Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[Cl:5][C:6]1[CH:7]=[C:8]([N:16]([C:21]2[C:40]([CH:41]3[CH2:43][CH2:42]3)=[CH:39][C:24]3[C:25]([C:35]([NH:37][CH3:38])=[O:36])=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[O:27][C:23]=3[CH:22]=2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=[CH:10][C:11]=1[C:12]([CH2:14][OH:15])=[CH2:13].CCN(C(C)C)C(C)C>ClCCl>[Cl:5][C:6]1[CH:7]=[C:8]([N:16]([C:21]2[C:40]([CH:41]3[CH2:42][CH2:43]3)=[CH:39][C:24]3[C:25]([C:35]([NH:37][CH3:38])=[O:36])=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[O:27][C:23]=3[CH:22]=2)[S:17]([CH3:20])(=[O:19])=[O:18])[CH:9]=[CH:10][C:11]=1[C:12]([CH2:14][O:15][CH2:2][O:3][CH3:4])=[CH2:13]
Reactant: COCCl
Reactant: C=C(CO)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(COCOC)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
Methyl chloromethyl ether (0.024 mL, 0.321 mmol) was added to a mixture of 6-(N-(3-chloro-4-(3-hydroxyprop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (83 mg, 0.146 mmol) and DIEA (0.076 mL, 0.438 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane and washed with water and brine, dried over sodium sulfate and concentrated to give 6-(N-(3-chloro-4-(3-(methoxymethoxy)prop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide as a white foam (76 mg, 85%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.89 (dd, J=8.78, 5.27 Hz, 2H) 7.60 (s, 1H) 7.48 (s, 1H) 7.38 (d, J=2.15 Hz, 1H) 7.26-7.31 (m, 1H) 7.16-7.24 (m, 2H) 5.77-5.94 (m, 1H) 5.56 (s, 1H) 5.31 (s, 1H) 5.22 (s, 1H) 4.65 (s, 2H) 4.34 (s, 2H) 3.33 (s, 3H) 3.27 (s, 3H) 3.00 (d, J=4.88 Hz, 3H) 1.87-2.29 (m, 1H) 0.14-1.47 (m, 4H). LCMS (m/z, ES+)=613 (M+H+).
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([CH3:35])[N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].O1CCOCC1>Cl.C(Cl)Cl>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[C:27]([CH3:35])[N:26]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](N)C3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
A solution of tert-butyl [(1R,3S)-3-isopropyl-3-(4-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (200 mg, 1.65 mmol) dissolved in 4 M of HCl in 1,4-dioxane (10 mL, 40 mmol) was stirred at room temperature for 1 h. The reaction was diluted with methylene chloride, washed with saturated NaHCO3 solution, dried with sodium sulfate, filtered, and concentrated in vacuo to provide the desired product (0.15 g, 94%). LCMS calculated for C20H30F3N4O: (M+1) 399.2; found 399.2.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([CH2:15][C:16]#[C:17][Si](C)(C)C)=[C:13]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:12]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CCOCC.O>[C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([CH:15]=[C:16]=[CH2:17])=[C:13]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:12]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nnc(-c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2CC#C[Si](C)(C)C)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C=Cc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(3-(trimethylsilyl)prop-2-ynyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole (300 mg, 0.46 mmol) in tetrahydrofuran (5 ml) at 0° C. was added tetrabutylammonium fluoride (0.7 ml, 1.0 M in tetrahydrofuran, 0.7 mmol). After reaction mixture was warmed up to room temperature, it was stirred for 10 minutes. After the resulting solution was diluted with ether (20 ml), water was added (10 ml). Organic layer was separated with ethyl acetate (20 ml twice). After evaporation, crude residue was purified with silica gel column (hexane/ethyl acetate=7/1 to hexane/ethyl acetate 5/1). The less polar compound 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(propa-1,2-dienyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole was obtained as light yellow solid (87 mg, 34% yield). And relatively more polar compound 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-(prop-2-ynyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazole was produced as yellow solid (140 mg, 54% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[OH:4].[OH-].[Na+].[Cl:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl.O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:16](=[O:17])[CH2:15][Cl:14])=[CH:6][CH:7]=1
Reactant: NCC(O)c1ccc(Br)cc1
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)NCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.4 %

Procedure:
To a solution of compound 2-amino-1-(4-bromophenyl)ethanol (2.0 g, 10 mmol) in CH2Cl2 (40 mL) and water (40 mL) was added NaOH (0.48 g, 12 mmol) and chloroacetyl chloride (1.7 g, 15 mmol) at 0° C. After addition, the mixture was allowed to warm to room temperature and stirred for 6 hours. The layers were separated. The organic was washed with 3% HCl and saturated NaHCO3, dried over sodium sulfate, and concentrated to afford the title compound (2.0 g, 76% yield) as a yellow solid. 1H NMR: (400 MHz, CDCl3):δ 7.45 (d, 2H), 7.19 (d, 2H), 6.98 (br. s, 1H), 4.80 (m, 1H), 4.01 (s, 2H), 3.68 (m, 1H), 3.30 (m, 1H), 2.82 (br. s, 1H):
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].[OH-].[Na+]>COCCO>[Cl:8][C:6]1[CH:7]=[C:2]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: C[C@H](Nc1cc(Cl)ccc1[N+](=O)[O-])C(=O)O

Procedure:
2,4-Dichloronitrobenzene (21.0 g, 0.109 mol) and 23.0 g (0.258 mol) of L-alanine were refluxed for 48 hours in 400 ml of 2-methoxyethanol with an addition of 120 ml of 2N sodium hydroxide solution. The mixture was subsequently concentrated in vacuo, and the residue was taken up in aqueous sodium hydrogen carbonate solution. The mixture was extracted three times using ethyl acetate, the extract was then acidified with 6N hydrochloric acid, and the yellow product was extracted using ethyl acetate. The organic phase was washed once with saturated aqueous sodium chloride solution and dried (magnesium sulfate), and the solvent was removed under reduced pressure. 14.7 g (55%) of a yellow solid of melting point 167-169° C. remained (after crystallization from ethyl acetate).
Reaction SMILES: CI.[Cl:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[C:9]([CH2:20]N(C)C)=[C:8]1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1.C[C:43](C)=[O:44]>>[Cl:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[C:9]([CH2:20][O:44][CH3:43])=[C:8]1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:34])[CH3:35])[CH2:25]1
Reactant: CN(C)Cc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Reactant: CC(C)=O
Solvent: CI
Product: COCc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (25 μl) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (112 mg) in acetone (5 ml), and the resulting mixture was stirred overnight in a sealed tube at room temperature. The reaction solution was concentrated under reduced pressure, and to a solution of the resulting residue in methanol (2 ml) was added 28% methanol methoxide (2 ml), followed by stirring with heating at 60° C. for 4 hours. The methanol was distilled off under reduced pressure and the residue was adjusted to pH 2 with an aqueous potassium hydrogensulfate solution and extracted with ethyl acetate (100 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a thin-layer silica gel column chromatography (hexane/ethyl acetate=1/5) to obtain the title compound (26 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:6]=[CH:7][C:8]([C:11]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)([OH:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCCCC[Mg]Br
Reactant: CCOC(=O)c1ccc(C(=O)c2ccc(Br)cc2)cc1
Solvent: C1CCOC1
Product: CCCCCCC(O)(c1ccc(Br)cc1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a solution of 4-(4-Bromo-benzoyl)-benzoic acid ethyl ester (2.0 g, 6 mmol) in THF (20 mL) at 0° C. is added hexylmagnesium bromide (2M, 3.3 mL). After stirring at room temperature for 2 hours, it is quenched with saturated ammonium chloride, extracted with EtOAc. The organic is concentrated and purified by column chromatography to give 4-[1-(4-Bromo-phenyl)-1-hydroxy-heptyl]-benzoic acid ethyl ester (0.48 g, 19%), which is taken into methanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving to afford the titled compound (0.47 g).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[CH2:9]1)=O)(C)(C)C.[ClH:18]>O1CCOCC1>[ClH:18].[NH:8]1[CH2:11][CH:10]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[CH2:9]1.[ClH:18]
Reactant: Cc1csc(C2CN(C(=O)OC(C)(C)C)C2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1csc(C2CNC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 47 mg (0.18 mmol) 3-(4-methyl-thiazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester was added 2 mL (8 mmol) HCl in dioxane (4 M), and the reaction was stirred at room temperature for 1 hour. The solvent was evaporated to give the desired product as a HCl salt, which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH2:12]([O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cs+]>CN(C=O)C>[C:23]([O:25][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:24])[CH2:22][CH2:21][C:20]([O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)CCCCl
Reactant: O=C([O-])CCC(=O)OCc1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCOC(=O)CCC(=O)OCc1ccccc1
Yield: 14.3 %

Procedure:
A solution of tert-butyl 4-chlorobutyrate (8.9 g, 50 mmol) and cesium monobenzylsuccinate (prepared from monobenzyl succinate and CsOH) (50 mmol) in 100 mL of DMF was heated at 80° C. for 2 days. DMF was evaporated and chromatographed on silica (hexane-ethyl acetate) to afford 2.5 g (14%) of the title compound 3 as a colorless liquid. 1H NMR (DMSO-d6) δ 7.35 (s, 5H), 5.09 (s, 2H), 3.99 (t, J=7 Hz, 2H), 2.58 (m, 4H), 2.25 (t, J=7 Hz, 2H), 1.93 (q, 2H), 1.41 (s, 9H).
Reaction SMILES: [C:1]([O:23]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19].N(CCCC)(CCCC)CCCC.O>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH3:21][O:20][C:18]([CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:23])=[O:19]
Reactant: COC(=O)CCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: COC(=O)C1CCCCCCC=CCCCCCCCC1=O
Yield: 27.9 %

Procedure:
Under an argon stream, to a suspension of ZrCl4 (338 mg, 1.45 mmol) in CH2Cl2 (1.0 ml) were added dropwise, at 0 to 5° C., a mixed solution of dimethyl cis-9-octadecenedioate (170 mg, 0.50 mmol) and Bu3N (278 mg, 1.50 mmol) in CH2Cl2 (4.0 ml) over a period of about 1 hour by means of a microfeeder. The whole was further mixed at the same temperature for 15 minutes. Water was added to the reaction mixture and the resulting mixture was stirred and then extracted with ether. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the evaporation of the solvent under reduced pressure, the crude product was purified by silica gel chromatography (hexane/ethyl acetate=20/1→10/1) to obtain the aimed product (43 mg, 28%) and a by-product (34-membered ring; 6 mg, 4%).
Reaction SMILES: [C:1]([C:3]1[CH:7]=[N:6][N:5]([C@@H:8]2[O:20][C@H:19]([CH2:21][O:22]C(=O)C)[C@@H:14]([O:15]C(=O)C)[C@H:9]2[O:10]C(=O)C)[N:4]=1)#[N:2].[OH:26]O>[Pt].N>[C@@H:8]1([N:5]2[N:4]=[C:3]([C:1]([NH2:2])=[O:26])[CH:7]=[N:6]2)[O:20][C@H:19]([CH2:21][OH:22])[C@@H:14]([OH:15])[C@H:9]1[OH:10]
Reactant: OO
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ncc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pt]
Agent: N
Product: NC(=O)c1cnn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 20 h

Procedure:
4-Cyano-2-(2,3,5-tri-O-acetyl-β -D- ribofuranosyl)-1,2,3-triazole (7) (0.35 g, 0.001 mol) was added to 15% aqueous ammonia (30 ml) and 30% hydrogen peroxide (3 ml). After stirring at room temperature for 6 hr an additional 3 ml of 30% hydrogen peroxide was added and stirring was continued for 20 hr. Platinum black was added to destroy the excess peroxide, the solution was filtered, and the filtrate was evaporated to dryness. The residue was dissolved in a minimum of methanol and applied to a 20 × 20 cm silica gel preparative plate which was developed in ethyl acetate-methanol (9:1). The band containing 4 was removed and the compound was extracted with ethyl acetate-methanol (1:1). The solvent, along with acetamide, was removed in vacuo. The compound was dissolved in hot 2-propanol; cooling of the solution and filtering provided 14 mg of 4.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[N:4]=[CH:3]1.S(Cl)(Cl)=O.[CH3:20]O>>[NH:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:20])=[O:12])=[CH:14][CH:15]=2)[N:4]=[CH:3]1
Reactant: O=C(O)c1ccc(-c2c[nH]cn2)cc1
Reactant: CO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a stirred solution of 4-(1H-imidazol-4-yl)benzoic acid hydrochloride (20 mg, 0.089 mmol) at 0° C. in MeOH (5 mL) was added thionyl chloride (11.6 mg, 0.097 mmol) and the solution was allowed to warm to rt. After stirring overnight the solution was concentrated under reduced pressure to dryness and the crude residue was partitioned between EtOAc (25 mL) and sat'd NaHCO3 (5 mL). The organic layer was collected, dried (Na2SO4) and concentrated under reduced pressure to afford the desired product as a pale yellow solid (15 mg, 86% yield). 1H NMR: 3.92 (s, 3H), 7.41 (s, 1H), 7.67-7.77 (m, 3H), 8.03 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[OH:9].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.CCOCC.S(O)(=O)(=O)C.[C:41]([NH:48][C:49]1([CH2:52]O)[CH2:51][CH2:50]1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>C(#N)C.O1CCCC1>[C:41]([NH:48][C:49]1([CH2:52][O:9][CH:3]2[C:4]([CH3:8])([CH3:7])[CH2:5][CH2:6][C:2]2([CH3:10])[CH3:1])[CH2:51][CH2:50]1)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: CC(C)(C)OC(=O)NC1(CO)CC1
Reactant: CC1(C)CCC(C)(C)C1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CS(=O)(=O)O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(COC2C(C)(C)CCC2(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2,5,5-Tetramethyl-1-cyclopentanol is added to a dry flask under argon at 0° C. Dry tetrahydrofuran is added with a syringe. Sodium hydride (60% dispersion in oil) is added quickly in one portion and the contents of the flask are stirred for one hour at room temperature. A 10 mM solution of 18-crown-6- ether in acetonitrile is added with a syringe and the flask cooled to 0° C. A tetrahydrofuran solution of N-Boc-1-amino-1-hydroxymethylcyclopropane mesylate is added with vigorous stirring over a 10 minute period. After completion of the reaction, as judged by thin layer chromatography, it is quenched with dimethyl sulfate, poured into saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried over MgSO4 and evaporated to yield N-Boc-O-(2,2,5,5-tetramethyl-1-cyclopentyl)-1-amino-1-hydroxymethylcyclopropane.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[NH2:13][C:14]1[C:26]([Br:27])=[CH:25][C:17]2[C:18]([C:21]([NH:23][CH3:24])=[O:22])=[CH:19][O:20][C:16]=2[CH:15]=1.C([N-]C(C)C)(C)C.[Li+].CON(C)[C:39](=[O:41])[CH3:40]>C1COCC1>[C:39]([C:19]1[O:20][C:16]2[CH:15]=[C:14]([NH2:13])[C:26]([Br:27])=[CH:25][C:17]=2[C:18]=1[C:21]([NH:23][CH3:24])=[O:22])(=[O:41])[CH3:40]
Reactant: CON(C)C(C)=O
Reactant: CNC(=O)c1coc2cc(N)c(Br)cc12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CNC(=O)c1c(C(C)=O)oc2cc(N)c(Br)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a solution of diisopropylamine (3.76 g, 37.1 mmol) in THF (25 mL) was slowly added a solution of n-BuLi (2.5 mol/L in hexane) (16.5 mL, 40.5 mmol) under N2 at −78° C. and the resulting solution was stirred at −78° C. for 30 minutes. A solution of compound 6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (2 g, 7.43 mmol) in THF (50 mL) was slowly added to the fresh lithium diisopropylamide at −78° C. and stirred for another one hour. To the resulting mixture was added N-methoxy-N-methylacetamide (3.83 g, 37.16 mmol) at −78° C. and stirred for another one hour. The reaction was quenched with saturated NH4Cl at −78° C. and the mixture was slowly warmed to room temperature. Water was added and the mixture extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography to give compound 2-acetyl-6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (700 mg, yield: 30%). 1H-NMR (CDCl3, 400 MHz) δ 10.00 (s, 1H), 8.76 (s, 1H), 6.86 (s, 1H), 4.54 (s, 2H), 3.00 (d, J=4.8 Hz, 3H), 2.70 (s, 3H). MS (M+H)+: 311/313.
Reaction SMILES: [CH:1]([N:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][C:5]1=[O:13])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:36][CH2:37][C:38]1[C:39]([OH:46])=[N:40][C:41]([CH3:45])=[CH:42][C:43]=1[CH3:44]>ClCCl.C(N(CC)CC)C>[OH:46][C:39]1[C:38]([CH2:37][NH:36][C:10]([C:7]2[CH:8]=[CH:9][N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:13])[CH:6]=2)=[O:12])=[C:43]([CH3:44])[CH:42]=[C:41]([CH3:45])[N:40]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(C)n1ccc(C(=O)O)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccn(C(C)C)c(=O)c2)c(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (50 mg, 0.28 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol), 1-Hydroxybenzotriazole (67 mg, 0.5 mmol), triethylamine (0.1 mL) in dichloromethane (5 mL) were stirred at 25° C. for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (50 mg, 0.33 mmol) was added to the above mixture. The mixture was stirred at 25° C. overnight and purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxamide (31 mg, 35%) as a white solid. LRMS (M+H+) m/z: 315.16. found 315. HPLC Purity (214 nm): 100%. 1H NMR (300 MHz, DMSO): δ 11.48 (d, J=4.2 Hz, 1H), 8.53 (t, J=5.1 Hz, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 6.56-6.53 (m, 1H), 5.85 (s, 1H), 5.03-4.98 (m, 1H), 4.24 (d, J=5.1 Hz, 2H), 2.14-2.09 (m, 6H), 1.28-1.22 (m, 6H).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C)C=O.S(Cl)(Cl)=O.[CH:38]1[C:43]([NH2:44])=[CH:42][CH:41]=[C:40]([OH:45])[CH:39]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[OH:45][C:40]1[CH:41]=[CH:42][C:43]([NH:44][C:24](=[O:26])[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:28][CH:27]=2)=[CH:38][CH:39]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)Nc2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, 4-n-octadecyloxybenzoic acid (100.0 g) and dimethylformamide (5ml) were suspended in chloroform (800 ml) and thereto was added dropwise thionyl chloride (33.4 g). After completion of the addition, the suspension was refluxed with heating for 1 hour to prepare the corresponding acid chloride. The reaction mixture was cooled and thereto were added p-aminophenol (30.8 g) and triethylamine (28.6 g), followed by refluxing with heating for 2 hours. The reaction mixture was cooled to room temperature to precipitate a white crystal. This crystal was filtered off under reduced pressure and washed with distilled water and then recrystallized from isopropanol to obtain 98.7 g of the desired product. Yield 80%; m.p. 193° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH3:16][NH:17][CH3:18]>O1CCCC1>[CH3:1][C:2]1[C:3]([S:12]([N:17]([CH3:18])[CH3:16])(=[O:14])=[O:13])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CNC
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1C
Solvent: C1CCOC1
Product: COC(=O)c1cccc(S(=O)(=O)N(C)C)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 33.5 g of the product from Example 9 in 300 ml tetrahydrofuran was cooled to 5°-10° and treated with dimethylamine. The resulting suspension was stirred at room temperature for one hour, filtered, and the filtrate concentrated in vacuo to afford a pale yellow solid. Recrystallization from n-butyl chloride gave 26.7 g of the title compound as a white solid, m.p. 40°-43°; NMR (CDCl3): δ 2.75 (3H, s, CH3), 2.8 (6H, s, SO2N(CH3)2), 3.85 (3H, s, CO2CH3), 7.25-7.55 (1H, m), 7.85-8.25 (2H, m).