Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]#[N:17])=[CH:6][CH:5]=1.[OH-:18].[NH4+].[OH-].[K+]>O.C(Cl)Cl>[ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:16]([NH2:17])=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: [OH-]
Reactant: N#Cc1ccccc1-c1ccc(CN)cc1
Agent: Cl
Agent: [K+]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: NCc1ccc(-c2ccccc2C(N)=O)cc1
Temperature: 72.5 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
4-Aminomethyl-2′-cyanobiphenyl hydrochloride (XVII) (100 g, 0.408 mole) was suspended in a mixture of water (500 ml) and methylene chloride (200 ml) at 25-30° C. and adjusted the pH to 9.0-9.5 with ammonium hydroxide (65 ml, 20% w/w) at 25-30° C. to get a clear solution. Organic layer was separated, washed with water (100 ml) and dried over sodium sulfate. Thereafter, organic layer was concentrated at below 60° C. and tert.butanol (300 ml) was added to the residue. The reaction mass was heated to 70-75° C. Thereafter, powdered potassium hydroxide (32.35 g, 0.491 mole) was added and heated to reflux for completion of the reaction. Water (400 ml) was added and aqueous layer was separated and extracted with methylene chloride (500 ml). The combined organic layer was washed with water (200 ml) and dried over sodium sulfate. Methylene chloride solution was cooled to 2-5° C. and the pH adjusted to 1.2-1.4 with hydrochloric acid. The precipitated product was stirred for one hour and filtered, washed with methylene chloride to afford the title compound as white powder (90 g, 84.1% yield).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:11][CH:12]([CH2:20][OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[OH:11][CH:12]([CH2:20][OH:21])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[CH2:16][CH2:15]1
Reactant: NC(=O)c1cccnc1Cl
Reactant: OCC(O)CN1CCNCC1
Solvent: CCO
Product: NC(=O)c1cccnc1N1CCN(CC(O)CO)CC1
Yield: 34.9 %

Procedure:
Operation was carried out in a manner similar to the one described in Example 2, using 1.6 g of 2-chloronicotinamide, 3.2 g of 1-(2,3-dihydroxypropyl)piperazine and 30 ml ethanol and refluxing overnight. Column purification of the residue gave 1 g of 2-[4-(2,3-dihydroxypropyl)piperazin-1-yl]nicotinamide, which, recrystallized from acetone, melted at 140°-142° C.
Reaction SMILES: N[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:5][NH:6][C:7]2=[O:13].N([O-])=O.[Na+].[I-:18]>Cl.O>[I:18][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[N:5][NH:6][C:7]2=[O:13]
Reactant: Cc1ccc2c(=O)[nH]ncc2c1N
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(=O)[nH]ncc2c1I
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
To a solution of 5-amino-6-methylphthalazin-1(2H)-one (7.57 g, 43 mmol) in conc. aqueous HCl (250 ml) charged to a 500 mL round bottom, sodium nitrite (3.6 g, 52 mmol) in 50 mL water was added at 0° C. The mixture was then allowed to stir for 90 min at that temperature. Then, KI (22 g, 130 mmol) in water (50 ml) was added. The reaction mixture was stirred at 70° C. for 2 hrs, forming a dark precipitate on initial addition of iodide. Upon cooling to ambient temperature, the dark ppt was collected by filtration and stirred in a solution of saturated sodium sulfite, forming a light yellow precipitate. This precipitate was collected by filtration and washed with excess water. The light yellow solid was dried in a vacuum oven overnight to give 5-iodo-6-methylphthalazin-1(2H)-one (8.5 g, 69% yield. MS (M+H)+ 287.
Reaction SMILES: C([C:8]([NH2:12])([OH:11])[CH2:9][CH3:10])(OC(C)(C)C)=O.[CH:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:24]=2)=[CH:17][CH:18]=1.C(OC(=O)C)C.[ClH:38].C(OCC)C>ClCCl>[NH2:12][CH:8]([OH:11])[CH2:9][CH3:10].[CH:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.[ClH:38]
Reactant: CCC(N)(O)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(N)O
Reaction time: 1.5 h

Procedure:
The Boc-aminopropanol-fenbufen obtained above (1.82 mmol) was dissolved in dichloromethane (4 ml), and under ice-cooling, 4 N hydrochloric acid ethyl acetate solution (4 ml) was added thereto, and then the mixture was gradually returned to room temperature and stirred for 90 minutes. Precipitation of white precipitate was observed just after the commencement of the reaction. After confirming disappearance of Boc-aminopropanol-fenbufen by TLC, diethyl ether was added to the reaction solution, and the resulting white precipitate was centrifuged. The precipitate was washed three times with diethyl ether and then dried under reduced pressure to give the titled compound (621.4 mg, yield 98%). The structure was identified by 1H-NMR (CDCl3:CD3OD=1:1).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:25]OC(OC)(C)C.C[Si](Cl)(C)C>CO>[CH3:25][O:6][C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:16][CH:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: COC(C)(C)OC
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
Crude 4-oxo-4-[4′-(trifluoromethoxy)-1,1′-biphenyl-4-yl]butyric acid (25 g, content: 65%, GC, silylated, 100% method) is dissolved in a mixture of methanol (50 ml) and 2,2-dimethoxypropane (11.5 g, 110 mmol), treated with trimethylsilyl chloride (0.75 g, 7 mmol) and stirred at 50° C. for 16 h. The reaction mixture is then concentrated and the residue is recrystallized from toluene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]([CH3:22])[CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[CH3:25]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]([CH3:22])[CH2:11][C:7]=3[N:8]([CH3:25])[C:9]=2[CH:10]=1
Reactant: CI
Reactant: CC1Cc2[nH]c3cc(Br)ccc3c2CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Cc2c(c3ccc(Br)cc3n2C)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
tert-Butyl 7-bromo-3-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (enantiomer A) (1.00 g, 2.73 mmol) was dissolved in DMF (10 mL), and NaH (60% disp, 131 mg, 3.28 mmol) was added. After stirring for 30 minutes, MeI (386 mg, 0.170 ml, 3.28 mmol) was added, and the reaction continued for 1 h. The mixture was poured into water (250 ml), and the solid was filtered off to provide the title compound (180 mg, 17%) as a yellow solid: ESI MS m/z 379 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:22]([O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH2:22]([O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-L-proline (4.3 g, 15 m mole), L-proline benzyl ester hydrochloride (3.7 g, 15.3 m mole) and HOBt (2.0 g, 15 m mole) were dissolved in methylene dichloride (40 ml). WSC (2.8 ml) was added dropwise to the above mixture while cooling to -15° C. and stirring. The reaction was carried out for 3 hours at a temperature of not more than 0° C., and then overnight at room temperature. The solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate, and washed with 1N hydrochloric acid, water, 5% sodium bicarbonate and water, in order. The mixture was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was crystallized with a mixture of ethyl acetate and n-hexan to give a crystal of N-t-butyloxycarbonyl-L-alanyl-L-prolyl-L-proline benzyl ester (6.3 g, 88.7%) having melting point of 143° to 145° C. and specific rotatory power of [α]D25 =-131.0° (C=1, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([CH2:14][OH:15])[C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1.[O-]Cl.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O.CC1(C)N([O])C(C)(C)CCC1.[K+].[Br-]>[F:1][C:2]1[CH:13]=[C:12]([CH:14]=[O:15])[C:5]2[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH2:9][C:4]=2[CH:3]=1
Reactant: CC1(C)OCc2cc(F)cc(CO)c2O1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: CC1(C)OCc2cc(F)cc(C=O)c2O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 146.4 %

Procedure:
The crude (6-fluoro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl)methanol (35.15 g, 166 mmol) was dissolved in biphasic mixture of CH2Cl2 (230 mL) and water (180 mL). The mixture was cooled to 0° C., and TEMPO (519 mg, 3.3 mmol) and KBr (2.0 g, 16.6 mmol) were added. Finally, NaClO (aq) (5%, 500 mL, 332 mmol) saturated with NaHCO3 was added gradually by addition funnel. The mixture was stirred for 15 min after the all the reagents were added. The layers were partitioned, and the aqueous phase was extracted with CH2Cl2. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was triturated sequentially with hexanes and methanol to yield a white crystalline solid. This procedure was repeated two more times on a further 38 g of (6-fluoro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl)methanol (179 mmol). The triturated solids of all three experiments were combined to provide 51.1 g of 6-fluoro-2,2-dimethyl-4H-1,3-benzodioxine-8-carbaldehyde (243 mmol, 70% yield). 1H NMR (400 MHz, CDCl3): δ 10.37 (d, 1H), 7.41 (dd, 1H), 6.96-6.94 (m, 1H), 4.88 (s, 2H), 1.61 (s, 6H).
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[NH2:15][C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][CH:21]=1>C(O)C>[O:14]=[C:5]1[NH:4][C:3]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[N:8][CH:7]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2cccc(C(F)(F)F)c2)[nH]c1=O
Reaction time: 17 h
Yield: 45 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (50 g) and 3-aminobenzotrifluoride (45.2 g) are added to ethanol (300 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-6-oxo-2-(3-trifluoromethylanilino)-5-pyrimidinecarboxylate (34.4 g). M.p. 229°-230° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:14])[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[OH:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.[Cu]I.[Cu].C(OCC)(=O)C>[CH2:11]([O:10][C:8](=[O:9])[C:7]1[C:6]([O:23][C:17]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=2[Cl:15])=[CH:5][C:4]([CH3:14])=[N:3][C:2]=1[Cl:1])[CH3:12]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Agent: [Cu]
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Oc2cc(Cl)ccc2Cl)cc(C)nc1Cl
Temperature: 120 °C
Reaction time: 18 h
Yield: 4.5 %

Procedure:
To a solution of 500 mg (2.136 mmol) ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (commercially available, CAS RN 86129-63-7) in 7.5 mL dry N,N-dimethylformamide was added 366 mg (2.243 mmol) 2,5-dichlorophenol and 590 mg (4.272 mmol) potassium carbonate and 41 mg (0.214 mmol) copper(I)iodide and 41 mg (0.641 mmol) copper nanopowder (avg. particle size 100 nm). The reaction mixture was stirred at 120° C. for 18 hours and then poured on 30 ml, 1N aqueous hydrochloric acid and 30 mL ethyl acetate. The layers were separated and the aqueous layer was extracted a second time with 30 mL ethyl acetate. The combined organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex Gemini column) with a gradient of acetonitrile:water (50:50 to 100:0) to afford 35 mg (18%) of the title compound as a light yellow oil. MS (ESI): 359.995 [M+H]+.
Reaction SMILES: C(O)(=O)C.C([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:27]=[CH:26][C:25]3[C:24](=[O:28])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.N1C2C(=CC=CC=2)C=NC=1>C(O)C.[Pd]>[N:15]1([C:18]2[N:27]=[CH:26][C:25]3[C:24](=[O:28])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]=2)[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1
Reactant: O=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Agent: [Pd]
Agent: c1ccc2ncncc2c1
Solvent: CCO
Solvent: CC(=O)O
Product: O=C1CCCc2nc(N3CCNCC3)ncc21
Temperature: 25 °C
Yield: 90.4 %

Procedure:
Dissolved in 30 ml of ethanol and 10 ml of acetic acid was 0.64 g (2 mmol, Referential Example 47) of 2-(4-benzylpiperazino)-5-oxo-5,6,7,8-tetrahydroquinazoline, followed by an addition of 64 mg of 10% Pd-C. The quinazoline derivative was hydrogenated at 50° C. for 1 hour under atmospheric pressure. After cooling the reaction mixture to room temperature, the catalyst was filtered off and the solvent was distilled off from the filtrate under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 0.42 g of the intended product as light yellowish crystals (yield: 90%).
Reaction SMILES: [NH2:1][CH:2]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:25][CH3:26])=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[C:8]([F:17])[CH:7]=1)=[O:4].[F:27][B:28]([F:56])[N:29]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[C:30]1/[CH:36]=[C:37]1\[N:38]=[C:39]([CH2:42][CH2:43][CH2:44][CH2:45][C:46](ON2C(=O)CCC2=O)=[O:47])[CH:40]=[CH:41]\1.O.O.C(#N)C>CN(C=O)C>[F:56][B:28]([F:27])[N:29]1[C:33]([CH3:34])=[CH:32][C:31]([CH3:35])=[C:30]1/[CH:36]=[C:37]1\[N:38]=[C:39]([CH2:42][CH2:43][CH2:44][CH2:45][C:46]([NH:1][CH:2]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][O:25][CH3:26])=[CH:22][CH:23]=2)[C:3]([NH:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([Si:13]([CH3:14])([CH3:15])[CH3:16])=[C:8]([F:17])[CH:7]=2)=[O:4])=[O:47])[CH:40]=[CH:41]\1
Reactant: COCc1ccc(C(N)C(=O)Nc2cc(F)c([Si](C)(C)C)c(F)c2)cc1
Reactant: Cc1cc(C)n(B(F)F)c1/C=C1/C=CC(CCCCC(=O)ON2C(=O)CCC2=O)=N1
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: COCc1ccc(C(NC(=O)CCCCC2=N/C(=C\c3c(C)cc(C)n3B(F)F)C=C2)C(=O)Nc2cc(F)c([Si](C)(C)C)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
To a solution of the crude 2-amino-N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-2-(4-(methoxymethyl)phenyl)acetamide (9.07 mg, 0.02 mmol) in DMF (0.5 mL) was added 1-((5-((2Z)-2-((1-(difluoroboryl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5-yl)pentanoyl)oxy)pyrrolidine-2,5-dione (BODIPY (registered trademark) FL-C5 succinimidyl ester) (5.0 mg, 0.01 mmol) at room temperature, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give 5-((2Z)-2-((1-(difluoroboryl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-2H-pyrrol-5-yl)-N-(2-((3,5-difluoro-4-(trimethylsilyl)phenyl)amino)-1-(4-(methoxymethyl)phenyl)-2-oxoethyl)pentanamide (3.8 mg, 5.58 μmol, 46.6%) as an orange solid, which is a fluorescent-labeled synthetic ligand.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][CH2:14][C@H:13]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])[CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:28][N:29]1[C:33]([CH3:34])=[C:32](B2OC(C)(C)C(C)(C)O2)[C:31]([CH3:44])=[N:30]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([N:17]([CH3:18])[C@H:13]1[CH2:14][CH2:15][C:16]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[C:32]2[C:31]([CH3:44])=[N:30][N:29]([CH3:28])[C:33]=2[CH3:34])[CH2:12]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(Cc1ccccc1)[C@H]1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)C1
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1nn(C)c(C)c1-c1cccc2c1CC[C@H](N(C)Cc1ccccc1)C2
Reaction time: 3 h

Procedure:
(6S)-6-[Benzyl(methyl)amino]-5,6,7,8-tetrahydronaphthalen-1-yl trifluoromethanesulfonate (5.0 g, 12.517 mmol), 1,3,5-trimethyl-1H-pyrazole-4-boronic acid pinacol ester (3.60 g, 15.246 mmol) and Pd(PPh3)4 (1.70 g, 1.471 mmol) were added to a solution of K2CO3 (3.31 g, 23.95 mmol) in a mixture of 1,2,-dimethoxyethane (120 mL) and H2O (15 mL). The reaction mixture was purged with N2 (g) for 10 min, and warmed up to reflux. The reaction was completed in 3 h (TLC analysis). It was allowed to reach room temperature, diluted with H2O (150 mL) and extracted with AcOEt (300 mL). The organic layer was filtered through Celite (washing with AcOEt), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (0-10-20% Et3N/AcOEt) to afford the desired product as a brown-colored oil. The material was dissolved in CH2Cl2 (100 mL) and acidified with HCl aqueous solution (6 N). The organic layer was discarded, and the aqueous layer was taken to pH>13 with NaOH aqueous solution (6 N). It was extracted with CH2Cl2 (3×200 mL), and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated, to give 3.67 g of the coupling product (Rf=0.3 (AcOEt), pale yellow oil, 81% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:18].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:31](OCCC(C)C)=O>C1(C)C=CC=CC=1>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:7]=[C:2]3[C:3](=[CH:4][CH:5]=2)[NH:18][N:31]=[CH:1]3)=[N:10][CH:11]=1)([O-:17])=[O:16]
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1N
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 20.9 %

Procedure:
To a mixture of 2-methyl-4-(5-nitro-pyridin-2-yloxy)-phenylamine (10 g, 41 mmol), potassium acetate (17 g, 160 mmol), acetic anhydride (17 g, 160 mmol) and toluene (140 mL) at 80° C. was added isoamyl nitrite (9.6 g, 82 mmol) dropwise via an addition funnel. After stirring for 24 h at 80° C., the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was treated with methanol (120 mL) containing 12 mL of concentrated ammonium hydroxide. After refluxing for 2 h, the mixture was cooled to room temperature and was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane to afford 2.2 g of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole as an orange solid. 1H NMR (CD3OD, 400 MHz): δ 8.96 (d, 1H, J=2.4 Hz), 8.56 (dd, 1H, J=2.8, 9.2 Hz), 8.05 (s, 1H), 7.60 (1H, d, 8.8 Hz), 7.56 (m, 1H), 7.21 (dd, 1H, J=2.0, 8.8 Hz), 7.13 (d, 1H, 9.2 Hz) ppm.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:13][CH3:14])=[O:4].[NH3:16]>>[NH2:16][CH:2]([CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:13][CH3:14])=[O:4]
Reactant: N
Reactant: CCc1cccc(C)c1NC(=O)C(C)Br
Product: CCc1cccc(C)c1NC(=O)C(C)N
Temperature: 55 °C

Procedure:
A slurry of 20.9 g 2-bromo-2'-ethyl-6'-methyl propionanilide, 125 ml 95% alcohol, and 75 ml concd. ammonia was saturated with gaseous ammonia and was heated to 55° C. for 30 hours in a pressure vessel. The reaction mixture was filtered and the filtrate concentration in vacuo. The residue was dissolved in 2 M hydrochloric acid and was extracted with ethyl acetate. The acid phase was made alkaline to pH 9 and was extracted with methylene chloride to give 15.5 g of a crystallizing oil. Recrystallized from ether-petroleum ether, the compound (2-amino-2'-ethyl-6'-methylpropionanilide) melted at 68.5°-70° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[C:6]([NH2:15])[CH:5]=1.[C:17](Cl)(Cl)=[O:18]>ClCCl.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:17](=[O:18])[NH:15][C:6]=2[CH:5]=1)=[O:16]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1ccc(NC2CCC2)c(N)c1
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C1CCC1
Reaction time: 2 h

Procedure:
To a solution of 3-amino-4-cyclobutylamino-benzoic acid methyl ester (15.94 g, 72.3 mmol) in dichloromethane (250 ml) at 23 C was added phosgene (38.3 ml of a 20% solution in toluene) dropwise over 30 minutes. The reaction was allowed to stand for 2 hours then was diluted with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and concentrated in vacuo to give 17.01 g of 1-cyclobutyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methyl ester.
Reaction SMILES: C([O:5][P:6]([CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:16]=1)[F:14])(=[O:12])[O:7]C(C)(C)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:26]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([CH2:22][O:21][C:17]2[CH:16]=[C:15]([CH:13]([P:6](=[O:5])([OH:7])[OH:12])[F:14])[CH:20]=[CH:19][CH:18]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=P(O)(O)C(F)c1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.5 %

Procedure:
The above fluoromethylphosphonic acid di-tert-butyl ester (1.29 g, 2.7 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (2.5 ml) was added and the mixture was stirred at room temperature for 16 h. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml) and a solid was formed in the aqueous phase. This was filtered off and dried in vacuo at 50° C. affording 55 mg (6%) of the title compound as a solid,