Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]2[N:30]=[N:31][N:32](CC3C=CC(OC)=CC=3)[CH:33]=2)=[CH:22][CH:21]=1>FC(F)(F)C(O)=O>[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]2[N:30]=[N:31][NH:32][CH:33]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(Cn2cc(CNCc3ccc(-c4ccc(N5C[C@H](CNC(C)=O)OC5=O)cc4F)cc3)nn2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(CNCc4c[nH]nn4)cc3)c(F)c2)C(=O)O1
Temperature: 67.5 °C
Reaction time: 12 h

Procedure:
A solution of the crude regioisomeric mixture of (5S)-N-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride and (5S)-1H-{3-[2-fluoro-4′-({[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-5-ylmethyl]-amino}-methyl)-biphenyl-4-yl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide hydrochloride (1013 and 1014, 29.17 g, 49.07 mmol) in trifluoroacetic acid (TFA, 150 mL) was warmed up to 65-70° C., and the resulting reaction mixture was stirred at 65-70° C. for 12 h. When TLC and HPLC/MS showed that the deprotection reaction was complete, the solvents were removed in vacuo. The residual solids were then treated with ethyl acetate (EtOAc, 100 mL) and H2O (150 mL) before being treated with a saturated aqueous solution of sodium carbonate (30 mL) at room temperature. The resulting mixture was then stirred at room temperature for 1 h before the solids were collected by filtration, washed with EtOAc (2×50 mL) and H2O (2×50 mL), and dried in vacuo at 40-45° C. to afford the crude, (5S)-N-[3-(2-fluoro-4′-{[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-methyl}-biphenyl-4-yl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide (1 as the free base, 18.9 g, 21.49 g theoretical, 87.9%) as off-white powders, which by HPLC/MS and 1H NMR was found to be one pure regioisomer and this regioisomer was found to be identical as the material obtained from deprotection of 1013 alone by the same method. For 1 as the free base: 1H NMR (300 MHz, DMSO-d6) δ 1.85 (s, 3H, COCH3), 3.44 (t, 2H, J=5.4 Hz), 3.74 (s, 2H), 3.77 (s, 2H), 3.79 (dd, 1H, J=6.4, 9.2 Hz), 4.17 (t, 1H, J=9.1 Hz), 4.72-4.81 (m, 1H), 7.39-7.62 (m, 7H, aromatic-H), 7.73 (s, 1H, triazole-CH), 8.29 (t, 1H, J=5.8 Hz, NHCOCH3), 9.72 (br. s, 2H, ArCH2N+H2), 15.20 (br. s, 1H, triazole-NH); C22H23FN6O3, LCMS (EI) m/e 439 (M++H) and 461 (M++Na).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
Benzyl alcohol (13 mL, 125 mmol) was slowly added to a stirred suspension of NaH (95%, 2.86 g, 113 mmol) in toluene (200 mL) at room temperature. After 30 min, 2,4-difluorobenzonitrile (15.3 g, 110 mmol; Aldrich) was added all at once and stirring continued overnight (18 h). After this, the reaction mixture was washed with water (2×25 mL) and brine (25 ml). The organic layer was dried (Na2SO4), filtered and concentrated to give a white slurry which was triturated with hexanes and filtered to afford the title compound as a white solid (20.34 g, 81% yield). 1H NMR (500 MHz, CDCl3): 7.59-7.55 (1H, m), 7.45-7.34 (5H, m), 6.75-6.71 (2H, m), 5.19 (2H, s); 13C NMR (125.76 MHz, DMSO-d6) δ ppm: 71.16, 98.75, 101.54, 101.75, 108.66, 108.84, 115.83, 127.16, 128.58, 128.94, 135.03, 135.44, 135.54, 162.22, 162.31, 165.26, 167.29. LCMS calcd for C14H11FNO: 228.2; found: 228.0.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[O:39][CH2:40][CH3:41])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[C:5]([O:7][CH3:8])=[O:6].CO[C:21]1C=CC=[C:25](OC)[C:26]=1[C:27]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C.O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][C:26]([CH3:27])=[CH:21][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(OC2CCCCO2)c(Br)c1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCCCO2)c(C=C(C)C)c1
Temperature: 70 °C
Yield: 495.1 %

Procedure:
A mixture of methyl 3-bromo-4-(tetrahydro-2H-pyran-2-yloxy)benzoate T6.6 (0.500 g, 1.6 mmol), palladium acetate (0.036 g, 0.16 mmol), S-Phos (0.13 g, 0.32 mmol) and tripotassium phosphate (0.32 mL, 4.0 mmol) in DMF (10.00 mL, 129 mmol) and water (0.40 mL, 22 mmol) was stirred. The mixture was purged with nitrogen and placed under vacuum and the process repeated three times. Before heating, 2-methylprop-1-enylboronic acid (0.24 g, 2.4 mmol, commercially available from Synthonix, Cat. No. D3007G1) was added, and the mixture was heated to 70° C. and stirred for 23 hours. The mixture was then cooled to room temperature, diluted with brine, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield T13.1 as a colorless oil (0.460 g, 100% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[CH2:9]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:21]2[CH:20]=[CH:19][C:18]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][CH:22]=2)[N:3]=1
Reactant: Fc1cccc(Br)n1
Reactant: CCCCCCCCCc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCc1ccc(-c2cccc(F)n2)cc1
Yield: 90.7 %

Procedure:
A solution of 232 mmol of 2-bromo-6-fluoropyridine in 400 ml of toluene is admixed with 290 mmol of 4-nonylphenylboronic acid, 200 ml of ethanol, a solution of 464 mmol of sodium carbonate in 200 ml of water and 2.3 mmol of tetrakis(triphenylphosphine)palladium(0) at room temperature. The mixture is heated at the boil for 3.5 h. After cooling, the phases are separated, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried with magnesium sulfate. The solvents are removed under reduced pressure and the raw product is purified by column chromatography over silica gel 60 using n-heptane/dichloro-methane 1:1 as eluent and recrystallization from acetonitrile/acetone 5:1, giving 63 g (91%) of 2-fluoro-6-(4-nonylphenyl)pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+](=[C:13]([C:18](=[O:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[N-]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH:13]([C:18](=[O:20])[CH3:19])[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C(=[N+]=[N-])C(C)=O
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C(Nc1ccc([N+](=O)[O-])cc1)C(C)=O
Temperature: 120 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Under an argon atmosphere, to a solution of 4-nitroaniline (3.84 g) in toluene (278 mL) were added methyl 2-diazo-3-oxobutanoate (5.13 g) and rhodium(II) acetate dimer (250 mg), and the mixture was stirred at 120° C. for 1 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=9:1→hexane:ethyl acetate=7:3 (volume ratio)] to give the title compound (4.63 g, yield 98%) as a yellow solid.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:10][CH:11]=[C:12]([CH2:14][N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[N:13]=3)=[CH:5][CH:4]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]
Reactant: Brc1ccc(-c2nc(CN3CCCC3)co2)cc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2ccc(-c3nc(CN4CCCC4)co3)cc2)cc1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
2-(4-Bromo-phenyl-4-pyrrolidin-1-ylmethyl-oxazole hydrochloride (See Example 2) (0.151 g, 0.439 mmol), 4-methylsulfonylphenylboronic acid (0.132 g, 0.66 mmol), tetrakis-(triphenylphosphine) palladium (0.010 g, 0.009 mmol), aqueous sodium carbonate (2M, 0.88 mL, 1.76 mmol) and 7 mL of dioxane is placed in a 10 mL CEM microwave tube. The tube is placed in a CEM microwave reactor for 30 minutes at 90° C., 25 psi, and 45 watts of power. The mixture is cooled and concentrated to a dark residue which is purified by radial silica gel chromatography (1% 2M NH3 in MeOH/dichloromethane) to give 0.125 g of the titled compound. MS (m/e): 383.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH3:11])[S:8][C:6]=2[N:7]=1
Reactant: Cc1nc2c(Cl)nc(Cl)nc2s1
Reactant: C1COCCN1
Solvent: CO
Product: Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To a solution of 5,7-dichloro-2-methyl-thiazolo[5,4-d]pyrimidine (4.1 g, 18.72 mmol) in MeOH (100 mL) was added morpholine (3.26 mL, 37.44 mmol) at 0° C. and the mixture stirred at 0° C. for 30 minutes. The resultant precipitate was collected by filtration and dried in vacuo at 40° C. to give the title compound as a cream solid (4.42 g, 89%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl[C:14]1[C:15]2[CH2:25][CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:16]=2[N:17]=[C:18]([NH2:20])[N:19]=1>>[NH2:20][C:18]1[N:19]=[C:14]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[C:15]2[CH2:25][CH2:24][CH2:23][C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[C:16]=2[N:17]=1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Reactant: CC(C)(C)OC(=O)NCCCN
Product: CC(C)(C)OC(=O)NCCCNc1nc(N)nc2c1CCCc1ccccc1-2

Procedure:
tert-Butyl 3-aminopropylcarbamate (120 mg, 0.690 mmol) and the product from Example 1C (113 mg, 0.460 mmol) were treated under the conditions described in Example 1D to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.47 (s, 9H) 1.65-1.81 (m, 2H) 2.06-2.27 (m, 4H) 2.58 (t, J=6.74 Hz, 2H) 3.22 (q, J=5.95 Hz, 2H) 3.56 (q, J=6.08 Hz, 2H) 4.93 (s, 2H) 5.47-5.76 (m, 2H) 7.16-7.23 (m, 1H) 7.28-7.40 (m, 2H) 7.64-7.71 (m, 1H); MS (ESI+) m/z 384.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1>CS(C)=O>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Oc1cncc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(Oc2cncc(Cl)c2)c1
Temperature: 120 °C
Yield: 22.8 %

Procedure:
A solution of 5-chloro-3-hydroxypyridine (0.45 g, 3.5 mmol) and NaH (0.15 g of 60% dispersion, 3.83 mmol) in DMSO (10 mL) was stirred at RT for 30 min and then treated with 1-fluoro-3-nitrobenzene (0.69 g, 4.9 mmol). The mixture was heated at 120° C. for 24 h, cooled to RT, quenched with satd. NH4Cl (50 mL), and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to yield a crude residue which was purified via column chromatography using to yield 3-chloro-5-(3-nitrophenoxy)pyridine (0.2 g, 23% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): □ 8.46 (d, J=−2.0 Hz, 1H), 8.35 (d, J=2.0 Hz, 1H), 8.09 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.89 (t, J=2.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.41-7.39 (m, 2H); MS (ESI) m/z: 251.0 (M+H+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[CH:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.I[C:14]1[CH:15]=[C:16]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH:1]1([NH:4][C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:14]3[CH:15]=[C:16]([C:21]4[NH:25][C:24]5[CH:26]=[C:27]([CH2:30][N:31]6[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]6)[CH:28]=[CH:29][C:23]=5[N:22]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Reactant: C#Cc1ccc(NC2CC2)nn1
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1ccc(NC2CC2)nn1

Procedure:
The title compound was synthesized from N-cyclopropyl-6-ethynylpyridazin-3-amine and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1 H-benzo[d]imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The intermediate compound N-cyclopropyl-6-ethynylpyridazin-3-amine was made as for Example 1 (Step 1 to 3) with the spectra below: 1H NMR (300 MHz, CDCl3) δ: 7.38-7.41 (1 H, d, J=9.0 Hz), 6.96-6.99 (1 H, d, J=9.0 Hz), 5.99 (1 H, s), 3.25-3.27 (1 H, m), 2.57 (1 H, s), 0.87-0.89 (2 H, s), 0.61-0.63 (2 H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=1[CH3:1]
Reactant: CO
Reactant: Cc1ccc(C)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C)ccc1C
Temperature: 25 °C

Procedure:
In methanol (30 ml), 2,5-dimethylbenzoic acid (1.772 g) was dissolved. The reaction solution was added with concentrated sulfuric acid (0.7 ml) and the whole was refluxed under heating for 17 hours. After having been cooled to room temperature, the reaction solution was concentrated under reduced pressure. The resultant residue was added with a saturated aqueous sodium hydrogen carbonate solution to make the pH thereof to 9, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After a drying agent was filtrated out, the filtrate was concentrated under reduced pressure. The resultant residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.9353 g) as a pale-yellow oily substance.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:32]=[N:33][CH:34]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncc(F)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 36 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (5-fluoropyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.39 min, m/z=463.1 [M+H]+, m/z=461.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.79 (m, 1H) 1.79-1.91 (m, 1H) 2.88 (d, J=11.00 Hz, 1H) 3.17-3.27 (m, 2H) 3.36-3.45 (m, 1H) 4.21 (br. s, 1H) 4.87 (br. s, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.79-7.90 (m, 3H) 8.08 (d, J=2.20 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.69 Hz, 1H) 8.78 (d, J=2.45 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.[Cl:41]C(O[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=O.Cl>C(OCC)(=O)C.C(Cl)Cl>[ClH:41].[CH3:26][C:15]1([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:7])[CH2:13][CH2:12]2)[O:19][C:18]2=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]2[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC1(CN2CCN(C(=O)OCc3ccccc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
A mixture of 2-(4-tert-butoxycarbonylpiperazin-1-yl)methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 306 (130 mg, 0.35 mmol), trifluoroacetic acid (3 ml) and methylene chloride (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 ml) and added triethylamine (107.5 mg, 1.06 mmol). To the solution, benzyl chloroformate (120 mg, 0.71 mmol) was added with cooling on ice-bath followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford a yellow oil. The oil was dissolved in ethyl acetate (5 ml). To the solution, a saturated hydrochloride solution in ethyl acetate was added, and the precipitates were filtered off to afford benzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate hydrochloride (46.8 mg, yield 30%) as a white powder.
Reaction SMILES: [CH2:1]([C@:4]1([CH2:37][CH2:38][O:39]CC2C=CC(OC)=CC=2)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.O.C([O-])(O)=O.[Na+].[Cl-].[Na+].O>[CH2:1]([C@:4]1([CH2:37][CH2:38][OH:39])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]([CH3:33])[S:27]([CH:30]2[CH2:32][CH2:31]2)(=[O:28])=[O:29])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(CCOCc2ccc(OC)cc2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Product: C=CC[C@]1(CCO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.09 g (4.33 mmol) N—((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-(4-methoxybenzyloxy)ethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide (Example 408, step C) in a mixture of DCM (82 mL) and water (4.56 mL) [18:1] was added 2,6-di-tert-butylpyridine (2.93 mL, 12.99 mmol) followed by DDQ (3.93 g, 17.32 mmol). The reaction mixture was stirred vigorously at ambient temperature for 15 min. The reaction mixture was diluted with 150 mL sat. NaHCO3/brine solution and extracted into 600 mL of ethyl acetate, then 200 mL of EtOAc×2 (precipitate was removed by filtration). The combined organic layers were dried over MgSO4, filtered and the filtrate was evaporated. Purification by chromatography on silica gel (eluent: 50-100%% EtOAc/hexane, gradient elution) provided the desired product as a foam.
Reaction SMILES: [C:1]([C:3]([C:16](=[O:29])[N:17]([CH3:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[CH:4][NH:5][C:6](=[NH:15])[N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]1=[O:14])#[N:2].ClC(Cl)(Cl)C(O)=O>C(O)(=O)C>[CH3:28][N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[C:16]([C:3]1[C:1]([NH2:2])=[N:15][C:6]([N:7]2[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]2=[O:14])=[N:5][CH:4]=1)=[O:29]
Reactant: CN(C(=O)C(C#N)=CNC(=N)N1CC(C)(C)NC1=O)c1cccc(C(F)(F)F)c1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CN(C(=O)c1cnc(N2CC(C)(C)NC2=O)nc1N)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A mixture of 2.45 g (6 mmol) of compound IV, 820 mg (5 mmol) of trichloroacetic acid and 4.25 ml of glacial acetic acid was stirred at 70° C. for 2 hours and subsequently evaporated in vacuo. The remaining residue was taken up in 100 ml of ethyl acetate and extracted successively twice each with 20 ml of 2N NaOH each time and 10 ml of water each time. The solution was dried over MgSO4 and then filtered and evaporated in vacuo. The residue was dissolved in 25 ml of ether, whereupon crystals separated out. The mixture was stirred at room temperature for 30 minutes and then evaporated in vacuo. The crystalline residue was suspended in diisopropyl ether, filtered off with suction and dried in vacuo at 100° C. for 15 hours. 1.36 g (=55.5% yield) of pure 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)-pyrimidine-5-carboxylic acid N-methyl-N-(3-trifluoromethylphenyl)amide were obtained, melting point 209°-210° C.