Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]([C:7](=[N:16][O:17][CH3:18])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=O)=[N:2]1.[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=O.O.[NH2:33][NH2:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH3:18][O:17][N:16]=[C:7]([C:3]1[O:4][CH2:5][CH2:6][O:1][N:2]=1)[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[N:33][N:34]=[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)[CH3:19]
Reactant: CON=C(C1=NOCCO1)c1ccccc1C=O
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CON=C(C1=NOCCO1)c1ccccc1C=NN=C(C)c1cccc(C(F)(F)F)c1
Yield: 28.9 %

Procedure:
0.9 g (0.0036 mol) of 2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzaldehyde, 0.69 g (0.0036 mol) of 3-trifluoromethylacetophenone, 0.18 g (0.0036 mol) of hydrazine hydrate and 25 mg of 4-toluenesulphonic acid are heated under reflux in 120 ml of toluene for 18 hours using a water separator. After cooling, the mixture is dried over magnesium sulphate and concentrated under reduced pressure. The residue is chromatographed over silica gel with cyclohexane/ethyl acetate (5:1). 0.45 g (29% of theory) of (5,6-dihydro-[1,4,2]dioxazin-3-yl)-(2-{[1-(3-trifluoromethylphenyl)-ethylidene]-hydrazonomethyl}-phenyl)-methanone O-methyl oxime is obtained.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[CH:6]1([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:13](O)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:6]1([CH2:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:13]([N:4]([O:3][CH3:2])[CH3:5])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CNOC
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
To a solution (80 mL) of N-methoxymethanamine hydrochloride (2.20 g) in N,N-dimethylformamide was added triethylamine (3.10 mL) for neutralization, and 3-cyclopentyl-2-[4-(methylsulfonyl)phenyl]propanoic acid (5.95 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (5.80 g) and 1-hydroxybenzotriazole (4.10 g) were added under ice-cooling. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, and washed with water, 1N aqueous hydrochloric acid solution and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (6.07 g, yield 89%) was obtained as colorless amorphous crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 340 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)c(Cl)c2)o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A mixture of 3.13 g (0.010 mole) of 4-[5-(3,4-dichlorophenyl)-2-furanyl]-4-oxobutanoic acid and 50 ml of 95% dioxane/water was treated portionwise with 0.95 g (0.025 mole) of NaBH4 while maintaining the temperature below 20° by means of an ice bath. The resulting near solution was allowed to stand overnight at room temperature and was then added to ice/water. After acidifying with 20% hydrochloric acid, the resulting oily mixture was extracted with ether and the ethereal extract dried over MgSO4. The ether was removed on a Calab evaporator yielding 3 g (96%) of product as a residual oil.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N+](C1C=CC(O)=CC=1)([O-])=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:1]([OH:16])(=[O:15])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCC=CC=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CN(C)C=O
Product: CCCCCCCCC/C=C/C=C/C(=O)O
Reaction time: 12 h

Procedure:
To a solution of trans-2-dodecenal (4.5 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenylphosphorane (8.3 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g). To a solution of potassium hydroxide (6.5 g) in a mixed solvent of ethanol-water (1:1) (100 ml) was added the methyl ester of trans,trans-2,4-tetradecadienoic acid (5.4 g), and the mixture was stirred at 60° C. for 40 minutes. The reaction mixture was cooled, and acidified to a weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-tetradecadienoic acid (4.3 g). To the tetradecadienoic acid dissolved in N,N-dimethylformamide (DMF, 50 ml) was added para-nitrophenol (2.67 g) and N,N'-dicyclohexylcarbodiimide (3.9 g), and the mixture was stirred for 12 hours. After precipitates produced were removed by filtration and DMF was evaporated, the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-tetradecadienoic acid (5.1 g). To the active ester (500 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-septaminyl-amino)purine hydrochloride (560 mg) and triethylamine (1.5 ml), and the mixture was stirred for 18 hours. The solvent was evaporated, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPT241 in the yield of 271 mg.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([C:16]#[N:17])([CH3:15])[CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:15])([C:16]#[N:17])[CH2:11][CH2:10]1
Reactant: CC1(C#N)CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C#N)CCC(CN)CC1
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 366A (480 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). The mixture was stirred for 3 hours. The mixture was then concentrated under vacuum and was used directly in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Cl[C:36]1[N:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:42]([C:39]1[CH:38]=[N:37][C:36]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[CH2:4][CH2:3][C:2]([F:33])([F:34])[F:1])=[C:7]([CH3:21])[CH:8]=2)=[N:41][CH:40]=1)[CH3:43]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCc1cnc(-c2ccc(C(CCC(F)(F)F)Nc3ccc(C(=O)OC)cc3)c(C)c2)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoate (14.3 g) obtained in Example 1, step F, 2-chloro-5-ethylpyrimidine (4.00 mL), tetrakistriphenylphosphinepalladium (3.46 g), 2M aqueous sodium carbonate solution (44.9 mL) and DME (135 mL) was stirred at 100° C. overnight under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was solidified with diisopropyl ether to give the title compound (12.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14](=O)[CH2:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)=[CH:27][NH:26][N:25]=1>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:15]=[C:16]([C:17]([F:20])([F:19])[F:18])[N:25]3[N:26]=[CH:27][C:28]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=4)=[C:24]3[N:23]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2]
Reactant: CCOc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(-c4ccnc(C)c4)c3n2)ccc1C(F)(F)F
Yield: 48.5 %

Procedure:
Reaction of 1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (164 mg, 0.5 mmol), prepared from 3-ethoxy-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2-methyl-pyridine, as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (113 mg, 49%). MS (ISP) 467.4 [(M+H)+]; mp 226° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[N:4][C:5]([Br:12])=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].N([O-])=O.[Na+].[N-:29]=[N+:30]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:3]([C:13]2[CH:14]=[N:15][C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:17][CH:18]=2)=[N:4][C:5]([Br:12])=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[N+:29]=[N-:30]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)nc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)nc(-c2ccc(N3CCOCC3)nc2)c1N=[N+]=[N-]
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Methyl 3-amino-6-bromo-6′-morpholino-2,3′-bipyridine-4-carboxylate (230 mg, 0.59 mmol) was dissolved in TFA (2.9 mL) and the solution was cooled in an ice bath. Solid sodium nitrite (89 mg, 1.29 mmol) was added slowly with stirring to give a red solution. After 30 min, powdered sodium azide (380 mg, 5.85 mmol) was added in portions with gas evolution. Et2O (29 mL) was added with stirring after 0.5 hr, water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with, water (3×), saturated Na2CO3 solution (until the aqueous phase was basic), and brine (1×). After drying the solvent with sodium sulfate, the solvent was removed. Flash chromatography (step gradient elution with DCM containing 0 to 20% EtOAc) afforded methyl 3-azido-6-bromo-6′-morpholino-2,3′-bipyridine-4-carboxylate (240 mg, 0.57 mmol, 98% yield) yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.73 (1H, d, J=2.44 Hz), 7.99 (1H, dd, J=9.00, 2.59 Hz), 7.71 (1H, s), 6.68 (1H, d, J=8.85 Hz), 4.00 (3H, s), 3.79-3.86 (4H, m), 3.59-3.66 (4H, m).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:17][CH:16]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].Cl>C1COCC1.O>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH:22]([CH3:23])[CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:17][CH:16]=1
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: COC(=O)CBr
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)CC(C)C(=O)c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (5.1 ml) in anhydrous THF (90 ml) at 0° C. is treated under N2 atmosphere with n-butyllithium (1.6 M, 22 ml) for 20 minutes. The mixture was cooled to -78° C., and a solution of 1(4-methoxyphenyl)-1-oxopropane (5 g) in anhydrous THF (40 ml) is added. The mixture was stirred 30 minutes at -78° C., then methyl bromoacetate (3.05 ml) was added dropwise and then mixture was warmed to ambient temperature over 2 hours. After stirring 18 hours at room temperature the mixture was Poured onto ice, water and conc. HCl (3 ml) was added and the solution was extracted with dichloromethane. The organic extracts were washed with brine, dried over N2SO4 and concentrated to an oil which was purified by chromatography on silica gel to provide the title compound as an oil.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:12]=2)[N:9]=1.[Cl-:20].[NH4+:21]>>[ClH:20].[F:17][C:16]([F:19])([F:18])[C:13]1[CH:12]=[C:11]([CH2:10][CH:8]2[NH:9][C:3](=[NH:21])[CH2:4][CH2:5][CH2:6][CH2:7]2)[O:15][N:14]=1
Reactant: COC1=NC(Cc2cc(C(F)(F)F)no2)CCCC1
Reactant: [Cl-]
Reactant: [NH4+]
Product: Cl
Product: N=C1CCCCC(Cc2cc(C(F)(F)F)no2)N1

Procedure:
The title product of Example 120 is reacted with ammonium chloride by the method of Example 5 to generate the title compound.
Reaction SMILES: C(OC([N:6]([CH2:13]/[CH:14]=[CH:15]/[P:16](=[O:19])([OH:18])[OH:17])[O:7]C(OCC)=O)=O)C.Cl.C>O.C(O)C.N1C=CC=CC=1>[OH:7][NH:6][CH2:13]/[CH:14]=[CH:15]/[P:16](=[O:17])([OH:19])[OH:18]
Reactant: CCOC(=O)ON(C/C=C/P(=O)(O)O)C(=O)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: O=P(O)(O)/C=C/CNO
Yield: 54.2 %

Procedure:
A mixture of 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-trans-1-propenylphosphonic acid (8.53 g.) and 1 N hydrochloric acid (250 ml.) was refluxed for 16 hours. The resultant mixture was concentrated under reduced pressure to give a residue, which was dissolved in water (30 ml.). The aqueous solution was treated with activated charcoal (0.5 g.) and concentrated under reduced pressure to give an oily residue (5.85 g.), which was dissolved in water (10 ml.). The aqueous solution was passed through a column of anion exchange resin, Amberlite IRA 400 (100 ml.). The column was washed with water (600 ml.) and the object compound was eluted with 1 N hydrochloric acid (300 ml.). The eluate was concentrated under reduced pressure to give an oily residue (3.9 g.), to which were added ethanol (10 ml.) and water (2 ml.). The mixture was adjuted to pH 4-4.5 with pyridine and then to the mixture was added ethanol (30 ml.). The supernatant was removed by decantation to give residue, which was pulverized with ethanol (30 ml.) to give powdery 3-(N-hydroxyamino)-trans-1-propenylphosphonic acid (2.38 g.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[N:9]=[N:8]1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: c1cnc(-n2nnc3c2CCNC3)nc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(nnn2-c2ncccn2)C1
Reaction time: 3 h

Procedure:
A solution of 1-pyrimidin-2-yl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (97 mg, 0.48 mmol), 2-chloro-3-(trifluoromethyl)-benzoic acid (118 mg, 0.53 mmol) and Et3N (0.1 ml, 0.72 mmol) in DMF (2.5 ml), was treated with HATU (219 mg, 0.58 mmol) and stirred for 3 h.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].B.C1COCC1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(OCC)C>C1COCC1.C(Cl)Cl>[CH2:7]([O:6][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[O:15])=[CH:17][CH:18]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cc1)OCC
Agent: O=[Cr](=O)([O-])Cl
Agent: B
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(C=O)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
Triethylphosphite (9.28 mL, 53.3 mmol) and α-bromo-p-toluic acid (10.4 g, 48.4 mmol) were suspended in toluene (25 mL) and the mixture was heated to reflux for 18 h. The mixture was cooled to room temperature. After 12 h, the resulting white solid was collected by suction filtration, washed with petroleum ether and dried to yield 4-(diethoxyphosphorylmethyl)benzoic acid as a white solid (10.2 g, 77%): mp 117-120° C.; 1H NMR δ 1.26 (t, J=6.8 Hz, 6H), 3.24 (d, J=25.6 Hz, 2H), 4.06 (m, 4H), 7.38-7.40 (m, 2H), 8.02 (d, J=7.6 Hz, 2H), 11.4 (br s, 1H); 13C NMR δ 16.5, 16.6, 33.4, 34.8, 62.8, 62.9, 129.1, 129.2, 130.00, 130.05, 130.10, 130.48, 130.51, 137.3, 137.4, 170.1; FABMS obsd 273.0896, calcd 273.0892; Anal. Calcd. for C12H17O5P: C, 52.94; H, 6.29. Found: C, 52.92; H, 6.28. A suspension of 4-(diethoxyphosphorylmethyl)benzoic acid (9.99 g, 36.7 mmol) in anhydrous THF (40 mL) at 0° C. was treated dropwise over 10 min with borane-THF complex (40.3 mL, 40.3 mmol, 1.0 M in THF). The reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by slow addition of water. The mixture was concentrated and the residue was partitioned between water (100 mL) and CH2Cl2 (100 mL). The aqueous layer was washed with CH2Cl2. The combined organic layers were washed with water, dried (MgSO4), and concentrated to give a yellow oil. Analysis by TLC and 1H NMR spectroscopy showed starting material (˜10%) and the desired benzyl alcohol. The latter (9.56 g) was dissolved in CH2Cl2 and rapidly added to a sample of PCC (10.8 g, 50.1 mmol) in CH2Cl2 (50 mL) with rapid stirring. After 2 h, ethyl ether (150 mL) was added and the organic solution was decanted from the tarry residue. The residue was washed with ethyl ether (3×50 mL). The combined organic solution was filtered through Florisil and concentrated to a brown oil. Kugelrohr distillation (190° C. @ 0.05 Torr) afforded a clear, colorless oil (6.54 g, 77%): 1H NMR δ 1.24 (t, J=7.2 Hz, 6H), 3.21 (d, J=22.4 Hz, 2H), 4.03 (m, 4H), 7.45-7.48 (m, 2H), 7.83 (d, J=7.6 Hz, 2H), 9.99 (s, 1H); 13C NMR δ 16.1, 16.2, 33.0, 34.9, 62.1, 62.2, 77.2, 129.49, 129.53, 129.6, 129.66, 129.71, 130.2, 130.2, 138.8, 138.9, 191.61, 191.63; 31P NMR δ 25.4, 25.9; FABMS obsd 257.0949, calcd 257.0943 (C12H17PO4).
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4][C@@H:5]1[O:8][C:7](=[O:9])[CH2:6]1.[OH-:19].[Na+]>C1COCC1.O>[OH:8][C@@H:5]([CH2:4][CH:3]([O:2][CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:6][C:7]([OH:19])=[O:9]
Reactant: [OH-]
Reactant: CCCCCCCCCC(C[C@H]1CC(=O)O1)OC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC(C[C@H](O)CC(=O)O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 7 (187 mg, 0.729 mmol, 1.0 equiv) in THF (2.5 mL) was added a solution of NaOH (32.) mg, 0.802 mmol, 1.1 equiv) in water (1 L). The reaction mixture was stirred at rt for 2 h, transferred to a separatory funnel, diluted with water (5 mL) and extracted with ether. The aqueous layer was acidified with 2 N HCl (3 mL) and extracted with ether (2×15 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford (3S)-1 (187 mg, 93%) as a colorless oil that was used without further purification: ATR/IR 2920, 2851, 1709, 1412, 1189, 1079, 738 cm−1; 1H NMR (CDCl3) 4.85-4.7 (m, 1H), 3.55-3.45 (m, 1H), 3.39, 3.38 (2s, 3H), 2.56-2.52 (m, 2H), 1.80-1.35 (m, 3H), 1.35-1.25 (m, 14H), 0.90 (t, 3H, J=6.9 Hz); 13C NMR (CDCl3) 176.5, 175.8, 81.5, 78.7, 68.0, 65.3, 56.7, 55.9, 41.5, 39.6, 39.0, 32.8, 32.6, 31.8, 29.7, 29.5, 29.2, 25.1, 24.4, 22.6, 14.1; MS (EI) m/z 274 (M+, 0.5), 256 (0.5), 171, 25, 129 (100), 97 (15).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[N:10]1([CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:19]C)=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.Cl>>[CH3:5][O:4][N:3]([CH3:2])[C:17](=[O:19])[CH:16]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNOC
Reactant: COC(=O)C(c1ccccc1)N1CCOCC1
Agent: C[Al](C)C
Agent: Cl
Product: CON(C)C(=O)C(c1ccccc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (1.66 g, 17.0 mmol) was suspended in 20 mL of dry TVF and cooled to 0° C. Trimethylaluminum (8.50 mL, 2.0M solution in toluene, 17.0 mmol) was added slowly and stirred for 30 minutes. Methyl morpholin-4-yl-(phenyl)acetate (1.00 g, 4.25 mmol) was added to the cooled mixture in an 8 mL TIFF solution. The reaction was allowed to warm to ambient temperature while for 18 hours. The mixture was poured into 1N HCl(aq) and stirred for 1 hour. The mixture was then poured into NaHCO3(sat) and extracted 3× with EtOAc. The combined organic layers were washed 1× with brine, dried with Na2SO4, filtered and concentrated in vacuo to provide N-methoxy-N-methyl-2-morpholin-4-yl-2-phenylacetamide. HRMS [M+H] C14H21N2O3 calc'd 265.1547. found 265.1553.
Reaction SMILES: C(N1CCN(C2C3[CH:15]=[CH:16][S:17][C:13]=3[CH:12]=C(C3C=CC(O)=CC=3)N=2)CC1)C.[H-].[Na+].[H][H].Br[CH2:30][C:31]([O:33]CC)=[O:32]>CN(C=O)C>[CH3:12][C:13]1[S:17][CH:16]=[CH:15][C:30]=1[C:31]([OH:33])=[O:32]
Reactant: [H][H]
Reactant: CCOC(=O)CBr
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3sccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 154.1 %

Procedure:
4-(4-Ethylpiprazin-1-yl)-6-(4-hydroxyphenyl)thieno[3,2-c]pyridine (1.10 g) was dissolved in DMF (30 ml), followed by the addition of 60% sodium hydride (0.18 g). After the evolution of hydrogen was ceased, ethyl bromoacetate (0.55 g) was added thereto, which was then stirred at 0° C. for 30 min. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, dried and evaporated. The resulting residue was dissolved in THF (30 ml), followed by the addition of 3M methylmagnesium bromide/ether solution (3.3 ml) under ice-cooling, and the mixture was reacted at room temperature for 1.5 hr. The reaction solution was partitioned between ethyl acetate and water, and the aqueous layer was extracted from the organic layer with 2N hydrochloric acid. The aqueous layer was basified with 2N sodium hydroxide and back-extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system) and NH-silica gel chromatography (ethyl acetate), to give the free compound of the title compound as a colorless oil (0.71 g, yield; 53.2%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-:3])=[O:2].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]=1[O:14][CH3:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
reacting 2-nitro-4-tertbutylanisole with an acid mixture of nitric acid, sulfuric acid and oleum to produce 2,6-dinitro-4-tertbutylanisole; and