Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.O=[CH:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:16][CH2:17]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: O=C1NC[C@@H](c2ccc(F)cc2)C12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN1CCC2(CC1)C(=O)NC[C@H]2c1ccc(F)cc1
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture containing 0.25 g (1.0 mmol) of (S)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one, 0.2 g (1.41 mmol) of tert-butyl 2-oxoethylcarbamate, 2 mL of THF, 1 mL of DCM, and 1 g (2.5 mmol) of MP-sodium triacetoxyborohydride resin was rotated overnight. The reaction mixture was filtered and the solvents were removed under reduced pressure. The residue was subjected to silica gel chromatography to give 131 mg (33%) of (S)-tert-butyl 2-(4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)ethylcarbamate as a colorless oil: 1HNMR (400 MHz, CD3OD) δ ppm 7.35-7.32 (m, 2H), 7.12-7.07 (m, 2H), 3.68 (dd, 1H, J=10.4 and 7.6 Hz), 3.57 (dd, 1H, J=10.4 and 6.4 Hz), 3.32-3.28 (m, 3H), 3.11-3.08 (m, 2H), 2.87-2.84 (m, 3H), 2.02-1.80 (m, 4H), 1.41 (s, 9H), and 1.34-1.27 (m, 2H); LCMS m/z: 392.3 (M+H)+.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)CCN(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.[N:27]1[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][CH:28]=1>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[CH:33]([C:30]1[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=1)[OH:34]
Reactant: COc1ccc(F)cc1
Reactant: O=Cc1ccncc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(C(O)c2ccncc2)c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
Butyl lithium (47.5 ml of 2.22M solution, 105.6 mmole) was added slowly to a solution of pentamethyldiethylenetriamine (15 ml) and 4-fluoroanisole (12.61 g, 0.1 mole) in THF (150 ml) at -70° C. The solution was stirred for 2 hr at -75° C. and a solution of pyridine-4-aldehyde (9.55 ml, 0.1 mole) in THF was added at -75° C. The mixture was allowed to warm to 25° C. slowly and then quenched with ammonium chloride solution. The mixture was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and 3N hydrochloric acid. The acid washes were then basified with sodium hydroxide and extracted with ether and the ether solution concentrated in vacuo. The crude product was recrystallized from 80% ethanol to give (2-fluoro-5-methoxy-phenyl)-4-pyridylmethanol as a white powder (12.22 g+3.12 g second crop, 65.8% total yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[C:39]3([CH2:44][CH2:43][CH2:42][NH:41][CH2:40]3)[C:38](=[O:45])[N:37]([CH3:46])[CH2:36]2)=[CH:31][CH:30]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC#N.C(=O)(O)[O-].[Na+].C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:18])[CH3:17])[C:11]([N:41]1[CH2:42][CH2:43][CH2:44][C:39]2([C:38](=[O:45])[N:37]([CH3:46])[CH2:36][CH:35]2[C:32]2[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:40]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: CN1CC(c2ccc(F)cc2)C2(CCCNC2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CN1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Reaction time: 20 h
Yield: 96.7 %

Procedure:
To a stirred solution of (R)-3-benzyloxy-2-(2-tert-butoxycarbonylamino-2-methylpropionylamino)-propionic acid (Intermediate 3A) (344 mg, 0.904 mmol) and 4-(4-fluorophenyl)-2-methyl-2,7-diazaspiro[4.5]decan-1-one (270 mg, 0.904 mmol) in MeCN (4 mL) was added dropwise a solution of ®T3P (50% in EtOAc) (1.055 ml, 1.807 mmol) at room temperature. The resulting colourless solution was stirred for 20 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (10 mL) and DCM (10 mL). The aqueous phase was separated and extracted using DCM (3×10 mL), the combined organic fractions were washed with 10% citric acid (10 mL), dried (MgSO4) and then concentrated under reduced pressure to afford tert-butyl 1-((2R)-3-(benzyloxy)-1-(4-(4-fluorophenyl)-2-methyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (546 mg, 97%) as a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][N:6]=1.[CH3:15][N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:17].F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.CNC>CN(C)C=O>[CH3:15][N:16]([CH3:17])[C:9]([C:8]1[CH:12]=[CH:13][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])=[N:6][CH:7]=1)=[O:10]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)Cc1ccc(C(=O)O)cn1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1ccc(C(=O)N(C)C)cn1
Reaction time: 8 h

Procedure:
A solution of 6-(2-methoxy-2-oxoethyl)nicotinic acid (37 mg, 0.19 mmol), HATU (72.6 mg, 0.19 mmol), and N-ethyl-N-isopropylpropan-2-amine (26.5 mg, 0.20 mmol) in N,N-dimethylformamide (2 ml) was stirred at room temperature for 15 min, then, dimethyl amine (0.05 mL, 1 mol solution in THF) was added and continued to stir overnight. The reaction is quenched with water, extracted with EtOAc and purified by a standard method to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[C:3]=1[N+:10]([O-:12])=[O:11].[N:13]([O-])=O.[Na+]>C(O)(=O)C>[N+:10]([C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[C:5]2[C:4]=1[CH:9]=[N:13][NH:6]2)([O-:12])=[O:11]
Reactant: O=N[O-]
Reactant: Cc1c(N)ccc(Cl)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(Cl)ccc2[nH]ncc12
Temperature: 25 °C

Procedure:
To 4-chloro-2-methyl-3-nitroaniline (1.63 g, 8.8 mmol) dissolved in acetic acid (75 mL) at room temperature was added a 2M aqueous solution of sodium nitrite (4.4 mL). The suspension was then diluted with acetic acid (100 mL) and then heated at reflux for 4 h. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was then partitioned between ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL). The separated organic layer was then washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography of the reside (hexane/ethyl acetate (2:1) afforded the desired product. 1H NMR (500 MHz) (DMSO-d6) δ 8.32 (s, 1H); 7.95 (d, J=8.7 Hz, 1H); 7.68 (d, J=8.7 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[C:12](Cl)=[O:13])([O-:8])=[O:7]>C(OCC)(=O)C>[CH2:1]([NH:5][C:12](=[O:13])[C:11]1[CH:10]=[C:9]([N+:6]([O-:8])=[O:7])[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(C)CN
Solvent: CCOC(C)=O
Product: CC(C)CNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 27.2 %

Procedure:
The general procedure was used with isobutyl amine (14.6 g, 0.200 mole) and 3,5-dinitrobenzoyl chloride (23.0 g, 0.100 mole) in ethyl acetate. Produced 7.28 g (26%) crystals, mp 149°-155° C. Proton NMR (90 MHz) shows resonances at 9.168 ppm (m, 1H; 4-aryl H); 8.955 ppm (d, 2 Hz, 2H; 2,6-aryl H's); 6.526 ppm (bs, 1H; N-H); 3.378 ppm (t, 6.4 Hz, 2H; N-CH2); 2.050 ppm (sep, 7 Hz, 1H; CH); 1.021 ppm (d, 6.2 Hz, 6H; CH3).
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][C@H:10]1[C:13]([O:15]C)=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.C(C(CCCC)C(O)=O)C>CCCCCCC>[CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][C@H:10]1[C:13]([OH:15])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1CCN1[C@@H](C)c1ccccc1
Agent: CCCCC(CC)C(=O)O
Solvent: O
Solvent: CCCCCCC
Product: C[C@@H](c1ccccc1)N1CC[C@H]1C(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 400.8 %

Procedure:
To a mixture of methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (161.6 g) and water (323 g) was added 2-ethylhexanoic acid (116.9 g) and resulting mixture was stirred at 60° C. for about 12 hours. Heptane (161 g) was added to the reaction mixture and separated. The organic layer was extracted with water (80 g). Combined water layer was washed with heptane (161.6 g×3) to give aqueous N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylic acid solution (606.2 g). Yield 94%.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3N3CCCC3)nc2c1
Temperature: 60 °C
Yield: 101.1 %

Procedure:
A mixture of 0.31 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.21 g of pyrrolidine, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 60° C. for one hour. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.37 g of 2-[3-(pyrrolidine-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 53”).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.O>C1(C)C=CC=CC=1>[CH3:5][C:4]1[CH2:11][C:1]2[C:6]([CH:3]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:5]1[C:6]2[C:1](=[CH:11][CH:2]=[CH:1][CH:6]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=Cc2cccc(-c3cccc4ccccc34)c2C1
Yield: 4030.6 %

Procedure:
The crude product was taken up in 200 cm3 of toluene, 0.5 g of p-toluene sulfonic acid was added, the reaction mixture was refluxed for 2 hours on a water separator and washed 3 times with 50 cm3 of saturated aqueous NaHCO3 solution, and the solvent was removed in vacuo. Filtration through 200 g of silica gel (hexane/methylene chloride) gave 10 g (86%) of 22 as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[N:28]#[C:29][NH2:30].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:29]([NH:30][C:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:18][C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:9][C:8]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:24]=1)=[O:26])#[N:28]
Reactant: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccccc3)[nH]c2c1
Reactant: N#CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(Cc3cccc(C(=O)NC#N)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 68.5 %

Procedure:
Under an argon atmosphere, to a suspension of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (100 mg) in dichloromethane (2.8 mL) were added cyanamide (12.9 mg), 4-dimethylaminopyridine (75 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118 mg) successively, and this mixture was stirred at room temperature for 60 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid, water, and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (73.1 mg). 1H-NMR (DMSO-d6) δ ppm: 3.78 (3H, s), 4.47 (2H, s), 6.64 (1H, dd, J=2.3, 8.8 Hz), 6.89 (1H, d, J=2.3 Hz), 7.18-7.39 (3H, m), 7.42-7.52 (2H, m), 7.56-7.68 (2H, m), 7.84-7.99 (2H, m), 11.24 (1H, s). ESI-MS (m/z): 383 (M+H)+
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24](Br)[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:42]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:42])[CH:23]=[CH:22][C:21]=3[C:27]3[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=3[O:37][CH3:38])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Br)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: CB1OB(C)OB(C)O1
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: [K+]
Solvent: C1COCCO1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4-bromo-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (82.5 mg, 0.13 mmol) in 1,4-dioxane (1 mL) was added trimethylboroxine (39 mg, 0.31 mmol), Pd(PPh3)4 (15 mg, 10 mol %) and potassium carbonate (35 mg, 0.25 mmol). The resulting reaction mixture was purged with nitrogen and sealed in a microwave vessel. The vessel was subject to microwave irradiation at 130° C. for 15 min. The crude mixture was diluted with brine and extracted with EtOAc. The combined organic extracts were dried over Na2SO4. The titled compound was obtained as a glassy material after two preparative TLC plates developed respectively by 20% EtOAc in hexanes and dichloromethane. LC-MS: 584.08 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.84 (s, 1H), 7.65-7.70 (m, 2H), 7.29 (s, 0.5), 7.18-7.22 (m, 1.5H), 7.10-7.15 (m, 1H), 7.01 (d, J=8.0 Hz, 0.5H), 6.98 (d, J=8.5 Hz, 0.5H), 6.66 (d, J=5.0 Hz, 0.5H), 6.64 (d, J=5.5 Hz, 0.5H), 5.54 (d, J=8.5 Hz, 0.5H), 5.31 (d, J=8.0 Hz, 0.5H), 4.82 (d, J=15.5 Hz, 1H), 4.02 (d, J=15 Hz, 0.5H), 3.71-3.82 (m, 5H), 3.15-3.24 (m, 1H), 2.42 (s, 1.5H), 2.41 (s, 1.5H), 1.13-1.27 (m, 6H), 0.48 (d, J=6.5 Hz, 1.5H), 0.31 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[O:26]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27]1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:32][CH2:31][C:28]2[CH:29]=[CH:30][O:26][CH:27]=2)=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: OCc1ccoc1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Product: O=[N+]([O-])c1ccc(OCc2ccoc2)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1

Procedure:
Prepared by the method of Example 44a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (400 mg, 1.2 mmol) in 3-furanmethanol (2 ml) the subtitle compound was obtained (392 mg, 79%). The product was used directly in the next step without purification.
Reaction SMILES: CC([O-])(C)C.[K+].[OH:7][C:8]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[F:17][C:18]([F:33])([S:29](F)(=[O:31])=[O:30])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22]>C1COCC1>[F:33][C:18]([F:17])([S:29]([O:7][C:8]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])(=[O:31])=[O:30])[C:19]([F:27])([F:28])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1cccc(C=O)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cccc(C=O)c1OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
A 1.04 M THF solution of t-BuOK (3.7 mL, 3.9 mmol) was added to a THF solution (0.5 mL) of 2-hydroxy-3-methylbenzaldehyde (500 mg, 3.7 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (1.16 g, 3.9 mmol) and the reaction was stirred at room temperature. After 30 min the temperature was increased to 40° C. After 5 min the resulting mixture was partitioned with DCM and water, and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated to yield a 4:1 w/w mixture of the title compound and starting material, which mixture was used in the next step without further purification.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.O[C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18]C=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.C1(C)C=CC=CC=1>[I-].[Na+].C1(C)C=CC=CC=1.O>[OH:2][CH2:3][CH2:4][O:5][C:1]1[CH:18]=[CH:19][C:14]([C:12]([C:11]2[CH:20]=[CH:21][CH:8]=[CH:9][CH:10]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: O=C1OCCO1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(OCCO)cc1
Temperature: 176 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
A mixture of ethylene carbonate (124.6 g; 1.07 eq.), sodium iodide (6.3 g; 0.03 eq.), 4-hydroxybenzophenone (262 g; 1 eq.) and toluene (8.1 g) was heated. At 99° C. a clear solution was obtained. The reaction mixture was heated with reflux condenser to 176° C. over one hour, during which gas evolution occurred. After an additional ½ hour at 176° C., the reaction mixture was cooled to 122° C. and toluene (350 g) and water (24 g) was added. The lower phase was cut and discarded. More water (14 g) was added and the lower phase was again cut and discarded. Water and toluene (95 g in total) was azeotropically removed, reaching a boiling point of 111° C. More toluene (114 g) was added and the product was isolated by filtration at 8° C. In total, 302 g of 4-(2-hydroxyethoxy)benzophenone (94%) was obtained after drying as white crystals (99.8% chromatographic purity).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]([F:55])([F:54])[C:14]1[CH:15]=[C:16]([C@H:24]2[O:28][C:27](=[O:29])[N:26]([CH2:30][C:31]3[C:36]([N:37]([CH2:40][C@H:41]4[CH2:46][CH2:45][C@H:44]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43][CH2:42]4)[CH2:38][CH3:39])=[CH:35][CH:34]=[CH:33][N:32]=3)[C@H:25]2[CH3:53])[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1>C(Cl)Cl>[F:55][C:13]([F:54])([F:12])[C:14]1[CH:15]=[C:16]([C@H:24]2[O:28][C:27](=[O:29])[N:26]([CH2:30][C:31]3[C:36]([N:37]([CH2:40][C@H:41]4[CH2:46][CH2:45][C@H:44]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:43][CH2:42]4)[CH2:38][CH3:39])=[CH:35][CH:34]=[CH:33][N+:32]=3[O-:9])[C@H:25]2[CH3:53])[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2cccnc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc[n+]([O-])c2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Chloroperbenzoic acid (77%, 120 mg, 0.486 mmol) was added to a solution of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate (152.9 mg, 0.243 mmol) in dry CH2Cl2 (10 mL) at 0° C. under N2. After 15 min at 0° C., the reaction was stirred at room temperature for 5 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with saturated Na2SO3 (10 mL) and saturated K2CO3 (2×20 mL). The organic layers were dried (Na2SO4) and concentrated in vacuo to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-1-oxidopyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate. LCMS calc.=646.3; found=646.3 (M+1)+.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[C:28]1[O:32][CH:31]=[N:30][CH:29]=1)[C:22](O)=[O:23]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([C:28]3[O:32][CH:31]=[N:30][CH:29]=3)=[C:19]([F:18])[CH:20]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(-c2cnco2)c(F)c1
Reactant: Cc1cnc(N2CCC(NC3CC3)CC2)cn1
Product: Cc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-methyl-pyrazin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-oxazol-5-yl-benzoic acid following a procedure analogous to that described in Example 17. LC (method 1): tR=1.20 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]2[C:30]3[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=3)[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15]2)=[O:13])=[N:8][CH:7]=1.Cl[C:33]([O:35][CH3:36])=[O:34]>>[Cl:31][C:27]1[CH:26]=[C:25]2[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15][N:14]([C:12](=[O:13])[NH:11][C:9]3[S:10][C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][C:33]([O:35][CH3:36])=[O:34])=[CH:7][N:8]=3)[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN)s1)c1ccc(Cl)cc12
Product: COC(=O)NCCCSc1cnc(NC(=O)N2CC3(CCN(C(=O)OC)C3)c3cc(Cl)ccc32)s1

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 3, with the exceptions that the methyl 1-((5-((3-aminopropyl)thio)thiazol-2-yl)carbamoyl)-5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate obtained in Step 1 of Example 454 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that methyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:23])[NH:17][C@@H:18]([C:20](F)=[O:21])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:23])[NH:17][C@H:18]([C:20](=[O:21])[NH:7][CH2:8][CH2:9][SH:10])[CH3:19])([CH3:12])([CH3:13])[CH3:14]
Reactant: NCCS
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 25 mL round-bottom flask charged with a solution of sodium bicarbonate (139.5 mg, 1.66 mmol) in 8.1 mL water was added 2-aminoethanethiol hydrochloride (101.2 mg, 0.89 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25b (155.1 mg, 0.81 mmol) in 8.1 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 72.6 mg (36% from 24b) of clean 26b as a colorless oil.