Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2.CN(C)[CH:20]=[O:21].C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[CH:20]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:6][CH2:5]2)=[O:21]
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)CCC2OC1CCCCO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCC2OC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8.1 g of 5-bromo-1-(tetrahydropyran-2-yloxy)indane was dissolved in 100 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere. To the solution was dropwise added 20 ml of a 1.5N n-butyllithium-hexane solution at -65° C. in 10 minutes. The resulting mixture was stirred at the same temperature for 5 minutes. Thereto was added 2.3 ml of anhydrous N,N-dimethylformamide. The reaction mixture was heated to room temperature and added to a mixture of 100 ml of ice water, 100 ml of diethyl ether and 2 g of ammonium chloride. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=15/1) to obtain 6.5 g of 5-formyl-1-(tetrahydropyran-2-yloxy)indane.
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>>[Cl:22][CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(CO)o1
Reactant: O=S(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(CCl)o1

Procedure:
2-(5-Hydroxymethyl-2-furanylmethyl)-1H-isoindole-1,3(2H)-dione (10 g) was dissolved in thionyl chloride (15 ml) with the aid of gentle heat. The solution was evaporated to dryness and the solid residue re-evaporated with cyclohexanebenzene (1:1). The residue was suspended in ether, the suspension filtered, washed with ether and dried to give 2-(5-chloromethyl-2-furanylmethyl)-1H-isoindole-1,3(2H)-dione (10.1 g) m.p. 119°-122° (dec.). Analysis Found: C, 61.32; H, 3.71; N, 5.00. C14H10ClNO4 requires: C, 60.99; H, 3.66; N, 5.08%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:17]2[CH:18]=[C:19]([OH:25])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH2:3][CH2:2]1.Cl[C:27]([F:32])([F:31])C([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:17]2[CH:18]=[C:19]([O:25][CH:27]([F:32])[F:31])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cc(O)c(=O)n(C)c2)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cc(OC(F)F)c(=O)n(C)c2)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 27.6 %

Procedure:
A mixture of 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-1-methylpyridin-2-one (50 mg, 0.14 mmol), sodium chlorodifluoroacetate (252 mg, 1.65 mmol), K2CO3 (70 mg, 0.51 mmol) in dioxane (4 mL) was stirred at 100° C. for 18 h. After the mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (16 mg, 28%) as a light pink solid. 1H NMR (CDCl3, 400 MHz) δ 7.84 (m, 1H) 7.77 (d, J=2.4 Hz, 1H) 7.63 (d, J=2.4 Hz, 1H) 7.49 (d, J=2.4 Hz, 1H) 7.04 (m, 1H) 3.95 (m, 2H) 3.69 (s, 3H) 3.13 (m, 3H) 1.33-1.26 (m, 4H) 0.72-0.67 (m, 2H) 0.39-0.36 (m, 2H). LCMS (M+H)+=414.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[S:26][C:19]3=[N:20][C:21]([CH3:25])=[CH:22][C:23](=[O:24])[N:18]3[N:17]=1)=[C:7]2[C:11]([OH:13])=[O:12].[C:27]1([C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N+]=[N-])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[C:27]1([CH:33]([O:12][C:11]([C:7]2[N:8]3[C@H:3]([S:4][CH2:5][C:6]=2[CH2:14][S:15][C:16]2[S:26][C:19]4=[N:20][C:21]([CH3:25])=[CH:22][C:23](=[O:24])[N:18]4[N:17]=2)[C@H:2]([NH2:1])[C:9]3=[O:10])=[O:13])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)sc2n1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Product: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](N)[C@H]4SC3)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a suspension of the product obtained in Step 1 (4.9 g) in acetone (40 ml) was added diphenyldiazomethane (8.2 g), and the mixture was stirred overnight at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 2.94 g of the objective compound as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1.O>CS(C)=O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:16]2[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:4][CH2:3]1
Reactant: CN1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
To a solution of 1-methyl-1,4-diazepane (1 g, 8.8 mmol) in DMSO (20 mL) were added K2CO3 (2.4 g, 18 mmol) and 5-bromo-2-nitropyridine (51-7) (1.78 g, 8.8 mmol). The mixture was stirred at 65° C. for overnight. It was allowed to cool to room temperature and poured into water. The resulting solid was collected and dried under vacuum. The solid was further purified by flash column eluting with 3:1 petroleum ether/ethyl acetate and then methylene chloride to give 338a as a yellow solid (800 mg, 69%). MS: [M+H]+ 236.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].O.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a 0° C. solution of Example 1a (25 g, 127 mmol) in N,N-dimethylformamide (200 mL) was slowly added sodium hydride (3.37 g, 133 mmol) over several minutes. After stirring for 30 minutes in the cold water bath, benzenesulfonyl chloride (17.18 ml, 133 mmol) was added via a syringe. The solution was allowed to warm to room temperature overnight, quenched slowly with 500 mL water, stirred for 30 minutes, and then filtered. The solid obtained was washed with water, followed by 300 mL of hexanes, dried over high-vacuum for 16 hours to give 34 g of the title compound which was used without further purification. MS (ESI+) m/z 338.7 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[C:3]=12.[CH3:25][O:26]C1C=C(C=CC=1)C(CC#N)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:26][CH3:25])[CH:18]=3)[C:3]=12
Reactant: COc1cccc(C(=O)CC#N)c1
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Product: COc1cccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)c1

Procedure:
Compound 17 was synthesised following similar procedures outlined in Example 1 (Compound 37), using 3-methoxybenzoylacetonitrile instead of 2-chlorobenzoyl acetonitrile in Step 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19])(=[O:12])=[O:11].[CH3:20]N(C)C=O.[OH-].[Na+].COS(OC)(=O)=O>O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH:9]([S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19])(=[O:12])=[O:11])[CH3:20]
Reactant: CN(C)C=O
Reactant: O=S(=O)(Cc1c(Cl)cccc1Cl)c1cccc[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CC(c1c(Cl)cccc1Cl)S(=O)(=O)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
2-(2,6-Dichlorophenyl)methylsulfonyl pyridine 1-oxide* (1.75 g, 5.5 mmol) was added in one portion to a stirring solution of 20 mls of dimethylformamide containing 0.24 g of sodium hydroxide and 0.77 g of dimethylsulfate (6.1 mmol). The mixture was allowed to stir at room temperature for 1 h, then poured into 300 ml of rapidly stirring water whereupon a precipitate formed. The precipitate was filtered off, washed with water, and air dried to afford 1.38 g product, m.p. 179°-183° (74% yield).
Reaction SMILES: Br[N:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][CH2:3]1.[O-:9][CH2:10][CH3:11].[Na+].CN(C)C=O.O>C(OCC)C>[Br:8][C:6]1[CH:7]=[N:2][CH:3]=[C:4]([O:9][CH2:10][CH3:11])[CH:5]=1
Reactant: CC[O-]
Reactant: BrC1=CN(Br)CC=C1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cncc(Br)c1
Temperature: 65 °C
Yield: 17.9 %

Procedure:
1,5-Dibromopyridine (98%) was purchased from Lancaster Chemical Company. Sodium ethoxide (96%) and N,N-dimethylformamide (DMF) (99.9+ %. HPLC grade) were purchased from Aldrich Chemical Company. Under a nitrogen atmosphere, a mixture of3,5-dibromopyridine (5.00 g, 21.1 mmol). sodium ethoxide (2.87 g, 42.2 mmol), and DMF (10 mL) was stirred and heated at 65° C. for 15 h. The mixture was poured into water (70 mL), and anhydrous diethyl ether (155 mL) was added. Because of insoluble solids, it was necessary to filter both phases. The aqueous layer was separated and extracted with ether (2 ×25,3 ×50 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation, producing a dark-brown syrup. The brown residue was purified by vacuum distillation, affording 0.76 g (17.9%) of an oil, bp 105° C. at 5 mm Hg. 1HNMR(CDCl3): δ 9.12 (br s, 1H), 8.83 (br s, 1H), 8.42 (dd, 1H), 4.41(q,2H), 1.42(t, 3H). 13C NMR (CDCl3): δ 142.72, 136.50. 1.23.78. 64.31.14.:57.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][NH:6][C:5]1=[O:15])[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[CH2:1]([N:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][N:6]([CH2:19][CH2:20][CH2:21][CH2:22][Cl:23])[C:5]1=[O:15])[CH:2]=[CH2:3]
Reactant: ClCCCCBr
Reactant: C=CCn1c(-c2cccnc2)n[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2cccnc2)nn(CCCCCl)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-allyl-5-(3-pyridyl)-1,2,4-triazol-3(2H,4H)-one (5 g) in dimethylformamide (50 ml) was added dropwise at ambient temperature under nitrogen to a stirred mixture of sodium hydride [0.92 g; 60% dispersion in mineral oil--pre-washed with petroleum ether (b.p. 40-60° C.)] and dimethylformamide (50 ml). The mixture was then stirred at ambient temperature for 1 hour, 1-bromo-4-chlorobutane (2.65 ml) was added, and stirring at ambient temperature was continued for 16 hours. The solvent was removed in vacuo, the residue was diluted with water (60 ml), and the product was extracted into ethyl acetate (2×200 ml). The extracts were dried (MgSO4), and the solvent was removed in vacuo to leave 4-allyl-2-(4-chlorobutyl)-5-(3-pyridyl)-1,2,4-triazol-3(2H,4H)-one as a yellow oil (6.93 g).
Reaction SMILES: [CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]=1[F:7].[P:25](=O)([OH:28])([OH:27])[OH:26]>P([O-])([O-])([O-])=O>[CH:22]1([N:14]2[C:3]3[C:2](=[CH:1][C:6]([F:7])=[C:5]([N:8]4[CH2:9][CH2:10][N:11]([P:25]([OH:28])([OH:27])=[O:26])[CH2:12][CH2:13]4)[CH:4]=3)[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)[CH2:23][CH2:24]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reactant: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(P(=O)(O)O)CC3)c(F)cc2c1=O

Procedure:
To a stirred solution of 2.34 g of the product of Example 40 in 25 ml of methylene chloride under argon was added 2.57 g of N,O-bis(trimethylsilyl)triflouroacetamide and then (after 10 minutes) 2.68 g of bromotrimethylsilane. After 17 hours, the solution was evaporated to dryness at 40° C./0.02 mm. The evaporation was then repeated twice after redissolving the residue in 25 ml portions of methylene chloride. A solution of the residual solid in 25 ml of methylene chloride was added to a stirred solution of 1 ml of water in 100 ml of acetone and then stirred for 15 minutes, to hydrolyze silyl ester groups. The resulting solid was collected and washed with acetone to give 2.24 g of cream-colored solid, m.p. 246°-252° (dec.); 31P-NMR (in DMSO with 5% triethylamine) δ 9.34 compared to δ 0.54 (at 50° C.) for a salt of ciprofloxacin with an equimolar amount of phosphoric acid, and δ 0.35 for phosphoric acid. The product was soluble in 0.1M phosphate buffer, pH 7.5, unlike ciprofloxacin.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].C(OC(=O)C)(=O)C>>[C:13]([O-:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[OH:16].[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O-:10])=[O:9]
Reactant: O=C(O)c1ccccc1O
Reactant: O=C(O)CCCCCCC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C([O-])CCCCCCC(=O)[O-]
Product: O=C([O-])c1ccccc1O

Procedure:
The procedure described in Example 1, above, was used with suberic acid (315 g, 1.8 mol), salicylic acid (250 g, 1.8 mol) and 725 mL acetic anhydride. The reaction mixture formed a clear solution and then a clear melt and the final product was a light colored, transparent, slightly fluid glass which weighed 489 g. NMR spectra indicated very little acetate and no starting materials were present.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:3]=1.[OH-:37].[K+].O>C(O)C>[NH2:1][C:2]1[C:7]([C:8](=[O:37])[NH2:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C#N)C1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3ccccc3OCc3ccccc3)nc(N)c2C(N)=O)C1
Temperature: 70 °C
Reaction time: 60 h
Yield: 73 %

Procedure:
To a stirred suspension of tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (0.300 g, 0.619 mmol), which was obtained in the step (1) of Example 1-1, in ethanol (10 mL) was added a solution of potassium hydroxide (0.695 g, 12.381 mmol) in ethanol (20 mL). The reaction mixture was stirred at 70° C. for 60 hrs. After cooled to room temperature, the reaction mixture was poured into water and the resulting solid was filtrated and dried under reduced pressure to give tert-butyl 3-{2-amino-6-[2-(benzyloxy)phenyl]-3-carbamoyl-4-pyridinyl}-1-piperidinecarboxylate as a white amorphous. (0.226 g, yield; 73%)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[N:9]1[C:15](=[O:30])[C@@H:16]([C@@H:21]([C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[OH:22])[CH2:17][CH2:18][C:19]#[CH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])(=O)=O>ClCCl>[CH2:1]([C@H:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[N:9]1[C:15](=[O:30])[C@@H:16]([C@H:21]([O:22][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[CH2:17][CH2:18][C:19]#[CH:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCC[C@@H](C(=O)N1C(=O)OCC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(Cl)nc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C#CCC[C@@H](C(=O)N1C(=O)OCC[C@@H]1Cc1ccccc1)[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 95.1 %

Procedure:
To a stirred solution of 29.7 g (71.9 mmol) of the title compound from Step B above and 15.0 mL (126 mmol) of 2,6-lutidine in 300 mL of anhydrous dichloromethane at 0° C. under an atmosphere of nitrogen was added 22 mL (94 mmol) of tert-butyldimethylsilyl trifluoromethanesulfonate at a rate slow enough to keep the internal temperature below 3° C. The reaction mixture was stirred for 16 h at 0° C. then evaporated in vacuo to remove all volatiles. The residue was diluted with 400 mL of water and extracted with diethyl ether (3×300 mL). The combined organics were washed sequentially with a 0.5 M aqueous hydrochloric acid solution (100 mL), water (100 mL), brine (100 mL) then dried over magnesium sulfate. After filtration and evaporation in vacuo the residue was purified by silica gel chromatography eluting with a 5-8% ethyl acetate in hexanes gradient to afford the title compound as a colorless foam (37 g, 97%). LC-MS: m/z (ES) 527.3 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.[Al](Cl)(C)C.[CH3:14][N:15]([CH3:42])[S:16]([C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](OCC)=[O:35])[CH:25]=2)=[CH:21][C:20]=1[F:41])(=[O:18])=[O:17]>ClCCCl.C(Cl)Cl>[CH3:42][N:15]([CH3:14])[S:16]([C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34]([NH:9][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=3)=[O:35])[CH:25]=2)=[CH:21][C:20]=1[F:41])(=[O:17])=[O:18]
Reactant: COc1ccnc(N)c1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(=O)(=O)N(C)C)c(F)c2)c2cc(C)oc2c1
Agent: C[Al](C)Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccnc(NC(=O)c2cc(Oc3ccc(S(=O)(=O)N(C)C)c(F)c3)c3cc(C)oc3c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
To a solution of 4-methoxypyridin-2-amine (295 mg, 2.37 mmol) in DCE at 0° C. was added Al(CH3)2Cl (3.0 mL, 1.0M) drop wise, and the reaction was stirred for 20 minutes at room temperature. Ethyl 4-{4-[(dimethylamino)sulfonyl]-3-fluorophenoxy}-2-methyl-1-benzofuran-6-carboxylate (100 mg, 0.24 mmol) was then added and the reaction was stirred at room temperature for an additional 14 hours. The sample was diluted with CH2Cl2 and quenched with potassium sodium tartrate tetrahydrate (20% w/w) (1 mL). The organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The crude sample was introduced into a silica gel column and eluted with MeOH/CHCl3 (5/95-10/90) to provide the product (110 mg, 93% yield) as white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.49 (s, 3 H) 2.84 (d, J=1.51 Hz, 6 H) 3.91 (s, 3 H) 6.26 (s, 1 H) 6.64 (dd, J=5.75, 2.35 Hz, 1 H) 6.71-6.91 (m, 2 H) 7.52 (s, 1 H) 7.81 (t, J=8.29 Hz, 1 H) 7.91 (s, 1 H) 8.01 (s, 1 H) 8.09 (d, J=5.84 Hz, 1 H) 8.59 (s, 1 H); MS (ESI, pos): 500.
Reaction SMILES: [CH:1]([O:4][NH2:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:15]>C(Cl)Cl.[Cl-].[Na+].O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:14]([NH:5][O:4][CH:1]([CH3:3])[CH3:2])=[O:15])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: CC(C)ON
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)ONC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To as solution of the crude O-isopropyl-hydroxylamine (200 mg) from above in CH2Cl2 (5 ml) was added Et3N (0.30 ml, 2.16 mmol) and 4-nitrophenyl chloroformate (430 mg, 2.13 mmol) and the mixture stirred at room temperature for 30 min. before diluting with CH2Cl2 (20 ml) and brine (15 ml). The aqueous layer was extracted with CH2Cl2 (1×15 ml) and the combined organic extracts dried (Na2SO4), concentrated and purified by column chromatography on silica gel (Hexanes/EtOAc, 4:1) to afford N-(4-nitrophenoxycarbonyl)isopropoxylamine (290 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:13][CH2:14][CH2:15][CH2:16][S:17]([NH:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:28])(=[O:19])=[O:18]>O>[Cl-:13].[CH3:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][S:17]([CH2:16][CH2:15][CH2:14][N+:10]1[CH:11]=[CH:12][N:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:9]=1)(=[O:19])=[O:18]
Reactant: Cc1cccc(C)c1NS(=O)(=O)CCCCl
Reactant: CCCCCCCn1ccnc1
Solvent: O
Product: CCCCCCCn1cc[n+](CCCS(=O)(=O)Nc2c(C)cccc2C)c1
Product: [Cl-]

Procedure:
Combine 15.0 g (0.0919 mole) 1-heptyl-1H-imidazole and 25.5 g (0.0974 mole) 3-chloro-N-(2,6-dimethylphenyl)propanesulfonamide and heat for about 24 hours at 130° C. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile: ammonium hydroxide, 9:1). At the completion of the reaction, dissolve the resulting cooled oil in 500 ml H2O. Extract the resultant solution with 6×500 ml hexane. Extract aqueous layer with 3×500 ml CH2Cl2. Wash combined CH2Cl2 layers 1×250 ml saturated NaCl solution. Dry the methylene chloride solution over Na2SO4. Evaporate the CH2Cl2 to provide the title compound as an oil. Triturate the oil with Et2O to provide solid. Recrystallize by dissolving the solid in a minimum of hot acetone. Seed and chill the solution to provide white crystals.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[CH3:21])[C:11]([N:22]([CH3:42])[C:23](=[O:41])[C:24]([C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)([CH3:26])[CH3:25])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:52](Cl)(=[O:54])[CH3:53]>ClCCl>[C:52]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[CH3:21])[C:11]([N:22]([CH3:42])[C:23](=[O:41])[C:24]([C:27]3[CH:28]=[C:29]([C:37]([F:39])([F:40])[F:38])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=3)([CH3:26])[CH3:25])=[CH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:54])[CH3:53]
Reactant: CC(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(N)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a solution of 80 mg (0.13 mmol) N-[4-amino-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide and 26 mg (0.20 mmol) N,N-diisopropylethylamine in 3 ml dichloromethane were added 12 mg (0.15 mmol) acetyl chloride at 0° C. The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with 10 ml dichloromethane and washed with 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 82 mg (95%) of the title compound as a white foam.