Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:21]2[C:20](=[O:22])[C:19]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]3[C:17]2=[O:27])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Temperature: 0 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
A mixture of 4-benzyl-2-chloromethylmorpholine (86.4 g), phthalimide potassium salt (78.0 g), and dimethylformamide (700 ml) is refluxed with stirring for 5 hours. The reaction mixture is poured into ice-water. The resulting precipitate is collected and recrystallized from isopropyl alcohol to give N-[(4-benzyl-2-morpholinyl)methyl]phthalimide (107 g), mp 136°-139° C. The starting material, 4-benzyl-2-chloromethylmorpholine, is prepared according to the method of F. Loftus [Syn. Commun., 10, 59-73 (1980)].
Reaction SMILES: O[CH:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(N(S(F)(F)[F:26])CC)C.OP([O-])(O)=O.[Na+]>ClCCl>[F:26][CH:2]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOP(=O)(OCC)C(O)c1ccc([N+](=O)[O-])cc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
The title compound was prepared as described in Taylor, W P, et. Al, Bioorg. Med. Chem. 4:1515-1520 (1996). The product from Example 30, Part A (500 mg, 1.729 mmol) was dissolved in dichloromethane (10 mL) and treated by drop wise addition of (diethylamino)sulfur trifluoride (DAST) (2.5 mL, 18.9 mmol). The mixture was stirred at room temperature for 18 h. A solution of half saturated sodium phosphate monobasic (20 mL) was added followed by dichloromethane (20 mL) addition and separation of the resulting organic phase. The organic solution was dried and concentrated under vacuum, and then subjected to column chromatography using silica gel eluting with a 1/1 mixture of hexanes/ethyl acetate to provide the title compound as an oil (215 mg, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]1(=O)[O:15][C:13](=[O:14])[CH:12]=[CH:11]1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]2=[O:15])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=C1C=CC(=O)O1
Product: Cc1cc(N2C(=O)C=CC2=O)ccc1Br

Procedure:
4-Bromo-3-methylaniline (1.55 g, 8.33 mmol) and maleic anhydride (0.898 g,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](O)=[O:9])[CH:3]=1.[NH2:11][C:12]1[N:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[CH:15]=[CH:14][CH:13]=1.CN1CCOCC1>CN(C)C=O>[CH3:21][O:20][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:11][C:8]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=2)=[O:9])[N:17]=1)=[O:19]
Reactant: COC(=O)c1cccc(N)n1
Reactant: O=C(O)c1cc(Cl)ccn1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Yield: 93 %

Procedure:
A solution of 4-chloro-pyridine-2-carboxylic acid (16.3 g, 103 mmol), methyl 6-aminopicolinate (3.0 g, 18.6 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylumnium hexafluorophosphate (HATU, 41.1 g, 108 mmol), and N-methyl morpholine (12.5 mL, 108 mmol) in N,N-dimethylformamide was stirred at room temperature for 12 hours. The solvent was removed under reduced pressure, and the residue suspended in acetonitrile. The solid thus obtained was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL) and diethyl ether (80 m L) and dried under reduced pressure to afford 6-[(4-chloro-pyridine-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester as a white powder (25.6, 93% yield).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:10]O)[C:4]=2[CH:3]=[CH:2]1.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.CCCCCCC=CCCC>O1CCCC1>[N:26]([CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cccc2[nH]ccc12
Agent: CCCC=CCCCCCC
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1cccc2[nH]ccc12
Reaction time: 5 h
Yield: 1810.1 %

Procedure:
To a solution of 1H-indole-4-methanol (71 mg, 0.48 mmol) in tetrahydrofuran (1 mL) at 0° C. was added diphenylphosphoryl azide (156 μL, 0.72 mmol) followed by 1,8-diaza[5.4.0]undec-7-ene (87.4 μL, 0.58 mmol). The cooling bath was removed and the solution was allowed to stir for 5 h. The solvent was evaporated and ethyl acetate was added. The solution was washed with 1 M HCl and brine, dried (MgSO4), filtered, concentrated and chromatographed (12% ethyl acetate/hexanes) to give 4-(azidomethyl)-1H-indole (1.496 g, 88%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:27])[CH3:26])=[O:5])[CH3:2].Cl>O1CCCC1.[OH-].[Li+].O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=1)[CH2:10][C:9]2([CH3:26])[CH3:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)OC)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(C(=O)O)c1)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.9 %

Procedure:
A mixture of 2-(3-methoxycarbonyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.5 g, 6.8 mmol) in tetrahydrofuran (20 mL), 2M lithium hydroxide in water (10 mL) was stirred for 4 h at 25° C. The mixture was neutralized with a 2 N aqueous hydrochloric acid solution, diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-carboxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.2 g, 50%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=354.2.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([CH:8]([CH3:10])[CH3:9])=[O:7].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C.CCOCC>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:5][C:6](=[O:7])[CH:8]([CH3:10])[CH3:9])=[CH:14][CH:13]=1
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
A sodium ethoxide solution (21% by weight in EtOH, 4.86 gm, 15 mmol) was added to a mixture of methylisopropylketone (8.61 gm, 100 mmol, from Aldrich) and 4-fluorobenzaldehyde (12.411 gm, 100 mmol, from Aldrich) in ethanol (150 ml). The solution was allowed to stir at room temperature for 3 hours. The solvent was evaporated to afford an orange oil. The oil was dissolved in ether, washed with saturated NH4Cl and brine, then dried over Na2SO4, filtered and concentrated to give an orange oil. The oil was purified by distillation (bp=106° C. at 1.3 mm Hg) to afford the title compound as a pale yellow oil (10.118 gm, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].N1C2C(=CC=CC=2)C=CC=1.Cl>O.N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: Nc1ccccc1Sc1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Heat a mixture of 466 g (3.72 moles) of 2-aminothiophenol, 250 g (1.24 moles) of 2-chloro-4-nitrobenzoic acid, 1.25 liters of quinoline, 192 g (1.34 moles) of cuprous oxide and 125 ml of pyridine in an oil bath at 160°-170° C. with mechanical stirring for 90 minutes. Cool the mixture to room temperature and add 1.87 liters of concentrated hydrochloric acid followed by 625 ml of water. Separate the precipitate and wash well with water. Extract the washed precipitate into boiling methanol and filter. Treat the hot filtrate with charcoal, filter and strip to dryness. Dissolve the residue in aqueous sodium hydroxide, filter and treat with charcoal. Acidify the filtrate and separate the precipitate. (Yield: 38 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Cl.[CH:19]12[NH:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([N:25]2[CH:19]3[CH2:24][CH2:23][CH:22]2[CH2:21][CH2:20]3)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: C1CC2CCC1N2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1Br
Temperature: 80 °C
Reaction time: 24 h
Yield: 77.1 %

Procedure:
To a solution of 2-bromo-4-fluoro-1-nitro-benzene 24 (1.1 g, 4.8 mmol) and K2CO3 (2.0 g, 14.3 mmol) in DMSO (8.400 mL) was added 7-azabicyclo[2.2.1]heptane 7a (765.4 mg, 5.7 mmol) portion-wise. The reaction was stirred at 80° C. for 24 h. The reaction was diluted with water to precipitate the product. The solid was redissolved in dichloromethane, washed with 1.0 N HCl, dried over MgSO4, filtered and concentrated to provide 7-(3-bromo-4-nitrophenyl)-7-azabicyclo[2.2.1]heptane 25 (1.1 g, 78% yield). The crude product was used directly in the next step. LC/MS m/z 299.1 [M+H]+, retention time 1.97 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C1(C)C=CC=CC=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]Cl)=[CH:16][CH:15]=1.[OH-].[Na+]>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:16][CH:15]=1
Reactant: ClCCc1ccc(Cl)cc1
Reactant: CC(O)CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
1-Aminopropan-2-ol (60.0 g, 799 mmol) was charged to a 250-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, and heated to 120° C. To this was slowly added the toluene solution of 1-chloro-4-(2-chloroethyl)benzene from Step A while maintaining the reaction temperature at 120-125° C. On completion of the addition, stirring was continued at 115-120° C. for 2.5 h. NaOH (50%, 12.78 g, 160 mmol) was added followed by water (25 mL) and the mixture was stirred at 70 to 75° C. for 15 min. The organic phase was separated and washed with water (4×25 mL) at 70 to 75° C. The combined aqueous phases were extracted with toluene (38 mL) for 15 min at 70 to 75° C. Then, the combined organic phases were concentrated under reduced pressure at 60° C. (bath). The residue was diluted with toluene to a total volume of 104 mL and the golden solution was stirred overnight at 50° C. (bath) under nitrogen. Karl Fischer titration showed 0.052% water.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].COC(C)(C)C>C(OC(=O)C)(=O)C>[N+:1]([C:4]1[C:5]2[C:13](=[O:14])[O:15][C:7](=[O:9])[C:6]=2[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Solvent: COC(C)(C)C
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 80 °C
Yield: 88.8 %

Procedure:
A solution of 474.8 g (2.25 mol) of 3-nitrophthalic acid in 450 ml of acetic anhydride was stirred under reflux for 1 h. The solution was slowly cooled to 80° C. Then 1000 ml of methyl-tert-butyl ether (MTBE) were added expeditiously and the solution was cooled to 15° C. The resulting solid was isolated, washed with MTBE and dried in a vacuum oven at 40° C. Yield: 88.8%
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:22]([NH2:24])=O.C[O-].[Na+].Cl>CN(C)C=O.CO.O>[CH2:15]([O:14][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][C:10]=1[O:12][CH3:13])[N:1]=[CH:22][NH:24][C:4]2=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)c(OC)cc1N
Reactant: NC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
Methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate (5.0 g) was dissolved in N,N-dimethylformamide (150 ml) and methanol (30 ml). Formamide (3.5 ml) and sodium methoxide (2.8 g) were added to the solution. The mixture was heated to 100° C. and was then stirred overnight. The reaction solution was then cooled to room temperature, and 10 ml of water was then added. The reaction solution was neutralized with a 1 M aqueous hydrochloric acid solution to precipitate a solid. The solid was collected by filtration, was washed with water and ether, and was then dried through a vacuum pump to give 3.7 g (yield 76%) of the title compound.
Reaction SMILES: OC1C=C(C=CC=1O)C=CC(Cl)=O.S(Cl)(Cl)=O.[C@H:18]1([O:29][C@@H:30]2[C@@H:35]([CH2:36][OH:37])[O:34][C@@H:33](Br)[C@H:32]([OH:39])[C@H:31]2[OH:40])[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]1[OH:20].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C)C=O.CS(C)=O>[C@H:18]1([O:29][C@@H:30]2[C@@H:35]([CH2:36][OH:37])[O:34][C@@H:33]([N:41]=[N+:42]=[N-:43])[C@H:32]([OH:39])[C@H:31]2[OH:40])[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:21]([OH:22])[C@H:19]1[OH:20]
Reactant: [N-]=[N+]=[N-]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](Br)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C(Cl)C=Cc1ccc(O)c(O)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O

Procedure:
A method for producing compounds of the formula: ##STR8## wherein A is selected from the group consisting of alkali metal cations and alkaline earth metal cations which comprises reacting 3,4-dihydroxycinnamic acid with acetic anhydride in pyridine for 18-30 hours, in organic solvents, giving 3,4-dihydroxycinnamic acid, diacetate, then converting to 3,4-dihydroxycinnamic acid chloride by treating with thionyl chloride in dimethylformamide at -20° to -18° C. for 30-90 minutes; reacting 4-O-α-D-glucopyranosyl-β-D-glucopyranosyl bromide, heptaacetate with sodium azide in dimethylsulfoxide at 55°-65° C. for 10-30 minutes, extracting in organic solvents, giving 4-O-α-D-glucopyranosyl-β-D-glucopyranosylazide, heptaacetate, then catalytically reducing, giving 4-Oα-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate (heptaester); reacting a solution of the 3,4-dihydroxycinnamic acid chloride in dimethylformamide at -20° to -15° C. with a solution of the 4-O-α-D-glucopyranosyl-β-D-glucopyranosylamine, heptaacetate in pyridine at -15° to -5° C. for 20-40 minutes, then at -5° to 20° C. for 1-2 hours followed by extracting with organic solvents, giving N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide, nonaacetate (nonaester), then converting to N-(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl)-3,4-dihydroxycinnamamide by reacting in a mixture of methanol, triethylamine and water, under an inert atmosphere for 20-30 hours followed by heating at reflux for 2-6 hours and extracting in organic solvents, reacting this derivative with triethylamine sulfur trioxide in N,N-dimethylacetamide under an inert atmosphere at 50°-70° C. for 15-20 hours, and then treating with an alkali metal or alkaline earth metal acetate in water.
Reaction SMILES: [Cl-].[CH2:2]([NH+:14]=[C:15]([NH2:17])[SH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:18]1([P:24](=[O:27])([OH:26])[OH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.O>[C:18]1([P:24](=[O:25])([O-:27])[O-:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:2]([NH+:14]=[C:15]([NH2:17])[SH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:2]([NH+:14]=[C:15]([NH2:17])[SH:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=P(O)(O)c1ccccc1
Agent: CCCCCCCCCCCC[NH+]=C(N)S
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: O=P([O-])([O-])c1ccccc1

Procedure:
n-Dodecyl thiouronium chloride (8.0 g), phenylphosphonic acid (10 g), and 200 ml of 50/50 (v/v) ethanol/water mixture were heated overnight and then cooled. After filtering and recrystallizing from water-methanol-ethanol, approximately 11.1 g of n-dodecyl thiouronium phenyl phosphonate was isolated (m.p. 154°-156° C.). Chemical analysis and infrared spectra confirmed n-dodecyl thiouronium phenylphosphonate formation.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C

Procedure:
Ethyl 4-hydroxybenzoate (60.0 g), 1-bromo-3-chloropropane (71.37 ml) and potassium carbonate (149.61 g) were heated under reflux in acetone (1445 ml) overnight. The reaction mixture was then allowed to cool to rt, filtered and evaporated. The residue was chromatographed [silica gel; step gradient 0-5% ethyl acetate/hexane]. Fractions containing pure product were combined and evaporated to give the subtitled compound as a clear oil (70.0 g). MS electrospray (+ion) 243 (MH+). 1H NMR δ (CDCl3): 8.00 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.8 Hz), 4.36 (2H, q, J=7.1 Hz), 4.18 (2H, t, J=5.8 Hz), 3.74 (2H, t, J=6.2), 2.25 (2H, m), 1.37 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].[N+:31]([CH3:34])([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C@@:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)([CH2:34][N+:31]([O-:33])=[O:32])[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
Alternatively, 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (0.075 g, 0.163 mmol) and antracen-9-yl-methyl quininium bromide (0.020 g, 0.034 mmol) were dissolved in toluene (2.0 ml). Nitromethane (10 molar equivalents) and potassium carbonate (0.025 g, 0.181 mmol) were added and the resulting suspension was stirred at 50° C. for 24 h. The reaction mixture was cooled to room temperature and water was added. The resulting mixture was extracted with dichloromethane (3×) and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (0.051 g, 60%) as a white foam. Chiral HPLC analysis (Chiralpack AS-RH, Heptane/2-propanol=90:10, 1 ml/min, retention time 6.13 minutes (major enantiomer), 7.35 minutes (minor enantiomer)) indicated that the reaction proceeded with 62% enantioselectivity.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19].[OH2:23]>ClCCl>[S:18]([OH:23])(=[O:20])(=[O:19])[CH3:21].[OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1
Reactant: O
Reactant: CS(=O)(=O)Cl
Agent: O=C1CCC(CCO)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 15.25 g (107.24 mmol) 4-(2-hydroxyethyl)cyclohexanone in 115 mL of dichloromethane cooled at a temperature close to 0° C., is added 18 mL (129.5 mmol) of triethylamine, then 9.25 mL (119.50 mmol) of mesyl chloride. The mixture is stirred for two hours at room temperature. Water (120 mL) is added. The organic phase is separated by decantation, washed with a saturated aqueous solution of sodium hydrogenocarbonate (100 mL), dried over magnesium sulfate and concentrated under reduced pressure to give 28 g of 4-(2-hydroxyethyl)cyclohexanone mesylate used without further purification in the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:17][S:18]([O:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:20])=[O:19]
Reactant: OCCC1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1CCOCC1

Procedure:
The product of Example 8A (2.9 mmol), triethylamine (1.2 mL, 8.7 mmol) and methanesulfonyl chloride (0.34 mL, 4.4 mmol) in 10 mL tetrahydrofuran (THF) were reacted and the product isolated as in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]1)(=[O:15])[CH3:14].C(N(CC)CC)C.Cl.[CH3:33][NH:34][O:35][CH3:36]>C1COCC1.C(#N)C>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:22]([N:34]([O:35][CH3:36])[CH3:33])=[O:24])[CH2:20][CH2:21]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1′-Carbonyldiimidazole (6.43 g, 39.64 mmol) was added slowly to a mixture of 1-acetylpiperidine-4-carboxylic acid (5 g, 29.21 mmol) in dry THF (40 mL). The mixture was stirred at room temperature for one hour. In a separate flask, triethylamine was added to a mixture of N,O-dimethylhydroxylamine hydrochloride (3.92 g, 40.18 mmol) in acetonitrile (32 mL). The two mixtures were combined and stirred at room temperature for 12 hours. The solvents were removed under reduced pressure and the residue dissolved in DCM. The organic mixture was washed with water, HCl (0.1 N aqueous solution) and finally a concentrated aqueous Na2CO3 solution. The organic layer was dried over MgSO4, filtered and evaporated to give a crude oil. The oil was purified by chromatography to provide the title compound visible by HPLC at 214 wavelength.