Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[CH2:43]([N:46]1[C:50]([CH2:51][S:52]([C:54]2[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=2)=[O:53])=[CH:49][N:48]=[CH:47]1)[CH2:44][CH3:45]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:26]([CH2:27][CH2:28][CH3:29])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:58][C:57]4[CH:56]=[CH:55][C:54]([S:52]([CH2:51][C:50]5[N:46]([CH2:43][CH2:44][CH3:45])[CH:47]=[N:48][CH:49]=5)=[O:53])=[CH:60][CH:59]=4)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCn1cncc1CS(=O)c1ccc(N)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCCN3CCC)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCCN3CCC)cc1
Reaction time: 0.5 h

Procedure:
(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)aniline di-p-toluoyl-D-tartarate monohydrate (962 mg) was dissolved in ethyl acetate (6 ml) and 1N hydrochloric acid (5.04 ml), followed by separation. To the aqueous layer was added an aqueous 25% potassium carbonate solution (5.04 ml), followed by extraction with 2-propanol-ethyl acetate (1:4) three times. The organic layers were combined and washed with saturated brine, dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resulting residue tetrahydrofuran was added, after which the solvent was distilled off again under reduced pressure to give (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. Then, to a solution of 9-(4-(2-butoxyethoxy)phenyl)-1-propyl-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylic acid (500 mg) in tetrahydrofuran (10 ml) was added a drop of DMF and then thionyl chloride (0.105 ml) was added, and the mixture was stirred under nitrogen atmosphere for 30 minutes. The resulting solution was added dropwise to a solution of (−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and triethylamine (0.77 ml) in tetrahydrofuran (10 ml) at 0° C. under nitrogen atmosphere. The mixture was returned to room temperature and stirred for 3 hours, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous acetic acid solution twice, with aqueous saturated sodium bicarbonate solution twice and with saturated brine once, after which the resultant was dried with magnesium sulfate. After distilling off the solvent under reduced pressure, the resultant was separated and purified with a basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate) to give (−)-9-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxamide (302 mg) (Compound 25) as a yellow amorphous material.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]([OH:19])=O)[C:6]=2[CH:20]=1.C1C=CC2N(O)N=[N:33][C:31]=2C=1.CCN=C=NCCCN(C)C.CN>CN(C=O)C.CCN(CC)CC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[O:9][C:5]3[CH:4]=[C:3]([N:21]4[CH2:25][CH2:24][CH2:23][C:22]4=[O:26])[CH:2]=[CH:20][C:6]=3[C:7]=2[C:17]([NH:33][CH3:31])=[O:19])=[CH:11][CH:12]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)c(Br)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N3CCCC3=O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A solution of 5-bromo-2-(4-fluorophenyl)-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxylic acid (280 mg, 0.67 mmol), HOBT (150 mg, 1.11 mmol) and EDCI (280 mg, 1.47 mmol) in dry DMF (2 mL) was allowed to stir at room temperature for 1 hour. Then Et3N (0.2 mL) and CH3NH2 (HCl salt, 100 mg, 1.48 mmol) was added to the mixture, and the reaction was allowed to stir for about 15 hours. After being concentrated in vacuo, water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried and concentrated in vacuo and the resulting resulting residue was purified using column chromatography (eluted with petroleum ether:EtOAc=1:1) to provide 5-bromo-2-(4-fluorophenyl-N-methyl-6-(2-oxopyrrolidin-1-yl)benzofuran-3-carboxamide (220 mg, yield: 73%), which was also prepared from 6-amino-5-bromo-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide and 4-chlorobutanoyl chloride using the method described in step 1 above. 1H-NMR (CDCl3, 400 MHz) δ 7.94 (s, 1H), 7.82˜7.86 (m, 2H), 7.32 (s, 1H), 7.09˜7.14 (m, 2H), 6.29 (s, 1H), 3.75˜3.78 (m, 2H), 2.97 (d, J=4.8 Hz, 3H), 2.56˜2.60 (m, 2H), 2.24˜2.26 (m, 2H). MS (M+H)+: 431/433.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl[Si](C)(C)C.[C:23]([N:26]1[CH2:33][C:32](=[O:34])[CH2:31][C@H:27]1[C:28](O)=[O:29])(=[O:25])[CH3:24].CN1CCOCC1.ClC(OC)=O.O=C1N=CC=CC1C(O)=O>ClCCl.C(N(CC)CC)C>[C:23]([N:26]1[CH2:33][C:32](=[O:34])[CH2:31][C@H:27]1[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)=[O:29])(=[O:25])[CH3:24]
Reactant: CC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Agent: COC(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(O)C1C=CC=NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)N1CC(=O)C[C@H]1C(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A suspension of 8.0 g (34.6 mM) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 10 g (99 mM of triethylamine, and 560 ml of dichloromethane was stirred at room temperature for 11.3 g (0.104 mol) of chlorotrimethylsilane was added and solution was observed in 30 min. A suspension of 11.9 g (0.069 mol) of N-acetyl-4-oxo-L-proline in 160 ml of dichloromethane was stirred at -10° and 6.9 g (0.069 mol) of N-methylmorpholine was added followed by 6.6 g (0.069 mol) of methyl chloroformate over a ten min period. The reaction was stirred at -10° for 30 min and cooled to -30°. The above oxonicotinic acid solution was added in aliquots keeping the temperature below -5°, and the reaction mixture was stirred in an ice bath overnight, allowing the bath to come to room temperature. The reaction was evaporated to a gum and water was added. The resulting solid was filtered, dried, and digested with hot ethanol. The purified solid was filtered and dried to give 12 g of 6-[4-(N-acetyl-4-oxo-L-prolylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid;
Reaction SMILES: C([N:8]1[C@@H:12]([C:13]#[CH:14])[CH2:11][O:10]C1(C)C)(OC(C)(C)C)=O.[F:17][C:18]1[C:19](I)=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22](=[O:27])/[C:21]/2=[CH:28]\[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35].O>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.FC(F)(F)C(O)=O.C(Cl)Cl.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.[Cu]I>[NH2:8][C@H:12]([CH2:11][OH:10])[C:13]#[C:14][C:19]1[C:18]([F:17])=[CH:26][CH:25]=[C:24]2[C:20]=1/[C:21](=[CH:28]/[C:29]1[NH:30][CH:31]=[CH:32][C:33]=1[O:34][CH3:35])/[C:22](=[O:27])[NH:23]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](N)CO)c21
Reaction time: 2 h

Procedure:
Using Method C above, (S)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine (140 mg, 0.62 mmol) (Example 93A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 0-50% THF in hexanes gradient. The intermediate that was obtained from this operation was directly dissolved in 5 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-4-(3-Amino-4-hydroxy-1-butynyl)-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 22 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[I:11]N1C(=O)CCC1=O.IC1C=C(Br)C=C(C=O)C=1O.BrC1C=C(C=O)C(O)=CC=1.[I-].[K+].CC1C=CC(S(NCl)(=O)=O)=CC=1>CN(C=O)C.C(#N)C>[I:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[OH:10]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=C1CCC(=O)N1I
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: O=Cc1cc(Br)cc(I)c1O
Agent: O=Cc1cc(Br)ccc1O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(I)c1O

Procedure:
Scheme II illustrates methodology useful for preparing the ethyl N-gly-amino-3-(3,5-dihalo-2-hydroxy) phenyl propionate portion of the present invention which can be coupled to the tetrahydropyrimidinobenzoic acid moiety. Briefly, 3,5-halo substituted salicylaldehydes may be prepared by direct halogenation as, for example, would be the case where 5-bromosalicylaldehyde is slurried in acetic acid and an equivalent or more of chlorine is added to yield 3-chloro-5-bromo-2-hydroxybenzaldehyde. Some product precipitates and can be recovered by filtration. The remainder may be recovered by diluting the filtrate with water and isolating the precipitate. Combining the solids and drying gives 3-chloro-5-bromo-2-hydroxybenzaldehyde. 3-iodo-5-chlorosalicycaldehyde may be prepared by reacting 5-chlorosalicylaldehyde with N-iodosuccinimide in DMF and subjecting the reaction mixture to usual work-up conditions. 3-iodo-5-bromosalicylaldehyde may be prepared by reacting 5-bromosalicylaldehyde in acetonitrile with potassium iodide and chloramine T. Work-up gives a material that when treated with hexanes gives the desired 3-iodo-5-chlorosalicylaldehyde.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([CH:7]1[CH2:14][CH:13]2[CH:15]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][N:24]=4)[C:18]([CH3:32])([CH3:31])[C:17]3=[O:33])[CH:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:6].CO.O>O1CCCC1>[C:29]([C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH:19]2[CH2:20][N:16]([CH:15]3[CH:9]4[CH2:10][CH2:11][CH2:12][CH:13]3[CH2:14][CH:7]([C:5]([OH:6])=[O:4])[CH2:8]4)[C:17](=[O:33])[C:18]2([CH3:32])[CH3:31])=[N:24][CH:25]=1)#[N:30]
Reactant: COC(=O)C1CC2CCCC(C1)C2N1CC(COc2ccc(C#N)cn2)C(C)(C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(=O)N(C2C3CCCC2CC(C(=O)O)C3)CC1COc1ccc(C#N)cn1
Reaction time: 8 h

Procedure:
LiOH (0.2 g, 4.84 mmol) was added in one portion to a stirred solution of the product of Example 7E (0.532 g, 1.21 mmol) in a mixture of tetrahydrofuran (6 mL), methanol (3 mL), and water (3 mL). The resulting solution was stirred overnight, followed by partitioning with diethyl ether and water. The organic layer was washed with water and the combined water layers were acidified with NaHSO4 solution and extracted with ethyl acetate. The combined ethyl acetate phases were dried (MgSO4), filtered, and evaporated. The acid product was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:20]2[C:16](=[CH:17][N:18]([CH3:21])[N:19]=2)[C:15]([CH2:22][OH:23])=[CH:14][CH:13]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Cl:11][C:12]1[C:20]2[C:16](=[CH:17][N:18]([CH3:21])[N:19]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1
Reactant: Cn1cc2c(CO)ccc(Cl)c2n1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cn1cc2c(C=O)ccc(Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of oxalyl chloride (2.93 mL, 34.6 mmol) in 30 dichloromethane (50 mL) was added dimethyl sulfoxide (3.68 mL, 51.9 mmol) at −78° C. To the reaction mixture was added a solution of (7-chloro-2-methyl-2H-indazol-4-yl)methanol (3.40 g, 17.3 mmol) in dichloromethane (10 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (14.6 mL, 104 mmol) at −78° C., and the mixture was stirred for 30 min. The reaction mixture was warmed to room temperature, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with dichloromethane. The combined extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by recrystallization (hexane/dichloromethane) to give the title compound (3.07 g, yield 91%).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[C:19]([NH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O.C(O)C>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:27]3[CH:28]=[C:23]([NH:22][C:19](=[O:21])[CH3:20])[CH:24]=[CH:25][CH:26]=3)=[CH:3][C:4]=2[N:5]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a 100 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.5 g, 0.0045 mol—Preparation 3), 3-acetamidophenylboronic acid (0.769 g, 0.0043 mol), sodium carbonate (1.2 g, 0.0113 mol), toluene (30 mL), ethanol (30 mL) and water (10 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.159 g, 0.00022 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to provide the title compound (1.3 g, 76%). 1H NMR (300 MHz, DMSO-d6): δ 10.15 (s, 1H), 9.05 (d, J=2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 8.11 (s, 1H), 7.46-7.66 (m, 3H), 4.52 (br s, 4H), 3.81 (t, J=5.1 Hz, 4H), 2.09 (s, 3H): LC-MS (ESI): Calculated mass: 383.1; Observed mass [M+H]+: 383.8. (RT=1.31 min).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.[CH3:46][N:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][N:50]=1)[NH2:48]>C(Cl)Cl>[CH3:46][N:47]([C:49]1[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:56])[F:57])=[CH:51][N:50]=1)[NH:48][C:13]([C:10]1[CH:11]=[N:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1)=[O:15]
Reactant: CN(N)c1ccc(C(F)(F)F)cn1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(NC(=O)c1cnc(-c2ccccc2)nc1)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
To a solution of 2-phenyl-pyrimidine-5-carboxylic acid (100 mg, 0.52 mmol), 1-hydroxybenzotriazole (77 mg, 0.57 mmol), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (111 mg, 0.57 mmol) and DIPEA (0.57 mmol) in DCM (5 mL) is added N-methyl-N-(5-trifluoromethyl-pyridin-2-yl)-hydrazine (109 mg, 0.57 mmol). The reaction mixture is stirred at rt for 18 hours and then concentrated. The residue is purified by silica gel chromatography eluting with 10-75% EtOAc in heptane to afford 2-phenyl-pyrimidine-5-carboxylic acid N′-methyl-N′-[5-trifluoromethyl-pyridin-2-yl]-hydrazide as a solid (189 mg). MS: 374 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.54 (s, 3H), 6.82 (d, 1H), 7.53-7.59 (m, 3H), 7.74 (d, 1H), 8.45 (d, 2H), 8.53 (d, 2H), 9.25 (s, 2H). IC50=100 nM.
Reaction SMILES: I/[CH:2]=[CH:3]/[CH:4]([O:10][C:11]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)([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)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC=CC=1.C([Li:44])CCC>CCCCCC>[CH2:24]([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:10][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])/[CH:3]=[CH:2]/[Li:44])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: [Li]CCCC
Reactant: CCCCCC(/C=C/I)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: [Li]/C=C/C(CCCCC)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1
Temperature: -40 °C

Procedure:
to a solution of 5.26 g. of 1-iodo-3-(p-anisyldiphenylmethoxy)-trans-1-octene (Example 956) in 10 ml. of toluene, cooled to -78° C., is added under an inert atmosphere 1 molar equivalent of n-butyllithium dissolved in hexane. The reaction mixture is allowed to warm to -40° C. and is maintained at that temperature for 1 hour to yield a hydrocarbon solution of 3-(p-anisyldiphenylmethoxy)-trans-1-octenyllithium.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.[C:29]([O:33][C:34](=[O:47])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39](/[CH:43]=[CH:44]\[CH2:45][OH:46])[CH:38]=1)([CH3:32])([CH3:31])[CH3:30].[C:48]1([N:54]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:55](Cl)=[O:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[Cl-].[NH4+]>O1CCCC1>[C:29]([O:33][C:34](=[O:47])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39](/[CH:43]=[CH:44]\[CH2:45][O:46][C:55](=[O:56])[N:54]([C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:38]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc(/C=C\CO)c1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: CC(C)(C)OC(=O)COc1cccc(/C=C\COC(=O)N(c2ccccc2)c2ccccc2)c1
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
2.0 M Lithium diisopropylamide in a solution of tetrahydrofuran/heptane/ethylbenzene (0.9 mL, 1.8 mmol) was added to a stirred solution of cis-[3-(3-hydroxypropenyl)phenoxy]acetic acid tert-butyl ester (421 mg, 1.56 mmol) in tetrahydrofuran (4.5 mL) at −78° C. under an argon atmosphere. The mixture was stirred for 10 minutes and solid diphenylcarbamoyl chloride (361 mg, 1.56 mmol) was added. The mixture was allowed to reach 0-5° C. and stirred for 16 hours. Saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate (9:1), gave cis-[3-(3-diphenylcarbamoyloxypropenyl)phenoxy]acetic acid tert-butyl ester (433 mg, 60.4%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[N:9]=2)[C:5]([CH3:23])=[CH:4][N:3]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:31][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=4)[N:9]=3)[C:5]([CH3:23])=[CH:4][N:3]=2)[CH2:25][CH2:26]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Cc1cnc(F)cc1-c1cccc(NCc2cccc(F)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cnc(N[C@H]2CC[C@H](N)CC2)cc1-c1cccc(NCc2cccc(F)c2)n1
Temperature: 130 °C

Procedure:
To a solution of 2′-fluoro-N-(3-fluorobenzyl)-5′-methyl-2,4′-bipyridin-6-amine (18 mg, 0.058 mmol) and trans-cyclohexane-1,4-diamine (39.6 mg, 0.347 mmol), in NMP (0.3 mL) was added DIPEA (20 μL, 0.115 mmol). The mixture was heated at 130° C. for 48 h. The mixture was allowed to cool then diluted with water and then extracted with EtOAc (×3). The combined organics were washed with saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was purified by reverse phase preparative HPLC and then lyophallized to yield N2′-(trans-4-aminocyclohexyl)-N6-(3-fluorobenzyl)-5′-methyl-2,4′-bipyridine-2′,6-diamine (4.2 mg), LCMS (m/z): 406.3 (MH+), retention time=0.53 min as a TFA salt.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N:4][CH:3]=1.C(N)(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([CH3:12])=[N+:4]([O-:14])[CH:3]=1
Reactant: NC(N)=O
Reactant: COC(=O)c1nc(Cl)cnc1C
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nc(Cl)c[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of methyl 6-chloro-3-methylpyrazine-2-carboxylate (8.6 g, 46.1 mmol) and hydrogen peroxide urea adduct (8.1 g, 86 mmol) in dichloromethane (100 mL) was added 2,2,2-trifluoroacetic anhydride (10.9 ml, 78 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and quenched with water. The aqueous layer was extracted with DCM. The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product 5-chloro-3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (8.83 g, 43.6 mmol, 95% yield) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 8.31 (1H, s), 4.02 (3H, s), 2.65 (3H, s).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]3[N:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:27]=[CH:26][CH:25]=3)=[N:16]2)=[C:11]([F:35])[CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CO>[F:35][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[N:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18](=[O:23])[C:17]([C:24]2[N:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:27]=[CH:26][CH:25]=2)=[N:16]1
Reactant: COc1cn(-c2ccc(OCc3ccccc3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cn(-c2ccc(O)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
A mixture of 1-[4-(benzyloxy)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (5.53 g, 11.8 mmol), 10% Pd—C (50% wet, 3.0 g), THF (150 mL), and MeOH (150 mL) was hydrogenated for 1.5 h at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from MeOH/H2O to give the title compound (4.07 g, 91% yield) as a pale yellow solid: mp 223-224° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 3.75 (3H, s), 6.60 (1H, ddd, J=1.1, 2.6, 8.7 Hz), 6.73 (1H, dd, J=2.6, 12.8 Hz), 6.90-6.96 (2H, m), 7.28-7.44 (5H, m), 7.78 (1H, d, J=1.9 Hz), 8.39 (1H, d, J=1.9 Hz), 10.44 (1H, brs). LC-MS (ESI) m/z 379 [M+H]+. Anal. Calcd for C20H15FN4O3.0.5H2O: C, 62.01; H, 4.16; N, 14.46. Found: C, 62.18; H, 4.16; N, 14.49.