Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([CH3:20])([S:7]([C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH3:6])C.O.[OH-].[Li+]>C(O)(C)C.C(Cl)(Cl)Cl>[CH3:20][C:5]([S:7]([C:10]1[CH:11]=[N:12][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:15]=1)(=[O:8])=[O:9])([CH3:6])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)c1ccc(C(F)(F)F)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C(=O)O)S(=O)(=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
To a solution of 7.67 g (23.6 mmol) of 2-methyl-2-(6-trifluoromethyl-pyridine-3-sulfonyl)-propionic acid ethyl ester in THF/water (1/1, 200 mL) were added 1.97 g (46.9 mmol) of lithium hydroxide monohydrate. The reaction was stirred at room temperature for 18 h. The organic solvent was removed under reduced pressure and the aqueous layer washed with diethyl ether (200 mL). The basic aqueous layer was cooled in an ice bath and acidified with 2M aqueous HCl solution to pH 2. The acidic aqueous layer was extracted with ethyl acetate (4×200 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and filtered. Concentration of the filtrate under reduced pressure afforded 6.34 g of 2-methyl-2-(6-trifluoromethyl-pyridine-3-sulfonyl)-propionic acid.
Reaction SMILES: [N:1]1([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[C:15]([C:16]=2[CH:17]=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:25]([CH:27]1[O:29][CH2:28]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:29]1[CH2:28][CH:27]1[CH2:25][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[C:15]([C:16]=2[CH:17]=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:2][CH2:3]1
Reactant: BrCC1CO1
Reactant: O=Cc1c(N2CCCNCC2)n(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1c(N2CCCN(CC3CO3)CC2)n(-c2ccccc2)c2ccccc12
Yield: 41 %

Procedure:
A solution of 2-[1,4]diazepan-1-yl-1-phenyl-1H-indole-3-carboxaldehyde (438 mg, 1.37 mmol), epibromohydrin (188 mg, 1.37 mmol) and potassium carbonate (758 mg, 5.49 mmol) in acetonitrile (20 mL) is refluxed for 2.5 hr. The reaction mixture is cooled, the solvent is removed and the residue is purified by chromatography eluting with dichloromethane-1 to 5% methanol. Fractions containing product are combined and concentrated to afford 2-(4-oxiranylmethyl-[1,4]diazepan-1-yl)-1-phenyl-1H-indole-3-carboxaldehyde (41% yield) as a yellow solid. LC/MS: 376 (M+H), RT 2.65 min; NMR (CDCl3): 10.28 (1H, s), 8.26 (1H, d), 7.43-7.65 (3H, m), 7.17-7.42 (3H, m), 7.13(1H, t), 6.96 (1H, d), 3.49 (4H, m), 3.03 (1H, m), 2.56-2.86 (4H, m), 2.30-2.50 (2H, m), 1.74(2H, m), 1.56 (2H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[CH:22]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:21](=O)[C:20]2[C:19]([C:31]([O:33]CC)=O)=[CH:18][CH:17]=[CH:16][C:15]=2[NH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:37][NH2:38]>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[NH:14][C:15]2[C:20]3[C:21](=[N:37][NH:38][C:31](=[O:33])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:22]1[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1Cc1ccccc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1nccn1Cc1ccccc1)C2c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of ethyl 2-(1-benzyl-1H-imidazol-2-yl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (280 mg, 0.59 mmol) and hydrazine monohydrate (2 mL, 85%) in methanol (4 mL) was stirred at 40° C. for 2 hr, and then evaporated to half of the original volume. The mixture was filtrated and washed the solid with ethyl acetate to obtain the title compound (200 mg, yield 96%). LC-MS (ESI) m/z: 437 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Cl.[C:13]1(=[O:20])[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1.[OH-].[K+].C(OCC)(=O)C>CO>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][CH:14]1[C:15](=[O:19])[CH2:16][CH2:17][CH2:18][C:13]1=[O:20]
Reactant: ClCCCc1ccccc1CCl
Reactant: O=C1CCCC(=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCCC(=O)C1Cc1ccccc1CCCCl

Procedure:
A solution of 155 g (0.75 mol) of 2-(3-chloropropyl)benzyl chloride 2 [Page, et al., J. Amer. Chem. Soc. 75:2053 (1953)], 91 g (0.81 mol) of 1,3-cyclohexanedione I [Aldrich Chem. Co. 10,160-5; Beilstein 7, 554], and 47 g of 85% KOH in 400 ml of methanol was refluxed 16 hours. After concentrating, the residue was partitioned between benzene and dilute aqueous NaOH solution. Acidification of the aqueous phase gave a solid that was recyrstallized from ethyl acetate to give 34 g of the dione 3, mp 143°-145° C.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:8]=1>ClCCl>[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:8]=1
Reactant: COc1ccc(C(=O)O)c(-c2ccc(F)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccc(O)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A solution of boron tribromide (0.066 mol) in dichloromethane (66 ml) was added dropwise to a solution of 4-methoxy-2-(4-fluorophenyl)benzoic acid (7.7 g; 0.029 mol) in dried dichloromethane (215 ml) under argon at 0° C. The reaction was stirred for 1 hour at 0° C. and allowed to warm to ambient temperature and stirred for a further 16 hours. It was then poured into ice water and extracted with firstly dichloromethane then with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate and the aqueous phase acidified to pH 1 with concentrated HCl and extracted with ethyl acetate. The ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to give 4-hydroxy-2-(4-fluorophenyl)benzoic acid as a yellow oil (4.5 g), which was used without further purification.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl>[C:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][Cl:24])=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(CCCOc1ccc(CO)cc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(CCCOc1ccc(CCl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
1.5 g of 4-(3-benzenesulfonylpropyloxy)benzyl alcohol were dissolved in 30 ml of chloroform, and the resultant solution was further fed dropwise with 0.7 g of thionyl chloride and then stirred for 1 hour at room temperature. After completed the reaction, the solution reacted was poured into ice-water and extracted with chloroform. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 1.6 g of 4-(3-benzenesulfonylpropyloxy)benzyl chloride.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6](=[O:13])[NH:7][S:8]2(=[O:10])=[O:9])=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:23]1([S:29][CH2:30]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH:14]([C:4]1[CH:3]=[C:2]([OH:1])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:13])[N:7]([CH2:30][S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:8]2(=[O:10])=[O:9])([CH3:16])[CH3:15]
Reactant: CC(C)c1cc(O)cc2c1C(=O)NS2(=O)=O
Reactant: ClCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CC(C)c1cc(O)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69.9 %

Procedure:
6-hydroxy-4-isopropylsaccharin (30.0 g, 0.12 mol) in methanol was treated with Cs2CO3 (20.28 g, 0.062 mol). The mixture was stirred at ambient temperature for 3-4 hours, the excess methanol was removed under reduced pressure and the residue was dried under high vacuum. The residue was dissolved in DMF and chloromethyl phenyl sulfide (21.72 g, 0.14 mol) was added. The mixture was heated at 70°-80° C. for 24 hours, cooled, treated with ice-water and extracted with ethyl acetate/ether. The organic layer was washed with water, then brine and was dried. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with ethyl acetate/hexane to afford 30.5 g (67%) of 4-isopropyl-6-hydroxy-2-phenylthiomethylsaccharin.
Reaction SMILES: C([N:14]1[C:18]2[CH:19]=[C:20]([C:23]3[CH:57]=[C:56]([CH3:58])[CH:55]=[CH:54][C:24]=3[O:25][C:26]3[C:31]([F:32])=[CH:30][C:29]([S:33]([N:36](CC4C=CC(OC)=CC=4OC)[C:37]4[S:41][N:40]=[CH:39][N:38]=4)(=[O:35])=[O:34])=[C:28]([F:53])[CH:27]=3)[CH:21]=[CH:22][C:17]=2[O:16][C:15]1=[O:59])(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[F:53][C:28]1[CH:27]=[C:26]([O:25][C:24]2[CH:54]=[CH:55][C:56]([CH3:58])=[CH:57][C:23]=2[C:20]2[CH:21]=[CH:22][C:17]3[O:16][C:15](=[O:59])[NH:14][C:18]=3[CH:19]=2)[C:31]([F:32])=[CH:30][C:29]=1[S:33]([NH:36][C:37]1[S:41][N:40]=[CH:39][N:38]=1)(=[O:34])=[O:35]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(Oc3ccc(C)cc3-c3ccc4oc(=O)n(C(c5ccccc5)c5ccccc5)c4c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Oc2cc(F)c(S(=O)(=O)Nc3ncns3)cc2F)c(-c2ccc3oc(=O)[nH]c3c2)c1
Temperature: 25 °C
Yield: 22 %

Procedure:
To a mixture of 4-(2-(3-benzhydryl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-4-methylphenoxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzene-sulfonamide (0.93 g, 1.11 mmol) in trifluoroacetic acid (10 mL) and triethylsilane (1.44 mL, 8.9 mmol) was added trifluoromethanesulfonic acid (0.5 mL, 5.7 mmol). The reaction mixture was heated under at reflux for 0.5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography eluting with a 20-100% gradient of ethyl acetate in hexanes followed by trituration in methanol (3 mL) to afford 2,5-difluoro-4-(4-methyl-2-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenoxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a light pink solid in 22% yield (0.13 g): 1H NMR (300 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.53 (s, 1H), 7.72 (dd, J=10.0, 6.4 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 7.29 (d, J=8.9 Hz, 1H), 7.27-7.23 (m, 1H), 7.17-7.11 (m, 3H), 6.90 (dd, J=10.6, 6.5 Hz, 1H), 2.37 (s, 3H), (NH not observed); MS (ES+) m/z 516.6 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)[C:10]([O:12][CH2:13][C:14]#[N:15])=[O:11])=O)(C)(C)C>C(OCC)C>[NH2:8][C@@H:9]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([I:23])=[CH:21][CH:22]=1)[C:10]([O:12][CH2:13][C:14]#[N:15])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)OCC#N
Solvent: CCOCC
Product: N#CCOC(=O)[C@@H](N)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
(S)-Cyanomethyl 2-((tert-butoxycarbonyl)amino)-3-(4-iodophenyl)propanoate (Compound 91) (0.89 g, 2.07 mmol) was dissolved in diethyl ether (20.0 ml). The solution was bubbled with hydrochloric acid gas and then stirred at room temperature for 2 hours. The solid in the reaction solution was filtered off and dried under reduced pressure to afford (S)-cyanomethyl 2-amino-3-(4-iodophenyl)propanoate (0.65 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: COCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl

Procedure:
The title compound was prepared from {4-chloro-5-[(2-methoxy-ethyl)-methyl-amino]-2-nitro-phenyl}-carbamic acid tert.-butyl ester (Example C3) (3.46 g, 9.62 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a yellow solid (2.25 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[C:5]([CH3:11])=[CH:4][N+:3]=1[O-].P(Br)(Br)[Br:14].[OH-].[Na+]>CCOC(C)=O>[Br:14][C:6]1[C:5]([CH3:11])=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(Br)c(C)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Bromination. To a solution of 1.65 g of 2,5-dimethyl-4-nitro-pyridine 1-oxide in 50 mL dry EtOAc was added 11.1 mL PBr3 at rt. The mixture was heated to reflux over 0.5 h. Reflux continued for 3 h, then cooled to rt and poured into ice and EtOAc. The resulting mixture was brought to pH 10 with addition of NaOH pellets and layers were separated. An additional EtOAc extraction was combined with the first and the organic layers were washed with brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexanes-EtOAc) to provide 4-bromo-2,5-dimethyl-pyridine (248 mg). LCMS (m/z) 186.
Reaction SMILES: [C:1]1([C:7](Cl)([Cl:9])[Cl:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(S)CCC.Cl>>[CH:7]([Cl:9])([Cl:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)(Cl)c1ccccc1
Agent: Cl
Solvent: CCCCS
Product: ClC(Cl)c1ccccc1
Yield: 73.9 %

Procedure:
19.5 g (0.1 mole) of benzotrichloride, 18 g (0.2 mole) of butanethiol and 0.2 g of copper-I bromide were heated to the reflux temperature, while stirring, and were left to react until the evolution of hydrogen chloride had ended (duration: 6 hours). The mixture was then subjected to fractional distillation to give 11.9 g (74%) of benzal chloride at a boiling point of 102°-106° C./30 mbar.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:24]([O-:26])=[O:25])=[C:18]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:21])=[O:22])[CH:19]=1
Reactant: COc1ccc([N+](=O)[O-])c(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 29.1 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (950 mg, 6.59 mmol), 5-methoxy-2-nitro-benzenesulfonyl chloride (Intermediate 447) (2.15 g, 8.57 mmol), pyridine (4 ml), DMAP (cat.) and DCM (8 ml) gave the title compound (690 mg, 30%) after purification by column chromatography with n-hexane/EtOAc (80:20) as the eluent.
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]2[O:25][C:12]3([CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:11](=[O:26])[C:10]=2[CH:27]=1.C(Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>>[CH2:18]([N:15]1[CH2:16][CH2:17][C:12]2([C:11](=[O:26])[C:10]3[CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:2])=[O:28])[CH:7]=[CH:8][C:9]=3[O:25]2)[CH2:13][CH2:14]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)C1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)C1(CCN(Cc3ccccc3)CC1)O2
Yield: 93 %

Procedure:
(E)-3-{1′-Benzyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid methyl ester was obtained starting from (E)-3-{3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid methyl ester (247 mg, 0.76 mmol, Intermediate 4) and benzyl bromide, according to the procedure described in Example 2, Step A (280 mg, 98%). The methyl ester was hydrolyzed with NaOH following the procedure described in Example 1, Step A, giving (E)-3-{1′-benzyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-acrylic acid as a white solid (249 mg, 93%). The resulting acid was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-benzyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (62 mg, 20%). Finally, removal of the THP protecting group following the procedure described in Example 1, Step C gave (E)-3-{1′-benzyl-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-5-yl}-N-hydroxy-acrylamide as its hydrochloride salt (30 mg, 50%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][C:5]=1[OH:22])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][C:5]=1[OH:22]
Reactant: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(O)c(N)c1
Temperature: 25 °C

Procedure:
A mixture of 61.4 g. (0.2 mole) of 2-nitro-4-dodecylphenol and 1 g. of 5% of palladium on carbon slurried in 100 ml of 95% ethanol was placed in a 250 ml hydrogenation bottle. The bottle was stoppered under an atmosphere of 45 psi of hydrogen and shaken at room temperature. The hydrogen was replenished during reaction. After 4 hours the hydrogen uptake was complete. The mixture then was filtered through a sintered glass funnel and the filtrate was stripped of solvent under reduced pressure. The yield of product, 2-amino-4-dodecylphenol, was quantitative. Infrared, nuclear magnetic resonance (nmr) and gas liquid chromatography (glc) analyses confirmed its structure and purity.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:3]=1[I:14].[OH-].[Na+].Cl[CH:18]([F:20])[F:19].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:18]([F:20])[F:19])=[C:4]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:3]=1[I:14]
Reactant: FC(F)Cl
Reactant: Oc1ccc(Br)c(I)c1OCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: FC(F)Oc1ccc(Br)c(I)c1OCC1CC1
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To 20 ml of toluene solution containing 1.84 g (5.0 mmol) of 4-bromo-2-cyclopropylmethoxy-3-iodophenol obtained in Reference example 12-(d) were added 0.8 g (2.5 mmol) of tetrabutylammonium bromide and 10 ml of 35% aqueous solution of sodium hydroxide, and then, 5.0 g (62 mmol) of chlorodifluoromethane was blown thereinto at 80° C. over 30 minutes. After completion of the reaction, 2N hydrochloric acid was added to the reaction mixture to adjust a pH thereof to 5. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.93 g of the title compound as a colorless oil. (Yield: 92%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (276 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (420 mg, 82%).
Reaction SMILES: [P:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][O:22][C:23](=[O:77])[C:24]1[CH:29]=[C:28](CC2C=CC=CC=2)[C:27]([NH:37][C:38]([C@H:40]2[C@H:44]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=3[F:52])[C@:43]([C:55]3[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][C:56]=3[F:62])([C:53]#[N:54])[C@H:42]([CH2:63][C:64]([CH3:67])([CH3:66])[CH3:65])[NH:41]2)=[O:39])=[C:26]([O:68][CH3:69])[C:25]=1CC1C=CC=CC=1)=[O:19])([OH:4])([OH:3])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[P:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][O:22][C:23](=[O:77])[C:24]1[CH:29]=[CH:28][C:27]([NH:37][C:38]([C@H:40]2[C@H:44]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:46]=3[F:52])[C@:43]([C:55]3[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][C:56]=3[F:62])([C:53]#[N:54])[C@H:42]([CH2:63][C:64]([CH3:66])([CH3:67])[CH3:65])[NH:41]2)=[O:39])=[C:26]([O:68][CH3:69])[CH:25]=1)=[O:19])([OH:3])([OH:4])=[O:2]
Reactant: [H][H]
Reactant: COc1c(Cc2ccccc2)c(C(=O)OCOC(=O)OCCOCCOCCOCCOP(=O)(O)O)cc(Cc2ccccc2)c1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OCOC(=O)OCCOCCOCCOCCOP(=O)(O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 83.4 %

Procedure:
A solution of chiral dibenzyl 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-{2-[2-(2-phosphonooxy-ethoxy)-ethoxy]-ethoxy}-ethoxycarbonyloxymethyl ester (Example 49, 106.7 mg, 0.095 mmol) in ethyl acetate (10 mL) was treated with 10% palladium on carbon (58 mg) under 1 atm of hydrogen for 1 h. The reaction mixture was filtrated and the filtrate was concentrated to give chiral 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-{2-[2-(2-phosphonooxy-ethoxy)ethoxy]-ethoxy}-ethoxycarbonyloxymethyl ester as a white solid (75 mg, 82% yield). MS (ES+) m/z calcd. for C41H49Cl2F2N3O14P: [(M+H)+]: 946, found: 946.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20]C3C=CC(Cl)=CC=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](OCC)=O)=[CH:33][CH:32]=1.FC(F)(F)C1C=CC(CC(OCC)=O)=CC=1.C(N)CC1C=CC=CC=1.ClC1C=CC(N)=CC=1>>[C:3]1([CH3:2])[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20][CH2:38][CH2:37][C:34]3[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1ccc(Cl)cc1
Reactant: O=c1c(-c2ccc(C(F)(F)F)cc2)c[nH]c2ccnc(Nc3ccc(Cl)cc3)c12
Agent: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Agent: NCCc1ccccc1
Agent: Nc1ccc(Cl)cc1
Product: Cc1ccc(-c2c[nH]c3ccnc(NCCc4ccccc4)c3c2=O)cc1

Procedure:
3-(4-Trifluoromethylphenyl)-1,4-dihydro-4-oxo-5-(4-chlorophenylamino)-1,6-naphthyridine The title compound was prepared as described in Example 1 above except that ethyl (4-chlorophenyl)acetate was replaced with ethyl (4-trifluoromethyl-phenyl)acetate and phenethylamine was replaced with 4-chloroaniline. MS 416 (M+1)+.