Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2][C:3]1[O:4][C:5]([CH3:28])=[C:6]([CH3:27])[C:7]=1[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:29]([Li])CCC.[F:34]/[C:35](=[C:41](\[CH:43]=O)/[CH3:42])/[C:36]([O:38][CH2:39][CH3:40])=[O:37].CCOCC>O1CCCC1.O>[F:34]/[C:35](=[C:41](/[CH3:42])\[CH:43]=[CH:29]\[C:7]1[C:6]([CH3:27])=[C:5]([CH3:28])[O:4][C:3]=1[CH3:2])/[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)/C(F)=C(\C)C=O
Reactant: [Li]CCCC
Reactant: Cc1oc(C)c([P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C(F)=C(C)/C=C/c1c(C)oc(C)c1C
Temperature: -60 °C

Procedure:
A suspension of 35 g. (75 mmol) of 2,4,5-trimethyl-3-furyl-triphenylphosphonium bromide in tetrahydrofuran was stirred under argon and cooled to -60° C. The ylide was formed by adding 1.1 equivalents of n-butyllithium and warming to -35° C. for 15 minutes. A solution of 10.6 g. (66 mmol) of ethyl 2Z-2-fluoro-3-formyl-butenoate in 50 ml. of ether was added slowly. After warming to 0° C., the reaction was poured into water and extracted with hexane. This was purified by partitioning between hexane and a 60% methanol/water solution. The hexane phase was washed with water, dried and partially evaporated. This solution containing ethyl 2Z,4E-2-fluoro-3-methyl-5-(2,4,5-trimethyl-3-furyl)pentadienoate was carried on to the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)(O)[O-].[Na+].[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.O1CCCC1>[CH2:15]([O:22][C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: NCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-aminocaproic acid (7.8 g) and 5.0 g of sodium bicarbonate in 50 ml of water is added by dropwise addition 16 g of N-benzyloxycarbonyloxysuccinimide in 60 ml of tetrahydrofuran. The mixture is stirred for one hour at room temperature and then the tetrahydrofuran is removed at reduced pressure. The residue is acidified to pH 3 and extracted with methylene chloride and dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by filtration and the solvent is removed by evaporation. Recrystallization from ethyl acetate/hexane provides N-benzyloxycarbonyl-6-aminocaproic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].[CH2:9](I)[CH3:10].[NH4+].[Cl-]>CN1C(=O)N(C)CCC1.C1COCC1.COC(C)(C)C>[CH2:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:10]
Reactant: Nc1ccccc1
Reactant: CCI
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCNc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of aniline 22 (386 mg, 0.474 mmol, 1.0 eq.) in DMPU (1.6 mL) at 0° C. was added lithium hexamethyldisalazide (0.950 mL, 0.950 mmol, 2.0 eq., lithium hexamethyldisalazide 1.0 M in THF). The resulting mixture was stirred at 0° C. during 30 min and added ethyl iodide (0.230 mL, 2.88 mmol, 6.1 eq.). The reaction mixture was stirred 10 min at 0° C., then allowed to warm up to rt and stirred at that temperature during 1 h. A saturated solution of NH4Cl, methyl-t-butyl ether and n-hexanes were added. Layers were separated and the aqueous one was extracted twice with methyl-t-butyl ether/hexane (1:1 mixture). The combined organic layers were washed with brine/water (1:1 mixture), then with brine, dried with sodium sulfate, filtered and concentrated to dryness. The resulting foam was purified by chromatography on silica gel 230-400 Mesh using the following solvent gradient: 15% and 20% ethyl acetate/hexane to elute. This procedure afforded N-ethyl-aniline 39, 349 mg, white foam, 87% yield.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>CCOC(C)=O.O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([CH:6]=1)[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [S-2]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 29 %

Procedure:
To a suspension of 5-tert-butyl-2-methoxy-1,3-dinitrobenzene (10.2 g, 0.04 mol) in EtOAc (150 mL) was added in a single portion a solution of sodium sulfide nonahydrate (19.2 g, 0.08 mol) in water (200 mL). Aliquate® 336 (0.8 g, 5 mole %) was added in a single portion, and the two-phase mixture was brought to a reflux. All solids dissolved, and the mixture became red/brown. After about 3 h, TLC (3:1 hexanes:EtOAc) revealed almost complete loss of starting material. The mixture was filtered warm through a pad of diatomaceous earth to remove insolubles, and the filter cake was washed with fresh EtOAc. The clarified two-phase mixture was separated, and the organic layer was washed with sodium carbonate solution, followed by water and then saturated sodium chloride solution. After drying over magnesium sulfate, the solution was concentrated under reduced pressure to a thick, dark oil. This oil was extracted three times with refluxing hexanes, leaving behind a dark residue. The orange extract deposited some more dark oil, from which the warm supernatant was decanted. The resulting orange solution was heated back to reflux, and treated with both activated charcoal and diatomaceous earth. The solution was filtered hot, and the filter cake washed with hot hexanes. Re-heating the orange filtrate resulted in a clear solution. Quickly cooling the solution in an ice/acetone bath and scratching the flask with a glass rod resulted in the deposition of an orange/yellow precipitate. The suspension was allowed to cool for 1 h, and then filtered. The filter cake was washed with a small portion of cold hexanes, and then dried on the filter, providing the title compound as a yellow/orange powder (2.6 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=O)=[N:4][C:5]([C:8]2[CH:13]=[C:12]([S:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[CH3:23])=[CH:6][N:7]=1.Cl.[CH3:33][O:34][NH2:35].C(O)C.C(N(CC)CC)C>O>[CH3:33][O:34][N:35]=[C:24]([C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]2[CH:13]=[C:12]([S:14]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[CH3:23])[N:4]=1)[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1-c1cnc(N)c(C(=O)c2cccnc2)n1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CON=C(c1cccnc1)c1nc(-c2cc(S(=O)(=O)N3CCOCC3)ccc2C)cnc1N

Procedure:
{3-Amino-6-[2-methyl-5-(morpholine-4-sulfonyl)-phenyl]-pyrazin-2-yl}-pyridin-3-yl-methanone (Ex. 2) (0.05 g, 0.11 mmol), O-methylhydroxylamine hydrochloride (0.095 g, 1.14 mmol), ethanol (4 ml), water (1 ml) and triethylamine (0.07 g, 0.68 mmol) are heated at 120° C. in a microwave for 3.5 hours. The reaction mixture is purified by reverse phase column chromatography (C18, 0-100% MeCN in water −0.1% TFA) to yield the title compound. 1H NMR (400 MHz, DMSO-6) δ 8.56 (1H, dd), 8.48 (1H, d), 8.35 (1H, s), 7.75 (1H, dt), 7.70 (2H, bs), 7.55-7.53 (2H, m), 7.48-7.43 (2H, m), 4.01 (3H, s), 3.61 (4H, t), 2.76 (4H, t) 2.19 (3H, s); MS m/z 469 [M+H]+
Reaction SMILES: [CH2:1]([NH:3][C:4]1([C:8]([NH2:10])=[O:9])[CH2:7][NH:6][CH2:5]1)[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:21]1[N:26]2[N:27]=[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:29]([I:30])=[C:25]2[N:24]=[C:23]([CH3:38])[N:22]=1>CN(C=O)C.C(Cl)Cl>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:28]1[C:29]([I:30])=[C:25]2[N:24]=[C:23]([CH3:38])[N:22]=[C:21]([N:6]3[CH2:7][C:4]([NH:3][CH2:1][CH3:2])([C:8]([NH2:10])=[O:9])[CH2:5]3)[N:26]2[N:27]=1
Reactant: CCNC1(C(N)=O)CNC1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(I)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC1(C(N)=O)CN(c2nc(C)nc3c(I)c(-c4ccccc4Cl)nn23)C1
Reaction time: 2 h

Procedure:
To a solution of 3-ethylaminoazetidine-3-carboxylic acid amide (I-2A-1g; 0.55 g, 2.5 mmol) and diisopropylethylamine (1.3 ml, 7.6 mmol) in DMF (10 ml) was added a solution of 4-chloro-7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-1A-1e; 0.93 g, 2.3 mmol) in methylene chloride (10 ml). After stirring 2 hours, the methylene chloride was removed, in vacuo, and the mixture was extracted from water, adjusted to pH 8 with saturated aqueous NaHCO3, with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), and then concentrated, in vacuo, to afford a yellow solid. The material was then triturated from methylene chloride/methanol to afford I-6A-1a (0.73 g, 62%) as a colorless solid: +APcI MS (M+1) 512.0; 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=7.9 Hz, 1H), 7.43-7.34 (m, 3H), 6.99 (d, J=4.7 Hz, 1H), 5.42 (d, J=4.7 Hz, 1H), 5.24 (br d, J=9.5 Hz, 1H), 4.81 (br d, J=9.5 Hz, 1H), 4.69 (br d, J=9.5 Hz, 1H), 4.13 (br d, J=9.5 Hz, 1H), 2.68-2.58 (m, 2H), 2.54 (s, 3H), 1.16 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:34]=1[C:35](N(OC)C)=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35](=[O:36])[C:34]3[CH:41]=[C:42]([CH3:45])[CH:43]=[CH:44][C:33]=3[Cl:32])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1cc(C)ccc1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1cc(C)ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (984 mg, 2.0 mmol) in THF (10 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 2.5 mL, 5.0 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of 2-chloro-N-methoxy-5,N-dimethyl-benzamide (852 mg, 4.0 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). The combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4), and concentrated under reduced pressure. The obtained residue was purified via column chromatography (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (543 mg) in 48% yield. ESMS m/z (relative intensity): 534.9 [(M-32+H)]+ (35), 588.9 (M+Na)+ (100).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[N:10]1([C:16]([S:18]C)=S)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:20](=O)([O-])[O-:21].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:13]1[CH2:14][CH2:15][N:10]([C:16](=[S:18])[O:21][CH3:20])[CH2:11][CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: ClCc1ccccc1Cl
Reactant: CSC(=S)N1CCNCC1
Agent: [Na+]
Solvent: CCO
Product: COC(=S)N1CCN(Cc2ccccc2Cl)CC1
Yield: 36.2 %

Procedure:
In 16 ml of ethanol, 1.61 g (10 mmol.) of 2-chlorobenzyl chloride, 1.76 g (10 mmol.) of methyl 1-piperazinecarbodithioate and 1.06 g (10 mmol.) of sodium carbonate were heated to reflux for 4 hours. Ethanol was distilled off under reduced pressure, and to the residue was added water. The aqueous mixture was extracted with 30 ml of ether. The ether extract was shaken with 15 ml of 3N-hydrochloric acid. There were separated three layers. The aqueous portion and the oil portion were taken out and combined. The combined mixture was made alkaline with 1-N aqueous sodium hydroxide solution and extracted with ether. The ether portion was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was purified over a silica gel column to give 1.03 g of methyl 4-(2-chlorobenzyl)-1-piperazinecarbothioate as a pale brown oil, yield 34.3%.
Reaction SMILES: COC([CH:5]1[CH2:11][CH2:10][N:9](C(OC(C)C)=O)[C:8]2[CH:18]=[C:19]([C:24]([F:27])([F:26])[F:25])[C:20]([CH2:22][CH3:23])=[CH:21][C:7]=2[C:6]1=[O:28])=O.[Cl-].[Na+]>CS(C)=O.O.C(OCC)(=O)C>[CH2:22]([C:20]1[C:19]([C:24]([F:27])([F:25])[F:26])=[CH:18][C:8]2[NH:9][CH2:10][CH2:11][CH2:5][C:6](=[O:28])[C:7]=2[CH:21]=1)[CH3:23]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCC(C(=O)OC)C2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cc2c(cc1C(F)(F)F)NCCCC2=O
Temperature: 25 °C
Yield: 60.8 %

Procedure:
Heat a mixture of 7-ethyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1,4-dicarboxylic acid 1-isopropyl ester 4-methyl ester (23.55 g, 58.61 mmol), sodium chloride (52.50 g), and water (10.0 mL) in dimethylsulfoxide (500 mL) at reflux for 46 h. Allow the mixture to cool to room temperature and dilute it with water (200 mL) and ethyl acetate (200 mL). Wash the organic layer with water (350 mL). Dry the organic layer over anhydrous sodium sulfate and filter. Remove the solvents under reduced pressure and purify the resulting residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the title compound as a yellow solid (9.17 g, 61%) TLC Rf 0.32 (3:1 hexanes/ethyl acetate); 1H NMR (CDCl3, 300 MHz) δ 1.10-1.23 (m, 3H), 2.13-2.21 (m, 2H), 2.63-2.71 (m, 2H), 2.83-2.92 (m, 2H), 3.22-3.31 (m, 2H), 4.74 (bs, 1H), 7.03 (s, 1H), 7.68 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([O:10][C:11]2[C:17]([CH3:18])=[CH:16][C:14]([NH2:15])=[C:13]([CH3:19])[CH:12]=2)[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:22][CH3:23])[CH3:21].[CH:24](OC)(OC)OC>>[C:1]([C:5]1[N:9]=[C:8]([O:10][C:11]2[C:17]([CH3:18])=[CH:16][C:14]([N:15]=[CH:23][N:22]([CH2:20][CH3:21])[CH3:24])=[C:13]([CH3:19])[CH:12]=2)[S:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(OC)OC
Reactant: Cc1cc(Oc2nc(C(C)(C)C)ns2)c(C)cc1N
Reactant: CCNC
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(C(C)(C)C)ns2)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
17.46 g (63.00 mmol) of 4-[(3-(tert-butyl)-1,2,4-thiadiazol-5-yl)oxy]-2,5-dimethylaniline are dissolved in 500 ml of trimethyl orthoformate and heated at reflux for 2 h. After cooling to ambient temperature (AT), the solvent is evaporated under vacuum and the residue is taken up in 630 ml of dichloromethane, treated with 8.65 ml (126.00 mmol) of N-ethyl-N-methylamine and stirred at ambient temperature for 18 h. After removing the solvent, the crude product is purified by column chromatography (13.4 g, 59% yield, 95% purity, log P (pH 2.3)=2.02).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[N:8]=1.[F:15][C:16]([F:33])([F:32])[C:17](=[O:31])[CH2:18][C:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH3:30])([CH3:21])[CH3:20]>C1COCC1>[F:33][C:16]([F:15])([F:32])[C:17]([CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[N:8]=1)([OH:31])[CH2:18][C:19]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH3:30])([CH3:21])[CH3:20]
Reactant: Cc1cc(C)nc(C)c1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(C)cc(C)n1)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
tert-Butyl lithium (1.7 M in pentane, 0.5 mL) was added dropwise to a solution of 2,4,6-trimethylpyridine (0.12 g) in THF (0.5 mL) cooled to −70° C. under argon. The mixture was stirred at −70° C. for 15 minutes and 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (0.10 g) (Example 1) in THF (0.5 mL) was added. The reaction mixture was stirred for 20 minutes and then quenched with acetic acid. The mixture was diluted with EtOAc, washed with water, dried, filtered, and concentrated in vacuo. Fractionation by preparative layer chromatography on silica gel (methylene chloride-hexanes) followed by crystallization gave 43 mg of the title compound, m.p. 95° C.-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:24][CH2:23]2)=[CH:12][CH:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(Cl)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(Oc3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-chlorophenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 566.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([OH:18])[CH:12]=2)=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C(#N)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]2[O:19][C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([OH:18])[CH:12]=3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NNC(=O)c2ccc(Cl)cc2)cc1O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1O
Reaction time: 0.08 h

Procedure:
To a solution of 3-hydroxy-4-methyl-benzoic acid N′-(4-chloro-benzoyl)-hydrazide (1.28 g, 4.20 mmol) (from Example 44 supra) in acetonitrile (20 mL) was added diisopropylethylamine (4.4 mL, 25.2 mmol) and triphenylphosphine (2.21 g, 8.40 mmol). After stirring 5 minutes, hexachloroethane (1.49 g, 6.30 mmol) (Aldrich) was added and the mixture was allowed to stir for 1 day at room temperature. The solvent was evaporated. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (1×). The combined organic phase washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 0-60% ethyl acetate in hexanes to give 5-[5-(4-chloro-phenyl)-[1,3,4]-oxadiazol-2-yl]-2-methyl-phenol. (Yield 0.34 g, 28%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH3:25][NH:26][CH2:27][C@H:28]([OH:37])[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([OH:36])[CH:30]=1.CS(C)=O>CC(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([N:26]([CH2:27][CH:28]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([OH:36])[CH:30]=3)[OH:37])[CH3:25])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC[C@H](O)c1ccc(O)c(O)c1
Solvent: CC(C)=O
Solvent: CS(C)=O
Product: CN(CC(O)c1ccc(O)c(O)c1)C(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.3 %

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.167 g (0.9111 mmol) of (R)-(-)-epinephrine were placed into a 10 ml round bottom flask with 2 ml dimethylsulfoxide (dried over barium oxide) and a magnetic stirring bar. The solution was stirred at room temperature (25°) and was initially heterogeneous. After about 45 minutes, as the epinephrine began to react with AIT-0081, the solution was a nearly homogeneous yellow orange color. The solution was stirred an additional two hours, drawn into a pasteur pipet, and added with stirring to a flask containing 50 ml acetone and a magnetic stirring bar. A copious white precipitate formed and the solution was stirred for ten minutes. The solution was filtered by vacuum and the white solid washed with acetone. The Buchner funnel was immediately placed under high vacuum to remove small traces of dimethylsulfoxide. 120 mg of a white solid, 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(3,4-dihydroxyphenyl)-2-hydroxyethyl]-N-methylpropanamide (AIT-0100), was obtained. Yield: 48%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=2)=[CH:4][CH:3]=1.C([O:22][N:23]=O)(C)(C)C.Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([F:16])[CH:11]=2)=[N:23][OH:22])=[CH:6][CH:7]=1
Reactant: CC(C)(C)ON=O
Reactant: O=C(Cc1ccnc(F)c1)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: O=C(C(=NO)c1ccnc(F)c1)c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)ethanone (43 g, 0.184 mol) in ethanol (800 mL) at −10° C. was added dropwise t-butylnitrite (24.1 mL, 0.20 mol) over 10 minutes followed by 2.5 M HCl in absolute ethanol (60 mL, 0.15 mol). The reaction temperature was maintained at −5° C. during these additions. After addition was complete, the dry ice bath was removed and the reaction was allowed to warm to RT and stirred overnight. The ethanol was removed under reduced pressure and the residue was diluted with H2O and made basic with saturated NaHCO3. It was extracted with EtOAc, the combined organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was taken up in methanol/isopropanol and mixed with toluene. The methanol/isopropanol mixture was concentrated under reduced pressure and the title compound was recrystallized from hexane/toluene (47.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14](=[O:19])/[CH:15]=[C:16](\[NH2:18])/[CH3:17].[C:20]([O:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])(=[O:25])[CH2:21][C:22]([CH3:24])=O>CC(O)C>[CH3:24][C:22]1[NH:18][C:16]([CH3:17])=[C:15]([C:14]([O:13][CH3:12])=[O:19])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:21]=1[C:20]([O:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])=[O:25]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Yield: 29.7 %

Procedure:
A solution of 3.02 g (0.02 mol) of 3-nitrobenzaldehyde, 2.36 g (0.02 mol) of methyl-3-aminocrotonate, and 5.72 g (0.02 mol) of 2-phthalimidoethyl acetoacetate in 150 ml of 2-propanol was refluxed for 15 hours under nitrogen. The solvent was removed in vacuo, and the residue was subjected to flash chromatography (silica gel, 1:1 dichloromethane/hexane). The product was isolated and recrystallized from 1:1 dichloromethane/hexane to yield 3.0 g (30%) of a pale yellow solid; m.p. 181.5°-182.5° C. NMR: (CDCl3); δ 2.3 (6H,s), 3.5 (3H,s), 3.9 (2H,m), 4.2 (2H,m), 4.9 (1H,s), 6.0 (1H,s), 7.0-8.0 (8H,m).