Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2](C)[CH2:3][Mg]Br.[CH3:7]C(C)CBr.[Mg].[C:13]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])(=[O:15])[CH3:14].[Cl-].[NH4+]>O1CCCC1>[OH:15][C:13]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH3:7])[CH2:14][CH:2]([CH3:3])[CH3:1]
Reactant: CC(C)C[Mg]Br
Reactant: CC(C)CBr
Reactant: CC(=O)c1sccc1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)CC(C)(O)c1sccc1NC(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A tetrahydrofuran solution of 2-methylpropylmagnesiumbromide prepared from 2.9 g of 2-methylpropylbromide, 0.47 g of magnesium and 20 ml of tetrahydrofuran was cooled to 10° C., a solution containing 1 g of 2-acetyl-3-t-butyloxycarbonylaminothiophene in 10 ml of tetrahydrofuran was dropwise added at 15° C. or less, and the mixture was stirred at room temperature for 2 hours. Thereafter a saturated aqueous ammonium chloride solution was dropwise added under cooling. The reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium solfate. The solvent was distilled off under reduced pressure to obtain 1.2 g of the product. The yield was 98%.
Reaction SMILES: O[N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1.CS(Cl)(=O)=O.C(N(C(C)C)C(C)C)C>C1COCC1>[O:5]1[C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:7][CH2:8][CH:4]1[C:3]([Cl:14])=[NH:2]
Reactant: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N=C(Cl)C1COC2(CCCCC2)O1
Temperature: 3 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
In a 4 neck 5 L flask was added (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 719 mmol) in 2.5 L of THF. The material was cooled to 3° C. and methanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portions over 10 minutes. N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol) was added through an addition funnel over 12 minutes. The reaction was stirred in an ice bath for 30 minutes and then at ambient temperature for 1 hour. The reaction was filtered and the solids washed with MTBE (3 L). The filtrate was concentrated and the residue was purified over silica gel (3 kg silica, 7:1 to 3:1 Hexane/EtOAc) to afford an oil that slowly solidified under vacuum. The solids were ground using a mortar and pestle, washed with hexanes (about 1000 mL) and dried to afford (R)-N-methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 531 mmol, 73.8% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([NH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 113.8 %

Procedure:
To a solution of 5-aminosalicylic acid (2.0 g, 13 mmole, purchased from Aldrich Chemical Company, USA) and triethylamine in dried DMF (25 ml) was added benzyl bromide (2.68 g, 1.90 ml, 15.6 mmole) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 4 hr at room temperature. Ice chips were added to the reaction mixture and then solvent was removed in vacuo. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous MgSO4. After evaporation of the solvent, the residue was purified by column chromatography and recrystallized from methanol/ethyl acetate/hexane (1:3:1) to give 3.6 g (73% yield) of 5-benzylaminosalylic acid as a white solid.: mp 173.5-174.5° C. (decompose).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:18]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:18]([N:25]1[CH2:31][CH2:30][CH2:29][N:28]([C:15](=[O:17])[CH2:14][CH:9]2[CH2:10][O:11][CH2:12][CH2:13][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1CC(=O)O
Reactant: c1ccc(CN2CCCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCOCC1CC(=O)N1CCCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
4-N-Boc-morpholine-3-acetic acid (500 mg, 2.04 mmol) and benzyl homopiperazine (388 mg, 2.04 mmol) were dissolved in DMF (20 mL) and cooled to 0° C. DIPEA (553 mg, 4.28 mmol) and HBTU (773 mg, 2.04 mmol) were added and the reaction mixture was stirred for 2 h. The solvents were removed in vacuo and the residue was partitioned between DCM (100 mL) and water (50 mL). The organic fraction was washed with 1 M aq Na2CO3 (25 mL), brine (25 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase column chromatography to give the title compound (730 mg, 86%) as a light yellow gum. LCMS (ES+): 418.4 [MH]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1CCCCC1>[C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: Oc1ccccc1
Solvent: C1CCCCC1
Product: C1=CCCCC1
Product: O=C1CCCCC1

Procedure:
In this example, the reaction temperature was set to 240° C., 280° C. and 320° C., respectively. The experimental results were described as follows. When the reaction temperature was 240° C., the selectivity of crude phenol was 100%. However, the increased reaction temperature caused hydrogenation of crude phenol to form cyclohexanone, cyclohexene and even cyclohexane. Thus, in order to produce crude phenol with a high yield, the reaction temperature was set to 240° C. An increase in the reaction temperature caused a low yield of crude phenol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][O:13][CH3:14].O1CCCC1.C(OP([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:5][C:4]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: COCOc1cc(C=O)ccc1OC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(OC)c(OCOC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
The compound (3.42 g, 17.4 mmol) of Example 9-1 was dissolved in N,N-dimethylformamide (30 ml) and tetrahydrofuran (30 ml) and then thereto were added ethyl diethylphosphonoacetate (3.91 g, 17.4 mmol) and sodium hydride (766 mg, 19.1 mmol). After stirring for 2 hours at 60° C., the mixture was allowed to cool to room temperature, and tetrahydrofuran was removed under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate-toluene (3:1). The organic layer was washed with water and an aqueous saturated sodium chloride solution in the order, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the subject compound (196 mg, 88.8%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[N:18]([CH3:31])[C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The title compound was prepared by dissolving the 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione from Example 10 (1.8 g, 4.6 mmol) in 10 ml of dimethylformamide at 0° C. After treating this solution with NaH (203 mg, 5 mmol) followed by 720 mg (5 mmol) of methyl iodide, the mixture was stirred at room temperature for 24 hours. The reaction was poured into water and extracted with CH2Cl2. The combined extracts were washed with water and brine and dried over MgSO4. Solvent removal produced a crude product which was purified by flash silica gel chromatography using 2% MeOH/CH2Cl2. The title compound was crystallized from CH2Cl2 /hexane to give a white solid (1.04 g, 54% yield), mp 176°-178° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C@H:7]([NH:21]C(OC(C)(C)C)=O)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:2].S(Cl)([Cl:32])=O>C(O)C>[ClH:32].[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C@H:7]([NH2:21])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)CC[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: CCO
Product: CCOC(=O)CC[C@H](N)Cc1ccc(-c2ccccc2)cc1
Product: Cl
Reaction time: 1.5 h

Procedure:
To a solution of (S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylaminopentanoic acid ethyl ester [9-a, R1=Boc, R2=H, R5=Et] (115 g) in ethanol (1.1 L) at 70° C. is added thionyl chloride (32 ml) over 45 min. After a further 1.5 hours, the mixture is concentrated to dryness. The crude material is suspended in ethyl acetate and filtered to give (S)-4-Amino-5-biphenyl-4-yl-pentanoic acid ethyl ester hydrochloride [10-a, R5=Et]. 1H NMR (DMSO): 1.08 (3H, d, CH3); 1.73 (2H, m, 3-CH2); 2.35-2.52 (2H, m, 2-CH2); 2.79 (1H, dd, 5-CHH); 2.97 (1H, dd, CHH); 3.38 (1H, m, 4-CH); 3.97 (2H, q, CH2CH3); 7.30 (3H, m, aromatic); 7.40 (2H, m, aromatic); 7.58 (4H, m, aromatic); 8.15 (3H, s, NH3+). m/z: 298 (MH+, 100%); 281 (4); 235 (3).
Reaction SMILES: O=[C:2]1[CH2:8][C@H:7]2[N:4]([C:5](=[O:26])[C@H:6]2[C:9]([CH3:25])([O:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH3:10])[C@H:3]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(N(C(C)C)CC)(C)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[N+:66]([C:69]1[CH:82]=[CH:81][C:72]([CH2:73][O:74][C:75]([NH:77][CH2:78][CH2:79][SH:80])=[O:76])=[CH:71][CH:70]=1)([O-:68])=[O:67]>CN(C1C=CN=CC=1)C.C(#N)C>[CH3:25][C:9]([C@@H:6]1[C:5](=[O:26])[N:4]2[C@@H:7]1[CH2:8][C:2]([S:80][CH2:79][CH2:78][NH:77][C:75]([O:74][CH2:73][C:72]1[CH:81]=[CH:82][C:69]([N+:66]([O-:68])=[O:67])=[CH:70][CH:71]=1)=[O:76])=[C:3]2[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])([O:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:13])[CH3:10]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C[C@H]12
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (602 mg) and 4-(N,N-dimethylamino)pyridine (13.6 ml) in acetonitrile (30 ml) was added a solution of diisopropylethylamine (0.232 ml) in acetonitrile (2.08 ml) at 0° C. To the mixture was further added a solution of diphenyl chlorophosphate (0.242 ml) in acetonitrile (2.18 ml). After stirring at 0° C. for an hour, the mixture was cooled to -15° C. To the mixture was added a solution of diisopropylethylamine (0.775 ml) in acetonitrile (6.97 ml) and N-(4-nitrobenzyloxycarbonyl)cysteamine (299 mg) were added. After standing overnight at -15° C., the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed in turn with water and saturated aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (18 g) eluting with a mixture of benzene and acetone (20:1 to 6:1) to give 4-nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (716 mg) as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[C:28]([NH2:30])[N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[C:28]([NH2:30])[N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:19]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Solvent: CCCCO
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Yield: 23 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine.2HCl (195 mg, 0.59 mmol), 6-chloro-9H-purin-2-ylamine (106 mg, 0.62 mmol) and DIPEA (415 μL, 2.38 mmol) in n-butanol (1 mL) was heated at 100° C. in a sealed vial for 24 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 5-60%, 0.1% NH4OH in acetonitrile/water) to afford 310 as a white solid (52 mg, 23%). LCMS (Method K): RT 2.89 min [M+H]+ 389.02. 1H NMR (CDCl3, 400 MHz): δ 7.67 (1H, dd, J=8.67, 4.59 Hz), 7.62-7.38 (5H, m), 7.20 (1H, s), 7.00 (1H, td, J=9.19, 2.45 Hz), 6.79 (1H, dd, J=8.61, 2.46 Hz), 5.65 (1H, s), 4.92 (1H, s), 1.64 (3H, d, J=6.94 Hz)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]2[C:13](=[O:19])[NH:14][C:15](=[S:18])[NH:16][CH:17]=2)=[CH:3]1.[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][C:27]=2[C:28]#[N:29])=[CH:23][C:22]=1[C:38]([F:41])([F:40])[F:39].CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:37]=[CH:36][C:24]([O:25][C:26]2[CH:33]=[CH:32][C:31]([CH2:34][S:18][C:15]3[NH:16][CH:17]=[C:12]([CH2:11][C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:2]([CH3:1])[CH:3]=4)[C:13](=[O:19])[N:14]=3)=[CH:30][C:27]=2[C:28]#[N:29])=[CH:23][C:22]=1[C:38]([F:39])([F:40])[F:41]
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)c2ccccc21
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1cc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)c2ccccc21
Yield: 71.1 %

Procedure:
The same procedure as E80 from 5-[(1-methyl-1H-indol-3-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (50 mg, 0.184 mmol), 2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-(chloromethyl)benzonitrile (77 mg, 0.221 mmol) and DIPEA (0.097 mL, 0.553 mmol) in chloroform (2 mL) was added to afford the title compound (76 mg, 71.0% yield). LCMS: rt=3.99 min, [M+H+]=581
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:23]1[CH2:33][CH2:32][CH:26]([C:27]([O:29]CC)=[O:28])[CH2:25][CH2:24]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>O.CC(N(C)C)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:23]1[CH2:33][CH2:32][CH:26]([C:27]([OH:29])=[O:28])[CH2:25][CH2:24]1)=[O:5]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 18 h

Procedure:
2-Fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (B)(3.1 g, 0.14 mol), ethyl isonipecotate (1.7 ml, 0.11 mol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (5.1 g, 0.13 mol) and N,N,-diisopropylethylamine (10.0 ml, 0.55 mol) were added to dimethylacetamide (15 ml) and stirred for 18 hours. Water (100 ml) was added to the reaction mixture and the product was extracted into dichloromethane (4×50 ml). The combined organic layers were, filtered, washed with water (3×100 ml), dried over MgSO4, filtered and evaporated in vacuo to yield an orange oil. The oil was purified by flash chromatography (ethyl acetate) to yield 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoyl]piperidine-4-carboxylic acid as the methyl ester (1.5 g, 33%, 96% purity). To a solution of the methyl ester in tetrahydrofuran:water (2:1, 40 ml) was added sodium hydroxide (0.3 g, 0.075 mol) and the reaction was stirred for 18 h. The reaction was concentrated, washed with ethyl acetate (2×20 ml) and acidified with 2M HCl to pH 2. The aqueous layer was extracted with dichloromethane (2×20 ml), and the combined extracts were dried over MgSO4 and evaporated to yield 1-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoyl]piperidine-4-carboxylic acid (D) as a yellow solid (0.6 g, 65%), m/z [M+1]+ 392 (96% purity)
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([NH2:16])=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][CH2:8]2>CO.[Pd]>[ClH:1].[BrH:2].[CH2:8]1[C:9]2[C:4](=[CH:3][CH:12]=[C:11]([NH2:13])[C:10]=2[NH2:16])[CH2:5][CH2:6][NH:7]1
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CNCC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Br
Product: Nc1ccc2c(c1N)CNCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
The product from Example 5 (7 g) in 250 mL of methanol was treated with 20% Pd/C (1 g) and shaken on a Parr apparatus under a hydrogen atmosphere (50 psi) for 16 h at ambient temperature. The catalyst was removed by filtration and the filtrate evaporated to give the product as a purple solid (6.3 g, 99% yield) that was used immediately without further purification.
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]([F:18])([O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1N)[CH:7]([F:9])[F:8].[ClH:19].[S:20](=[O:22])=[O:21]>O.C(O)(=O)C>[F:5][C:6]([F:18])([O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[S:20]([Cl:19])(=[O:22])=[O:21])[CH:7]([F:9])[F:8]
Reactant: Nc1ccccc1OC(F)(F)C(F)F
Reactant: Cl
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Cl)c1ccccc1OC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution containing 3.8 g (55 mmol) of sodium nitrite in 6 mL of water was added slowly with cooling and stirring to a mixture of 12.3 g (50 mmol) of 2-(1,1,2,2-tetrafluoroethoxy)aniline, 18 mL of concentrated aqueous hydrochloric acid, and 5 mL of acetic acid that was precooled to -10° C. After 45 min, the resulting mixture was added in portions to a -10° C. solution of 1.3 g (18 mmol) of cuprous chloride and 0.5 g (4 mmol) of cupric chloride in 50 mL of acetic acid saturated with sulfur dioxide (more than 12 g). The mixture was then warmed to ambient temperature and stirred for 90 min after which it was poured onto ice. The mixture obtained was extracted with diethyl ether and the extract was washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate. The fractions containing product were combined and concentrated by evaporation under reduced pressure to obtain 11.0 g (75 percent of theory) of the title compound as a yellow oil. NMR: 1H (CDCl3): 8.07(dd, 1H, J=1.7, 8.0), 7.76(ddd, 1H, J=1.7, 7.8, 8.1), 7.59(dd, 1H, J=1.2, 8.1), 7.45(ddd, 1H, J=1.2, 7.8, 8.0), 6.05(tt, 1H, J=4.0, 53.0). The mass spectrum had a parent peak M+ 292.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11](Br)[CH:12]=[CH2:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)[CH:12]=[CH2:11]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
5-Hydroxy-1H-indole (500 mg, 3.76 mmol) and allyl bromide (499.7 mg, 4.13 mmol) were dissolved in DMF (15 mL), then Cs2CO3 (1.468 g, 4.51 mmol), and water (6 drops) were added. The reaction mixture was stirred at rt for 12 h, after which it was concentrated under reduced pressure, diluted with water, and the aqueous layer was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:11) gave 514 mg (79%) of the title compound as a light-yellow oil. 1H NMR (400 MHz, CDCl3): δ 4.59 (d, 2H), 5.29 (d, 1H), 5.45 (d, 1H), 6.12 (m, 1H), 6.48 (d, 1H), 6.90 (d, 1H), 7.11 (s, 1H), 7.19 (s, 1H), 7.28 (m, 1H), 8.04 (br, 1H).
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([OH:29])C>>[OH:29][C:16]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]1[N:14]=[CH:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:2]=1
Reactant: CCO
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: Nc1ccccc1-c1ccccc1
Product: OC1(c2ccccc2)C=CC=CC1N=Cc1cccc2ccccc12
Temperature: 70 °C

Procedure:
3.44 g (20.0 mmol) of 2-hydroxy-1-naphthaldehyde was dissolved in 50 ml ethanol under heating, and 3.38 g (20.0 mmol) of 2-aminobiphenyl was added. After stirring under reflux at 70° C. for 1 hour, completion of the reaction was confirmed by TLC. The solution was concentrated with an evaporator to about 30 ml, whereupon a crystal was formed, which was filtered by Kiriyama funnel. Drying under reduced pressure at 25° C. for 24 hours gave 2-hydroxy-1-naphthylmethylidene-2-phenylaniline (hereinafter, also referred to as “HNBP”) as a yellow crystal (5.62 g, 87%).