Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][C:18]=4[CH3:25])[C:15]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[OH-].[Li+]>C1COCC1.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][C:18]=4[CH3:25])[C:15]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(CN)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CN)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (30C) (300 mg) in THF/H2O (v/v=1/1, 6 mL) was added lithium hydroxide monohydrate (50.4 mg, 2.10 mmol). The solution was stirred at room temperature overnight. THF was removed under reduced pressure and the resulting solution was acidified with 10% hydrochloric acid to pH=6.0. The resulting precipitate was isolated by centrifuge, rinsed with water, dried under reduced pressure and purified by prep-HPLC to afford 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-(aminomethyl)-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid (30D) (170 mg, 74%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH3:21]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:20][CH3:21])[CH:7]=[O:8])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C=O)cc1OCC
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
3-Ethoxy-4-hydroxy-benzaldehyde (Aldrich, 100 g, 0.602 mole) was dissolved in N,N-dimethylformamide (1 L). The reaction was placed under N2. Solid potassium carbonate (103 g, 0.662 moles) was added and the reaction was stirred 10 minutes. Iodoethane (175 g, 1.26 moles) was added and the reaction was stirred for 16 hours at room temperature. The reaction was monitored by thin-layer chromatography which indicated complete consumption of the phenol to give a new product. The reaction was filtered to remove the potassium carbonate and solvent removed in vacuo. The residue was dissolved in methylene chloride and filtered. Silica gel (200 g) was added and the dichloromethane removed in vacuo. The crude product absorbed on silica gel was submitted to flash chromatography (hexane, 100%, 2 L, then ethyl acetate:hexane, 1:3, 2 L, then ethyl acetate:hexane, 1:1) to yield 109.36 g of 3,4-diethoxy-benzaldehyde 1HNMR (CDCl3): 9.83 (s, 1H), 7.41 (m, 2H), 6.96 (d, 1H), 4.17 (m, 4H), 1.50 (t, 3H) 1.47 (t, 3H).
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([CH2:9][OH:10])[CH2:5][CH:6]([CH3:8])[CH3:7].[C:11](#N)C.CI>C1COCC1>[CH2:5]([C@H:4]([NH2:3])[CH2:9][O:10][CH3:11])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](N)CO
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H](N)CC(C)C
Temperature: 55 °C

Procedure:
Sodium hydride (60% dispersion in oil: 9.39 g, 0.24 mol) was added to a stirred solution of L-leucinol (25 ml, 0.20 mol) in a mixture of dry acetonitrile (12 ml) and dry THF (60 ml) at room temperature under argon. The mixture was heated at reflux for 2 h, cooled to 55° C. and methyl iodide (12.8 ml, 2.1 mol) carefully added. The reaction mixture was heated at reflux overnight and allowed to cool to room temperature. Ice cold brine (100 ml) was added carefully and the mixture extracted with ethyl acetate (3×100 ml). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated. The residue was distilled under reduced pressure to give (S)-1-isobutyl-2-methoxyethylamine as a colourless oil which was used directly in the next step.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]([CH2:15][O:16][CH2:17][C@@H:18]1[CH2:22][C@@H:21]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][N:19]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])(=O)[NH2:13].Cl.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>O1CCCC1.O.C(OCC)(=O)C.C(N(CC)CC)C.CO>[CH3:42][S:43]([NH:13][CH2:12][CH2:15][O:16][CH2:17][C@@H:18]1[CH2:22][C@@H:21]([O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][N:19]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCOC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium borohydride (0.5 g) in tetrahydrofuran (30 ml) was dropwise added boron trifluoride etherate (5.8 ml) under ice-cooling. After 30 minutes, a solution of (2S,4R)-2-(carbamoylmethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.40 g) in tetrahydrofuran (10 ml) was added to the mixture under ice-cooling, and the mixture was stirred under the same condition for 2 hours and at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was stirred in a mixture of concentrated hydrochloric acid (4 ml) and methanol (40 ml) at ambient temperature for 16 hours, and evaporated under reduced pressure to give a syrup. To a solution of the syrup in tetrahydrofuran (30 ml) were added triethylamine (1.2 ml) and methanesulfonyl chloride (0.5 ml) in turn under ice-cooling. After stirring for 1 hour, the reaction mixture was poured into a mixture of ethyl acetate (150 ml) and water (100 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (30 g) and eluted with a mixture of methanol and chloroform (3:97 V/V) to give (2S,4R)-2-[2-(methanesulfonylamino)ethyloxymethyl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.30 g).
Reaction SMILES: C([O:5][C:6]([NH:8][CH2:9][CH2:10][C@@H:11]1[C:15]2[C:16]3[N:17]([N:20]=[C:21]([CH3:28])[C:22]=3C(OCC)=O)[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1)=O)(C)(C)C.[CH2:29](N(CC)CC)C.C(OC(=O)C)(=O)C.O>Cl.O1CCCC1>[CH3:28][C:21]1[CH:22]=[C:16]2[C:15]3[C@@H:11]([CH2:10][CH2:9][NH:8][C:6](=[O:5])[CH3:29])[CH2:12][CH2:13][C:14]=3[CH:19]=[CH:18][N:17]2[N:20]=1
Reactant: CCOC(=O)c1c(C)nn2ccc3c(c12)[C@@H](CCNC(=O)OC(C)(C)C)CC3
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NCC[C@H]1CCc2ccn3nc(C)cc3c21
Temperature: 100 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
A mixture of ethyl (9R)-9-{2-[(tert-butoxycarbonyl)amino]ethyl}-2-methyl-8,9-dihydro-7H-cyclopenta[c]pyrazolo[1,5-a]pyridine-1-carboxylate (135 mg, 0.348 mmol) in 12M hydrochloric acid (4 mL) was stirred at 100° C. for 3 days, and concentrated under reduced pressure. To a mixture of the residue and triethylamine (485 μL, 3.48 mmol) in tetrahydrofuran (3.5 mL) was added acetic anhydride (98.7 μL, 1.04 mmol) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Water (50 μL) was added, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (86.0 mg, yield 96%, 99.9% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD-H mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=95/5, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.5 mg/mL (hexane/ethanol=95/5), injection volume: 10 μL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH2:22][NH:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:28]I.O>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH2:22][N:21]2[CH3:28])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CI
Reactant: CS(=O)(=O)c1ccc(Oc2c(Cl)cc(N3NCC(=O)NC3=O)cc2Cl)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CC(=O)NC(=O)N1c1cc(Cl)c(Oc2ccc(S(C)(=O)=O)cc2)c(Cl)c1
Reaction time: 3 h

Procedure:
1 g of 2-[3,5-dichloro-4-(4-methylsulfonylphenoxy)phenyl]hexahydro-1,2,4-triazine-3,5-dione in 10 ml of N-methylpyrrolidone was heated at 140° to 160° C. with 10 ml of methyl iodide for four hours and, after addition of a further 10 ml of methyl iodide, for a further three hours. After the mixture had been cooled, water was added and an oil separated out, which slowly became solid and was recrystallized from methanol with the addition of active charcoal. Melting point 223° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7][Br:8])=[CH:4][CH:3]=1.CO.Cl.[CH3:15][O:16][NH2:17].[Br-].[Li+]>CC(C)=O>[CH3:15][O:16][N:17]=[C:6]([C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:7][Br:8]
Reactant: CON
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CO
Solvent: CC(C)=O
Product: CON=C(CBr)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
A 2.0 L round bottom flask was charged with 4-fluorophenacyl bromide (97.6 g, 450 mmol), then methanol (750 mL), then O-methylhydroxylamine hydrochloride (75.1 g, 899 mol), and the mixture was heated to 65° C. for 2 hours. The reaction mixture was then concentrated under reduced pressure, charged with acetone (750 mL), and lithium bromide (195 g, 2.25 mol), and heated to 60° C. for 15 hours. The reaction mixture was then concentrated under reduced pressure, suspended in 1.0 L methylene chloride, and washed with 3×200 mL water. The aqueous extracts were then pooled and back-extracted with 2×200 mL methylene chloride. All organic extracts were then pooled, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield O-methyloxime 30. Yield of 30: 92.3 g (83%). 1H NMR (500 MHz, CDCl3) δ 4.10 (s, 3H), 4.35 (s, 2H), 7.11 (t, J=8.8 Hz, 2H), 7.72 (m, 2H). MS (ESI+) 246.0.
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[F:7])[C:3](=[S:5])[NH2:4].Cl[CH:12]([C:18](=O)[C:19]([F:22])([F:21])[F:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14].FF.C(N(CC)CC)C>C(#N)C>[F:1][C:2]([F:10])([C:3]1[S:5][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]([C:19]([F:20])([F:22])[F:21])[N:4]=1)[C:6]([F:9])([F:8])[F:7]
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: NC(=S)C(F)(F)C(F)(F)F
Agent: FF
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1sc(C(F)(F)C(F)(F)F)nc1C(F)(F)F
Reaction time: 48 h
Yield: 53.4 %

Procedure:
557 mg (3.10 mmol) of 2,2,3,3,3-pentafluoropropanethioamide and 746 mg (3.41 mmol) of ethyl 2-chloro-4,4,4-trifluoro-3-oxobutanoate (commercially available or can be prepared in accordance with Journal of Fluorine Chemistry 2004, 125, 1287-1290) are dissolved in 15 ml of acetonitrile, and 0.86 ml (6.19 mmol) of triethylamine is added dropwise. The reaction mixture is heated at reflux for 5 hours and then left at room temperature for two days. Chromatographic purification on silica gel gives 568 mg of ethyl 2-(pentafluoroethyl)-4-(trifluoromethyl)-1,3-thiazole-5-carboxylate (13%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1.N1[CH:27]=[C:26]([C:28]2[S:32][C:31]([O:33][C@@H:34]3[CH:41]4[CH2:42][N:37]5[CH2:38][CH:39]([CH2:43][CH:35]3[CH2:36]5)[CH2:40]4)=[N:30]C=2)[CH:25]=N1.[NH3:44]>>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[C:26]([C:28]1[S:32][C:31]([O:33][C@@H:34]2[CH:41]3[CH2:42][N:37]4[CH2:38][CH:39]([CH2:43][CH:35]2[CH2:36]4)[CH2:40]3)=[N:30][N:44]=1)([CH3:25])([CH3:12])[CH3:27]
Reactant: c1n[nH]cc1-c1cnc(OC2C3CC4CC2CN(C4)C3)s1
Reactant: N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)c1nnc(OC2C3CC4CC2CN(C4)C3)s1

Procedure:
The free base of the title compound was prepared from the product of Example 56A (929 mg, 3.02 mmol) according to Method C, and then converted to the p-toluenesulfonate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) δ ppm 1.42 (s, 9H) 1.99 (d, J=13.6 Hz, 2H), 2.21 (s, 1H), 2.32 (s, 2H), 2.36 (s, 3H), 2.73 (s, 2H), 3.52-3.81 (m, 6H), 5.52 (s, 1H), 7.23 (d, J=7.8 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H). MS (DCI/NH3) m/z=294 (M+H)+. Anal. Calcd. for C15H23N3OS.C7H8O3S: C, 56.75; H, 6.71; N, 9.02. Found: C, 56.62; H, 6.81; N, 8.98.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](F)=[C:11]([F:33])[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[C:13]([CH:24]=1)[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:35]=[N+:36]=[N-:37].[Na+].O>CN(C=O)C>[N:35]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][C:13]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[C:12]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])[C:11]=1[F:33])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1c(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c(Nc2ccccc2F)c1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
To a solution of benzyl 5-benzyloxy-3,4-difluoro-2-((2-fluoro-phenyl)amino)benzoate (21.42 g, 46.22 mmol) in DMF (150 mL) was added NaN3 (3.61 g, 55.46 mmol). The mixture was stirred at 90° C. for 3 h. Then water (300 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) and gave the desired product (pale yellow solid, 14.63 g, 65% yield). 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.49 (s, 1H), 7.39 (m, 10H), 7.07 (m, 1H), 7.04 (m, 1H), 6.90 (m, 1H), 6.83 (m, 1H), 5.31 (s, 2H), 5.13 (s, 2H).
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[CH3:14][CH:15]([CH3:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19].CC(C)([O-])C.[K+]>>[CH:15]([C:16]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][NH:11][CH:12]=1)([CH3:22])[CH3:14]
Reactant: COC(=O)/C=C/C(C)C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)c1c[nH]cc1C(C)C
Yield: 53.8 %

Procedure:
Using p-toluenesulfonylmethyl isocyanide (7.6 g), methyl (2E)-4-methylpent-2-enoate (5.0 g) and potassium tert-butoxide (5.25 g), a procedure as in Reference Example 39 was performed to give the title compound as a pale-yellow oil (yield 3.5 g, 54%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1.[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[S:47](Cl)(=[O:49])=[O:48]>O1CCCC1>[CH3:17][O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:30]=[C:29]([CH:31]2[CH2:36][CH2:35][N:34]([S:47]([C:41]3[CH:42]=[CH:43][C:44]([Cl:46])=[CH:45][C:40]=3[Cl:39])(=[O:49])=[O:48])[CH2:33][CH2:32]2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:37])[CH:27]=2)[CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1cc(C2CCNCC2)c2cc(F)ccc2c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
Diisopropylethylamine (0.6 mL, 3.4 mmol) was added at 0° C. to a solution of (6-fluoro-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt (which may be prepared as described above; 150 mg, 0.36 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 30 min. 2,4-Dichlorobenzenesulfonyl chloride (available from Sigma-Aldrich; 133 mg, 0.54 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using a Biotage purification system, eluting with 10% ethyl acetate/hexanes, to give {4-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (120 mg, 65%) as a sticky off-white solid. MS cald. for C24H23Cl2FNO4S [(M+H)+]: 510, obsd. 510.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]2[C@H:13]([O:14]C(=O)CCl)[CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)=[C:4]([N+:26]([O-:28])=[O:27])[CH:3]=1.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]2[C@H:13]([OH:14])[CH2:12][N:11]([C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:10]2)=[C:4]([N+:26]([O-:28])=[O:27])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@H](OC(=O)CCl)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 101.7 %

Procedure:
To a solution of the (3S,4R)-tert-butyl 3-(4-bromo-2-nitrophenylamino)-4-(2-chloroacetoxy)pyrrolidine-1-carboxylate (2.20 mmol, 1.0 g) in methanol add 2.0 M aqueous lithium hydroxide (5 mL) and stir at room temperature for 3.5 h. Remove the solvent, dilute the residue with ethyl acetate (50 mL), and wash with water and brine. Dry over anhydrous sodium sulfate, filter, and evaporate the solvent. Purify by column chromatography eluting with 50% ethyl acetate in methylene chloride to obtain the title compound as a yellow solid (900 mg, 98%). APCI MS m/z 462 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@H:19]([C:32]([N:34]([C@@H:46]([CH3:54])[CH:47]([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])[CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[CH2:52]([O:51][CH:47]([O:48][CH2:49][CH3:50])[C@@H:46]([N:34]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[C:32](=[O:33])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH3:54])[CH3:53]
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 69 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-13) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[N:9][S:10][CH:11]=1)(=O)=O.O[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[C:22]([CH3:33])[C:21]=1[CH3:34]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:8]2[C:7]([CH2:6][O:5][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([CH3:33])[C:21]=3[CH3:34])=[CH:11][S:10][N:9]=2)=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: Cc1c(CCC(=O)O)ccc(OCc2csnc2-c2ccc(Br)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(4-bromophenyl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.60 (abq, J=10.5, 4.5 Hz, 4H), 6.98 (d, J=7.5 Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 5.05 (s, 2H), 2.95 (t, J=7.0 Hz, 2H), 2.62 (t, J=7.0 Hz, 2H), 2.25 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:18])[N:4](CC)[C:5](CC)=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:7]=1.ONC(=N)C1C(=O)N(CC)C(CC)=C(C2C=CN=CC=2)C=1>>[NH2:1][C:2]1[C:3](=[O:18])[NH:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CCc1c(-c2ccncc2)cc(N)c(=O)n1CC
Agent: CCc1c(-c2ccncc2)cc(C(=N)NO)c(=O)n1CC
Product: Nc1cc(-c2ccncc2)c[nH]c1=O

Procedure:
D-12. 3-Amino-1,6-diethyl-5-(4-pyridinyl)-2(1H)pyridinone, using N-hydroxy-1,6-diethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](OB(O)O)[CH:22]=[CH:23][CH:24]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]2=[O:1])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Reactant: COc1cccc(OB(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc2ccccc2n(-c2cccc(OC)c2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 205.6 %

Procedure:
2.0 g (9.2 mmol) of ethyl 2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in dichloromethane (100 mL), and 2.8 g (1.8 mmol) of 3-methoxyphenylboric acid, 3.3 g (1.8 mmol) of anhydrous copper (II) acetate and 1.4 g (1.8 mmol) of pyridine were added thereto. The mixture was stirred for 72 hours at room temperature. After completion of the reaction, the inorganic matter was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by column chromatography (developing solvent:ethyl acetate:hexane=1:1), to obtain 1.2 g (yield: 42%) of ethyl 1-(3-methoxyphenyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:12]([CH3:24])[C:11]([CH2:25][OH:26])=[N:10]1.[H-].[Na+].[CH2:29]([O:31][C:32](=[O:37])[C:33](Br)([CH3:35])[CH3:34])[CH3:30]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:29]([O:31][C:32](=[O:37])[C:33]([O:26][CH2:25][C:11]1[C:12]([CH3:24])=[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:10]=1)([CH3:35])[CH3:34])[CH3:30]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(CO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)OCc1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2 g of [1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-methanol in 15 ml of DMF were added 997 mg of sodium hydride (60% in mineral oil) at room temperature. After 15 min 1.8 g of tetrabutylammonium iodide and 2.9 g of 2-Bromo-2-methyl-propionic acid ethyl ester were added and the reaction mixture was stirred for 16 h at room temperature. After dilution with saturated aqueous sodium hydrogen carbonate solution the reaction mixture was filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g.