Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([Sn](C)(C)C)=[CH:14][CH:13]=1.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[O:10])[CH3:9])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccccc1Br
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 150 °C
Yield: 71.2 %

Procedure:
A vigorously stirred solution of 13.25 g (66 mmol) of 2'-bromoacetophenone and 22.8 g (89 mmol) of 4-methylphenyltrimethylstannane in 190 mL of dimethylformamide under a nitrogen atmosphere was treated with 8.64 g (12 mmol) of bis(triphenylphosphine)palladium(II) chloride and the resulting mixture heated at 150° C. for 6 hours. The reaction mixture was cooled, poured into water (1000 mL) and the resultant suspension extracted with ethyl ether. The combined extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (10:1) to give 9.8 g (47 mmol, 71%) of product as an oil. EI-MS: calculated for C15H14O 210: found 210 (M+). 1H NMR (200 MHz, CDCl3): 1.98 (s, 3H), 2.37 (s, 3H), 7.20 (s, 4H), 7.3-7.5 (m, 4H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][C:11]=1[O:20][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 18 h

Procedure:
Benzyl bromide (21.4 ml) was added to a stirred mixture of 2-bromo-4-trifluoromethylphenol (46.4 g) and potassium carbonate (39 g) in DMF (200 ml). After 18 h, the mixture was partitioned between diethylether and water, the organic layer washed with water, 2M sodium hydroxide solution, water, dried and the solvent evaporated under reduced pressure. Yield 58.7 g
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([OH:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)=[N+]=[N-].Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:19]=[CH:18][N:17]=1.[H-].[Na+].CCOC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:24]=[CH:23][C:22]([C:20]2[CH:21]=[CH:16][N:17]=[C:18]([O:14][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:6]=3[N:5]=[C:4]([NH2:1])[CH:13]=[CH:12]4)[CH:19]=2)=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Reactant: [N-]=[N+]=Nc1ccc2cccc(O)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ccn3)c2n1
Temperature: 180 °C

Procedure:
A mixture of 2-azido-quinolin-8-ol (0.28 g, 1.5 mmol), 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.26 g, 1 mmol), and sodium hydride (64 mg, 1.6 mmol) in DMF (2 mL) was heated in a 180° C. oil bath for 48 h. The reaction mixture was then transferred to a 5-mL tube, and irradiated in the Microwave Smith Synthesizer at 250° C. for 10 min. EtOAc and brine were added, and the aqueous layer was extracted with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The compound was purified on a Biotage 40S column (98:2 dichloromethane: MeOH) followed by recrystallization from EtOAc/hexanes to give the title compound as a light-yellow shiny crystal. MS (ESI, pos. ion) m/z: 382 (M+1). Mp: 196.5-199.5° C. Anal. Calcd for C21H14F3N3O: C, 66.14; H, 3.70; N, 11.02. Found: C, 66.18; H, 3.69; N, 11.08.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([O:24][CH3:25])[C:8]=1[CH:9]([NH:17]S(C(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].Cl.O1CCOCC1>CO>[NH2:17][CH:9]([C:8]1[C:7]([O:24][CH3:25])=[CH:6][N:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)cncc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CCCC(N)c1c(OC)cncc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) yellow solution of methyl 5-(3,5-dimethoxypyridin-4-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate (780 mg; 2.09 mmol) in MeOH (16 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (1.05 ml; 4.20 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate as a beige solid. LC-MS (conditions B): tR=0.43 min.; [M+H]+: 269.02 g/mol.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([N:9]2[C@H:13]([C:14](=[O:30])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[CH2:12][C@@H:11]([NH:31]C(=O)OCC3C=CC=CC=3)[CH2:10]2)=[O:8])=[CH:4][N:3]=[CH:2]1>[Pd].CO>[NH:1]1[C:5]([CH2:6][C:7]([N:9]2[CH2:10][C@H:11]([NH2:31])[CH2:12][C@H:13]2[C:14]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)=[O:30])=[O:8])=[CH:4][N:3]=[CH:2]1
Reactant: O=C(N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cc2cnc[nH]2)C1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cc2cnc[nH]2)C1
Reaction time: 4 h
Yield: 85.3 %

Procedure:
A flask was charged with benzyl (3R,5S)-1-(2-(1H-imidazol-5-yl)acetyl)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate (800 mg, 1.43 mmol), prepared as in Example 1, palladium on carbon (10%, 80 mg) and methanol (30 mL) and the mixture was placed under a hydrogen atmosphere at 40 psi (parr shaker). The reaction was allowed to proceed for 4 hours and the mixture was filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give (2S,4R)-1-(2-(1H-imidazol-5-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (516 mg, 1.22 mmol, 85%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20](B(O)O)[CH:21]=1>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>[CH3:7][O:6][C:4]([C:3]1[C:2]([C:18]2[CH:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])=[CH:11][CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=1)=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(Cl)ccc1OC
Yield: 55 %

Procedure:
Methyl (5′-chloro-2′-methoxy-4-nitro-2-biphenyl)carboxylate (Structure 39 of Scheme XI, Where R1=H, R2=Cl) This compound was prepared in a manner similar to that of methyl-(5′-fluoro-2′-methoxy-4-nitro-2-biphenyl)carboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (1.25 g, 4.8 mmol, 1.0 equivuiv), tetrakis(triphenylphosphine)palladium (Aldrich: 0.16 g, 0.14 mmol, 2.9 mol %), and 5-chloro-2-methoxyphenylboronic acid (1,30 g, 6.9 mmol, 1.5 equivuiv) to afford 0.85 g (55%) of methyl-5′-chloro-2′-methoxy-4-nitro-2-biphenylcarboxylate as a yellow-orange solid. Data for methyl-5′-chloro-2′-methoxy-4-nitro-2-biphenylcarboxylate: 1H NMR (400 MHz, CDCl3): 8.73 (d, J=2.4, 1H); 8.38 (dd, J=8.5, 2.5, 1H); 7.49 (d, J=8.5, 1H); 7.36 (dd, J=8.7, 2.5, 1H); 7.23 (d, J=2.5, 1H); 6.85 (d, J=8.7, 1H); 3.76 (s, 3H); 3.70 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[C:19](=[O:24])[C:20]([O:22][CH3:23])=[O:21].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C1(C)C=CC=CC=1.C(#N)C.C(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:18])[C:3]=1[C@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(=O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1Cl
Temperature: -40 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
To a stirred solution of methyl 2-(7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (1.8 g, 4.94 mmol) in anhydrous toluene (30 mL) was added 1.1M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole/toluene (1.797 mL, 1.977 mmol). The mixture was cooled to −40° C. (acetonitrile/dry ice bath) and a solution of 50% (by weight) catechoborane in toluene (1.695 mL, 6.92 mmol) was added over 30 min. After stirred at −45-−35° C. for 2 hrs, the reaction mixture was stirred at −25° C.-−15° C. for additional 1 h. Saturated Na2CO3 solution (20 mL) was added to quench the reaction. The mixture was stirred vigorously for 30 min and extracted with EtOAc. The organic layer was washed with saturated Na2CO3 solution and dried (Na2SO4). The solvent was evaporated and the residue was purified by silica gel chromatography (15-50% EtOAc/hexane) to afford (1.5 g, 83%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.05-7.97 (m, 1H), 7.88 (dt, J=6.7, 1.8 Hz, 1H), 7.44-7.38 (m, 2H), 6.93 (s, 1H), 5.76 (s, 1H), 3.84 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [H-].[Na+].Br[CH:4]([CH3:24])[CH2:5][CH2:6][C:7]([NH:9][N:10]=[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].C(OCC)(=O)C>O1CCCC1>[C:12]1([C:11](=[N:10][N:9]2[CH:4]([CH3:24])[CH2:5][CH2:6][C:7]2=[O:8])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(Br)CCC(=O)NN=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CCC(=O)N1N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
At 0° C., 2.7 g (68.0 mmol) of sodium hydride are added a little at a time to a solution of 33.0 g (68.0 mmol) of 4-bromo-N′-(diphenylmethylene)pentane hydrazide in 200 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 16 h, and ethyl acetate/saturated aqueous NH4Cl solution is then added. The organic phase is separated off and the aqueous phase is extracted with 3×250 ml of ethyl acetate. The combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 17.8 g (89%) of the desired product; log P(HCOOH): 2.73; 1H-NMR (ppm): δ (DMSO-d6)=1.22 (d, 3H), 2.05-2.15 (m, 4H), 3.86 (m, 1H), 7.24-7.26 (m, 2H), 7.40-7.43 (m, 4H), 7.48-7.53 (m, 4H); LC-MS: m/z=279 [M+H]+
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].N[C:11]1[C:12](C)=CC=C[CH:16]=1>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:11]([CH3:12])[CH3:16])[C:4]=1[NH2:5])[CH3:2]
Reactant: Cc1ccccc1N
Reactant: CCc1ccccc1N
Product: CCc1cccc(C(C)C)c1N

Procedure:
The procedure of Example 6 was repeated, except that 2-ethylaniline was substituted for ortho-toluidine. Table 5 sets forth the reaction conditions and product selectivity.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:12]([O-])([O-])OCC>>[S:8]1(=[O:9])(=[O:10])[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]=2[NH:1][CH:12]=[N:11]1
Reactant: Nc1ncccc1S(N)(=O)=O
Reactant: CCOC([O-])[O-]
Product: O=S1(=O)N=CNc2ncccc21

Procedure:
A mixture of 2 g of 2-aminopyridine-3-sulfonamide (Preparation 6) and 20 cm3 of ethyl orthoformate is brought to reflux for 1 hour. After cooling, the crystalline precipitate obtained is collected on a filter and washed with ether.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:41])([F:40])[C:9]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([OH:21])=O)[CH2:14][C@@H:13]1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.CN(C=O)C.[Si]([CH:51]=[N+:52]=[N-:53])(C)(C)C>C(Cl)Cl.C1COCC1.CC#N>[F:41][C:8]([F:40])([F:7])[C:9]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][C:19]([CH:51]=[N+:52]=[N-:53])=[O:21])[CH2:14][C@@H:13]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=1
Reactant: O=C(O)C[C@H]1CCN(Cc2cc(C(F)(F)F)ccc2C(F)(F)F)[C@@H](c2ccc(C(F)(F)F)cc2)C1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC#N
Product: [N-]=[N+]=CC(=O)C[C@H]1CCN(Cc2cc(C(F)(F)F)ccc2C(F)(F)F)[C@@H](c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
Oxalyl chloride (65 μl, 0.77 mmol) was added to a suspension of (±)-cis-{1-[2,5-bis(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetic acid (Example 56) (157 mg, 0.30 mmol) in DCM (10 ml). DMF (5 μl) was added and the pale yellow solution obtained was stirred at RT under N2, for 2 h. The yellow solution was concentrated in vacuo and oxalyl chloride removed by azeotroping with toluene to yield a yellow solid. This was dissolved in THF/MeCN (5 ml/5 ml) cooled to 0° C. and TMS diazomethane (0.3 ml, 2M in hexane, 0.60 mmol) was added under N2. The mixture was stirred for 5 h at 0° C. and then at RT for 16 h. The yellow solution was evaporated in vacuo to give a pale brown gum (164 mg). The crude product was purified by chromatography (silica, 10% EtOAc/isohexane) to give a clear gum (91 mg, 56%). M/Z (ES+) 488 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:46][CH2:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:56](=[O:68])[C:57]2[CH:62]=[C:61]([F:63])[CH:60]=[CH:59][C:58]=2[C:64]([F:67])([F:66])[F:65])[CH2:52][CH2:51]1)=[O:49]>CN(C=O)C.O>[F:63][C:61]1[CH:60]=[CH:59][C:58]([C:64]([F:66])([F:65])[F:67])=[C:57]([CH:62]=1)[C:56]([N:53]1[CH2:54][CH2:55][N:50]([C:48](=[O:49])[CH2:47][NH:46][C:21]([C:19]2[N:18]=[N:17][N:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:23])[CH2:51][CH2:52]1)=[O:68]
Reactant: O=C(O)c1cn(-c2ccccc2)nn1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cn(-c2ccccc2)nn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 83.1 %

Procedure:
DIPEA (140 mg, 0.19 mL, 1.08 mmol) was added to a stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid (40 mg, 0.21 mmol) in DMF (5 mL). HOBT (32 mg, 0.23 mmol) and EDCI (102 mg, 0.53 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (90 mg, 0.24 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated out to afford 88 mg (82.2% yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 100%. 1H NMR (DMSO-d6): δ 9.4 (s, 1H), 8.76 (t, 1H), 8.04 (m, 3H), 7.7-7.46 (m, 5H), 4.3 (d, 2H), 3.8-3.4 (m, 6H), 3.28 (d, 2H).
Reaction SMILES: C(OC1C=CN(C2C=CC(O)=CC=2)C(=O)C=1)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:32](=[O:43])[CH:31]=2)=[CH:26][CH:25]=1.[F:46][CH2:47][C@@H:48]1[CH2:52][CH2:51][CH2:50][N:49]1[CH2:53][CH2:54]O>>[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][O:29][C:30]2[CH:35]=[CH:34][N:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:54][CH2:53][N:49]4[CH2:50][CH2:51][CH2:52][C@H:48]4[CH2:47][F:46])=[CH:38][CH:37]=3)[C:32](=[O:43])[CH:31]=2)=[CH:44][CH:45]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)ccn1-c1ccc(O)cc1
Reactant: OCCN1CCC[C@H]1CF
Agent: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Product: O=c1cc(OCc2ccc(F)cc2)ccn1-c1ccc(OCCN2CCC[C@H]2CF)cc1

Procedure:
Step (3) of Example 12 was repeated except that 4-benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one and 2-(1-pyrrolidine)ethanol were replaced with 4-(4-fluorobenzyloxy)-1-(4-hydroxyphenyl)-1H-pyridin-2-one (Step (2) of Example 28) and 2-[(S)-2-fluoromethyl-1-pyrrolidinyl]ethanol, respectively, to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[C:12]([NH:14][C@H:15]([C:19]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=2[N:20]=1)[CH2:16][CH2:17][CH3:18])=[O:13])[C:6](O)=[O:7].CN(C(O[N:39]1N=NC2C=[CH:43][CH:44]=[CH:45][C:40]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CC=CC1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:19]([C@@H:15]([NH:14][C:12](=[O:13])[C:11]3[CH:10]=[CH:9][C:5]([C:6]([N:39]4[CH2:40][CH:45]=[CH:44][CH2:43]4)=[O:7])=[CH:4][C:3]=3[C:2]([F:1])([F:29])[F:30])[CH2:16][CH2:17][CH3:18])=[N:20][C:21]=2[CH:27]=1
Reactant: CCC[C@H](NC(=O)c1ccc(C(=O)O)cc1C(F)(F)F)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C1=CCNC1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)cc1C(F)(F)F)c1nc2cc(Cl)ccc2[nH]1
Yield: 64 %

Procedure:
Prepared analogously to Example 1g from (1S)-3-trifluoromethyl-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)butyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and 3-pyrroline in tetrahydrofuran. Yield: 64%; Rf value: 0.47 (silica gel: dichloromethane/ethanol=9:1); C24H22ClF3N4O2 (490.911); mass spectrum: (M+H)+=491/493 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH:30][NH2:31])=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:32])[CH:3]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]3[O:29][C:33](=[O:34])[NH:31][N:30]=3)=[CH:22][CH:21]=2)=[C:4]([CH3:32])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)NN)cc3)c(-c3ccc(F)cc3C)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(/C=C/c4n[nH]c(=O)o4)cc3)c(-c3ccc(F)cc3C)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylohydrazide (38 mg, 0.085 mmol) was dissolved in THF (2 mL). The vial was charged with 1,1′-carbonyldiimidazole (16.49 mg, 0.102 mmol) and the reaction was stirred at room temperature for 1 h. The reaction mixture was acidified with 6 N HCl which caused a precipitate to form. The mixture was diluted with DCM to dissolve the precipitate. The organic phase was collected (phase separator) and concentrated to afford (E)-5-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1,3,4-oxadiazol-2(3H)-one (31 mg, 0.065 mmol, 77% yield) as an off white solid which was used without further purification. LC/MS (m/z, M-H): 473.0
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=[O:35].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(O)=O.[Na+]>O1CCOCC1.[Cu]I>[F:28][C:3]1[C:2]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]2=[O:35])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1
Reactant: O=C1CCCCN1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1cn(-c2cccc(N3CCCCC3=O)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 22.8 %

Procedure:
A suspension of 1-(3-bromo-2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (221 mg, 0.500 mmol), 2-piperidone (59.5 mg, 0.600 mmol), N,N′-dimethylethylenediamine (0.022 mL, 0.200 mmol), CuI (19 mg, 0.10 mmol) and K3PO4 (212 mg, 1.00 mmol) in 1,4-dioxane (2.0 mL) was stirred at 90° C. under Ar atmosphere. The reaction mixture was poured into 5% NaHCO3 aqueous solution (20 mL) and extracted with AcOEt (20 mL×3). The combined organic phase was washed with brine (40 mL), dried with MgSO4, and evaporated. The residue was purified by basic silica gel column chromatography (AcOEt/hexane=50%-100%) to give the title compound (52.3 mg, 23% yield) as an amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 1.97 (4H, t, J=3.4 Hz), 2.54-2.63 (2H, m), 3.56 (2H, brs), 3.88 (3H, s), 6.36 (1H, dd, J=15.5, 1.9 Hz), 7.03 (1H, dd, J=16.2, 1.5 Hz), 7.22 (1H, dd, J=14.7, 1.9 Hz), 7.29 (1H, d, J=2.3 Hz), 7.35-7.44 (2H, m), 7.40 (3H, d, J=4.5 Hz), 7.78 (1H, d, J=1.9 Hz), 7.82 (1H, d, J=2.6 Hz). LC-MS (ESI) m/z 460 [M+H]+. Anal. Calcd for C25H22FN5O3.0.5H2O: C, 64.34; H, 4.93; N, 15.00. Found: C, 64.12; H, 4.73; N, 15.13.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:23].[Na+].OO>O1CCCC1>[CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19](/[CH:13]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH:20]([O:23][C:1](=[O:9])[CH3:2])[CH3:21])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OC(C)=O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 160.9 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 6.2 g (17 mmol) of 5-octyloxy-2-(4-bromophenyl)-pyrimidine, 0.23 g (0.2 mmol) of tetrakis-triphenylphosphine-palladium, 2.4 g (60 mmol) of sodium hydroxide and 60 ml of tetrahydrofuran. Subsequently, 50 ml of a solution prepared by dissolving 20 mmol of the above-obtained E-6-acetoxy-1-heptenylcatecholborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 6 hours. After cooling the reaction mixture to room temperature, 5 ml of 10% aqueous solution of sodium hydroxide and 2 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 20 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 6.0 g (yield 78%) of 5-octyloxy-2-{4-(6-acetoxy-1-trans-heptenyl)-phenyl}-pyrimidine.