Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:19](C=O)C.[NH4+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:19])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(C(N)=O)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a slurry of 3-bromo-4-methylbenzoic acid (2.53 g, 85% purity; 10 mmol) in CH2Cl2 (20 mL) at 0° C., under N2, was added oxalyl chloride (0.91 mL; 10.5 mmol), followed by dropwise addition of DMF (0.04 mL; 0.5 mmol). The mixture was stirred 5 min at 0° C., 15 min at rt, and then heated at reflux under N2 for 1 h. The mixture was cooled, and poured into NH4OH (30 mL; ca. 30% NH3). Precipitated solids were collected by filtration and purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid. LC/MS (method A) tR 2.05 min; m/z 214, 216 (M+H, Br isotopes).
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:10][CH:11]=1>CO>[CH3:1][O:14][C:13](=[O:15])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([OH:5])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1cccc(O)c1
Solvent: CO
Product: COC(=O)Cc1cccc(O)c1
Yield: 99 %

Procedure:
To methanol (300 mL) was added acetyl chloride (8.9 mL) dropwise in 10 minutes with stirring. 3-Hydroxyphenylacetic acid (25 g, 164 mmol) was added to the mixture at one time. The reaction mixture was stirred at room temperature for 15 hrs. The solvent was evaporated and the residue was concentrated in vacuo to afford 3-hydroxyphenyl acetic acid methyl ester (27.3 g, 99% yield) as a red oil.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]=[C:10]([CH2:12][O:13][CH2:14][CH3:15])[NH:9][C:8](=[O:16])[CH:7]=1.[OH-].[Na+].S(=O)(=O)(O)O>O>[NH2:5][C:6]1[N:11]=[C:10]([CH2:12][O:13][CH2:14][CH3:15])[NH:9][C:8](=[O:16])[C:7]=1[N:1]=[O:3]
Reactant: CCOCc1nc(N)cc(=O)[nH]1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc(N)c(N=O)c(=O)[nH]1

Procedure:
17.7 g (0.256 mole) of sodium nitrite are added to a solution of 39.5 g (0.233 mole) of 6-amino-2-(ethoxymethyl)-4(3H)-pyrimidinone in 336 ml (0.336 mole) of 1N sodium hydroxide. A solution of 17.9 ml (0.320 mole) of 96% sulphuric acid diluted in 179 ml of water is then added dropwise at between 0° and 5° C. The precipitate formed is isolated by filtration immediately after completion of the addition. The solid obtained is washed with cold water and then with ethyl ether. After drying, it is used in the next step without further purification. Yld: 46.2 g (quantitative), m.p. 163°-165° C. An analytical sample was obtained by recrystallization from methanol. M.p. 166°-167° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:4][C:5]2[C:10]([C:11]=1I)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[Na+].[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.O>[F:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:4][C:5]2[C:10]([C:11]=1[NH:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Fc1ccccc1-c1nc2ccccc2c(I)c1F
Reactant: Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccccc1-c1nc2ccccc2c(Nc2ccncc2)c1F
Temperature: 110 °C
Yield: 72 %

Procedure:
To a solution of 3-fluoro-2-(2-fluoro-phenyl)-4-iodo-quinoline (from Step F, 0.02 g, 0.05 mmol) in toluene (1 mL) was added S-BINAP (0.007 g, 0.01 mmol), sodium tert-butoxide (0.105 g, 1 mmol) and 4-aminopyridine (0.015 g, 0.05 mmol). The resulting mixture was degassed for 5 min., after which tris(dibenzylidineacetone) dipalladium(0) (0.0025 g, 0.0025 mmol) was added. The reaction mixture was heated to 110° C. for 48 h. and then diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in rotary evaporator. The residue was purified using HPLC over a gradient of acetonitrile and water containing 0.1% trifluoroacetic acid to yield the desired compound (0.012 g, 65%). MS (ES) 334.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][C:22]([NH:29][C:30]([O:32][CH3:33])=[O:31])([CH3:28])[C:23](OCC)=[O:24].[BH4-].[Li+].C(O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][C:22]([NH:29][C:30]([O:32][CH3:33])=[O:31])([CH3:28])[CH2:23][OH:24]
Reactant: CCOC(=O)C(C)(CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl)NC(=O)OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)NC(C)(CO)CCCc1ccc(Sc2cccc(C(F)(F)F)c2)cc1Cl
Yield: 90.2 %

Procedure:
To a solution of the compound of Example 40 (15.6 g) in THF (249 mL) was added under ice cooling lithium borohydride (3.75 g), and then ethanol (16.6 mL) was added dropwise. The resultant solution was then stirred for 1 hour under ice cooling. To The reaction solution was added 10% aqueous citric acid, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the target product (12.9 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]1([NH:38][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCC1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with cyclopentylamine (20 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with a 3:1 ethyl acetate-hexanes mixture. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 54 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](O)=[O:9])[CH:2]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH3:16][O:15][N:14]([CH3:13])[C:8](=[O:9])[CH2:7][C:3]1[CH:2]=[C:1]([CH3:11])[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(CC(=O)O)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A mixture of 2-m-tolylacetic acid (1 g, 6.7 mmol), N,O-dimethylhydroxylamine hydrochloride (654 mg, 6.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.28 g, 6.7 mmol), hydroxybenzotriazole (910 mg, 6.7 mmol) and triethylamine (3.38 g, 33.5 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. When TLC indicated that 2-m-tolylacetic acid was consumed, the reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=10:1) to afford N-methoxy-N-methyl-2-m-tolylacetamide (900 mg, yield 70%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:21]4=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]4[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:21]4=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]4[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc2c(cnn2-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc2c(cnn2-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c1
Reaction time: 15 h
Yield: 13.8 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.1 g, 208 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(5-methyl-pyrazolo[3,4-b]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (10 mg, 14%). MS (M+H)+=350; 1H NMR (DMSO-d6) δ: 9.08 (s, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.50 (s, 1H), 8.39 (s, 1H), 8.28 (s, 1H), 8.21 (dd, J=2.0, 0.8 Hz, 1H), 1.49 (s, 9H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][N:36]=5)[CH:31]=[CH:30][C:29]4=[O:38])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:39].C(OCC)(=O)C>>[ClH:39].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][N:36]=5)[CH:31]=[CH:30][C:29]4=[O:38])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cccnc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1ccc2cccnc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 1.4 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 50 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, thereto was added ethanol, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resultant residue, and after stirring, the solid was filtered off to obtain 1.2 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,8-naphthyridin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>C1COCC1>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccccc4F)cc23)CC1
Yield: 115.3 %

Procedure:
By a method similar to Example 31, using 2-fluorobenzenesulfonyl chloride (234 mg, 1.2 mmol) added dropwise to a solution of 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (231 mg, 1.0 mmol) in 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) and THF (5 mL) gave 448 mg of the title compound as a crystalline solid. The product was recrystallized from ethyl acetate/hexanes to give 320 mg (82%) of the title compound an off white powder: mp=180-182° C.; MS(m/e): 389 (M+1); Calculated for C20H21FN2O3S: Calcd: C, 61.84; H, 5.45; N, 7.21. Found: C, 61.83; H, 5.57; N, 7.26.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:17]=[C:18](I)[CH:19]=[CH:20][CH:21]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][N:9]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][C:14]([F:13])([F:23])[F:24])[CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Reactant: FC(F)(F)Oc1cccc(I)c1
Product: CCOC(=O)c1c(C)nn(-c2cccc(OC(F)(F)F)c2)c1C
Yield: 73.6 %

Procedure:
The title compound was prepared in analogy to intermediate 6A by reaction of 3,5-Dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2 g, 12 mmol) with 3-trifluoromethoxyiodobenzene (6.7 g, 14 mmol) affording the desired product (2.9 g, 73%) as a colourless liquid. MS: 329.2 (MH1).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[C:22]4[O:41][CH:42]=[CH:43][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Cl[Sn:53]([CH3:56])([CH3:55])[CH3:54]>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[C:22]4[O:41][C:42]([Sn:53]([CH3:56])([CH3:55])[CH3:54])=[CH:43][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2ccoc12
Reactant: C[Sn](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2cnn([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)c2)c2cc([Sn](C)(C)C)oc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (−78° C.) solution of di-tert-butyl {4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-7-yl}imidodicarbonate (400 mg, 0.653 mmol) in anhydrous THF (10 mL) was added lithium diisopropylamide (2 M in THF, 1.6 mL, 3.3 mmol), and the mixture stirred for 30 minutes. Chlorotrimethylstannane (1 M in THF, 3.92 mL, 3.92 mmol) was added, and the mixture warmed to RT. The mixture was then cooled to −78° C., quenched by addition of glacial acetic acid (0.2 mL), and warmed to RT. The solution was adsorbed onto silica gel and purified by ISCO chromatography (10 to 20% EtOAc:heptane) to afford 347 mg (69%) of the title compound as a tan solid. 1H NMR (400 MHz, CDCl3): δ 0.10 (s, 6 H), 0.45 (s, 9 H), 0.92 (s, 9 H), 1.39 (s, 18 H), 1.50-1.62 (m, 2 H), 1.87-2.09 (m, 4 H), 2.24 (d, J=12.1 Hz, 2 H), 3.69-3.80 (m, 1 H), 4.21 (tt, J=11.5, 3.9 Hz, 1 H), 7.08-7.11 (m, 1 H), 7.78 (s, 1 H), 7.88-7.91 (m, 1 H), 8.31 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Br[CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:29][CH2:28][CH2:27][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[C:16]([CH3:25])=[N:17][C:18]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: ClCCBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
6-Methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (200 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare a solution. 1-Bromo-2-chloroethane (432 mg) and potassium carbonate (416 mg) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (186 mg, yield 78%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.[N+:10]([C:13]1[C:14](F)=[C:15]([C:22]([F:25])([F:24])[F:23])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1)([O-:12])=[O:11].Cl>CN(C=O)C>[N+:19]([C:17]1[CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[C:15]([C:22]([F:23])([F:24])[F:25])[C:16]=1[O:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)c(C(F)(F)F)c1
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2C(F)(F)F)n[nH]1
Temperature: 70 °C
Yield: 34.9 %

Procedure:
Sodium hydride (60% in oil, 0.2 g, 5.5 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (0.49 g, 5.0 mmol) and 3,5-dinitro-2-fluorobenzotrifluoride (1.35 g, 5.0 mmol) in DMF (10 ml), and the mixture was stirred under heating at 70° C. for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (30 ml) and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a yellowish solid of 3-(2,4-dinitro-6-trifluoromethylphenyloxy)-5-methylpyrazole (0.58 g, yield: 34.9%). mp: 145-147° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.29 (s, 3H), 5.84 (s, 1H), 8.82 (m, 2H), 9.01 (d, J=2.7 Hz, 1H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:14]2)=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:17](=[O:22])[C:18]([F:19])([F:20])[F:21])[CH2:14]2)=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=C(N1CCc2cc(S(=O)(=O)Cl)c(Br)cc2C1)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Chlorosulfonic acid (35.6 mL) was added dropwise to a solution of 1-(7-bromo-3,4-dihydroisoquinolin-2(1 H)-yl)-2,2,2-trifluoroethanone obtained (25.4 g, 82.3 mmol) in chloroform (35 mL) while cooling in ice, and the mixture was stirred at room temperature for 1 hr and at 60° C. for 4 hr. After cooling, the reaction mixture was added dropwise to ice water and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The concentrate was powdered with hexane and ethyl acetate (5:1) and then collected by filtration to afford 7-bromo-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonyl chloride as a pale yellow powder (22.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([OH:22])[CH:14]=2)[CH:7]=1.[K+].[Br-]>>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][C:4]3[CH:23]=[CH:24][C:25]([NH2:26])=[C:2]([OH:1])[CH:3]=3)[CH:7]=2)=[CH:14][C:15]=1[OH:22]
Reactant: O=[N+]([O-])c1ccc(Oc2cccc(Oc3ccc([N+](=O)[O-])c(O)c3)c2)cc1O
Agent: [Br-]
Agent: [K+]
Product: Nc1ccc(Oc2cccc(Oc3ccc(N)c(O)c3)c2)cc1O
Yield: 81 %

Procedure:
1,3-Bis(4-amino-3-hydroxyphenoxy)benzene was synthesized in a manner analogous to Example 2 from 1,3-bis(3-hydroxy-4-nitrophenoxy)benzene. Yield: 81%; mp 171˜174° C.; IR (KBr): 3414, 3342, 1588, 1518 cm−1; MS (EI) m/z 324 (M+, 100); Elemental Anal. Calcd. for C18H16N2O4: C, 66.67; H, 4.94; N, 8.64. Found: C, 66.45; H, 5.02; N, 8.53.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH:7]2[CH2:12][CH2:11][C:10]3([C:20]4[C:15](=[CH:16][CH:17]=[N:18][CH:19]=4)[C:14](=[O:21])[O:13]3)[CH2:9][CH2:8]2)[NH:4][N:3]=1.[CH2:22](Cl)[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[N:3]([CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[N:4]=[C:5]([CH:7]2[CH2:12][CH2:11][C:10]3([C:20]4[C:15](=[CH:16][CH:17]=[N:18][CH:19]=4)[C:14](=[O:21])[O:13]3)[CH2:9][CH2:8]2)[CH:6]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: Nc1cc(C2CCC3(CC2)OC(=O)c2ccncc23)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(C2CCC3(CC2)OC(=O)c2ccncc23)nn1CC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
3-Amino-5-[3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexan]-4′-yl]-1H-pyrazole (180 mg, 0.633 mmol), phenacyl chloride (150 mg, 0.94 mmol) and potassium carbonate (180 mg, 1.27 mmol) were stirred overnight at room temperature in N,N-dimethylformamide (10 mL). The mixture was stirred for further 1 hour at 80° C. The reaction solution was cooled down to room temperature and ethyl acetate was added thereto. The reaction solution was washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to remove the solvent. The residue was separated and purified by a silica gel column chromatography (C-300, methanol:chloroform=1:50 to 1:30) to obtain the title compound (26.5 mg, 10.4%) as a cis and trans mixture.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([Br:15])[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][Br:17])[N:6]2[C:7]=1[C:2]([NH2:1])=[N:3][CH:4]=[N:5]2
Reactant: Nc1ncnn2c(CCCO)cc(Br)c12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnn2c(CCCBr)cc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of 3-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol (1.20 g, 4.43 mmol) in anhydrous THF (22 mL) at 0° C. was added carbon tetrabromide (1.62 g, 4.87 mmol, 1.1 eq) and triphenylphosphine (1.16 g, 4.43 mmol, 1.0 eq). After 5 minutes the ice bath was removed and the reaction mixture was stirred at RT for 1 hour. Then another 0.1 equivalents of both carbon tetrabromide (0.15 g, 0.44 mmol) and triphenylphosphine (0.12 g, 0.44 mmol) were added. The reaction was stirred another hour at ambient temperature before it was filtered to remove some solid which was rinsed with some THF. The combined filtrate and rinse were concentrated at reduced pressure to give a crude product which was purified by MPLC on 120 g of silica gel eluted with a gradient from 0-100% EtOAc in hexane to give 950 mg (64.2%) of desired product as a white solid after evaporation of best fractions which eluted from 55-65% EtOAc. 1H-NMR (DMSO-d6) 7.84 (s, 1H), 6.65 (s, 1H), 3.54 (t, 2H, J=6.4), 2.94 (t, 2H, J=6.4), and 2.16 (q, 2H, J=6.4); MS LC-MS [M+H]+=333.3/335.1/337.1, RT=2.77 min. Evidence showed in the NMR and the LC-MS for about 16% contamination with 5,6-dibromo-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine which came from an analogous contaminant (3-(4-Amino-5,6-dibromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-propan-1-ol) in the starting material. Products that came from this contaminant were removed by chromatography of the product of step 5 below.