Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH2:14][CH2:15][CH:16]([OH:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH:16]([OH:29])[CH2:15][CH2:14][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: OC(CCCl)COc1cccc(C(F)(F)F)c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: OC(CCN1CCN(c2ccccn2)CC1)COc1cccc(C(F)(F)F)c1
Yield: 35.4 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 6. A mixture of 3.3 g (0.02 mole) of 1-(2-pyridyl)piperazine, 5.4 g (0.02 mole) of 4-chloro-1-(3-trifluoromethylphenoxy)-2-butanol, 6.4 g (0.06 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 2.8 g (35%) of the title compound as an off-white solid, m.p. 81°-81.5° C. Recrystallizing solvent used was isopropyl ether.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4].C1C=CC2N(O)N=[N:34][C:32]=2C=1.C(N(CC)CC)C.C(Cl)CCl>CN(C=O)C>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH:34][CH3:32])=[O:17])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(=O)NC
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Boc-Gly-Pro-Nleu-OH (0.77 g, 2 mmol), HClNH2CH3 (0.27 g, 4 mmol.) and HOBt (0.35 g, 2.5 mmol) were dissolved in DMF and the solution was chilled to 0° C. on a water-ice bath. Triethylamine (0.7 ml) was added slowly while stirring the solution. After 5 minutes, EDC (0.46 g, 2.4 mmol.) was added to the solution and the stirring continued overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 150 ml chloroform. The chloroform solution was washed by H2O, saturated NaHCO3, brine, saturated NaHSO4 and brine again until the pH of the brine layer was approximate 7. The organic layer was dried using Na2SO4 and the chloroform was distilled under reduced pressure to obtain the Boc-Gly-Pro-Nleu-NHCH3. TLC Rf=0.44 (developing solvents: CMA, 85:15:3). This product was used directly in next step without further purification and characterization. 30 ml solution of 30% TFA in DCM was used to remove the Boc group. The deprotection was allowed to proceed 30 minutes. Then, the DCM and TFA was removed under reduced pressure and benzene 3×20 ml was added and distilled to remove trace TFA. The TFA salt of Gly-Pro-Nleu-NHCH3 was dissolved in 50 ml and the solution was chilled to 0° C. Triethylamine was added slowly to neutralize the peptide. After a while, acetic anhydride (2 ml) was added and the acetylation was allowed to proceed 40 minutes. The DCM was removed and the resulting mixture was dissolved in 100 ml chloroform. The chloroform solution was washed by H2O, saturated NaHCO3, brine, saturated NaHSO4 and brine again until the pH of the brine layer was approximately 7. The organic layer was dried using Na2SO4 and the chloroform was distilled under reduced pressure to obtain the final product Ac-Gly-Pro-Nleu-NHCH3 (0.6 g, 88%). Analytical HPLC profile, single peak, RT=10.5 min. (10-50% B in 30 min.). FAB-MS, observed (M+H)+=341. 1H-NMR (500 MHz, DMSO-d6, 28° C., assignment by TOCSY) δ8.04 (m, C-terminal NH), 7.93 (m, Gly-NH), 7.71 (m, C-terminal NH), 7.48 (m, C-terminal NH), 4.94 (d, Pro-α), 4.81 (m, Pro-α), 4.68 (m, Pro-α), 4.50 (m, Pro-α), 4.29-3.52 (sets of bands, Nleu-α, Gly-α), 3.52-3.42 (m, Pro-δ), 3.36 (m, Pro-δ), 3.29-2.86 (sets of bands, Nleu-β), 2.59 (m, C-terminal N-CH3), 2.53 (m, C-terminal N-CH3), 2.31-2.03 (sets of bands, Pro-β), 1.96 (m, Pro-β, Pro-γ), 1.92-1.61 (m, acetyl-CH3, Pro-β, Nleu-α, Pro-γ), 0.86 (dd, Nleu-δ), 0.75 (m, Nleu-δ).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH3:33])[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH2:35](C1N=C(C(O)=O)C(NC)=C(C)N=1)C.OCC(NCC(O)COC1C(C)=CC(C(=N)NO)=CC=1C)=O>>[CH2:32]([N:31]([CH3:35])[C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:18]=[C:3]([CH3:1])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:15]([CH3:34])[CH:16]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)[CH3:33]
Reactant: CCc1nc(C)c(NC)c(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Agent: Cc1cc(C(=N)NO)cc(C)c1OCC(O)CNC(=O)CO
Product: CCN(C)c1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{4-[5-(2-(Ethyl-methylamino)-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-ethyl-methylamino-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenoxy}-propyl]-acetamide; LC-MS: tR=0.98 min; [M+H]+=471.26.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:4][N:3]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[Cl:30])[NH2:26].N.O>C(O)C.Cl.O1CCOCC1>[Cl:30][C:29]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:4][N:3]=2)=[CH:24][C:23]=1[C:22]([F:21])([F:31])[F:32]
Reactant: Clc1nnc(CCCc2cccnc2)c2ccccc12
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(Nc2nnc(CCCc3cccnc3)c3ccccc23)ccc1Cl

Procedure:
A solution of 321 mg (1.13 mmol) 1-chloro-4-[3-(pyridin-3-yl)propyl]phthalazine, 243 mg (1.24 mmol) 3-trifluoromethyl-4-chloroaniline in 6 ml ethanol and 0.28 ml 4 N HCl in dioxane is stirred for 100 min at 60° C. The cooled reaction solution is poured onto a mixture of 2 ml sat NH3 solution and 20 ml water and extracted immediately 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; EtOAc/acetone 9:1) and stirring in EtOAc/DIPE yield the title compound: m.p. 165-166° C.; TLC (EtOAc/acetone 9:1) Rf=0.21; 1H-NMR (DMSO-d6) 9.50 (s, HN), 8.58 (m, 2H), 8.47 (s, 1H), 8.39 (dd, 1H), 8.33 (dd, 1H), 8.16 (d, 1H), 8.01 (m, 2H), 7.67 (m, 2H), 7.30 (dd, 1H), 3.22 (t, 2H), 2.76 (t, 2H), 2.11 (quint., 2H); FAB-MS (M+H)+=443; an. calc. (C23H18N4ClF3): C, 62.38%; H, 4.10%; N, 12.65%; Cl, 8.01%; F, 12.87%; meas. C, 62.41%; H, 4.07%; N, 12.58%; Cl, 7.99%; F, 12.84%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[CH:8]([CH2:12][CH:13]=O)[C:9](=[O:11])[CH3:10]>C(O)C>[CH3:13][C:12]1[N:1]=[C:2]2[N:6]([C:8]=1[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][S:3]2
Reactant: Nc1nccs1
Reactant: CC(=O)C(Cl)CC=O
Solvent: CCO
Product: CC(=O)c1c(C)nc2sccn12
Yield: 11.7 %

Procedure:
2-Aminothiazole was recrystallized from anhydrous ethanol, filtered and dried before use. A solution of 2-aminothiazole (16) (20.9 g, 202.4 mmoL) and 3-Chloro-2,5-pentanedione (2) (33.7 g, 97%, 242.9 mmol, 1.2 eq) in 180 mL of anhydrous ethanol was refluxed for 72 h in an oil bath. The black reaction mixture was cooled and concentrated under reduced pressure. The residue was treated with saturated sodium bicarbonate solution in portions, and then extracted with dichloromethane. The organic phase was dried and concentrated. The residue was purified by flash chromatography on a silica gel column using dichloromethane-methanol (80:1). The product fractions were collected (TLC, Rf 0.60 neutral form; Rf=0.5 salt form, dichloromethane-methanol 40:1) and concentrated providing white solid product 17 in 11.7% yield, 1.6 g neutral form and 3.2 g salt form. 1H NMR (CDCl3) δ 2.55 (s, 3H, 5-COCH3), 2.70 (s, 3H, 6-CH3), 6.78 (d, 1H, J=4.8 Hz), 8.39 (d, 1H, J=4.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([NH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1N
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-amino-1benzyl-4-ethoxycarbonylpyrazole (0.5 g) in DMF (10 ml), was added 60% NaH (0.082 g). After stirring for 5 min at room temperature, benzyl bromide (0.307 ml) was added, and the mixture was stirred for 1 h at room temperature. The reaction mixture was evaporated under reduced pressure followed by silica-gel column chromatography (toluene/ ethyl acetate=50/1) to give 3-benzylamino-1-benzyl-4-ethoxycarbonylpyrazole (0.3 g). This intermediate was derived to the title compound by the similar method to Reference Example 1 (yield 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]#[N:11])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][NH:26][CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21]>ClC1C=CC=CC=1>[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20]([C:22]1[S:23][C:24]2[CH2:25][N:26]([C:10](=[NH:11])[NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:27][CH2:28][C:29]=2[N:30]=1)=[O:21]
Reactant: Nc1ccccc1NC(=O)c1nc2c(s1)CNCC2
Reactant: COc1ccc(NC#N)cc1
Solvent: Clc1ccccc1
Product: COc1ccc(NC(=N)N2CCc3nc(C(=O)Nc4ccccc4N)sc3C2)cc1

Procedure:
A solution of 4-methoxy-phenyl-cyanamide (2 eq) obtained in step I above and N-(2-aminophenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine-2-carboxamide obtained in step VIII of example I (1.0 eq) in chlorobenzene was refluxed for 6 h. Solvent was evaporated and the residue was treated with ethereal HCl at room temperature for 5-15 h. Solvent was evaporated and the residue was dissolved in methanol—DCM system and neutralized. Organic layer was separated, dried on anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which was then purified, by either column chromatography or preparative HPLC to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3Cl)[N:12]=2)[CH3:10])[C:5]([C:29]#[N:30])=[CH:4][N:3]=1.[CH3:31][C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1.C([O-])([O-])=O.[Na+].[Na+].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>CC([O-])=O.CC([O-])=O.[Pd+2].O.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:35]3[CH:34]=[N:33][C:32]([CH3:31])=[N:37][CH:36]=3)[N:12]=2)[CH3:10])[C:5]([C:29]#[N:30])=[CH:4][N:3]=1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](Nc1nc(N)ncc1C#N)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ncc(-c2cccc3nc([C@H](C)Nc4nc(N)ncc4C#N)n(-c4ccccc4)c(=O)c23)cn1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-2-amino-4-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 59 (50 mg, 0.12 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (40 mg, 0.18 mmol) in a 4:1 mixture of 1,4-dioxane and water (4 mL) in a sealed tube, Na2CO3 (38 mg, 0.36 mmol), RuPhos (28 mg, 0.06 mmol) and Pd(OAc)2 (6.8 mg, 0.03 mmol) were added. The mixture was degassed and back-filled with argon (three cycles) and then stirred at 120° C. for 1 h. The reaction mixture was allowed to cool to RT, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-2-amino-4-((1-(5-(2-methylpyrimidin-5-yl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile 63. ESI-MS m/z: 476.2 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:19])([F:18])[C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[C:28](#[N:32])[CH2:29][C:30]#[N:31].Cl>CS(C)=O>[F:18][C:8]([F:19])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:7][C:29]([CH2:7][C:8]([F:18])([F:19])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:12])[F:13])([C:28]#[N:32])[C:30]#[N:31]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)C(F)(F)F
Reactant: N#CCC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#CC(C#N)(CC(F)(F)C(F)(F)C(F)(F)C(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 1.3 %

Procedure:
14.6 g of 2,2,3,3,4,4,5,5-octafluoropentyl trifluoromethanesulfonate was dissolved in 30 ml of dimethyl sulfoxide, and 5.5 g of potassium carbonate was added. Further, 2.6 g of malononitrile dissolved in 10 ml of dimethyl sulfoxide was added dropwise, and the mixture was stirred at room temperature for 3 hours. Further, 7.0 g of 2,2,3,3,4,4,5,5-octafluoropentyl trifluoromethanesulfonate and 2.7 g of potassium carbonate were added, and the mixture was stirred for 1 hour. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The resulting fraction was concentrated and washed with chloroform to obtain 0.13 g of 2,2-bis(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (49)).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][C@H:17]1[CH2:26][OH:27])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>CCCCCC>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][C@H:19]([O:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][C@H:17]1[CH2:26][O:27][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCOC(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1

Procedure:
A 1.6M solution (4.2 ml) of butyllithium in hexane was added to a solution of (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-methanesulfonyloxypyrrolidine (2.00 g) at -30°-20° C. with stirring in a stream of nitrogen and the mixture was stirred at the same temperature for 30 minutes. Ethyl bromoacetate (2.4 ml) was added to the mixture at -30°~-20° C. and the solution was stirred at 10-15° C. for 3 hours. The solution was poured into 0.1N hydrochloric acid (50 ml) extracted with ethyl acetate (50 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with chloroform to give (2S,4R)-1-benzyloxycarbonyl-2-(ethoxycarbonylmethyl)oxymethyl-4-methanesulfonyloxypyrrolidine (1.87 g).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[CH:32]=[C:31]([C:36]3[NH:40][C:39]([C@@H:41]5[CH2:45][C@H:44]([CH3:46])[CH2:43][N:42]5C(OC(C)(C)C)=O)=[N:38][C:37]=3[Cl:54])[CH:30]=[CH:29]4)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C>O1CCOCC1.CO>[Cl:54][C:37]1[N:38]=[C:39]([C@@H:41]2[CH2:45][C@H:44]([CH3:46])[CH2:43][NH:42]2)[NH:40][C:36]=1[C:31]1[CH:30]=[CH:29][C:28]2[C:33](=[CH:34][CH:35]=[C:26]([C:23]3[CH:22]=[CH:21][C:20]([C:17]4[NH:16][C:15]([C@@H:10]5[CH2:11][C@H:12]([CH3:14])[CH2:13][NH:9]5)=[N:19][CH:18]=4)=[CH:25][CH:24]=3)[CH:27]=2)[CH:32]=1
Reactant: C[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc5cc(-c6[nH]c([C@@H]7C[C@H](C)CN7C(=O)OC(C)(C)C)nc6Cl)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1CN[C@H](c2ncc(-c3ccc(-c4ccc5cc(-c6[nH]c([C@@H]7C[C@H](C)CN7)nc6Cl)ccc5c4)cc3)[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4N HCl in dioxane (5 mL) was added to a stirred solution of (2S,4S)-tert-butyl 2-(5-(6-(4-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-4-chloro-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (30 mg, 0.041 mmol) in MeOH (1 mL) and the mixture was stirred at RT for 2 h, concentrated, and dried under high vacuum for 2 h. LC-MS retention time 3.31 min; calcd. for C32H34ClN6: 537 26 m/z Found 537.37 [M+H]. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][N:9]2[CH:20]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]([C:40]([F:43])([F:42])[F:41])=[C:35]([CH:39]=1)[C:36](Cl)=[O:37]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([C:36](=[O:37])[C:35]4[CH:39]=[C:31]([F:30])[CH:32]=[CH:33][C:34]=4[C:40]([F:43])([F:41])[F:42])[CH2:16][CH2:15]3)=[N:10][N:9]2[CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2nc(N3CCNCC3)ccc2n1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 6-piperazin-1-ylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (1.016 g, 3.69 mmol) and diisopropylethylamine (1.29 mL, 7.38 mmol) in anhydrous dichloromethane (20 mL) was added 5-fluoro-2-trifluoromethylbenzoyl chloride dropwise at room temperature. The reaction mixture was stirred at room temperature for 15 minutes, then diluted with dichloromethane and washed with water. The organic layer was dried and concentrated in vacuo. The title compound was obtained in 82% yield (1.365 g) after purification by column chromatography.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1.[C]=O.[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=O>B(F)(F)F>[CH3:15][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: FB(F)F
Agent: [C]=O
Solvent: c1ccc(-c2ccccc2)cc1
Product: Cc1ccc(-c2ccccc2)cc1

Procedure:
A process for producing a 4-formyl-4'-methylbiphenyl from a biphenyl which comprises conducting the carbonylation of the biphenyl with carbon monoxide in the presence of a HF-BF3 catalyst in a carbonylation reactor to obtain the resulting reaction product solution containing a 4-formylbiphenyl, separating the 4-formylbiphenyl from the reaction product solution, hydrogenating the separated 4-formylbiphenyl to obtain a 4-methylbiphenyl, recycling the 4-methylbiphenyl to the carbonylation reactor, and then conducting both the carbonylation of the biphenyl with carbon monoxide to obtain a formylbiphenyl and the carbonylation of the 4-methylbiphenyl with carbon monoxide to obtain a 4-formyl-4'-methylbiphenyl simultaneously in the presence of the HF-BF3 catalyst in the carbonylation reactor.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCCCCOc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
A mixture of 4-bromophenol (10 g), 1,6-dibromohexane (49.4 g) and potassium carbonate (9.59 g) in N,N-dimethylformamide (50 ml) was stirred for 4 hours at 60° C. (bath temp.), and then cooled to ambient temperature. To the reaction mixture was added ethyl acetate (200 ml), and the mixture was washed with water (200 ml×2) and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (1:0-1:1 hexane-ethyl acetate) to give 1-bromo-4-(6-bromohexyloxy)benzene (15.61 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([CH3:15])[CH2:4][CH2:3]1.[H-].[Na+].[C:18]([C:20]1[CH:25]=[CH:24][N:23]=[C:22](F)[CH:21]=1)#[N:19]>CS(C)=O>[C:18]([C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:1][C@H:2]2[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([CH3:15])[CH2:4][CH2:3]2)[CH:21]=1)#[N:19]
Reactant: N#Cc1ccnc(F)c1
Reactant: C[C@@H]1CC[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H]1CC[C@@H](Oc2cc(C#N)ccn2)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate (4.50 g, 22.9 mmol) in DMSO (42 mL) was treated with NaH (0.60 g, 25.1 mmol) in portions, then allowed to stir for 15 min. Solid 4-cyano-2-fluoropyridine (3.83 g, 31.4 mmol) was then added and the reaction was stirred at RT overnight. The reaction was quenched by addition of saturated, aqueous NaHCO3, then diluted further with water. The mixture was extracted three times with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography (0-25% ethyl acetate in hexanes), providing the titled compound as a colorless oil which quickly solidified to give white crystals. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=5.2 Hz, 1H), 7.05 (dd, J=5.18, 1.3 Hz, 1H), 6.96 (d, J=1.1 Hz, 1H), 5.16 (s, 1H), 4.51 (s, 1H), 4.34 (d, J=15.0 Hz, 1H), 3.05-3.08 (m, 2H), 2.07-2.20 (m, 1H), 1.89-1.95 (m, 2H), 1.35-1.38 (m, 2H), 1.30 (s, 9H), 1.19 (d, J=7.2 Hz, 3H) ppm. LRMS m/z (M+H) 318.4 found, 318.2 required.