Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[OH:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[O:16])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(O)c2ccco2)cc1OC1CCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccco2)cc1OC1CCCC1
Yield: 59.8 %

Procedure:
The alcohol (3.2 g) was stirred with manganese (IV) oxide (10 g) in CH2Cl2 (100 ml) at RT for 3 h. The mixture was filtered through Celite® and the filtrate concentrated in vacuo. The residual dark oil was subjected to chromatography (SiO2) to give (3-cyclopentyloxy-4-methoxyphenyl)-(2-furyl)ketone (1.9 g); νmax (neat) 1620 cm-1.
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH2:10]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:6][O:5][C:3]([CH2:2][CH2:7][CH2:8][CH2:9][N:20]1[CH2:21][CH2:22][CH:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][CH2:19]1)=[O:4]
Reactant: CCCC(Br)C(=O)OC
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCN1CCC(Cc2ccccc2)CC1
Yield: 77.7 %

Procedure:
A mixture of methyl bromovalerate (1.56 g, 8.0 mmol), 4-benzylpiperidine (1.49 g, 8.5 mmol) and potassium carbonate (2.93 g, 21.25 mmol) in 30 mL of acetonitrile was refluxed under N2 for 12 hr. The inorganic salt was removed through a short column of silica gel and washed with ethyl acetate (3×30 mL). The filtrate was evaporated in vacuo to give a residue, which was purified by flash chromatography, giving 1.8 g (78%) of the product as a pale yellow oil. 1H NMR (CHCl3), 1.312 (m, 2 H), 1.505-1.593 (m, 7 H), 1.831 (m, 2 H), 2.292 (m, 4 H), 2.505 (d, J=6.9 Hz, 2 H), 2.860 (d, J=11.4 Hz, 2 H), 3.647 (s, 3 H), 7.136 (m, 5 H).
Reaction SMILES: [CH:1]1[C:5]([CH:6]=O)=[CH:4][O:3][CH:2]=1.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])C=CC=CC=1>>[O:3]1[CH:2]=[CH:1][C:5](/[CH:6]=[CH:16]/[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4]1
Reactant: O=Cc1ccoc1
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CCOC(=O)CC/C=C/c1ccoc1

Procedure:
3-Furfural and triphenyl-(3-ethoxycarbonylpropyl)phosphonium bromide were processed as in 5A to yield the title compound: 1H NMR (300 MHz, CDCl3) δ 7.46 (br s, 1H), 7.39 (t, J=1.36 Hz, 1H), 6.47 (d, J=2.03 Hz, 1H), 6.20 (d, J=11.53 Hz, 1H), 5.53 (dt, J=11.44, 6.99 Hz, 1H) 4.12 (q, J=7.12 Hz, 2H), 2.61 (t, J=6.78 Hz, 2H), 2.45 (td, J=7.63, 1.36 Hz, 2H), 1.25 (t, J=7.12 Hz, 3H); MS (DCI/NH3) m/z 197 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.C(=O)([O-])[O-:13].[K+].[K+].C(=NO)C.O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([OH:13])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ncc(Cl)cc1Cl
Agent: [K+]
Solvent: CC=NO
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1ncc(O)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 29.1 %

Procedure:
To a solution of 3.8 g of the 1-(3,5-dichloropyridin-2-yl)ethanone prepared in Step 1 in Synthetic Example 2 and 13.8 g of potassium carbonate in 20 ml of dimethylsulfoxide, 5.9 g of acetaldoxime was added, and the mixture was stirred at 80° C. for 4 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 50 ml of water and washed with diethyl ether (30 ml×1), the resulting aqueous layer was acidified with 6N aqueous hydrochloric acid and extracted with ethyl acetate (25 ml×2). The resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 1.0 g of desired crude product as brown crystals. The crystals were used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:21])([F:20])[C:13]2[N:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:11][O:10]1.Cl[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].N#N>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:20])([F:21])[C:13]2[CH:14]=[CH:15][C:16]([O:19][C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=3)=[CH:17][N:18]=2)[CH2:11][O:10]1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1ccc(C(F)(F)C2(c3ccc(F)cc3F)CO2)nc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1ccc(C2(C(F)(F)c3ccc(Oc4ccc(C(F)(F)F)cn4)cn3)CO2)c(F)c1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 78.1 %

Procedure:
To a magnetically stirred mixture of 6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-ol (250 mg, 0.836 mmol) (prepared as in WO 2012/177635 A1) and 2-chloro-5-(trifluoromethyl)pyridine (910 mg, 5.01 mmol) in dry DMSO (10.4 mL) was added cesium carbonate (Cs2CO3) (544 mg, 1.671 mmol) in a 20 mL vial under N2 atmosphere. The reaction mixture was stirred at 60° C. for 2.5 h, then the reaction was stopped by allowing it to cool to rt. The reaction was quenched with H2O, then extracted Et2O (3×). The combined organic extracts were washed with H2O (2×) and brine, dried by passing through a phase separator and volatiles were removed under rotary evaporation. The resulting residue was loaded onto a pad of Celite® and purified by flash chromatography (SiO2, 10-30% EtOAc/Hexanes over 10 min) to yield the title compound as a colorless oil (290 mg, 78%): 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=2.5 Hz, 1H), 8.44-8.39 (m, 1H), 7.98 (dd, J=8.6, 2.4 Hz, 1H), 7.62 (dd, J=8.6, 2.5 Hz, 1H), 7.59-7.53 (m, 1H), 7.41 (dd, J=14.7, 8.2 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 6.89-6.82 (m, 1H), 6.77 (ddd, J=9.8, 9.0, 2.5 Hz, 1H), 3.47 (d, J=5.0 Hz, 1H), 3.03-2.97 (m, 1H). 19F NMR (376 MHz, CDCl3) δ −61.78 (s, 3F), −106.89 (dd, J=257.7, 8.4 Hz, 1F), −107.48-−108.26 (m, 2F), −109.29 (q, J=8.3 Hz, 1F); ESIMS m/z 446 ([M+H]+).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([OH:13])([CH3:12])[CH3:11])=[N:6][C:5]=12.Br[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OC(C)C)(=O)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[Cl:22][C:17]1[CH:16]=[C:15]([C:3]2[N:4]3[CH:9]=[CH:8][C:7]([C:10]([OH:13])([CH3:11])[CH3:12])=[N:6][C:5]3=[N:1][CH:2]=2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: CC(C)(O)c1ccn2ccnc2n1
Reactant: Fc1ccc(Br)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)OC(C)C
Solvent: C1COCCO1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2n1
Temperature: 90 °C
Yield: 88.3 %

Procedure:
A 500 ml round-bottomed flask equipped with a mechanical stirrer, thermocouple and nitrogen/vacuum inlet was charged with 2-(imidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (10.62 g, 60.0 mmol), 4-bromo-2-chloro-1-fluorobenzene (8.00 ml, 66.0 mmol), palladium(II) acetate (270 mg, 1.20 mmol), triphenylphosphine (630 mg, 2.40 mmol), cesium carbonate (19.6 g, 60.2 mmol), and anhydrous 1,4-dioxane (120 ml). The slurry was degassed using five vacuum/nitrogen back-fill cycles, and then heated to 90° C. and aged for 12 hours. The mixture was cooled to 60° C. then water (150 ml) and EtOAc (150 ml) were added to the crude reaction mixture and the slurry was stirred at 45° C. until all of the solids were dissolved. The layers were partitioned and the aqueous phase was extracted again with EtOAc (50 ml). The organic phases were combined and extracted twice with 2N HCl (100 ml then 30 ml). The acidic aqueous phases were combined with EtOAc (250 ml) and NaOH (10.9 g, final pH=10) was added slowly with stirring and the mixture was warmed to 65° C. to dissolve the solids. The phases were separated and the organic phase was concentrated to about 200 ml to provide a slurry. Isopropyl acetate (110 ml) was added and the slurry was concentrated again to about 200 ml. The slurry was warmed to 90° C. then cooled over several hours to 0° C. The crystalline solids were collected on a frit, rinsed with isopropyl acetate/EtOAc (1:1) and air dried to provide 2-[3-(3-chloro-4-fluorophenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol (16.19 g) as a cream-colored crystalline solid: m.p. 180-182° C.; 1H NMR (CDCl3, 400 MHz) δ 8.53 (1H, d, J 7.2), 7.86 (1H, s), 7.59 (1H, dd, J 6.8, 2.0), 7.42 (1H, m), 7.34 (1H, m), 7.14 (1H, d, J 7.2), 1.63 (6H, s); 13C NMR (CDCl3, 100.64 MHz) δ 167.8, 158.1 (d, J 252.2), 148.0, 133.8, 131.4, 130.0, 127.8 (d, J 7.2), 125.5 (d, J 4.0), 122.4 (d, J 18.5), 122.1, 117.8 (d, J 20.9), 105.7, 72.5, 29.9.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]([O:18][CH2:19][CH3:20])([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[F:17])[C:6]([NH2:8])=[O:7].[CH2:27]([S:34](Cl)(=[O:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:25]([C:23]1[CH:22]=[CH:21][C:3]([CH2:4][C:5]([O:18][CH2:19][CH3:20])([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[F:17])[C:6]([NH2:8])=[O:7])=[C:2]([NH:1][S:34]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:36])=[O:35])[CH:24]=1)#[N:26]
Reactant: CCOC(Cc1ccc(C#N)cc1N)(C(N)=O)c1ccc(OC)cc1F
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: CCOC(Cc1ccc(C#N)cc1NS(=O)(=O)Cc1ccccc1)(C(N)=O)c1ccc(OC)cc1F

Procedure:
In analogy to example 95.4, (RS)-(2-amino-4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide (example 322.4) was reacted with benzyl sulfonylchloride to give (RS)-(4-cyano-2-phenylmethanesulfonylamino-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Off-white foam. MS 512.3 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]1[C:16]([OH:18])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:20][C:21]1([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22]1>>[CH3:31][O:30][C:28]([C:27]1[CH:32]=[CH:33][C:24]([C:21]2([NH:20][C:16]([CH:9]3[CH2:10][C:11]([CH3:14])([CH3:15])[CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:18])[CH2:22][CH2:23]2)=[CH:25][CH:26]=1)=[O:29]
Reactant: CC1(C)CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)C3CC(C)(C)CCN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 46.7 %

Procedure:
The title compound (D58) (250 mg) was prepared according to the general procedure for amides preparation (Method C) starting from 1-(tert-butoxycarbonyl)-4,4-dimethylpiperidine-2-carboxylic acid (320 mg; described in J. Med. Chem. 1997, 40, 2491-2501) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (312 mg). Reaction time: 18 hrs
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([NH:14]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3](=[O:34])[CH:4]([NH2:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1
Reactant: COC(=O)C(COc1ccc(Br)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(N)COc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
The compound obtained in step b above (22b) (2.21 g, 4.10 mmol) was stirred in TFA (8 mL) and CH2Cl2 (10 mL) at 0° C.→rt for 1 h, the solvent was removed under vacuum. MeOH (10 mL) was added and then NaHCO3 (344 mg, 4.10), the mixture was stirred at room temperature for 4 h and then concentrated. The residue was dissolved in CH2Cl2 and washed with brine, dried and concentrated to give crude title compound (1.07 g, 91%).
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[C:8](/[CH:12]=[C:13](\[CH3:34])/[CH2:14][N:15]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:9]=[CH:10][CH:11]=1)(=[NH:5])[NH2:4].Cl.[C:36](=[NH:41])(OCC)[CH3:37].C(N(CC)CC)C.Cl>C(O)C.O1CCOCC1.CO>[ClH:1].[ClH:1].[C:36]([N:31]1[CH2:32][CH2:33][CH:28]([O:27][C:24]2[CH:23]=[CH:22][C:21]([N:15]([CH2:14]/[C:13](/[CH3:34])=[CH:12]/[C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[NH:4])[NH2:5])[CH:7]=3)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:26][CH:25]=2)[CH2:29][CH2:30]1)(=[NH:41])[CH3:37]
Reactant: CCS(=O)(=O)N(C/C(C)=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N(C/C(C)=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C(C)=N)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104.1 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-methyl-2-(E)-propenyl]-N-[4-(piperidin-4-yloxy)phenyl]ethanesulfonamide dihydrochloride (303 mg) in ethanol (10 ml) were added ethyl acetimidate hydrochloride (246 mg) and triethylamine (0.460 ml). The resulting mixture was stirred at room temperature for 12 hours. After addition of a 4M solution of hydrogen chloride in dioxane (0.9 ml), the resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 20% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.4 ml) and the mixture was concentrated to dryness in vacuo. The resulting amorphous solid was dissolved in water (10 ml) and the solution was lyophilized to give the title compound (170 mg, yield 45%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([OH:23])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][CH2:20][C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:23])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Product: COC1=C(OC)C(=O)C(Cc2cccc(CCC(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 36.3 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (65 mg, 0.19 mmol) obtained in Example 31 and morpholine (0.019 ml, 0.21 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (29 mg, 0.069 mmol, yield 36%).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:37])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH2:36])=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21].CCN(CC)CC.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.O>[CH3:8][O:9][C:10](=[O:37])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[NH:36][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2N)cc1)NC(=O)c1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2NS(C)(=O)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-aminophenyl)-L-phenylalanine methyl ester TFA salt (90 mg) was dissolved in dry CH2Cl2 (5 mL). To this solution was added Et3N (85 μL) and MsCl (30 μL). The mixture was stirred at room temperature for 3 h and diluted with water. The organic phase was dried (MgSO4) and evaporated to give N-(2,6-dichlorobenzoyl)-4-[2-(methanesulfonylamino)phenyl]-L-phenylalanine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C(C)=CC=CC=1C.O([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[O:9][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Oc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](Oc1cc(Cl)cc(Cl)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
To a solution of 3,5-dichloro-phenol (5.9 g, 36 mmol) in methylene chloride (50 mL) was added 2,6-lutidine (8.38 mL, 72.4 mmol) and triisopropylsilyl triflate (9.7 mL, 36 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 4 h. The reaction was quenched with 0.1 N HCl and diluted with ethyl acetate. The organic solution was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with flash chromatography (5% ethyl acetate/hexanes) to give the desired product as a colorless oil (10.5 g, 91%). 1H NMR (400 MHz, CDCl3): δ 6.95 (t, J=1.8 Hz, 1H), 6.76 (d, J=1.8 Hz, 2H), 1.26 (m, 3H), 1.09 (d, J=7.0 Hz, 18H).
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[N:18]([CH:19]=2)[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15]3)=[CH:8][CH:7]=1)=[O:4].[CH3:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41](O)=[O:42])[CH:36]=[C:37]([CH3:39])[CH:38]=1.CC(C)N=C=NC(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][C:33]1[CH:34]=[C:35]([CH2:40][C:41]([NH:1][C@@H:2]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[N:18]([CH:19]=3)[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]4)=[CH:8][CH:7]=2)=[O:4])=[O:42])[CH:36]=[C:37]([CH3:39])[CH:38]=1
Reactant: Cc1ccc(CC(N)C(=O)Nc2ccc(-c3cn4c(n3)sc3ccccc34)cc2)cc1
Reactant: Cc1cc(C)cc(CC(=O)O)c1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C[C@H](NC(=O)Cc2cc(C)cc(C)c2)C(=O)Nc2ccc(-c3cn4c(n3)sc3ccccc34)cc2)cc1

Procedure:
HATU (258 mg, 0.68 mmol) and DIPEA (197 μl, 1.13 mmol) were added to a solution of 4-[(imidazo[2,1-b]benzothiazol-2-yl)]aniline (150 mg, 0.56 mmol) and N-Boc-4-methylphenylalanine (158 mg, 0.56 mmol) in dry THF (11 ml). After 48 h at room temperature the solvent was removed under reduced pressure and the crude mixture was purified by flash chromatography (DCM containing 1% MeOH) to afford the desired N-Boc derivative that was dissolved in dry DCM (5 ml). TFA (5 ml) was then added and the reaction mixture was stirred at room temperature for 4 hours. Then the solvent was removed under reduced pressure and the crude mixture was purified by flash chromatography (DCM containing 10% EtOH) to afford 2-amino-3-(4-methylphenyl)-N-[4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl]-propanamide in nearly quantitative yield. A suspension of 2-amino-3-(4-methylphenyl)-N-[4-(imidazo[2,1-b]benzothiazol-2-yl]phenyl]propanamide (150 mg, 0.35 mmol) in dry DCM (4 ml) was then mixed to 3,5-dimethylphenylacetic acid (60.6 mg, 0.37 mmol) and DMAP (21.5 mg, 0.17 mmol). Once the solution was obtained, DIC (83 l, 0.53 mmol) was added. After 4.5 h at room temperature the solvent was removed under reduced pressure and the crude mixture was purified by flash chromatography (DCM containing 2% EtOH) to afford (S)-2-(3,5-dimethylphenylacetamido)-3-(4-methylphenyl)-N-[4-(imidazo[2,1-b]benzothiazol-2-yl]phenyl]propanamide that was further on purified by crystallization in CHCl3 (32% c.y.)
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]1[CH:14]([C:15]([O:17]C(C)(C)C)=[O:16])[CH2:13][N:12]([CH3:22])[C:11]1=[O:23])[CH3:9]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:8]([N:10]1[CH:14]([C:15]([OH:17])=[O:16])[CH2:13][N:12]([CH3:22])[C:11]1=[O:23])[CH3:9]
Reactant: CCN1C(=O)N(C)CC1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)N(C)CC1C(=O)O

Procedure:
A stirred solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (0.501 g, 2.5 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml) was cooled to −10° C. under argon and treated with iodoethane (0.404 ml, 5.00 mmol). Sodium hydride (60% dispersion in oil) (0.100 g, 2.500 mmol) was added portion wise. The mixture was allowed stirred warm to room temperature over 3 hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (20 ml) and brine (10 ml). The aqueous layer was re-extracted with ethyl acetate (20 ml) and the organic extracts were combined, washed with saturated sodium hydrogen carbonate solution (20 ml), water (2×20 ml) and brine (20 ml), dried and evaporated. The residue was purified by silica gel chromatography eluting with 25-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (433 mg, 76%). LC/MS [M+H]+=229. (ii) A solution of 1,1-dimethylethyl 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylate (433 mg, 1.897 mmol) in TFA/DCM (1:2, 6 ml) was stirred at room temperature for 18 hours. The solution was evaporated and the residue was co-evaporated with dichloromethane and dried to give crude 3-ethyl-1-methyl-2-oxo-4-imidazolidinecarboxylic acid, (assume ˜1.9 mmol). LC/MS [M+H]+=173.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH2:11]C)[C:7]=1[C:13]([OH:15])=O)=[O:5])[CH3:2].S(Cl)([Cl:18])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:13]([Cl:18])=[O:15])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)O
Product: CCOC(=O)c1cnn(C)c1C(=O)Cl

Procedure:
A mixture of 2-ethyl-2H-pyrazole-3,4-dicarboxylic acid 4-ethyl ester (Example 10, steps 1-3, 3 g, 15 mmol) and thionyl chloride (40 ml) was heated to reflux (4 h). The thionyl chloride was evaporated, and the residue (3.38 g, 64%) was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=O)[CH2:25][O:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])=[C:18]([CH3:36])[CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH:23][CH2:24][CH2:25][O:26][C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])=[C:18]([CH3:36])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(NC(=O)COc4c(C)cccc4C)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3cc(C)c(NCCOc4c(C)cccc4C)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 79.8 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-2-(2,6-dimethylphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%). Mass spectrometry value (ESI-MS, m/z): 473 (M++1)