compound (128 mg, 73%) (MS (ESI): mass calculated for C21H23N7O, 389.20; m/z found 390.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.68-8.59 (m, 1H), 7.63 (d, J=9.1, 2H), 7.32-7.20 (m, 1H), 6.80 (d, J=2.2, 1H), 6.33-6.19 (m, 1H), 3.92-3.55 (m, 5H), 3.54-2.78 (m, 5H), 2.37-2.24 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:16][C:5]2=[CH:6][C:7]3[CH2:8][C:9](=[O:15])[N:10]([CH2:13][CH3:14])[C:11]=3[CH:12]=[C:4]2[CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:8]2[C:7]3[CH:6]=[C:5]4[O:16][C:2]([CH3:1])([CH3:17])[CH2:3][C:4]4=[CH:12][C:11]=3[N:10]([CH2:13][CH3:14])[C:9]2=[O:15])=[O:27])=[CH:21][CH:20]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCN1C(=O)Cc2cc3c(cc21)CC(C)(C)O3
Product: CCN1C(=O)C(C(=O)Nc2ccc(F)cc2)c2cc3c(cc21)CC(C)(C)O3
Yield: 62 %

Procedure:
Employing the procedure of Example 1, and starting with 500 mg. (2.16 mmoles) of 2,2-dimethyl-5-ethyl-6-oxo-2,3,6,7-tetrahydro-furo[2,3-f]indole and 0.34 ml. (2.99 mmoles) of 4-fluorophenylisocyanate, 493 mg. (62% yield) of N-(4-fluorophenyl)-2,2-dimethyl-5-ethyl-6-oxo-2,3,6,7-tetrahydro-furo[2,3-f]indole-7-carboxamide (2, R1 =C2H5, R2 =4-fluorophenyl, R3 and R4 =CH3, and n=1) m.p. 160°-162° C., was obtained.
Reaction SMILES: [C:1]([CH2:4][C:5]([NH2:7])=[NH:6])(=[O:3])[NH2:2].Br[CH:9]([CH3:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>C(O)C>[NH2:6][C:5]1[NH:7][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:9]([CH3:18])[C:4]=1[C:1](=[O:3])[NH2:2]
Reactant: N=C(N)CC(N)=O
Reactant: CC(Br)C(=O)c1ccccc1
Solvent: CCO
Product: Cc1c(-c2ccccc2)[nH]c(N)c1C(N)=O
Yield: 4.9 %

Procedure:
To a solution (20 ml) of carbamoylacetamidine (5.1 g) in ethanol was added a solution of 2-bromopropiophenone (4.0 g) in ethanol dropwise thereto under ice-cooling with stirring and the mixture was then stirred at room temperature overnight. The insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. The obtained product was washed with benzene, purified by silica gel column chromatography (Wakogel C-200, 200 g; eluent: 50% ethyl acetate/n-hexane), and recrystallized from ethyl acetate/diethyl ether to provide the title compound as colorless crystals (0.2 g). m.p. 195-197° C.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:11])[CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:19]1[CH2:26][CH:25]2[CH2:27][CH:21]([CH2:22][NH:23][CH2:24]2)[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[C:1]1([NH:7][C:8](=[O:11])[CH2:9][CH2:10][N:23]2[CH2:24][CH:25]3[CH2:27][CH:21]([CH2:20][N:19]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:26]3)[CH2:22]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CN2CC3CNCC(C3)C2)cc1
Reactant: C=CC(=O)Nc1ccccc1
Solvent: CCO
Product: O=C(CCN1CC2CC(C1)CN(Cc1ccccc1)C2)Nc1ccccc1
Reaction time: 10 h
Yield: 97 %

Procedure:
N1-Phenylacrylamide (1.0 g; 6.8 mmol; from step (a) above) was added to a stirred solution of 3-benzyl-3,7-diazabicyclo[3.3.1]nonane (1.5 g; 6.8 mmol; see Example E above) in EtOH (7 mL). The reaction mixture was stirred for 10 h and concentrated to give the sub-title compound in a 97% yield.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=2[CH3:16])=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=2[CH3:16])=[CH:8][CH:9]=1)[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2cc(C#N)c(=O)[nH]c2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 1.16 g, 29.0 mmol) in N,N-dimethylformamide (50 mL), was added at 0° C. a solution of 5-(4-hydroxy-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (6, 3.25 g, 14.4 mmol) in N,N-dimethylformamide (50 mL). The mixture was stirred at ambient temperature for 30 min. A solution of ethyl 2-bromoacetate (2.0 mL, 18.0 mmol) in N,N-dimethylformamide (10 mL) was added at 0° C., the mixture was stirred for 30 min at 0° C., for 30 min at ambient temperature and then for 45 min at 80° C. The mixture was allowed to cool to room temperature, concentrated in vacuo and re-dissolved in ethyl acetate (300 mL). The solution was extracted with water (3×150 mL). The combined aqueous layers were acidified to pH 2 with aqueous hydrochloric acid (1 N) and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried (MgSO4) and evaporated to dryness. The residue was purified by column chromatography on silica gel (50 g) using 2% methanol in dichloromethane as eluent to give [4-(5-Cyano-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)phenoxy]-acetic acid ethyl ester (7) as light yellow powder (1.3 g, 29% yield, 80–90% pure by LC-MS and 1H NMR), 1H NMR (400 MHz; CDCl3): δ 7.70 (d, 1H); 7.19 (m, 2H); 6.72 (m, 2H); 4.90 (s, 2H); 4.12 (q, 2H); 1.71 (s, 3H); 1.30 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].Cl[CH:15]([F:17])[F:16]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:15]([F:17])[F:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(O)cc(Cl)c1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(Cl)cc(OC(F)F)c1
Reaction time: 2 h
Yield: 75.3 %

Procedure:
3-Chloro-5-hydroxybenzoic acid (6.4 g, 37.2 mmol; see step (ii) above) dissolved in chloroform (200 mL) was transferred to a 500 mL three-necked round-bottomed flask fitted with a dry ice condenser and a gas inlet tube. Sodium hydroxide (100 mL, 5 M) was added and with vigorous stirring. Chlorodifluoromethane (Freon 22; 25 g, 290 mmol) was added portionwise through the gas inlet tube at ambient temperature. After 2 hours, the reaction was complete. Extractive work up gave 6.2 g, 28 mmol (yield: 75%) of the sub-title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH:2]=[CH2:3].C(O)(=O)C1C=CC=CC=1.[C:19]([C:23]1[CH:28]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:26]=[C:25]([CH2:33]OCCCC)[C:24]=1[OH:39])([CH3:22])([CH3:21])[CH3:20]>C(O)CCC>[C:29]([C:27]1[CH:26]=[C:25]2[C:24](=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:28]=1)[O:39][CH:2]([C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[CH2:3][CH2:33]2)([CH3:31])([CH3:32])[CH3:30]
Reactant: CCCCOCc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)OCCCC
Agent: O=C(O)c1ccccc1
Solvent: CCCCO
Product: CCCCOC(=O)C1CCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O1
Temperature: 157.5 °C
Yield: 87 %

Procedure:
Butyl acrylate (771.2 g, 6.02 mol) and benzoic acid (12.26 g, 0.10 mol) were added to 2,4-di-t-butyl-6-butoxymethyl-1-hydroxybenzene (665.2 g, net 586.71 g, 2.01 mol) obtained in Example 1, and the mixture was stirred while heating at 150-165° C. for 30 h. 1-Butanol produced by the reaction was removed. After the completion of the reaction, the reaction mixture was quantitatively analyzed by liquid chromatography according to the internal standard method. As a result, 6,8-di-t-butyl-2-butoxycarbonylchroman was obtained in a yield of 87% (1.74 mol). At this time, 6,8-di-t-butyl-3-butoxycarbonylchroman (a position isomer) was produced in about 8%. For use in the next step, excess butyl acrylate was distilled away under reduced pressure, toluene was added to the residue, and benzoic acid was removed with aqueous sodium hydrogen carbonate solution. The 1H-NMR data of the obtained 6,8-di-t-butyl-2-butoxycarbonylchroman are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>C(#N)C.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Fc1ccc(Br)c(OCC(F)(F)F)c1
Temperature: 150 °C
Yield: 186.6 %

Procedure:
To a stirred solution of 2-bromo-5-fluorophenol (1.5 g) in acetonitrile (0.5 mL) and DMF (8.5 mL) in a microwave tube was added potassium carbonate (2.1 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.37 g). The mixture was heated to 150° C. in a microwave oven for 30 minutes. In a second microwave tube the same reaction was repeated. Both mixtures were combined. The solvent was removed in vacuum, ethyl acetate and hexane (1:1) was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 4.0 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([OH:13])[C:9]2[C:4](=[CH:5][C:6]([C:26]([F:29])([F:28])[F:27])=[C:7]([O:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH:8]=2)[N:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([O:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:26]([F:28])([F:29])[F:27])=[C:7]([O:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=3)[CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[CH3:12])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc2cc(C(F)(F)F)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(O)c1C
Product: CC(=O)Oc1c(C)c(C)nc2cc(C(F)(F)F)c(Oc3ccc(OC(F)(F)F)cc3)cc12
Temperature: 122.5 °C

Procedure:
Acetic anhydride (40 mL) was added to 1.73 g of 2,3-dimethyl-4-hydroxy-6-(4-trifluoromethoxyphenoxy)-7-trifluoromethyl-quinoline obtained as crystals, and the mixture was heated at 120 to 125° C. for one hr. This reaction solution was concentrated under the reduced pressure, ethyl acetate was then added to the concentrate, and the mixture was washed with brine. Thereafter, the solvent was removed under the reduced pressure, and the crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 0.82 g of 4-acetoxy-2,3-dimethyl-6-(4-trifluoromethoxyphenoxy)-7-trifluoromethyl-quinoline.
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[CH2:14][CH2:15][N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:36][C:5]1[C:4]2[N:11]=[C:12]3[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:14][N:13]3[C:3]=2[C:2]2[C:7](=[CH:8][CH:9]=[CH:10][N:1]=2)[N:6]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCn2c1nc1cnc3cccnc3c12
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCn2c1nc1c(N)nc3cccnc3c12
Reaction time: 2 h

Procedure:
A solution of tert-butyl 9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c][1,5]naphthyridine-8-carboxylate (1 g, 3 mmol) in dichloromethane (100 mL) was treated with MCPBA (1 g, 77% purity), and the reaction was stirred for two hours. Analysis by LC/MS indicated the presence of starting material, and additional MCPBA (1 g) was added. The next day, the reaction cooled in an ice bath and was treated with 100 mL of concentrated ammonium hydroxide. The reaction was stirred for several minutes, and then p-toluenesulfonyl chloride (730 mg, 3.8 mmol) was added. The reaction was stirred for several minutes, removed from the ice bath, and stirred for three hours at room temperature. Water was added, and the mixture was extracted with dichloromethane. The combined organic fractions were purified by automated flash chromatography on silica gel (eluting with a gradient of 2% ammonium hydroxide methanol as the polar component in dichloromethane). The resulting oil was triturated in diethyl ether to provide a yellow solid, which was isolated by filtration to provide 0.64 g of tert-butyl 6-amino-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c][1,5]naphthyridine-8-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[CH:7]=3)=[CH:4][C:3]=1[F:20].BrC1C(=O)C(Br)=C(Br)C(C)([N+:29]([O-:31])=[O:30])C=1Br>FC(F)(F)C(O)=O.CCOC(C)=O>[NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:12]2)[CH2:10][CH2:9][C:8](=[O:19])[C:7]=3[N+:29]([O-:31])=[O:30])=[CH:4][C:3]=1[F:20]
Reactant: CCCCC12CCC(=O)C=C1c1cc(F)c(N)cc1C2
Reactant: CC1([N+](=O)[O-])C(Br)=C(Br)C(=O)C(Br)=C1Br
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCCCC12CCC(=O)C([N+](=O)[O-])=C1c1cc(F)c(N)cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7-amino-9a-butyl-6-fluoro-1,2,9,9a-tetrahydro-3H-fluoren-3-one (34.6 mg, 0.126 mmol) in trifluoroacetic acid (0.25 mL) was treated with 2,3,5,6-tetrabromo-4-methyl-4-nitro-2,5-cyclohexadien-1-one (59 mg, 0.126 mmol). The resulting mixture was placed under a N2 atmosphere, sonicated briefly, and stirred at room temperature for one hour. The mixture was diluted with EtOAc (15 mL), washed successively with water, 5% NaHCO3 and brine, dried over MgSO4, filtered, and evaporated under vacuum to a brown oil (86 mg). The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, developing with 2:1 hexanes-EtOAc. The major UV visible band was eluted with 5% MeOH in CH2Cl2, the eluant was concentrated under vacuum to an orange oil (16 mg, 40%), and the oil was lyophilized from benzene to afford 7-amino-9a-butyl-6-fluoro-4-nitro-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:13]([C:14]1[O:10][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:15])[CH3:12]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc2cc(Br)ccc2o1
Temperature: 60 °C
Yield: 69.5 %

Procedure:
A mixture of 5.0 g (24.9 mmol) of 5-bromo-salicylaldehyde, 3.0 g (32.3 mmol, 2.6 mL) of chloroacetone and 12 g (37.2 mmol) of Cs2CO3 in 30 mL of dry DMF was heated to 60° C. overnight. After cooling at room temperature, water (100 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was directly recrystallized from hexane to afford 4.14 g (17.3 mmol, yield: 70%) of 2-acetyl-5-bromo benzo[b]furan as a pale orange crystal. 1H NMR (CDCl3), δ: 7.84 (d, J=1.9 Hz, 1H), 7.56 (dd, J=9.0, 2.1 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.42 (s, 1H), 2.60 (s, 3H).