Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][F:35])=[CH:27][CH:26]=2)[C:21](O)=[O:22])=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:36][O:37][CH2:38][C@@H:39]([NH2:41])[CH3:40].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@H:20]([NH:19][C:17]([C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][N:11]2[S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:9])=[O:10])=[O:18])[C:21](=[O:22])[NH:41][C@@H:39]([CH3:40])[CH2:38][O:37][CH3:36])=[CH:26][CH:27]=1
Reactant: O=C(N[C@@H](Cc1ccc(OCCCF)cc1)C(=O)O)C1CCCCN1S(=O)(=O)c1cccc(F)c1
Reactant: COC[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC[C@H](C)NC(=O)[C@H](Cc1ccc(OCCCF)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
(S)-2-{[1-(3-Fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-[4-(3-fluoro-propoxy)-phenyl]-propionic acid (compound 18b) (80 mg, 0.16 mmol), (S)-1-methoxy-2-propylamine (14 mg, 0.16 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol) were mixed in dichloromethane (2 mL). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane, washed twice with a saturated aqueous sodium bicarbonate solution, and the organic layer was dried over magnesium sulfate. After manual filtration and subsequent concentration the resulting oil was chromatographed on silica gel (dichloromethane/methanol, 9/1) on silica gel to provide 66 mg (72%) of the title compound. MS: m/e 582.2 (M+H). 1H NMR (300 MHz, d6-DMSO): δ0.75-1.60 (m, 9H), 1.85-2.15 (m, 3H), 2.75 (m, 1H), 2.85 (m, 1H), 3.10 (m, 1H), 3.20 (m, 1H), 3.60 (d, 1H, J=12 Hz), 3.85 (m, 1H), 4.00 (t, 2H, J=6 Hz), 4.30 (q, 1H J=7.5 Hz), 4.50 (m, 2H), 4.65 (t, 1H, J=6 Hz), 6.85 (d, 2H, J=9 Hz), 7.15 (d, 2H, J=9 Hz), 7.40 (m, 4H), 7.75 (d, 1H, J=9 Hz), 7.90 (d, 1H, J=6 Hz).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7](=[O:17])[C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9].[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[CH3:5][O:6][C:7](=[O:17])[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][Cl:18])=[CH:14][CH:15]=1)([CH3:9])[CH3:16]
Reactant: COC(=O)C(C)(C)c1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 110.9 %

Procedure:
MDC (600 ml) and aluminum chloride (347 gms) were charged to a reactor and chilled to −10° C. Methyl-2-methyl-2 phenyl-propanoate (Intermediate 4) (500 gms) was dissolved in MDC (650 ml) and added slowly through a dropper at −10 to 0° C. to obtain mixture A. MDC (600 ml) and aluminum chloride (520 gms) were charged to a different reactor, and chilled to −10° C. 4-chloro butyryl chloride (550 gms) was dissolved in MDC (650 ml) and added slowly through a dropper at −10 to 0° C. to obtain mixture B. Both mixtures A and B were stirred for 45 minutes at −10 to 0° C. separately. Mixture A was added to mixture B slowly at −10 to 0° C. and the reaction monitored by GC for completion (24 hours). The mass was quenched slowly in conc. HCl (1 ltr) at 10-20° C. and stirred for 30 minutes. The MDC layer was separated and the aqueous layer extracted with MDC (500 ml). The combined MDC layer was dried over sodium sulfate and concentrated under vacuum to obtain 880 gms of the title compound as an oil.
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])(=[O:4])=[O:3].[C:11](Cl)(=[O:13])[CH3:12]>>[CH3:1][S:2]([O:5][CH:6]([CH3:10])[C:7]([O:9][C:11](=[O:13])[CH3:12])=[O:8])(=[O:4])=[O:3]
Reactant: CC(=O)Cl
Reactant: CC(OS(C)(=O)=O)C(=O)O
Product: CC(=O)OC(=O)C(C)OS(C)(=O)=O

Procedure:
The acyl halides can be converted to the symmetrical or mixed acid anhydrides corresponding to the compounds of formula II when Y is acyloxy, by contacting the acyl halide with an appropriate acid. For example, 2-methanesulfonyloxypropionyl chloride is allowed to react with acetic acid to afford the mixed anhydride, acetic 2-methanesulfonyloxypropionic anhydride. Additionally, for example, 2-methanesulfonyloxypropionyl chloride is allowed to react with 2-methanesulfonylotypropionic acid to afford bis(2-methanesulfonyloxypropionic)anhydride, a symmetrical anhydride. Alternatively, the acid precursors of the acyl halides of formula II can be contacted with an appropriate acyl halide to afford the symmetrical or mixed acid anhydrides. For example, 2-methanesulfonyloxypropionic acid is allowed to react with acetyl chloride to afford the mixed anhydride, acetic 2-methanesulfonyloxypropionic anhydride.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.CCCCCC.[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]\[CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:30])=C)[CH:23]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[C:13]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[CH2:30])[CH:23]=2)[CH3:20])=[CH:2][CH:1]=1)([CH3:12])([CH3:31])[CH3:32]
Reactant: C=C(C)c1cccc(CN(C)C/C=C\C#CC(C)(C)C)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: c1ccccc1
Product: C=Cc1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
Methyl triphenylphosphonium bromide (1.07 g; 3.00 mmol) was added to benzene (20 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 1.9 ml; 3.00 mmol) was added dropwise. The mixture was stirred for 10 minutes, and Compound 5 (0.59 g; 2.00 mmol) in benzene (15 ml) was added dropwise thereto, followed by stirring for 3 hours at room temperature. Reaction was stopped by pouring the mixture into ice/water, followed by extraction with benzene (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 0.29 g of the target compound as pale yellow oily matter (yield: 49.4%).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[C:10]([CH2:31][CH3:32])([CH2:29][CH3:30])[NH:9]1)=[O:7])(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[C:10]([CH2:29][CH3:30])([CH2:31][CH3:32])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CCC1(CC)NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(CC)NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 48c (0.33 g, 0.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5,5-diethyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white foam (0.35 g, 96%).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[CH:4]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[CH3:18][N:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=1
Reactant: N#Cc1cc(Nc2cccnc2)ccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cccnc1)c1ccnc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
NaH (185 mg, 7.71 mmol, 1.10 eq) was added to a flame-dried round-bottom flask and anhydrous THF (17.5 mL) was added. The slurry was cooled to 0° C. and compound 10 (1.374 g, 7.003 mmol, 1.000 eq) was added as a solution in THF (17.5 mL). After stirring at 0° C. for 30 minutes methyl iodide (481 μL, 7.71 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 473 mg (32%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J=2.5 Hz, 1H), 8.56 (dd, J=1.2, 4.7 Hz, 1H), 8.24 (d, J=6.0 Hz, 1H), 7.81 (dq, J=1.4, 8.2 Hz, 1H), 7.56-7.53 (m, 1H), 7.25 (d, J=2.6 Hz, 1H), 6.80 (dd, J=2.7, 6.0 Hz, 1H), 3.36 (s, 3H); ES-MS [M+1]+:211.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N+:9]([O-])=O)[C:5]([Cl:12])=[C:4]([Cl:13])[N:3]=1.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C@H:27]([CH2:30]N)[C@H:26]([OH:32])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1>C1COCC1>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:9][C:6]2[C:7]([Cl:8])=[C:2]([Cl:1])[N:3]=[C:4]([Cl:13])[C:5]=2[Cl:12])[CH:26]([OH:32])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)nc(Cl)c1Cl
Reactant: NC[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2c(Cl)c(Cl)nc(Cl)c2Cl)C(O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,3,5,6-tetrachloro-4-nitropyridine (S. M. Roberts et al., J. Chem. Soc. C, 2844–2848(1968)) (1.7 g, 6.5mmol) was added to a solution of (cis)-4-aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (1.71 g, 6.49 mmol) and N-methylmorpholine (0.785 mL, 7.15 mmol) in THF (50 mL) at room temperature. The resulting reaction mixture was stirred for 18 h at room temperature then partitioned between EtOAc and water, The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and the solvent evaporated to give crude product purified by flash column chromatography (20–80% EtOAc hexane) to give 3-hydroxy-4-[(2,3,5,6-tetrachloro-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester compound. M.S (M+1): 478.
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH3:12])[CH2:3][CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C1CCN2C(=NCCC2)CC1.[N+:24]([CH3:27])([O-:26])=[O:25]>C(#N)C>[CH3:1][CH:2]([CH2:11][CH3:12])[CH2:3][CH:4]([CH2:27][N+:24]([O-:26])=[O:25])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C=CCC(C)CC
Reactant: C[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CC(CC(C)CC)C[N+](=O)[O-]
Yield: 39.2 %

Procedure:
Ethyl 5-methyl-2-heptanoate 12 (6.75 g, 39.70 mmol), DBU (6.0 g, 39.7 mmol), nitromethane (21.97 g, 359.9 mmol) in acetonitrile 80 mL was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated to an oil. A solution of the oil in ether was washed with 1N HCl, brine and dried. It was evaporated to give a light oil which was chromatographed on silica gel, eluting with 5% to 10% ether in Pet. ether to give 13 (3.6 g, 42%). 1H-NMR (CDCl3) δ 4.49–4.39 (m), 4.12–4.07 (m), 3.61 (m), 2.36 (m), 1.36–1.18 (m), 0.86–0.79.
Reaction SMILES: Br[C:2]1[C:3](=[O:13])[N:4]([CH3:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][C:22](N(OC)C)=[O:23])([CH3:17])([CH3:16])[CH3:15].C([Mg]Cl)(C)C>C1COCC1.ClCCl>[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][C:22]([C:2]1[C:3](=[O:13])[N:4]([CH3:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:23])([CH3:17])([CH3:15])[CH3:16]
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reactant: Cn1c(=O)c(Br)cc2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1c(=O)c(C(=O)CNC(=O)OC(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0.3 M solution of 3-bromo-1-methylquinolin-2(1 H)-one (1 equiv; prepared as described in Tetrahedron, 64 (26), 6030-6037; 2008) and tert-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (1.2 eq) in dry THF, isopropylmagnesium chloride (3 eq) was added dropwise at room temperature. The mixture was stirred for 30 min at room temperature, diluted with dichloromethane, washed with sat. aq. NH4Cl dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, Pethroleum ether/EtOAc, from 7% to 60% EtOAc). The pooled fractions were concentraded under vacuum to the title compound. MS (ES) C17H20N2O4 requires: 316.35, found: 317. 1H-NMR (400 MHz, DMSO-d6) δ: 8.53 (1 H, s), 7.99 (1 H, d, J=7.2 Hz), 7.78 (1 H, t, J=6.8 Hz), 7.61 (1 H, d, J=8.4 Hz), 7.35 (1 H, t, J=7.2 Hz), 6.97 (1 H, bt, J=5.6 Hz), 4.45 (1 H, d, J=5.6 Hz), 3.70 (3 H, s), 1.39 (9 H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([OH:18])=[N:16][CH:17]=1.CS(O[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([O:18][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)=[N:16][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)c(F)c1
Reactant: CC(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(COc2cnc(-c3ccc(S(C)(=O)=O)cc3F)cn2)CC1

Procedure:
The title compound (80 mg, 49%) was prepared as a white solid from 5-[2-fluoro-4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 161, Step 2, 98 mg, 0.37 mmol), 1-methylethyl 4-{[(methylsulfonyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 131, Step 4, 0.138 g, 0.49 mmol) and K2CO3 (0.102 g, 0.73 mmol) in DMF (4 mL) in a manner similar to Example 152, Step 3. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 50% EtOAc/hexanes to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.66 (s, 1H), 8.33 (d, 1H, J=1.3 Hz), 8.23 (t, 1H, J=7.8 Hz), 7.85-7.70 (m, 2H), 4.91 (septet, 1H, J=6.2 Hz), 4.30-4.15 (m, 4H), 3.09 (s, 3H), 2.85-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.85-1.75 (m, 2H), 1.35-1.20 (m, 8H); LRMS (ESI), m/z 452 (M+H).
Reaction SMILES: C([O:8][C:9](=[O:31])[CH:10]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:11]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:23]([O:22][C:20]([CH2:19][N:11]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH:10]([C:9]([OH:31])=[O:8])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:21])([CH3:24])([CH3:25])[CH3:26]
Reactant: [H][H]
Reactant: CC(C)CC(C(=O)OCc1ccccc1)N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(C(=O)O)N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 100.9 %

Procedure:
N-(t-butyloxycarbonyl)methyl-N-t-butyloxycarbonyl-D,L-leucine benzyl ester (3.5 g) was dissolved in methanol (25 ml), and 10% palladium-carbon (200 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (2.8 g, 100%), which was directly used for the next reaction.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13]([CH:16]=O)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:27][S:28][CH2:29][CH2:30][CH2:31][O:32][NH2:33]>C(Cl)Cl.CO>[F:1][C:2]1[C:3]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=2[F:26])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:33]/[O:32][CH2:31][CH2:30][CH2:29][S:28][CH3:27])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CSCCCON
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Solvent: CO
Solvent: ClCCl
Product: CSCCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
The title compound was obtained by a procedure similar to that in Step B of Example 9 using 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide obtained in Step F of Example 1 as a starting material and O-(3-methylsulfanyl-propyl)-hydroxylamine obtained in Step B as a reagent. Namely, 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (76 mg, 0.158 mmol) was dissolved in a mixed solvent of methylene chloride (5 mL) and methanol (1 mL). O-(3-Methylsulfanyl-propyl)-hydroxylamine (100 μL) was added thereto, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to give a pale yellow crude product. The residue was triturated with a proper amount of ethyl acetate:hexane (1:9) to give (E)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylsulfanyl-propoxyimino)-methyl]-benzamide (88.8 mg, 96%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([OH:12])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:18])[C:5]1([CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]2=[O:13].Cl[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[O:13]=[C:6]1[C:7]2[C:3](=[C:2]([Cl:1])[C:10]([CH3:11])=[C:9]([O:12][CH2:20][C:21]#[N:22])[CH:8]=2)[C:4](=[O:18])[C:5]21[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: Cc1c(O)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(OCC#N)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O
Temperature: 65 °C

Procedure:
A stirred mixture of 4'-chloro-5'-methyl-6'-hydroxyspiro(cyclopentane-1,2'-indan)-1' ,3'-dione (9.3 g., 0.035 mole), chloroacetonitrile (2.83 g., 0.0375 mole), potassium carbonate (5.2 g., 0.0375 mole) and potassium iodide (6.2 g., 0.0375 mole) in dimethylformamide (100 ml.) is heated at 65°C. for 21/2 hours, cooled, then poured into water (1.5 1.) affording 10.7 g. of [1' ,3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxylacetonitrile which melts at 137°-9°C. after recrystallization from ethanol-water.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH:6]=[N:7][OH:8].CN(C=O)C.[Cl:14]N1C(=O)CCC1=O>[Cl-].[Na+].O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](=[N:7][OH:8])[Cl:14]
Reactant: ON=CC1CCCO1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ON=C(Cl)C1CCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A 250 mL round-bottomed flask was charged with tetrahydrofuran-2-carbaldehyde oxime (2.0 g, 17 mmol) and DMF (100 mL). 1-Chloropyrrolidine-2,5-dione (2.3 g, 17 mmol) was added and stirred at ambient temperature overnight. The reaction was poured into 1:1 brine:water (800 mL) and extracted with EtOAc). The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated to afford tetrahydrofuran-2-carbonyl chloride oxime (2.6 g, 100%).
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][S:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[Na].[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>CO>[C:2]([C:3]1[S:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=12)(=[O:1])[CH3:10]
Reactant: O=C1CCCCC1=O
Reactant: COC(=O)CSCC(C)=O
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sc(C(C)=O)c2c1CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27.5 %

Procedure:
Add methyl 2-(2-oxopropylthio)acetate (35.4 g, 183.2 mmol) to a freshly prepared solution of solid sodium (8.78 g, 381.5 mmol) in dry MeOH (300 mL) at 0° C., followed by addition of a solution of cyclohexane-1,2-dione (20 g, 152.6 mmol) in MeOH (30 mL). Stir the mixture at 0° C. for 30 min and then at 50-60° C. for additional 1.5 hour. Remove the solvent under vacuum and dilute the residue with water (100 mL). Extract the aqueous mixture with ethyl acetate (100 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na2SO4, and evaporated under vacuum. Purify the residue by a flash column on silica gel eluting with PE:EtOAc (50:1 to 30:1) to afford methyl 3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxylate as a white solid (10 g, 27.6%). MS (m/z): 239 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=2[O:9][C:10]2[CH:11]=[C:12]([NH:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[C:1]1([C:7]2[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=2[O:9][C:10]2[CH:11]=[C:12]([N:16]([CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccccc2Oc2cccc(NCc3cccnc3)c2)cc1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(Oc2ccccc2-c2ccccc2)c1

Procedure:
Using the procedure of Example 342 using N-(3-(2-phenylphenoxy)phenyl)pyrid-3-ylmethylamine and ethanesulfonyl chloride (Aldrich) and purifying via preparative HPLC eluting with 99:1 to 97:3 DCM/MeOH gave the title compound. Anal Calcd for C26H24N2O3S: C, 70.25; H, 5.44; N, 6.30. Found: C, 70.13; H, 5.39; N, 6.26. MS found 445.1 [M+H]+
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:34][CH:35]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CN1CCN(Cc2ccc(Br)cc2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Product: CN1CCN(Cc2ccc(Nc3nc4cccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Yield: 40 %

Procedure:
[5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine was prepared from 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (125 mg, 0.43 mmol) and 1-(4-bromobenzyl)-4-methylpiperazine (129 mg, 0.48 mmol) in a manner analogous to Example 77 to yield [5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amine (82 mg, 40%) as a yellow powder following purification on a 4 g Isco silica gel column using methanol in dichloromethane (0-20%) as eluent. MP=207-208° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.64 (s, 1H), 8.33 (d, J=8.0 Hz, 2H), 8.14 (d, J=8.0 Hz, 2H), 7.68 (m, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.30 (d, J=7.0 Hz, 1H), 7.18 (d, J=7.5 Hz, 2H), 3.40-3.33 (m, 5H), 2.46-2.18 (m, 8H), 2.14 (s, 3H). MS=477 (MH)+.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:36])([F:35])[CH2:30][S:31]([NH2:34])(=[O:33])=[O:32]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:34][S:31]([CH2:30][C:29]([F:36])([F:35])[F:28])(=[O:33])=[O:32])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)CC(F)(F)F
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)CC(F)(F)F)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2,2,2-trifluoroethanesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method A described hereinabove. Yield (34%); 1H NMR (d6-DMSO) δ 7.39-7.01 (m, 13H), 6.83 (d, J=8.1 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.85 (s, 1H), 2.69 (s, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); ESI m/z: 498 (M−H−).