Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=2)[S:31]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:29]=[C:30]1[NH:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:41][CH2:42][C:43]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([N:15]5[CH:19]=[CH:18][N:17]=[CH:16]5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:44])=[CH:46][CH:47]=2)[S:31]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-n3ccnc3)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-n3ccnc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 90.7 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-{2-amino-5-[4-(imidazole-1-yl)phenoxy]phenyl}-N-methylcarbamate (1.14 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.93 g), diethyl cyanophosphonate (0.54 g), triethylamine (0.33 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.75 g).
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH:8]=[O:9]
Reactant: Clc1ccc(CBr)cc1
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccc(Cl)cc2)c(Cl)c1
Temperature: 150 °C

Procedure:
To acetonitrile (15.0 mL) were added 3-chloro-4-hydroxy-benzaldehyde (29, 0.6 g, 4 mmol), 4-chlorobenzyl bromide (22, 1.2 g, 6 mmol), and potassium carbonate (0.9 g, 7 mmol). The reaction was heated to 150° C. for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate:hexanes) (31, 0.85 g, 76%).
Reaction SMILES: Cl.[C:2]1([N:11]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]2)[C:3]2[N:4]([CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[C:17]1([C:23]2[O:27][N:26]=[C:25]([C:28](O)=[O:29])[N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:17]1([C:23]2[O:27][N:26]=[C:25]([C:28]([NH:16][C@H:13]3[CH2:14][CH2:15][N:11]([C:2]4[C:3]5[N:4]([CH:8]=[CH:9][CH:10]=5)[CH:5]=[CH:6][N:7]=4)[CH2:12]3)=[O:29])[N:24]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N[C@H]1CCN(c2nccn3cccc23)C1
Reactant: O=C(O)c1noc(-c2ccccc2)n1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
To a suspension of (S)-1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-amine hydrochloride salt (90 mg, 0.32 mmol) and 5-phenyl-1,2,4-oxadiazole-3-carboxylic acid (58 mg, 0.3 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (120 mg, 0.31 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue was purified by silica gel flash chromatography (2 to 5% MeOH in CH2Cl2 as eluent) followed by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 15 mg of the title compound (18% yield) as white solid. MS: (ES) m/z found 374.1.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[O:14][C:13]([CH2:17][F:18])([CH2:15][F:16])[CH:12]=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]=2[CH:24]=1.S(=O)(=O)(O)O.[I-:30].[K+]>CCCCCC.C(OCC)(=O)C.O.C(Cl)Cl>[F:16][CH2:15][C:13]1([CH2:17][F:18])[CH:12]=[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]2[CH:24]=[C:6]([I:30])[CH:7]=[CH:8][C:9]=2[O:14]1
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(N)cc21
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
A mixture of 1.09 g of sodium nitrite, 10 ml of methylene chloride and 10 ml of water was added to a mixture of 4.0 g of ethyl 6-amino-2,2-bisfluoromethyl-2H-1-benzopyran-4-carboxylate, 1.66 g of sulfuric acid and 40 ml of water under ice cooling, followed by stirring under ice cooling for 10 minutes. Further, a mixture of 2.85 g of potassium iodide and 5 ml of water was added to the reaction mixture, followed by stirring at room temperature for 1.5 hour. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was washed with a 20% aqueous solution of sodium sulfite and a brine and then dried over sodium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (an eluting solvent, ethyl acetate:hexane=1:1) to obtain 3.67 g of ethyl 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylate having a melting point of 89°-90° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21]Cl)[CH3:18].[I-].[K+]>CC(C)=O>[CH2:17]([N:19]([CH2:24][CH3:25])[C:20](=[O:23])[CH2:21][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2)[CH3:18]
Reactant: CCN(CC)C(=O)CCl
Reactant: Oc1cccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)C(=O)COc1cccc2cc[nH]c12
Yield: 88.7 %

Procedure:
To a solution of 7-hydroxyindole (2.65 g, 20 mmol) in acetone (20 ml) are added potassium carbonate (3.32 g), chloroacetic acid diethylamide (3.29 g, 22 mmol) and potassium iodide (0.33 g), and the mixture is refluxed for 4 hours. After cooling with ice, the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure to remove the solvent. To the residue are added chloroform (40 ml) and water (20 ml), and the mixture is stirred. The chloroform layer is separated, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and isopropyl ether (100 ml) is added to the residue. The precipitated crystals are collected by filtration, and dried to give the title compound N,N-diethyl-2-(1H-indol-7-yloxy)acetamide (4.37 g, yield: 89%) as white crystals.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:34]2[C:43]3[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=3)[N:37]=[CH:36][CH:35]=2)[OH:33])=[CH:28][CH:27]=1.[CH3:46][C:47]1[N:51]([CH2:52][CH2:53][CH3:54])[N:50]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49](=[O:61])[C:48]=1[C:62](O)=[O:63].C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>CN(C=O)C.ClCCl>[OH:33][CH:32]([C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=2)[N:37]=[CH:36][CH:35]=1)[C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:62]([C:48]2[C:49](=[O:61])[N:50]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[N:51]([CH2:52][CH2:53][CH3:54])[C:47]=2[CH3:46])=[O:63])=[CH:31][CH:30]=1
Reactant: COc1ccc2c(C(O)c3ccc(N)cc3)ccnc2c1
Reactant: CCCn1c(C)c(C(=O)O)c(=O)n1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCn1c(C)c(C(=O)Nc2ccc(C(O)c3ccnc4cc(OC)ccc34)cc2)c(=O)n1-c1ccccc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 90.7 %

Procedure:
In a 10 mL sealed tube under N2, were dissolved HATU (250 mg, 658 μmol), (4-aminophenyl)(7-methoxyquinolin-4-yl)methanol (123 mg, 439 μmol), 5-methyl-3-oxo-2-phenyl-1-propyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (143 mg, 548 mmol) and K2CO3 (182 mg, 1316 mmol) in 2 mL of DMF at rt. After 10 h, the reaction mixture was heated at 60° C. for 3 h and then diluted with dichloromethane, and treated with aqueous NaOH (1N). The aqueous phase was extracted with dichloromethane, and then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO, dichloromethane:MeOH 100:0 to 90:10) to afford N-(4-(hydroxy(7-methoxyquinolin-4-yl)methyl)phenyl)-5-methyl-3-oxo-2-phenyl-1-propyl-2,3-dihydro-1H-pyrazole-4-carboxamide (208 mg, 90.7% yield) as an off-white solid. MS (ESI pos. ion) m/z: 523 (MH+). Calc'd exact mass for C31H30N4O4: 522. 1H NMR (400 MHz, DMSO-d6) 10.67 (s, 1 H), 8.83 (d, J=4.55 Hz, 1 H), 8.05 (d, J=9.35 Hz, 1 H), 7.53-7.61 (m, 3 H), 7.46-7.52 (m, 3 H), 7.36-7.44 (m, 3 H), 7.31 (d, J=8.59 Hz, 2 H), 7.16 (dd, J=9.16, 2.72 Hz, 1 H), 6.32 (d, J=4.42 Hz, 1 H), 6.15 (d, J=4.29 Hz, 1 H), 3.88 (s, 3 H), 3.79 (t, J=7.20 Hz, 2 H), 2.71 (s, 3 H), 1.33-1.41 (m, 2 H), 0.66 (t, J=7.39 Hz, 3 H).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:25])[CH2:8][CH:7]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][C:16]([C:19](Cl)=[O:20])=[CH:17][CH:18]=[C:11]3[C:10]2=[O:22])[CH2:6][C:5]([CH3:24])([CH3:23])[NH:4]1.[CH2:26]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl.O.CN(C)C=O>[CH3:2][C:3]1([CH3:25])[CH2:8][CH:7]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][C:16]([C:19]([N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])=[CH:17][CH:18]=[C:11]3[C:10]2=[O:22])[CH2:6][C:5]([CH3:24])([CH3:23])[NH:4]1
Reactant: CC1(C)CC(N2C(=O)c3ccc(C(=O)Cl)cc3C2=O)CC(C)(C)N1
Reactant: CCCCNCCCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1ccc2c(c1)C(=O)N(C1CC(C)(C)NC(C)(C)C1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 125 ml reaction flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere were placed 5.0 g (0.013 mol) of acid chloride of Example 2 and 50 ml of 2% dimethylformamide in methylene chloride. This mixture was stirred during the addition of 1.7 g (0.013 mol) of di-n-butylamine accompanied by a 10° C. exotherm. The reaction mixture was cooled to ambient temperature and 2.8 g (0.028 mol) triethylamine were added, producing an exotherm of about 10° C. The reaction was cooled to room temperature and allowed to stir for 1 hour, then transferred to a separatory funnel with 50 ml methylene chloride and 50 ml water. Upon shaking, an emulsion formed which was broken by the addition of 25 ml of 5% sodium hydroxide. The phases were separated and the organic phase was further extracted with three 50 ml portions of 5% sodium hydroxide and three 50 ml portions of water. The organic solution was dried with anhydrous magnesium sulfate and the solvent stripped using aspirator and high vacuum systems. The product was 5.0 g of a yellow liquid. The infrared spectrum (between salt plates) showed two carbonyl absorptions at 1718 cm-1 (imide) and 1642 cm-1 (amide). The NMR spectrum showed the anticipated aromatic ring (7.5-8.0 ppm, multiplet, 3H), the amide methylene hydrogens (2.9-3.8 ppm, broad doublet, 4H) and the HALS group [4.4-4.9 ppm, multiplet, 1H; 0.5-2.3 ppm, several multiplets including two singlets (1.2 and 1.3 ppm)].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C:8](=[C:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:24]=[CH:23]/[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: Oc1ccc(C(=C2CCOCC2)c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Temperature: 160 °C
Reaction time: 0.08 h
Yield: 58.9 %

Procedure:
4-[(4-Bromophenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenol (46) (0.106 g, 0.307 mmole) was dissolved in DMF (1 mL). tert-Butyl acrylate (0.090 mL, 0.614 mmole), P(o-tolyl)3 (0.0099 g, 0.0325 mmole) and Et3N (0.130 mL, 0.933 mmole) were added followed by Pd(OAc)2 (0.0037 g, 0.0165 mmole). The mixture was heated to 160° C. in a microwave synthesizer for 30 min then was cooled to RT. Water (20 mL) was added and the mixture was extracted with Et2O (3×10 mL). The organics were dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (Isco Sg100c, RediSep 12 g cartridge, 15% EtOAc:hexanes for 5 min, 15% to 40% EtOAc:hexanes over 15 min, 40% EtOAc:hexanes for 5 min to yield 0.071 g (59%) of 47 as a white solid. 1H NMR (CDCl3): δ 7.55 (d, J=16.0 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.10 (d, J=8.1 Hz, 2H), 6.97 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.5 Hz, 2H), 6.32 (d, J=16.0 Hz, 1H), 5.01 (s, 1H), 3.74 (m, 4H), 2.40 (dd, J=11.1, 5.6 Hz, 4H), 1.53 (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[F:28][C:29]([F:46])([F:45])[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37]([C:42](Cl)=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:32][CH:31]=1>N1C=CC=CC=1>[F:28][C:29]([F:45])([F:46])[C:30]1[CH:31]=[CH:32][C:33]([C:36]2[C:37]([C:42]([N:1]3[CH:5]=[CH:4][C:3]([C:6]4[CH:11]=[CH:10][C:9]([C:12]([N:14]5[C:20]6[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=6[CH2:18][N:17]6[CH:25]=[CH:26][CH:27]=[C:16]6[CH2:15]5)=[O:13])=[CH:8][CH:7]=4)=[N:2]3)=[O:43])=[CH:38][CH:39]=[CH:40][CH:41]=2)=[CH:34][CH:35]=1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: c1ccncc1
Product: O=C(c1ccc(-c2ccn(C(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)n2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 48.9 %

Procedure:
In the manner of Example 32, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.71 g) in dry pyridine (20 ml) and 4′-trifluoromethyl-2-biphenylcarbonyl chloride (0.71 g), the title compound (0.59 g) was obtained as an amorphous solid, MS, m/z: 602 (M)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH2:9][NH2:10])=[N:7][CH:8]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C1(C)C=CC=CC=1>[Br:2][C:3]1[CH:4]=[C:5]([Cl:11])[C:6]([CH2:9][N:10]2[C:15](=[O:16])[C:14]3[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:17])=[N:7][CH:8]=1
Reactant: NCc1ncc(Br)cc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1ncc(Br)cc1Cl
Yield: 50.8 %

Procedure:
To a stirred solution of (5-bromo-3-chloropyridin-2-yl)methanamine hydrochloride (0.3 g, 1.4 mmol) in toluene (40 mL) was added TEA (0.41 g, 4.08 mmol) and phthalic anhydride (0.24 g, 1.63 mmol), and the reaction mixture was heated at reflux for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-30% EtOAc in hexane) to afford the title compound as a white solid (0.25 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.45 (s, 1H), 7.88 (m, 2H), 7.74 (m, 2H), 4.56 (m, 2H); ESIMS m/z 349 ([M−H]−); IR (thin film) 3307, 1665, 1114, 813 cm−1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:26]=[C:25]2[C:27]3=[C:28]4[C:18]([CH:19]=[CH:20][CH:21]=[C:22]4[CH:23]=[CH:24]2)=[CH:17][CH:16]=[C:15]3[C:14]=1[O:29]C)=[O:12].C(S)CCCCCCCCCCC.[OH-].[K+].Cl>CN(C)C=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([C:13]1[CH:26]=[C:25]2[C:27]3=[C:28]4[C:18]([CH:19]=[CH:20][CH:21]=[C:22]4[CH:23]=[CH:24]2)=[CH:17][CH:16]=[C:15]3[C:14]=1[OH:29])=[O:12]
Reactant: COc1c(C(=O)c2ccc3ccccc3c2)cc2ccc3cccc4ccc1c2c34
Agent: CCCCCCCCCCCCS
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2ccccc2c1)c1cc2ccc3cccc4ccc(c1O)c2c34
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The synthesized 2-naphthoyl methoxy pyrene (30.9 g, 0.08 mol), 1-dodecanethiol (48.58 g, 0.24 mol), potassium hydroxide (16.8 g, 0.3 mol), and N,N-dimethylformamide (350 g) were put in a flask and then agitated at 100° C. for 2 hours. The reaction mixture was cooled down to ambient temperature and agitated and then neutralized to about pH 7 by adding a 10% hydrogen chloride (hydrochloric acid) solution thereto. Then, the resultant was extracted by using ethyl acetate, obtaining 2-naphthoyl hydroxy pyrene.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])(=[O:27])=[O:26])=[C:12]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:5]1=[O:39].Cl>CO.O1CCCC1.O>[CH3:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:27])=[O:26])=[C:12]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[S:13][C:7]=2[N:6]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:5]1=[O:39]
Reactant: COC(=O)CCCS(=O)(=O)c1c(Cc2cccc3ccccc23)sc2c1c(=O)n(C)c(=O)n2CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)(=O)CCCC(=O)O)c(Cc3cccc4ccccc34)sc21
Reaction time: 4 h
Yield: 28.7 %

Procedure:
Sodium hydroxide solution (1M, 1 ml) was added to a stirred suspension of methyl 4-[(1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-5-yl)sulfonyl]butanoate (0.10 g) in methanol (3 ml) and tetrahydofuran (3 ml). After 4 hours, the reaction mixture was diluted with water (20 ml), acidified with hydrochloric acid (2M) and extracted with ethyl acetate (2×30 ml). The organic extracts were evaporated under reduced pressure. The residue was partitioned between ether (30 ml) and aqueous sodium hydroxide solution (0.1M, 30 ml). The aqueous phase was acidified with hydrochloric acid (2M) and extracted with ethyl acetate (2×30 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was triturated with ethyl acetate/hexane to give the title compound (0.028 g).
Reaction SMILES: S(Cl)(Cl)=O.CC1SC(C(O)=O)=CC=1.CC1SC(C(Cl)=O)=CC=1.[CH3:23][C:24]1[S:28][C:27]([C:29]([N:31]=[C:32]=[S:33])=[O:30])=[CH:26][CH:25]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][C:50]=1[F:56]>C(O)C.C1(C)C=CC=CC=1>[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH:53][C:32]([NH:31][C:29]([C:27]2[S:28][C:24]([CH3:23])=[CH:25][CH:26]=2)=[O:30])=[S:33])=[CH:51][C:50]=1[F:56]
Reactant: Cc1ccc(C(=O)N=C=S)s1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: Cc1ccc(C(=O)Cl)s1
Agent: Cc1ccc(C(=O)O)s1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)s4)cc3F)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 5-methyl-2-thiophenecarboxylic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 5-methyl-2-thiophenecarbonyl isothiocyanate was prepared using the resultant 5-methyl-2-thiophenecarbonyl chloride as a starting compound according to the description of the literature. 5-Methyl-2-thiophenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 62%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([O:14][C:15]([NH:17][C@H:18]([C:27]([OH:29])=O)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:16])([CH3:13])[CH3:12].[NH2:30][C@H:31]([C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34].CC1C=CC(S(O)(=O)=O)=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>C(Cl)Cl>[C:11]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]([NH:30][C@@H:31]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])=[O:29])=[O:16])([CH3:10])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 100 %

Procedure:
Referring to FIG. 45, DIPEA (2 mL, 12 mmol, 2.7 eq) was added to a mixture of Boc-HoPhe-OH (1.25 g, 4.4 mmol, 1 eq). H-Leu-OBn.TsOH (1.75 g, 4.5 mmol, 1.0 eq) and HATU (2 g, 5 mmol, 1.1 eq) in CH2Cl2 (50 mL) and the mixture was stirred for four hours at RT. The mixture was poured into 0.5N aq. HCl and extracted twice with CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-30% EtOAc in heptanes) and product (2.7 g, 100%) was isolated as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])[C:5]([C:13]#[N:14])=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.O>[C:13]([C:5]1[C:6]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[N:7][C:2]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)=[C:3]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([CH:22]([CH3:24])[CH3:23])[N:16]=2)[N:4]=1)#[N:14]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2Cl)ccc1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1nc(-c2nc(C#N)c(N=CN(C)C)nc2-c2ccc(F)cc2)ccc1=O
Temperature: 90 °C
Reaction time: 15 h
Yield: 103.2 %

Procedure:
A mixture of N′-[6-chloro-3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (100 mg), 4-fluorophenylboronic acid (122 mg), tetrakistriphenylphosphine palladium (10 mg) and Na2CO3 (123 mg) in dioxane (5 ml) and water (1 ml) was stirred at 90° C. for 15 hours. Water and EtOAc were added to the reaction mixture. The organic layer was separated, and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography eluted with a mixture of n-hexane and EtOAc. The fractions were concentrated in vacuo to obtain N′-[3-cyano-6-(4-fluorophenyl)-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-pyrazinyl]-N,N-dimethylimidoformamide (121 mg) as white powder.