Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][P:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CCCC)CCCC)CCC.C1([SiH](Cl)Cl)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:45]1([P:37]([CH2:36][C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]=2[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[CH2:15][P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=P(Cc1ccc2ccccc2c1-c1c(CP(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12)(c1ccccc1)c1ccccc1
Agent: Cl[SiH](Cl)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: c1ccc(P(Cc2ccc3ccccc3c2-c2c(CP(c3ccccc3)c3ccccc3)ccc3ccccc23)c2ccccc2)cc1

Procedure:
20.48 g (0.03 mol) of 2,2'-bis(diphenylphosphinylmethyl)-1,1'-binaphthyl are suspended in 80 ml of xylene and 30.6 g (0.165 mol) of tri-n-butylamine in the absence of air and moisture, and 26.57 g (0.15 mol) of phenyldichlorosilane are added dropwise with stirring. The mixture is then refluxed for 13 hours to give a clear solution. Xylene is distilled off at atmospheric pressure, and the mixture is allowed to cool with stirring. This results in the formation of 2,2'-bis(diphenylphosphinomethyl)-1,1'-binaphthyl as a colorless solid, which is filtered off under an inert gas and washed with 20 ml of degassed acetone. 18.5 g (95%) of colorless crystals of melting point 160° to 161° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(#N)C>[CH:13]1([NH:19][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of 4-chloro-3-nitrobenzonitrile (5.28 g, 28.9 mmol), cyclohexylamine (5.0 mL, 43.7 mmol), and triethylamine (6.0 mL, 43.0 mL) in acetonitrile (75 mL) was stirred at 50° C. for 15 h. The reaction mixture was cooled to rt and then poured into 100 mL ice water. The solid precipitate was filtered, washed with water, and dried to afford compound 3 as a yellow solid (6.42 g, 90%). ESI-MS m/e 246.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:12])(=[O:11])[NH:14][C:6]2[CH:5]=[CH:4][CH:3]=[C:22]3[C:23]=2[N:18]=[CH:19][CH:20]=[CH:21]3)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: c1ccncc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)Nc2cccc3cccnc23)c([N+](=O)[O-])c1
Yield: 40 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (0.60 g, 4.16 mmol), 4-chlorosulfonyl-3-nitro-benzoic acid methyl ester (Intermediate 438) (1.5 g, 5.41 mmol), DMAP (cat), pyridine (6 ml) and DCM (3 ml) gave the title compound (0.65 g, 40%) after purification by column chromatography with n-hexane/EtOAc (80:20) as the eluent.
Reaction SMILES: [Na].[S:2]1(=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3]1.[F:14][C:15]1[N:20]=[C:19]([F:21])[C:18]([F:22])=[C:17](F)[C:16]=1[F:24].C1OCCOCCOCCOCCOC1>C(#N)C.O>[F:21][C:19]1[C:18]([F:22])=[C:17]([N:3]2[C:4](=[O:11])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:2]2(=[O:12])=[O:13])[C:16]([F:24])=[C:15]([F:14])[N:20]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: C1COCCOCCOCCOCCO1
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2S(=O)(=O)N1c1c(F)c(F)nc(F)c1F
Reaction time: 3.5 h
Yield: 77 %

Procedure:
A mixture of the sodium salt of 1,2-benzisothiazol-3(2H)-one 1,1-dioxide (0.81 g, 3.95 mmol), pentafluoropyridine (0.68 g, 4.0 mmol) and 15-Crown-5 (0.88 g, 4.0 mmol) in acetonitrile (15 ml) was heated to reflux for 6 hours, cooled, and the solvent evaporated in vacuo. The oily residue thus obtained was suspended in water and stirred for 3-4 hours. The solid which percipitated was collected by filtration and dried to afford 1.01 g (77%) of 2-(2,3,5,6-tetrafluoro-4-pyridyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, m.p. 164°-165° C. after recrystallization from carbon tetrachloride.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CNC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 18 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 60 mg, 0.139 mmol), 2-amino-N-methylacetamide (12.26 mg, 0.139 mmol), 4-methylmorpholine (56.3 mg, 0.556 mmol), and HATU (68.8 mg, 0.181 mmol) were added to DMF (1 mL). The mixture was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.4 min) to provide 2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (13 mg, 0.025 mmol, 18.02% yield) as a single enantiomer. LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.25 (2 H, m), 7.53-7.82 (7 H, m), 5.20 (1 H, s), 3.77-4.01 (2 H, m), 2.75 (3 H, s); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][PH:11](=[O:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:14]([O:13][PH:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[PH](O)CCCCc1ccccc1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=[PH](CCCCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110 %

Procedure:
To a solution of the compound of example 80 (1.75 g, 8.83 mmol) in dry CH2Cl2 (40 mL) was added benzyl alcohol (1.83 mL, 17.7 mmol), DMAP (108 mg, 0.88 mmol) and EDC (1.91 g, 10.0 mmol). The mixture was then stirred at room temperature for 18 h. The mixture was concentrated in vacuum, taken-up in ethyl acetate and washed with NaHCO3 (5%) and H2O. Drying (Na2SO4) and concentration gave 2.8 g of a pale yellow oil which was purified by flash chromatography (SiO2, ethyl acetate:hexane (1:1)) to give 1.92 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19](O)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(OCC1C=CC=CC=1)N.O[N:38]1C2C=CC=CC=2N=[N:39]1.CN1CCOCC1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([NH:38][NH2:39])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: NC(=O)OCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A solution of 19 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 220 ml of dimethylformamide was cooled to 0° C. and was treated in succession with 9.22 g of benzyl carbamate, 8.43 g of 1-hydroxybenzotriazole, 7.05 ml of N-methylmorpholine and 11.7 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The mixture was allowed to warm to room temperature and was then stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The ethyl acetate layer was washed with 5% sodium hydrogen carbonate and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the ethyl acetate was evaporated and the residue dissolved 200 ml of methanol and 2.5 g of 10% palladium-on-charcoal added. The mixture was shaken in a hydrogen atmosphere for 4 hours and then the catalyst was removed by filtration. The methanol was evaporated and the residue stirred with hexane and filtered. There was obtained 17.41 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=NO)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:24]>CC#N.O>[C:1]([C:3]1[N:4]=[C:5]2[C:18](=[O:24])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Solvent: CC#N
Solvent: O
Product: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A suspension of 33 (522 mg, 1.97 mmol) and [bis(trifluoroacetoxy)iodo]benzene (1.69 g, 3.9 mmol) in CH3CN/H2O (9:1, 20 ml) was stirred 24 h at room temperature. The solid was collected by filtration and washed with CH3CN. The residue was dissolved in DMSO (2 ml) and precipitated by addition of H2O. The obtained solid was filtered and dried under vacuum, affording 36 (286 mg, 58%) as light brown solid. 1H NMR (300 MHz, DMSO d6): δ 8.65 (bs, 1H), 8.31 (bs, 1H), 8.09 (dd, 1H), 7.93 (m, 2H), 7.77 (ddd, 1H). ESI+MS: calcd for C13H6N4O2: 250.22; found: 251.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[H-].[Na+].[C:14]([C:18]1[CH:19]=[C:20]([C:24](Cl)=[O:25])[N:21]([CH3:23])[N:22]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:24]([C:20]2[N:21]([CH3:23])[N:22]=[C:18]([C:14]([CH3:16])([CH3:15])[CH3:17])[CH:19]=2)=[O:25])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Nc1cc(Br)ncc1[N+](=O)[O-]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1C(=O)Nc1cc(Br)ncc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 2-bromo-5-nitro-pyridin-4-ylamine (62 mg, 0.28 mmol) in THF (5 mL), was treated with NaH (34 mg, 0.85 mmol) under Ar. The resulting solution was stirred for 10 min and then treated with 5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (62 mg, 0.31 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was purified by direct application to silica preparative TLC plates (2000 micron) and eluted with 3:7 EtOAc-hexanes to yield 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid (2-bromo-5-nitro-pyridin-4-yl)-amide. 1H-NMR (400 MHz, CDCl3) δ: 11.2 (s, 1H), 9.18 (s, 1H), 9.11 (s, 1H), 6.65 (s, 1H). 4.18 (s, 1H), 1.34 (s, 9H).
Reaction SMILES: [Li]C(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.CON(C)[C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C1COCC1>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:20]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[O:30])=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: COc1ccc(CC(=O)N(C)OC)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101 %

Procedure:
To a solution of sec-BuLi (1.3 M in THF, 22.6 mL, 29.5 mmole) in dry THF (50 mL) was added 4-bromobenzotrifluoride (3.3 g, 14.7 mmole) in dry THF (20 mL) dropwise at −78° C. After 20 min, N-methoxy-N-methyl-2(4-methoxyphenyl)acetamide (1.5 g, 7.4 mmole) in dry THF (20 mL) was added dropwise. After 1 hr the mixture was quenched with saturated NH4Cl (10 mL), warmed to RT, and extracted with Et2O (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel (15% EtOAc/hexanes) to give the title compound (2.2 g, 100%) as a slightly-yellow solid: TLC (1.5% EtOAc/hexanes) Rf0.81; 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J=8.2 Hz, 2 H), 7.72 (d, J=8.2 Hz, 2 H), 7.18 (d, J=8.7 Hz, 2 H), 6.88 (d, J=8.7 Hz, 2 H), 4.25 (s, 2 H), 3.79 (s, 3 H).
Reaction SMILES: Cl.[F:2][C:3]([F:22])([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:11][CH:10]=1)[C:4]([F:7])([F:6])[F:5].C(N(C(C)C)CC)(C)C.[CH2:32]([C@@:34]1([CH2:41][S:42](Cl)(=[O:44])=[O:43])[C:38](=[O:39])[NH:37][C:36](=[O:40])[NH:35]1)[CH3:33]>ClCCl>[CH2:32]([C@:34]1([CH2:41][S:42]([N:17]2[CH2:18][CH2:19][CH:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:3]([F:2])([F:22])[C:4]([F:7])([F:6])[F:5])=[CH:21][CH:20]=3)[CH2:15][CH2:16]2)(=[O:43])=[O:44])[NH:35][C:36](=[O:40])[NH:37][C:38]1=[O:39])[CH3:33]
Reactant: FC(F)(F)C(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: CC[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@]1(CS(=O)(=O)N2CCC(Oc3ccc(OC(F)(F)C(F)(F)F)cc3)CC2)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[4-(pentafluoroethoxy)phenoxy]piperidine hydrochloride (0.17 g) and diisopropylethylamine (0.19 mL) in dichloromethane (100 mL) was added [(4S)-4-ethyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (0.13 g). The reaction was stirred at ambient temperature for 18 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:5]=[CH:6][C:7]=1OC.OCCC1C=C([F:44])C=C(F)C=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:44][C:6]1[CH:5]=[C:4]([CH2:10][CH2:11][N:12]([C@H:28]2[CH2:29][CH2:30][C@H:31]([CH3:34])[CH2:32][CH2:33]2)[C:13](=[O:27])[NH:14][C:15]2[S:16][C:17]([S:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:18][N:19]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: OCCc1cc(F)cc(F)c1
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1F
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2cc(F)cc(F)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-{2-[3-[2-(3-fluoro-4-methoxy-phenyl)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 1-(2-hydroxy-ethyl) -3,5-difluoro-benzene and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Yield: 99.5 %

Procedure:
To a solution of tert-butyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 206 (0.25 g, 0.54 mml) in methanol (15 mL) was added 10% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 207 (0.20 g, 99%) as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.CCO>[Pd].C1COCC1>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][C:2]([CH3:1])([C:17]([O:19][CH3:20])=[O:18])[CH2:3][CH2:4]2)=[N:9][CH:10]=1
Reactant: COC(=O)C1(C)CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)C1(C)CCN(c2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 4-methyl-1-(5-nitropyridin-2-yl)piperidine-4-carboxylate (3.32 g, 11.89 mmol) in abs EtOH (200 mL) and THF (200 mL) was added 10% Pd/C (400 mg) and then the reaction mixture was evacuated with hydrogen (5 cycles) and allowed to stir at ambient temperature overnight. The reaction mixture was filtered and then concentrated and the black residue purified on a 120 g silica Crawford silicyle cartridge loading in 40% EtOAc/isohexane with some DCM and eluting a gradient of 40-80% EtOAc using an Isco companion to provide the title compound (2.96 g, 11.89 mmol, 100%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][S:4][C:5]1[N:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:8]1[CH:9]=[N:10][C:5]([S:4][CH2:3][C:2]([F:15])([F:14])[F:1])=[CH:6][CH:7]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(=O)c1ccc(SCC(F)(F)F)nc1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(SCC(F)(F)F)nc1
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (0.56 g, orange oil) from 1-(6-((2,2,2-trifluoroethyl)thio)pyridin-3-yl)ethanone (0.39 g, 1.64 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)nc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Yield: 102.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 6-bromonicotinic acid (2 g) and 1-(2,4-dimethylphenyl)piperazine (1.9 g), the title compound (3.8 g) was obtained.
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[K+].[CH3:51][C@@H:52]1[CH2:57][CH2:56][CH2:55][CH2:54][C@H:53]1[O:58][C:59](=[O:64])[O:60][CH:61](Cl)[CH3:62]>CN(C=O)C>[CH3:51][C@@H:52]1[CH2:57][CH2:56][CH2:55][CH2:54][C@H:53]1[O:58][C:59](=[O:64])[O:60][CH:61]([O:16][C:14]1[N:13]([C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[N:12]=[C:11]([CH:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([NH2:1])=[N:36][C:37](=[O:45])[C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[CH:8][CH:7]=2)[C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[N:15]=1)[CH3:62]
Reactant: CC(Cl)OC(=O)O[C@@H]1CCCC[C@H]1C
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccc(C)cc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccc(C)cc3)cc2)c2nc(OC(C)OC(=O)O[C@@H]3CCCC[C@H]3C)n(-c3ncccn3)n2)c1
Temperature: 55 °C
Reaction time: 48 h
Yield: 43.2 %

Procedure:
To a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]-4-methylbenzamide (230 mg) and DMF (3 mL), potassium hydrogen carbonate (113 mg) and carbonic acid 1-chloroethyl ester (1R,2R)-2-methylcyclohexyl ester (250 mg) were sequentially added, and the resulting mixture was stirred at 55° C. for 24 hours and at room temperature for another 2 days. The reaction solution was purified by reverse phase silica gel column chromatography (mixed solvent of acetonitrile-water) to obtain the captioned compound (129.2 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=O.Cl.Cl.[NH2:27][OH:28].[OH-].[Na+].O>CO>[N:27](=[C:16]1[CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]34[CH2:6][CH2:5][N:4]([CH2:3][CH:2]=[CH2:1])[C@@H:21]2[CH2:22][C:9]2[CH:10]=[CH:11][C:12]([OH:24])=[C:13]([O:14][C@@H:15]13)[C:8]4=2)[OH:28]
Reactant: NO
Reactant: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=NO)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of naloxone hydrochloride (1.085 g, 3 mmol) and hydroxylamine hydrochloride (0.28 g, 4 mmol) was taken up in 30 mL of MeOH containing 2.8 mL of 10% aqueous NaOH. The mixture was stirred at room temperature for 24 h. Water was added (100 mL), and the oxime extracted into CHCl3 (3×50 mL). The extract was dried (MgSO4), and the solvent evaporated. The residue obtained was recrystallized from CH2Cl2 -petroleum ether. Yield: 840 mg (81.8%); mp: 119 C. IR: (KBr): No C=O absorption at 1717 cm-1. 1H NMR (CDCl3) δ 4.98 (s,C5H); Rf: silica gel 60 in EtOAc--EtOH--NH4OH (100:1:1) 0.13. Anal. Calcd for: C19H22N2O4C, 66.65; H, 6.48; N, 8.18. Found: C, 66.70; H, 6.52; N, 8.08.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1F)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][C:8]1([CH3:10])[O:7][C:6](=[O:12])[C:5]2[CH:13]=[CH:14][C:2]([O:1][C:23]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][C:16]=3[F:15])=[CH:3][C:4]=2[O:9]1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: CC1(C)OC(=O)c2ccc(O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2ccc(Oc3ccc(C=O)cc3F)cc2O1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
7-Hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (I-1a: 12.9 g), 3,4-difluorobenzaldehyde (9.45 g) and potassium carbonate (27.6 g) were combined in dimethylformamide (100 mL) and stirred as the reaction mixture was heated to 80° C. After 24 hours, the reaction mixture was cooled to ambient temperature, combined with water, and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography on silica gel eluting with 10-15% ethyl acetate in heptane to give the title compound (I-1b-1).