Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:16]([Li])[CH2:17][CH2:18]C.C(Br)CC>C1COCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:16][CH2:17][CH3:18])[CH:10]=[CH:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: [Li]CCCC
Reactant: COc1cccc(C2=CCN(C)CC2)c1
Solvent: CCCBr
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC1(c2cccc(OC)c2)C=CN(C)CC1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A solution of 900 g (4.43 mol) of 1,2,3,6-tetrahydro-4-(3-methoxyphenyl)-1-methylpyridine dissolved in 10.8 liters of dry THF was added to a dry, nitrogen purged 22 liter reaction flask equipped with a stirrer, low temperature thermometer, and addition funnel. The temperature of the reaction mixture was lowered to approximately -10° C. whereupon 3.04 liters of 1.6 molar n-butyllithium in hexane was added at a rate so as to maintain the temperature below -5° C. The resulting deep red solution was stirred for 15 minutes at -5° C. and 572 g (4.65 mol) of n-propylbromide in 2.4 liters of dry tetrahydrofuran were added at such a rate so that the temperature remained below -5° C. The reaction mixture was stirred for 10 minutes at -5° C. and then carefully quenched by the addition of 1.5 liters of water to destroy any excess n-butyllithium. The organic phase was separated, washed with 1.5 liters of water, 1.5 liters of saturated sodium chloride solution and dried over 500 g of anhydrous sodium sulfate. Evaporation of the solvent gave 1126 g of crude 1,2,3,4-tetrahydro-4-(3-methoxyphenyl)-1-methyl-4-propylpyridine (75% pure). 78% yield. bp=113° C./0.2 torr. NMR: (CDCl3) δ0.80 (3H,t), 2.57 (3H,s), 3.80 (3H,s), 4.58 (1H,d,A of AX, J =8), 5.95 (1H,d,X of AX, J=8), 6.8-7.3 (4H, m, aryl).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[CH:20]=[CH:19]2)=[CH:13][C:12]=1[NH:32][C:33](=[O:50])[C:34]1[CH:39]=[C:38]([S:40]([F:45])([F:44])([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:46](O)([CH3:48])[CH3:47])[CH:35]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([N:18]2[C:25]3[N:21]([N:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[CH:20]=[CH:19]2)=[CH:13][C:12]=1[NH:32][C:33](=[O:50])[C:34]1[CH:39]=[C:38]([S:40]([F:45])([F:44])([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:46]([F:7])([CH3:48])[CH3:47])[CH:35]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(C(C)(C)O)cc(S(F)(F)(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)c(-n2ccn3nc(-c4cccnc4)cc23)cc1NC(=O)c1cc(C(C)(C)F)cc(S(F)(F)(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., a solution of 27 μl (0.203 mmol) of diethylaminosulphur trifluoride (DAST) in 0.5 ml of anhydrous dichloromethane was added to a solution of 100 mg (0.169 mmol) of the compound of Example 148 in 3.5 ml of anhydrous dichloromethane. After the reaction mixture had been stirred at −78° C. for 1 h, 1 ml of saturated aqueous sodium bicarbonate solution was added and the mixture was warmed to RT. Using an Extrelut cartridge NT3 (from Merck, Darmstadt, Germany), the mixture was freed from salts and aqueous components. After concentration, the residue obtained was separated into its components by preparative HPLC (Method 36). Evaporation of the product fractions and drying of the residue under high vacuum gave 50 mg (50% of theory) of the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C(OCC)(=O)C.Cl>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Yield: 104.4 %

Procedure:
To 5 g of N-BOC-isonipecotic acid (21.8 mmol, Bachem) dissolved in 100 ml THF, cooled in a dry ice/acetone bath, was slowly added 43.6 ml 1 M borane-THF complex in THF (43.6 mmol). The reaction was stirred to −40 C and then replaced with an ice/water bath. After 3 hours the reaction was neutralized by careful addition of water and then worked up by addition of ethyl acetate and 1 M HCl. The layers were separated and the aqueous layer was extracted one more time with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over sodium sulfate and evaporated to give 4.9 g 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (MS: M+H=238).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[C:14]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)#[CH:15]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[C:15]#[C:14][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: C#Cc1cccnc1
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C(#Cc1nccs1)c1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
2-Bromo-1,3-thiazole (0.15 mL, 1.6 mmol), CuI (98 mg, 0.51 mmol), PdCl2(PPh3)2 (120 mg, 0.17 mmol) and triethylamine (2.8 mL, 20 mmol) were combined in DMF (6.8 mL) and cooled in an ice bath. 3-Ethynylpyridine (520 mg, 5.04 mmol) was then added to the mixture as a solution in DMF (3.0 mL). The ice bath was removed and the reaction was allowed to stir at ambient temperature for 16 h. The reaction mixture was filtered through a pad of Celite™, and the pad was washed thoroughly with ethyl acetate. The filtrate was washed with brine (3×20 mL). A partial emulsion was observed. The mixture was concentrated in vacuo and the residue was taken up in CH2Cl2, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 80:20 followed by 30:20 hexane:ethyl acetate to afford 3-(1,3-thiazol-2-ylethynyl)pyridine (160 mg) as a mixture with another product exhibiting a mass of 204 in the GC/MS, assigned as pyridylalkyne dimer. A portion of the mixture (100 mg) was further purified by preparative reverse-phase HPLC eluting with a gradient of 80:20 to 0:100 water:acetonitrile over twenty minutes. The fractions containing the desired product were collected (detection by uv at 210 nm) to afford 3-(1,3-thiazol-2-ylethynyl)pyridine as a white waxy solid (15 mg). 1H NMR (CDCl3, 300 MHz) δ 9.3-8.5 (br s, 2H), 7.92-7.90 (m, 2H), 7.50-7.30 (m, 2H). MS (ESI) 187.0 (M++H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]([OH:23])=O)[S:20][C:13]=13)=[CH:6][CH:5]=2.[NH:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[C:29]([OH:32])([CH3:31])[CH3:30]>>[OH:32][C:29]([C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:21]([C:19]1[S:20][C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:12]=2[NH:11][C:7]2[CH:6]=[C:5]3[C:4](=[CH:9][CH:8]=2)[NH:3][C:2]([CH3:10])=[CH:1]3)[CH:18]=1)=[O:23])([CH3:31])[CH3:30]
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)O)sc34)ccc2[nH]1
Reactant: CC(C)(O)[C@@H]1CCCN1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCC[C@H]5C(C)(C)O)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carboxylic acid and (S)-2-pyrrolidin-2-yl-propan-2-ol by a procedure analogous to Example 21B. MS: 435.3; HPLC Rf: 4.134 min.; HPLC purity 95%.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[C:9](Cl)(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>[OH-].[Na+]>[C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.9 %

Procedure:
L-proline (11.6 g, 0.1 mol) was dissolved in 150 mL of 1 M NaOH solution and cooled in an ice both. To this solution dodecanoyl chloride (24.1 g or 0.11 mol) and 200 mL of 1 M NaOH solution were added simultaneously over a period of 20 min. The solution was stirred at room temperature for 45 min and acidified with concentrated HCl (pH 2-3). The solution was extracted with diethyl ether and the organic phase was washed with 12% NaCl solution. The organic phase was then dried over sodium sulfate and evaporated to provide 30 g of N-dodecanoyl-L-proline as an oil (100% yield) which was carried on without purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:15]>CN(C)C=O>[CH3:15][N:6]1[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2ncn(C)c2cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 5.00 g (34.20 mmol) of 5,6-dimethylbenzimidazole in 20 mL of dry dimethylformamide is reacted with 1.51 g (37.62 mmol) of sodium hydride at room temperature for 4 h. 2.34 mL (37.62 mmol) of iodomethane is added and reaction is allowed to stir at room temperature overnight. Reaction is quenched with water, layers are separated, extract aqueous 3×50 mL ethyl acetate, dry (MgSO4), and concentrate. The crude mixture is purified by chromatography using dichloromethane: methanol as a solvent system. Product containing fractions are combined to obtain 3.75 g of the title compound, 68% yield. MS, ES+=161.1. H1NMR (CDCl3) δ 7.98 (s, 1H); 7.37 (s, 1H); 7.29 (s, 1H); 3.74 (s, 3H); 2.31 (s, 3H); 2.28 (s, 3H) ppm
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+]([O-])=O)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F-:13].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: [F-]
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: N#Cc1ncc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At room temperature, to a tetrahydrofuran solution (60 ml) of 5-bromo-3-nitropyridine-2-carbonitrile (6.00 g) was added a tetrahydrofuran solution (1 M, 52.8 ml) of tetrabutylammonium fluoride, followed by stirring for 1 hour. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 5-bromo-3-fluoropyridine-2-carbonitrile. To a mixed solvent solution of this in 1,2-dimethoxyethane (120 ml) and water (30 ml) were added 2-hydroxyphenylboronic acid (4.37 g), sodium carbonate (8.39 g) and tetrakis(triphenylphosphine)palladium (1.52 g), followed by stirring under heating at reflux for 2 hours. The reaction solution was brought back to room temperature, poured into ice water, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 3-fluoro-5-(2-hydroxyphenyl)pyridine-2-carbonitrile (2.73 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[O:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH2:45][NH:46][CH3:47]>C1COCC1.O>[CH3:31][C:29]([O:28][C:26]([N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:1])[CH3:3])=[O:7])[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:46]([CH2:45][C:41]2[O:40][CH:44]=[CH:43][CH:42]=2)[CH3:47])[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:27])([CH3:32])[CH3:30]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: CNCc1ccco1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1ccco1)c1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Reaction time: 8 h
Yield: 101.4 %

Procedure:
Tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (6.22 g, 12.54 mmol) was dissolved in THF (15 mL). To this solution was added triethylamine (2.1 mL, 15.0667 mmol), followed by commercially available (2-furanylmethyl)methylamine (1.394 g, 12.32 mmol) which was dissolved in THF (3 mL). The reaction was left to stir overnight. Then the reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated to produce tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(2-furanylmethyl)(methyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate as a beige solid (7.1439 g). LCMS: (M+H)+=572.3.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([C:15]1([S:18]([NH:21]C(=O)OC(C)(C)C)(=[O:20])=[O:19])[CH2:17][CH2:16]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14]>O>[CH2:8]([C:15]1([S:18]([NH2:21])(=[O:19])=[O:20])[CH2:17][CH2:16]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCCCCC1(S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: C=CCCCCCC1(S(N)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
4.0M HCl in dioxane (4.285 mL, 17.14 mmol) was added to tert-butyl 1-(hept-6-enyl)cyclopropylsulfonylcarbamate (544 mg, 1.714 mmol) and stirred at r.t. for 3 h. Poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated in vacuo. The residue was purified by Biotage column, eluted with gradient 5%˜60% EtOAc-Hexane to afford the desired product 1-(hept-6-enyl)cyclopropane-1-sulfonamide (350 mg, 1.578 mmol, 92% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) ppm 0.82-0.94 (m, 2 H) 1.28-1.53 (m, 8 H) 1.84-1.97 (m, 2 H) 2.06 (q, J=6.94 Hz, 2 H) 4.49 (b, NH2) 4.89-5.07 (m, 2 H) 5.70-5.90 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.CO.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22]>>[CH2:25]([O:24][C:20](=[O:23])[C:21]([CH:8]([OH:9])[C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[CH2:22])[CH3:26]
Reactant: Cc1ncccc1C=O
Reactant: C=CC(=O)OCC
Agent: C1CN2CCN1CC2
Solvent: CO
Product: C=C(C(=O)OCC)C(O)c1cccnc1C
Temperature: 45 °C
Reaction time: 72 h
Yield: 62 %

Procedure:
To 2-methylpyridine-3-carbaldehyde (5 g, 0.04 mol) in ethyl acrylate (10 mL) were added DABCO (1 g, 0.01 mol) and methanol (1 mL). The reaction mixture was stirred at 45° C. for 3 days. The reaction mixture was then concentrated and purified by column chromatography (SiO2, 60-100% EtOAc/DCM) to give the title compound (62%) as a colourless oil. δH (DMSO-d6) 8.32 (dd, J 4.8, 1.7 Hz, 1H), 7.51 (dd, J 7.7, 1.7 Hz, 1H), 7.17 (dd, J 7.7, 4.8 Hz, 1H), 6.28 (t, J 1.3 Hz, 1H), 5.91 (t, J 1.6 Hz, 1H), 5.78 (d, J 5.0 Hz, 1H), 5.62 (d, J 5.0 Hz, 1H), 4.10-4.00 (m, 2H), 3.29 (s, 3H), 1.10 (t, J 7.0 Hz, 3H). LCMS (ES+) 222 (M+H)+, RT 1.11 minutes.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@:3]1([F:11])[C:7]([O:9][CH3:10])=[O:8].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C@@H:2]2[CH2:6][CH2:5][CH2:4][C@:3]2([F:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)[C@@]1(F)CCC[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@@]1(F)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl (1R,2R)-2-amino-1-fluorocyclopentanecarboxylate (0.47 g, 2.4 mmol, 1 eq) in CH2Cl2 (10 mL) was added 4-benzyloxy-benzenesulfonyl chloride followed by saturated sodium bicarbonate (10 mL). The reaction was stirred overnight, and then taken up in ethyl acetate. The organics were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified using silica chromatography eluting with 30% ethyl acetate/hexanes to afford methyl (1R,2R)-2-({[4-(benzyloxy)phenyl]sulfonyl}amino)-1-fluorocyclopentanecarboxylate as an off white solid (0.575 g, 60%). MS: 408.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:7]=[CH:6]1)([CH3:4])[CH3:3].C(OC(=O)C)(=[O:21])C>>[CH3:1][C:2]([N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([OH:21])[C:8]=2[N:7]=[CH:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)n1cnc2c[n+]([O-])c3ccccc3c21
Reactant: CC(=O)OC(C)=O
Product: CC(C)(C)n1cnc2c(O)nc3ccccc3c21
Temperature: 20 °C

Procedure:
To 50 mL of acetic anhydride was added 11.5 g (0.0477 mole) of 1-(1,1-dimethylethyl)-1H-imidazo-[4,5-c]quinoline-5oxide (produce of Example 25) and the slurry was heated on a steam bath for a few minutes, then allowed to cool to about 20° C. The solid was separated by filtration and washed with an ethanol-hexane mixture. Slurrying with dilute ammonium hydroxide, filtration and washing with water provided solid which has recrystallized from an ethanol-dichloromethane mixture to provide colorless (white) crystals of 1-(1,1-dimethylethyl)-1H-imidazo[4,5-c]quinolin-4-ol, m.p. greater than 300° C. Analysis: Calculated for C14H15N3O: %C, 69.7; %H, 6.3; %N, 17.4; Found: %C, 69.5; %H, 6.3; %N, 17.3.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl.C(#N)C>[CH3:13][O:12][C:6]1[CH:5]=[N:4][C:3]2[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cccc2[nH]c(=O)cnc12
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: COc1cnc2c(N)cccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
To a suspension of 5-aminoquinoxalin-2(1H)-one (440 mg, 2.73 mmol) in methanol (1 mL), DCM (8 mL) and acetonitrile (8 mL), at 0° C., was added TEA (1.14 mL, 8.19 mmol), followed by (trimethylsilyl)diazomethane (2 mL, 4.10 mmol; 2.0M in hexanes). The reaction mixture was allowed to warm to RT and stirred for additional 3 hours. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 10%-50% ethyl acetate in hexane, to provide the title compound (167 mg, 0.953 mmol) as a light-yellow powder. LC/MS (ESI+) m/z=176 (M+H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:34]([C:36]1[S:40][C:39]([O:41][C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)=O>C1COCC1>[CH3:2][O:3][CH:4]=[CH:34][C:36]1[S:40][C:39]([O:41][C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1
Reactant: N#Cc1ccc(Oc2ccc(C=O)s2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc(Oc2ccc(C#N)cc2)s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Combine a solution of methoxy methyl triphenyl phosphonium chloride (358 mg, 1.047 mmol) in THF (3.6 mL) with a solution of KHMDS (0.5M in toluene, 2 mL, 1.047 mmol) at 0° C. for 20-40 min. Cool the resulting orange solution to about −78° C., then add a solution of 4-(5-formyl-thiophen-2-yloxy)-benzonitrile in THF (1 mL) dropwise over about 10 min. Stir at about −78° C. for 45 min, then allow the reaction mixture to warm to room temprature and quench with H2O (5 mL). Extract the reaction mixture with ether (5 mL), wash with H2O, dry over magnesium sulfate, filter and concentrate. Purify the crude product by flash chromatography (CH2Cl2) to provide 155 mg of 4-[5-(2-methoxy-vinyl)-thiophen-2-yloxy]-benzonitrile. Redissolve the product in i-PrOH (about 0.8 mL)—H2O (about 0.8 mL) and add pTsOH.H2O (4 mg, 0.018 mmol). Stir the reaction mixture at reflux for 2-3 hours. Cool the reaction mixture to room temprature, dilute with H2O (5 mL) and extract with diethyl ether (6 mL). Wash the organic layer with sodium bicarbonate, brine, dry over magnesium sulfate, filter and concentrate under reduced pressure to give the title compound.
Reaction SMILES: C(N([CH2:9][CH:10]=[CH:11][C:12]1[CH:16]=[CH:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:24])[CH:13]=1)OC(=O)C)(=O)C.CC1C=CC=C(C)C=1N1C=CC(C=[O:39])=C1.C(OC(OCC)C(CC)(CC)P(O)(O)=O)C>>[CH3:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:17]=1[N:14]1[CH:15]=[CH:16][C:12]([CH:11]=[CH:10][CH:9]=[O:39])=[CH:13]1
Reactant: CC(=O)ON(CC=Cc1ccn(-c2c(C)cccc2C)c1)C(C)=O
Reactant: Cc1cccc(C)c1-n1ccc(C=O)c1
Agent: CCOC(OCC)C(CC)(CC)P(=O)(O)O
Product: Cc1cccc(C)c1-n1ccc(C=CC=O)c1

Procedure:
Similarly prepared is N-acetyl-N-acetyloxy-3-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-allylamine. The starting material is prepared by condensing 1-(2,6-dimethylphenyl)-1H-pyrrole-3-carboxaldehyde with diethyl phosphonoacetaldehyde diethylacetal to obtain 3-[1-(2,6-dimethylphenyl)-1H-pyrrol-3-yl]-acrolein. The aldehyde is then converted to the oxime and reduced to the hydroxylamine according to previously described procedures.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:53]=[CH:52][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][C:28]([O:30]CC3C=CC(OCC4N=C(C5C=CC=CC=5)OC=4C)=CC=3)=[O:29])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:53]=[CH:52][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][C:28]([OH:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COC(=O)Cc2cccc(OCc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cccc(CC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a mixture of 4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl 2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (2.40 g), tetrahydrofuran (7 mL) and ethanol (7 mL) was added 1N aqueous sodium hydroxide solution (7.0 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and water and diethyl ether were added to the residue. Dilute hydrochloric acid was added to acidify the aqueous layer, and the precipitated solid was collected by filtration, and dried with air to give crystals (1.24 g, 85%) of 2-[3-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 159-160° C.