Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].O.[CH2:9]([O:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([O:31][CH2:32][C@@H:33]3[CH2:36][CH2:35][N:34]3C(OC(C)(C)C)=O)[CH:30]=2)=[CH:21][CH:20]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:34]1[CH2:35][CH2:36][C@H:33]1[CH2:32][O:31][C:29]1[CH:28]=[N:27][CH:26]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:21]=2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2ccc(CCOCc3ccccc3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: c1ccc(COCCc2ccc(-c3cncc(OC[C@@H]4CCN4)c3)cc2)cc1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (1.0 mL) and water (0.11 mL) were added to CH2Cl2 (5.5 mL). This mixture was added to 3-[4-[2-(benzyloxy)ethyl]phenyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine (220 mg, 0.46 mmol) in a 25 mL round-bottom flask with a magnetic stirrer under N2. After stirring at 30° C. for 24 h, TLC analysis indicated that the starting material had disappeared. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (SunFire Prep C18 column, 19×150 mm, 5 μm particle size; UV detection at 254 nm; flow 15 mL/min; CH3CN/water gradient with addition of 0.05% CF3COOH, from 20-40% CH3CN in 6 min) to provide the title compound (140 mg, light-yellow solid) as a partial trifluoroacetate.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[N:15]=[CH:16][S:17][C:18]=1[NH2:19])=[O:13])[CH3:10]>C(#N)C.CCOC(C)=O>[NH2:19][C:18]1[S:17][C:16]([Br:1])=[N:15][C:14]=1[C:12]([O:11][CH2:9][CH3:10])=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncsc1N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)sc1N
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
N-Bromosuccinimide (0.54 g, 3.03 mmol) was added to a solution of 5-aminothiazole-4-carboxylic acid ethyl ester (0.44 g, 2.53 mmol) [prepared according to the procedure described by Golankiewicz et al. (Tetrahedron, 41 (24), 5989-5994 (1985))] in acetonitrile (10 mL), and the mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with 5% K2CO3 aq. solution (25 mL) followed by brine (25mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluted with 15% EtOAc in hexane to give 0.37 g (58% yield) of the titled compound.
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:5]=1[CH:6]=[O:7]>O.[N+]([O-])([O-])=O.[Ag+]>[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:8][C:5]=1[C:6]([OH:1])=[O:7]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(OC(F)(F)F)ccc1O
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a stirring solution of NaOH (8.15 g, 203.8 mmol) in water (35 mL, 5.8 M) was added an aq solution of silver nitrate (17.3 g, 101.9 mmol, 35 mL water, 2.9 M). A brownish solid formed. The flask was placed in an ice bath and to the stirring suspension was added 2-hydroxy-5-trifluoromethoxy-benzaldehyde in 500 mg portions (10.0 g, 48.5 mmol). After addition was complete and the reaction was stirred for 10 min in an ice bath, the mixture was filtered and the brownish precipitate was washed with hot water. The combined washings were acidified with conc HCl to pH 1 and the precipitate was collected by vacuum filtration. This solid was then dissolved in ethyl acetate. The ethyl acetate was washed with saturated aq NaCl, dried over Na2SO4, and filtered. The aqueous layer was also extracted with ethyl acetate. This organic layer was washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated to provide 2-hydroxy-5-trifluoromethoxy-benzoic acid (9.8 g, 91%) as a white solid: Rf 0.38 (20% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 10.30 (bs, 1 H), 7.79 (d, J=3.0 Hz, 1 H), 7.41 (dd, J l=9.3 Hz, J2=3.0 Hz, 1 H), 7.05 (d, J=9.0 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[F:12][C:5]1[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])=[CH:3][C:2]([NH:1][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1F
Reactant: COc1ccc(C=O)cc1
Product: COC(=O)c1cc(NCc2ccc(OC)cc2)cc(N2CCCC2=O)c1F

Procedure:
Methyl 2-fluoro-5-({[4-(methyloxy)phenyl]methyl}amino)-3-(2-oxo-1-pyrrolidinyl)benzoate (D154) was prepared from methyl 5-amino-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (D150) in an analogous manner to the process described for Ester 35 (B35) using 4-(methyloxy)benzaldehyde instead of propionaldehyde. [M+H]+=373.4, RT=2.85 min.
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2=[N:6][C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8](I)[C:9](=[O:10])[N:4]2[CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[Cl:1][C:2]1[S:28][C:5]2=[N:6][C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:8]([C:34]3[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=3)[C:9](=[O:10])[N:4]2[CH:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COc1cccc(/C=C/c2nc3sc(Cl)cn3c(=O)c2I)c1OCC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(/C=C/c2nc3sc(Cl)cn3c(=O)c2-c2ccc(C#N)cc2)c1OCC(C)(C)C
Yield: 149.6 %

Procedure:
The title compound was prepared from Intermediate 19 (100 mg, 0.181 mmol) and 4-cyanophenylboronic acid (30 mg, 0.200 mmol) using Pd[(C6H5)3P]4 (9 mg, 0.007 mmol) in toluene (5 ml) and ethanol (2 ml) followed by sodium carbonate (119 mg, 1.110 mmol) in water (2 ml) according to the procedure outlined in Example 1 to afford 137 mg of the desired compound; 1H NMR (300 MHz, DMSO-d6) δ 1.01 (s, 9H), 3.52 (s, 2H), 3.76 (s, 3H), 6.75 (d, J=15.6 Hz, 1H), 6.96-7.02 (m, 3H), 7.53 (d, J=8.4 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 8.22 (d, J=15.6 Hz, 1H), 8.28 (s, 1H); ESI-MS (m/z) 506.55, 508 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NCCOc1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCOc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A solution of 4-nitro 2-aminoethyl ether (610 mg, 2.93 mmol) from Example 213 in 10 mL of THF/water (9:1 ) was treated with triphenyl phosphine (768 mg, 3.0 mmol) at ambient temperature. After stirring for 3 h, the solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel (eluant 1:9 methanol/methylene chloride) to give 480 mg (95%) of the title compound: 1H NMR (200 MHz, CD3OD) δ8.18 (d, 2H, J=9Hz), 6.96 (d, 2H, J=9Hz), 4.13 (t, 2H, J=5.5Hz), 3.27 (t, 2H, J=5.5Hz).
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[F:7][C:8]([F:19])([F:18])[O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.S(=O)(=O)(O)O.CCOCC>C1COCC1>[F:7][C:8]([F:18])([F:19])[O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)[Mg]Cl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of commercially available t-butyl magnesium chloride in THF (1.0 mol) is added at 38°-40° C. a solution of 4-trifluoromethoxybenzaldehyde (56 g, 0.4 mol) in THF (50 ml) under nitrogen atmosphere. The reaction solution is stirred at room temperature overnight and cautiously acidified with dilute sulfuric acid at 15°-20° C. Ether is added and the organic phase is washed with water, dried (Na2SO4) and evaporated to a gummy solid. The crude material is purified by silica gel chromatography to give the alcohol which is used in Example 25.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:40](=[O:41])[N:13]3[C:14]([C:24]([O:26][CH:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])=[C:15]([CH2:19][S:20][CH2:21][CH:22]=[CH2:23])[CH2:16][S:17](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)Cl.O>C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:40](=[O:41])[N:13]3[C:14]([C:24]([O:26][CH:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:25])=[C:15]([CH2:19][S:20][CH2:21][CH:22]=[CH2:23])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: C=CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 87 %

Procedure:
To a solution of benzhydryl 7-(2-phenylacetamido)-3-allylthiomethyl-3-cephem-4-carboxylate-1-oxide (26 g) in methylene chloride (500 ml) was added dropwise phosphorus trichloride (20 ml) at 5° C. with stirring, and the stirring was continued for an hour. The mixture was poured into a mixture of methylene chloride (200 ml) and water (400 ml), followed by separating out the organic layer, which was washed twice with an aqueous solution of sodium chloride (200 ml) and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was pulverized with diisopropyl ether to give benzhydryl 7-(2-phenylacetamido)-3-allylthiomethyl-3-cephem-4-carboxylate (22 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=O.Cl.[CH:19]([O:22][NH2:23])([CH3:21])[CH3:20]>CO>[CH3:1][O:2][C:3](=[O:17])/[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([Cl:16])[CH:7]=1)=[N:23]/[O:22][CH:19]([CH3:21])[CH3:20]
Reactant: COC(=O)C(=O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: CC(C)ON
Agent: Cl
Solvent: CO
Product: COC(=O)/C(=N/OC(C)C)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 70 °C
Reaction time: 7 h

Procedure:
(3-Chloro-4-methanesulfonyl-phenyl)-oxo-acetic acid methyl ester (prepared as in Example 1, 1.30 g, 4.70 mmol) was stirred in methanol (9.5 mL) and warmed in a 70° C. oil bath. O-Isopropyl-hydroxylamine hydrochloride (786 mg, 7.04 mmol) was added. After 7 h, the reaction mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 0.2 M aqueous potassium bisulfate solution (50 mL), 50% aqueous sodium bicarbonate solution (50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 20% ethyl acetate/hexanes to 33% ethyl acetate/hexanes) afforded (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid methyl ester as a faintly yellow oil contaminated with an unknown impurity (645 mg, <41%): LC-MS (ESI) m/e calcd for C13H16ClNO5S [M+] 333.04, found 334 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:28])[CH:9]([CH2:13][C:14]2[CH:27]=[CH:26][C:17]3[O:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[O:21][C:16]=3[CH:15]=2)C(O)=O)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:36])C=CC=CC=1.C([N:48]([CH2:51]C)CC)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:28][C:51](=[O:36])[NH:48][CH:9]2[CH2:13][C:14]2[CH:27]=[CH:26][C:17]3[O:18][C:19]([F:24])([F:25])[C:20]([F:23])([F:22])[O:21][C:16]=3[CH:15]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(c2ccc(F)cc2)O1

Procedure:
To a solution of (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]propanoic acid (3.3 g, 8.16 mmol) in tetrahydrofuran (120 ml) were added diphenylphosphoryl azide (1.94 ml, 8.98. mmol) and triethylamine (1.71 ml, 12.2 mmol), and the mixture was heated under reflux for 1 hr. The reaction solution was allowed to cool and the mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (2.74 g, 84%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][Br:15])=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:16][C:17]([CH2:21]O)([CH2:19][OH:20])[CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][Br:15])=[C:4]([C:9]2([CH3:10])[O:20][CH2:19][C:17]([CH3:21])([CH3:18])[CH2:16][O:11]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)cc(Br)c1OCCBr
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)COC(C)(c2cc(Cl)cc(Br)c2OCCBr)OC1
Yield: 63 %

Procedure:
A solution of 3′-bromo-2′-(2-bromoethoxy)-5′-chloroacetophenone (Reference compound No. 4-1, 4.4 g, 10 mmol), neopentylglycol (1.2 g, 1.2 mmol) and p-toluenesulfonic acid monohydrate (0.22 g, 12 mmol) in anhydrous toluene (50 mL) was refluxed overnight. After cooling, ethyl acetate (50 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) were added to the reaction mixture and the whole was partitioned. The organic layer was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the title reference compound (2.8 g) as a pale yellow oil (Yield 63%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:15](=O)[CH3:16])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].Cl.[OH-:19].[NH4+:20].[OH-].[Na+]>C1COCC1>[OH:19][N:20]=[C:15]([C:9]1[CH:8]=[C:7]2[C:12]([CH2:13][CH2:14][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]2)=[CH:11][CH:10]=1)[CH3:16]
Reactant: [OH-]
Reactant: COC(=O)N1CCc2ccc(C(C)=O)cc2C1
Reactant: [NH4+]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N1CCc2ccc(C(C)=NO)cc2C1
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of 7-acetyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid methyl ester, Preparation 8 (11.65 g, 50 mmol), ammonium hydroxide hydrochloride (7 g, 100 mmol) and sodium hydroxide (10N) (10 mL, 100 mmol) in THF (50 mL) was heated under reflux for 24 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the resultant filtrate was concentrated in vacuo. The residue obtained was purified by flash column chromatography on silica eluted with hexane/EtOAc (1:1) to provide the title compound as an oil (11.7 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58]([C:60]1[O:61][C:62]2[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][C:63]=2[N:64]=1)=[O:59]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:69][C:66]2[CH:67]=[CH:68][C:62]3[O:61][C:60]([C:58]([O:57][CH3:56])=[O:59])=[N:64][C:63]=3[CH:65]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1nc2cc(N)ccc2o1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1nc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2o1
Reaction time: 0.33 h

Procedure:
A solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (59.8 mg, 0.128 mmol) in dichloromethane (3 ml) was treated with DIPEA (66.8 mg, 0.517 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (80.7 mg, 0.341 mmol) and stirred for 20 min under argon. 5-AMINO-BENZOOXAZOLE-2-CARBOXYLIC ACID METHYL ESTER (25.8 mg, 134 μmol, JW PharmLab) was added and stirred 2 hrs. The reaction mixture was diluted with dichloromethane and washed with water, sat'd NaHCO3, water and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving chiral methyl 5-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)benzo[d]oxazole-2-carboxylate (73.7 mg., 89.8%) as a white lyophilized solid. MS (ES+) m/z Calcd: [(M+H)+]: 641.15. found: 641.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(#N)C.CN(C)C1C=CN=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:23]([C:20]2[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:27])[F:28])=[CH:22][CH:21]=2)(=[O:25])=[O:24])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=S(=O)(Nc1ccc(Br)cn1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To 2-Amino-5-bromopyridine (15, 1.50 g, 8.67 mmol) in acetonitrile (20.0 mL) were added pyridine (6.0 mL, 0.074 mol), 4-dimethylaminopyridine (0.10 g, 0.82 mmol) and 4-trifluoromethyl-benzenesulfonyl chloride (48, 2.14 g, 8.75 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated, poured into water, acidified with 1N HCl to pH=2, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was washed with ethyl acetate to give a white solid as desired compound (49, 2.80 g, 84.8%). MS (ESI) [M+H+]+=381.0, 383.0.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.CC(C)=[O:14]>Cl.C1(NN)C=CC=CC=1.CO>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:14])[CH2:1]1
Reactant: CC(C)=O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: Cl
Solvent: NNc1ccccc1
Solvent: CO
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 75 %

Procedure:
A flask with attached condenser was charged with 80 g of acetonine, 80 g of acetone, 16 g methanol and 1.6 g N-phenylhydrazine monohydrochloride and the mixture reacted at 50°-55° C. for 18 hours, while stirring. The reaction solution was stripped under reduced pressure, to obtain a light red residue. This residue was distilled in vacuo to obtain 60.4 g of triacetonamine. White crystals were obtained by recrystallization from petroleum ether having the melting point of 34°-36° C. The compound was confirmed to be the objective matter by IR spectrum and gas chromatography.
Reaction SMILES: [NH2-].[Na+].N.[CH:4]([N:7]([CH:19]([CH3:21])[CH3:20])[CH2:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:11]#[N:12])([CH3:6])[CH3:5].[CH3:22][C:23]([CH3:27])=[CH:24][C:25]#[N:26]>CCOCC.O>[CH:19]([N:7]([CH:4]([CH3:6])[CH3:5])[CH2:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)([C:23]([CH3:27])([CH3:22])[CH2:24][C:25]#[N:26])[C:11]#[N:12])([CH3:21])[CH3:20]
Reactant: CC(C)=CC#N
Reactant: CC(C)N(CCC(C#N)c1ccccn1)C(C)C
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)N(CCC(C#N)(c1ccccn1)C(C)(C)CC#N)C(C)C
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
The mixture of 4.7 g of sodium amide and 400 ml of liquid ammonia is cooled to -40° C., then the solution of 24.5 g of 4-diisopropylamino 2-(2-pyridyl) butane nitrile (Example 1a) in 30 ml of anhydrous ether is added, the temperature being maintained between -40° C. and -33° C. The mixture is stirred for 15 mins. at this temperature then the solution of 9 g of 3,3-dimethyl acrylonitrile in 40 ml of ether is added, still at the same temperature. The temperature is allowed to rise slowly up to ambient temperature (duration: about 5 hrs.). 200 ml of ether are added then water is added drop by drop. The ethereal phase is separated and the aqueous phase is re-extracted with ether. The ethereal extracts are collected and dried over sodium sulfate. The solvent is evaporated to dryness and the residue is chromatographed over a column of alumina with the eluting ethyl acetate-pentane (2.5-100) vol/vol mixture.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[NH2:18])([CH3:3])[CH3:2].N[C:21]1C([N+]([O-])=O)=CC=C[C:22]=1OCC1OC1.C(N)(C)C.C(N)(C)(C)C>>[CH3:21][C:22]1[NH:18][C:10]2[C:9]([O:8][CH2:7][CH:6]([OH:19])[CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])=[CH:14][CH:13]=[CH:12][C:11]=2[N:15]=1
Reactant: Nc1c(OCC2CO2)cccc1[N+](=O)[O-]
Reactant: CC(C)NCC(O)COc1cccc([N+](=O)[O-])c1N
Solvent: CC(C)N
Solvent: CC(C)(C)N
Product: Cc1nc2cccc(OCC(O)CNC(C)C)c2[nH]1

Procedure:
The 1-isopropylamino-2-hydroxy-3-(2-amino-3-nitrophenoxy)-propane (m.p. 108° - 110°C.) used as starting material can be obtained, in the manner described in Example 1, from 1-(2-amino-3-nitrophenoxy)-2,3-epoxy-propane, using 35 g. isopropylamine instead of 35 g. tert.-butylamine.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:8]=[CH:9][C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=O)(=[O:6])=[O:5])[CH3:2].[CH3:17][C:18]([C:26]1[S:30][C:29]([NH2:31])=[N:28][N:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>>[CH2:1]([NH:3][S:4]([C:7]1[CH:8]=[CH:9][C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([NH:31][C:29]1[S:30][C:26]([C:18]([CH3:19])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:17])=[N:27][N:28]=1)=[O:14])(=[O:5])=[O:6])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CC(C)(c1ccccc1)c1nnc(N)s1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Product: CCNS(=O)(=O)c1ccc(F)c(C(=O)Nc2nnc(C(C)(C)c3ccccc3)s2)c1
Yield: 15.6 %

Procedure:
To the mixture of 5-[(ethylamino)sulfonyl]-2-fluorobenzoic acid (24.7 mg, 0.1 mmol), prepared according to Scheme 4, and above crude 5-(1-methyl-1-phenylethyl)-1,3,4-thiadiazol-2-amine (21.9 mg, 0.1 mmol) in 2.0 mL of mixed solvents (DCM:DMF=10:1) was added EDC (19.2 mg, 0.1 mmol) and HOAt (13.6 mg, 0.1 mmol). The resultant mixture was stirred at room temperature for overnight, and then concentrated in vacuo. The residue was purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 10% B to 90% B in 10 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 5-[(ethylamino)sulfonyl]-2-fluoro-N-[5-(1-methyl-1-phenylethyl)-1,3,4-thiadiazol-2-yl]benzamide (7.0 mg).