Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[BH3-][C:11]#[N:12].[Na+].[CH3:14]C(O)=O>>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([OH:9])=[C:2]([N:12]([CH3:11])[CH3:14])[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: CC(=O)O
Reactant: [BH3-]C#N
Agent: [Na+]
Product: CN(C)c1cc(Br)ccc1O
Temperature: 40 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2-Amino-4-bromo-phenol (3.9 g, 20.74 mmol) was dissolved into AcOH (120 mL) and heated to 40° C. To this stirring solution at 40° C. was added (HCHO)n (1.9 g, 62.23 mmol), followed by NaBH3CN (3.9 g, 62.23 mmol). The reaction mixture was stirred for 1 hr at 40° C., then another (HCHO)n (1.9 g, 62.23 mmol) and NaBH3CN (3.9 g, 62.23 mmol) were added. The mixture was stirred for 16 hrs at 40° C. The solvent was removed under reduced pressure. The residues were partitioned between EtOAc and water. The organic layer was collected and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (30:70) to afford 4-bromo-2-dimethylamino-phenol as a light yellow solid (3.7 g, 83%): 1H NMR (300 MHz, DMSO-d6): δ 9.44 (s, 1 H), 6.92 (m, 2 H), 6.71 (d, J=8.4 Hz, 1 H), 2.69 (s, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=20% ethyl acetate in hexanes; Rf=0.57.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Cl.C(OC(C)C)(C)C>CN(C)C=O.O>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(C=O)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
To a solution of 61.1 g of p-hydroxybenzaldehyde in 240 ml of N,N-dimethylformamide was added 138 g of potassium carbonate, 80.7 g of 2-dimethylaminoethyl chloride and 30 ml of isopropyl ether. The mixture was stirred at 60° C. for 1.5 hours. After cooling, the reaction mixture was poured into 720 ml of water, and the whole was extracted with chloroform. The chloroform layer was extracted with aqueous hydrochloric acid. The aqueous layer was made alkaline with aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was distilled to give 69.1 g of colorless oil, b.p. 142°-144° C. (4 mmHg).
Reaction SMILES: N1CCOCC1.C([Li])CCC.Br[C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][CH3:25])=[CH:17][C:14]=1[CH:15]=[O:16].[F:26]NS(C1C=CC=CC=1)(=O)=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:24]([O:23][C:18]1[C:19]([O:21][CH3:22])=[CH:20][C:13]([F:26])=[C:14]([CH:17]=1)[CH:15]=[O:16])[CH3:25]
Reactant: CCOc1cc(C=O)c(Br)cc1OC
Reactant: O=S(=O)(NF)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Product: CCOc1cc(C=O)c(F)cc1OC
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 2.62 ml of morpholine in 50 ml of THF there was added 11.2 ml of n-butyllithium (2.71 M, hexane solution) at −78° C. under a nitrogen atmosphere, and the mixture was stirred at −40° C. for 30 minutes. To this solution there was added dropwise a solution of 6.5 g of 2-bromo-5-ethoxy-4-methoxybenzaldehyde [CAS No. 56517-30-7] in 40 ml of THF at −78° C., and the mixture was stirred at −78° C. for 1 hour. After further adding 14.8 ml of n-butyllithium (2.71 M, hexane solution) at −78° C., the mixture was stirred at −78° C. for 40 minutes, and then a solution of 15.8 g of N-fluorobenzenesulfonamide in 40 ml of THF was added dropwise at −78° C. and the mixture was stirred overnight while raising the temperature to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (3.33 g) as a light yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH3:17].[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])OC2C=CC=CC=2)=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:1])[C:28](=[O:36])[NH:27][C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)=[C:4]([CH3:17])[CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNc1ccc(OCc2ccccc2)cc1C
Reactant: O=C(Nc1ccc(F)cc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)ccc1N(C)C(=O)Nc1ccc(F)cc1
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 62.9 %

Procedure:
After dissolving N-methyl-4-benzyloxy-2-methylaniline (2.64 g, 11.61 mmol) in N,N-dimethylformamide (20 ml), sodium hydride (1.16 g, 29.00 mmol, 60% in oil) was added and the mixture was stirred at 85° C. for 45 minutes under a nitrogen atmosphere. Phenyl N-(4-fluorophenyl)carbamate (3.50 g, 12.76 mmol) was added and the mixture was further stirred at 85° C. for 1 hour under a nitrogen atmosphere. After cooling to room temperature, water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto NH silica gel and subjected to crude purification by NH silica gel column chromatography (hexane-ethyl acetate-ethanol) to obtain N′-(4-benzyloxy-2-methylphenyl)-N-(4-fluorophenyl)-N′-methylurea (2.66 g) as a yellow oil. This was dissolved in methanol (50 ml), and then 10% palladium carbon (0.2 g) was added and the mixture was stirred for 2 hours at room temperature under a nitrogen atmosphere. The catalyst was filtered off, the filtrate was washed with ethanol, and the solvent was distilled off under reduced pressure. The precipitated crystals were suspended in ethanol, the suspension was diluted with diethyl ether and hexane, and the crystals were filtered out, washed with hexane and dried by aspiration to obtain the title compound (0.83 g, 3.0258 mmol, 41.86%) as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([C:18](=[O:33])[NH:19][C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([O:30][CH3:31])[CH:22]=1)[NH:10]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18](=[O:33])[NH:19][C:20]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([O:30][CH3:31])[CH:22]=2)=[N:10]1
Reactant: COc1cc(C(=O)NC(=O)N(NC(=O)OC(C)(C)C)c2c(Cl)cccc2Cl)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.2 %

Procedure:
To a solution of tert-butyl 2-(2,6-dichlorophenyl)-2-((3-methoxy-4-nitrobenzoyl)carbamoyl)hydrazinecarboxylate (1.0 g, 2.002 mmol) in DCM (20 mL) was added trifluoro acetic acid (2.0 mL). The reaction mass was stirred at RT for 2-3 h. Excess of solvent was removed at low temperature. The reaction mass was quenched in ice and filter off to afford 0.200 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.98 (s, 3H), 7.56-7.62 (m, 2H), 7.69-7.75 (m, 3H), 8.02 (d, J=8.4 Hz, 1H), 11-12 (br s, 1H); MS (m/z): 382.07 (M+H)+.
Reaction SMILES: [O:1]1[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[OH:20]O>[Pt].CO>[OH:1][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][N+:14]1([O-:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CCCCCCCCCCC1=CO1
Reactant: OO
Reactant: C1COCCN1
Agent: [Pt]
Solvent: CO
Product: CCCCCCCCCCC(O)C[N+]1([O-])CCOCC1
Temperature: 50 °C

Procedure:
20 grams of 1,2-epoxydodecene (b.p. 97°-98° C. at 3.5 mm Hg A) is heated with 9.7 grams of morpholine at 100° C. in a sealed container for 16 hours. The resulting mixture is then fractionally distilled and the product is collected at a temperature of 119° C. and a pressure of 0.05 mm Hg A. 23.4 grams of N-2-hydroxydodecyl-morpholine having an equivalent weight of 273, by titration (as compared to the calculated equivalent weight of 271 for this compound) are obtained. This product (23.4 grams) is mixed with 9.74 grams of aqueous 30% hydrogen peroxide and 50 ml of methanol and heated at 50° C. for 2 hours. Thereafter any excess peroxide is decomposed by adding 0.1 gram platinum black on charcoal (of 5% Pt content) and heating the mixture at 40° C. for 4 hours. The platinum-on-charcoal catalyst is filtered off, and the filtrate is evaporated to recover the crude product, which is then recrystallized from 300 ml of acetone to produce 17.5 grams of purified N-2-hydroxydodecyl-morpholine N-oxide having a melting point of 151°-2° C. (and having an equivalent weight by potentiometric titration in methanol, equivalence point at pH 3.25, of 290; as compared to the calculated equivalent weight of 287 for this compound).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH2:5])[CH3:4].[CH3:6][C:7]([CH3:11])(O)[C:8]#N.[OH2:12]>CC(C)=O>[CH3:6][C:7]1([CH3:11])[NH:1][CH2:2][CH:3]([CH3:4])[NH:5][C:8]1=[O:12]
Reactant: O
Reactant: CC(C)(O)C#N
Reactant: CC(N)CN
Solvent: CC(C)=O
Product: CC1CNC(C)(C)C(=O)N1
Reaction time: 24 h

Procedure:
In a manner analogous to that described in U.S. Pat. No. 2,920,077, 148.3 g (2 moles) of 1,2-diaminopropane and about 500 ml water are placed in a 2-liter 3-necked flask. While stirring, 170.2 g (2moles) of acetone cyanohydrin in 100 ml water are added in 20 min. The reaction is allowed to proceed at 80°-92° C. for 24 hr then water and unreacted materials are removed at 15 mm Hg. The residue, which formed a solid on standing, when dissolved in acetone and recrystallized was found to melt at 115°-117°.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:16]4[CH2:21][CH:20]([CH3:22])[NH:19][CH:18]([CH3:23])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[O:27])=[CH:5]2)[CH2:3][CH2:2]1.[O:38]1[C:40]([CH3:42])([CH3:41])[CH2:39]1>>[ClH:36].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:16]4[CH2:17][CH:18]([CH3:23])[N:19]([CH2:39][C:40]([OH:38])([CH3:42])[CH3:41])[CH:20]([CH3:22])[CH2:21]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[O:27])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(C)CO1
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Product: COc1c(N2CC(C)N(CC(C)(C)O)C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Product: Cl

Procedure:
The compound is prepared in analogy to Example 89 from the compound of Example 12 and 1,2-epoxy-2-methylpropane.
Reaction SMILES: [S:1]([Cl:4])([Cl:3])=[O:2].[Cl:5][C:6](=[C:10]([Cl:14])[CH:11]([Cl:13])[Cl:12])[C:7](O)=[O:8].S(=O)=O.[ClH:18]>CN(C)C=O>[S:1]([Cl:4])([Cl:3])=[O:2].[Cl:5][C:6](=[C:10]([Cl:14])[CH:11]([Cl:13])[Cl:12])[C:7]([Cl:18])=[O:8]
Reactant: O=C(O)C(Cl)=C(Cl)C(Cl)Cl
Reactant: Cl
Agent: O=S=O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)C(Cl)=C(Cl)C(Cl)Cl
Temperature: 50 °C

Procedure:
An agitated flask is charged with 800 g (6.72 mole) of thionyl chloride together with 2 ml of dimethylformamide as accelerator; the mixture is heated under agitation to 50° C. and, within 2 hours, 350 g (1.56 mol) of crystalline 2,3,4,4-tetrachloro-2-butenoic acid is added in incremental portions. During this step a strong evolution of gas occurs. After the addition has been completed, the mixture is heated for 1-2 hours to boiling (79° C.) until the evolution of sulfur dioxide and hydrogen chloride has ceased (bubble counter at the cooler outlet). Thereafter the reaction mixture is distilled over a 10 cm column, thus obtaining 604 g (5.07 mol) of unreacted thionyl chloride and 359 g (1.48 mol) of 2,3,4,4-tetrachloro-2-butenoic acid chloride; b.p. 102° C./26 mbar; nD20 =1.5478. Yield: 95% of theory.
Reaction SMILES: [O:1]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[N+:2]([O-:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH3:18].[C:20]([O-:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([O-:25])=[O:24]>CC(C)=O>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH2:17]([N:8]1[CH2:9][CH2:10][CH:5]([O:1][N+:2]([O-:4])=[O:3])[CH2:6][CH2:7]1)[CH3:18]
Reactant: CCI
Reactant: O=[N+]([O-])OC1CCNCC1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCC(O[N+](=O)[O-])CC1
Product: O=C(O)/C=C/C(=O)O

Procedure:
6.9 g. 4-Nitroxypiperidine are dissolved in 50 ml. acetone, mixed with 13.8 g. potassium carbonate and 6.1 ml. ethyl iodide and stirred for 18 hours at ambient temperature. After filtering with suction, the filtrate is evaporated, the residue is dissolved in ethyl acetate and extracted twice with aqueous sodium chloride solution. The organic phase is dried with anhydrous sodium sulphate. The crude product (8.2 g.) remaining after suction filtration and evaporation is converted into the fumarate by dissolving in ethanol and adding 2.7 g. fumaric acid. After filtering off with suction, there are obtained 2.6 g. of the fumarate of the title compound, i.e. 23% of theory; m.p. 131°-134° C.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH-].[K+:38]>C(O)C.O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[K+:38]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Placed 245.12 mg of the product of Example 49-7 into a 10 mL receiver flask. Added 6 mL of 50/50 ethanol/water. Warmed to in an oil bath on a hot-plate set to 90° C. and added 29.02 mg of potassium hydroxide. Solution clarified. Cooled in 10° C. increments to 55° C. Solid precipitated. Cooled to 40° C. and held for ˜1 hour. Cooled to ambient temperature and stirred overnight. Collected solid via vacuum filtration the next morning and dried the solid at 50° C./vacuum for 3 days.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]=[C:14]=S)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C1(C([O-])=O)C=C(C)C=C(C)C=1.[NH2:27][N+:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[NH2:34].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.[Cl:55]CCl>>[Cl:55][C:30]1[C:29]2[N:28]([N:27]=[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:8][CH:9]=3)[N:34]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Nc1cncc[n+]1N
Reactant: ClCCl
Reactant: S=C=Nc1ccc(N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1cc(C)cc(C(=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccn2nc(Nc3ccc(N4CCOCC4)cc3)nc12
Reaction time: 6 h
Yield: 84.17 %

Procedure:
To a solution of 4-morpholinophenylisothiocyanate (2 g, 8.99 mmol) in dry dichloromethane (200 ml), 1,2-diamino-pyrazinium mesitylenate (3.86 g, 11.24 mmol), diisopropylethylamine (5.81 g, 44.99 mmol) and EDCI (3.44 g, 17.98 mmol) are added and stirred for 6 hours. The reaction mixture is concentrated and the residue is taken in water (100 ml), triturated and filtered, washed with water (50 ml×2) and dried, the crude solid is purified by silica column using (60-120) mesh to get the titled product as light brown solid (2.5 g, 84.17%); TLC: chloroform/methanol (9.5/0.5) Rf—0.3; HPLC puritiy (method A) 98%; Rt (min): 2.21; LCMS: mass found (M+, 331.0), Rt (min): 2.08;
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8](=O)[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.Cl.[NH2:13][OH:14].O.[OH-].[Na+]>CCO.N1C=CC=CC=1>[CH3:2][CH:3]1[C:8](=[N:13][OH:14])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2
Reactant: CC1C(=O)C2CCN1CC2
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: CC1C(=NO)C2CCN1CC2
Temperature: 25 °C
Reaction time: 120 h
Yield: 96.4 %

Procedure:
The product from Step 158b (3.2 g, 23.0 mmol, 1 eq) and hydroxylamine hydrochloride (1.6 g, 23.0 mmol, 1 eq) are dissolved in 20 mL EtOH/pyridine (4:1) and stirred at room temperature. After 5 days, water and solid NaOH are added to adjust pH to pH 11. The mixture is extracted with several portions of CHCl3. The combined organic layers are dried over MgSO4, filtered and concentrated to give 3.42 g (96%) of 2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime as a 1:2.6 mixture of oxime isomers. Partial 1H NMR (CDCl3, 300 MHz) δ 1.53 ppm (d, 2-CH3, 0.8H), 1.38 (d, 2-CH3. 2.2H). MS (ESI) for C8H14N2O m/z 154.8 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:9]([CH2:11][NH2:12])O.N1C=CC=CC=1.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>>[Cl:19][CH:20]([Cl:24])[C:21]([N:12]1[C:5]2([CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]2)[O:8][CH2:9][CH2:11]1)=[O:22]
Reactant: NCCO
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC1CCC(=O)CC1
Solvent: c1ccncc1
Product: CC1CCC2(CC1)OCCN2C(=O)C(Cl)Cl

Procedure:
From a boiling mixture of 11.2 g. (0.1 moles) of 4-methyl-cyclohexanone and 6.1 g. (0.1 moles) of ethanolamine in 100 ml. of benzene the formed water is continuously distilled off. Boiling is continued until 1.8 ml. of water are separated. The reaction mixture is then cooled and 8 g. (0.1 moles) of pyridine are added followed by dropwise addition of 14.7 g. (0.1 moles) of dichloroacetyl chloride with external salt/ice cooling. Further following the procedure described in Example 2, 20.7 g. (0.078 moles) of a rose, oily product are obtained. Recrystallization from absolute ethanol affords a white, crystalline product melting at 119° to 120° C. The structure of the compound obtained can be verified by IR spectrum analysis.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.S(Cl)([Cl:12])=O>>[CH3:1][N:2]1[C:6]([C:7]([Cl:12])=[O:9])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cn1nccc1C(=O)Cl
Yield: 51 %

Procedure:
To a stirred solution of 1-methyl-1H-pyrazole (77.0 g 0.916 mol) in absolute ether (960 mL) under an atmosphere of argon was added a 1.6 M solution of n-BuLi in hexane (600 mL, 0.96 mol) dropwise at −40° C. over a period of 2 h. The reaction mixture was stirred at this temperature for a further 1 h, then siphoned into a mixture of solid carbon dioxide with ether. After heating to room temperature, the resulting mass was treated with water (1.5 L), the aqueous layer was separated, washed with ether (500 mL), concentrated to half volume under reduced pressure on a rotary evaporator, cooled to 2-3° C., and acidified while stirring with concentrated HCl to pH=3. The resulting precipitate was separated by filtration, washed with ice-cold water (25 mL), dried first in open air, and then in a vacuum desiccator over P2O5 to give 86.5 g (76%) of 1-methyl-1H-pyrazole-5-carboxylic acid as a white powder. To thionyl chloride (650 mL) was added 1-methyl-1H-pyrazole-5-carboxylic acid (86.5 g, 0.67 mol) in portions over a 35 min period, such that each portion was consumed before addition of the next. After this, the reaction mixture was refluxed for 4.5 h. The excess thionyl chloride was removed under vacuum at a bath temperature below 35° C. The residue was subjected to vacuum fractional distillation through a 15-cm Vigreux column. A fraction boiling at 71-72° C. at 15-16 mm Hg was collected to obtain the title product (49.0 g, 51%) as a colorless liquid.
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH2:30])=[O:29])[CH:23]=1>CS(C)=O.O>[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH2:30])=[O:29])[CH:23]=2)=[CH:15][C:14]=1[F:20]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: NC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
Potassium tert-butoxide (214 g) was dissolved in dimethyl sulfoxide (750 ml) and tetrahydrofuran (250 ml) under a nitrogen stream, and a solution of 4-amino-3-fluorophenol ½ naphthalene-2,6-disulfonate (242 g) and 4-chloropyridine-2-carboxamide (100 g) in dimethyl sulfoxide (1000 ml) was added dropwise to the solution with stirring and cooling on ice. The reaction mixture was stirred at room temperature for 30 minutes, then in an oil bath at 90° C. (external temperature) for 2 hours. The reaction mixture was allowed to cool down to room temperature, and water (3000 ml) was added, and the reaction mixture was stirred for 2 hours. The precipitated crystals were collected by filtration, and washed with water (500 ml, twice). The residue was suspended in water (2000 ml), stirred for 30 minutes, collected by filtration again, and washed with water (500 ml, twice). Drying by hot air at 60° C. gave the title compound (119 g, 75.3%).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCC1C=CC2C(=CC=CC=2)C=1.BrC1C=CC(C=[O:38])=CC=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCCCCC>[C:14]1([P:7](=[O:38])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 92 %

Procedure:
0.50 g (1.91 mmol) of triphenylphosphine, 0.42 g (1.90 mmol) of 2-bromomethylnaphthalene, 0.36 g (1.98 mmol) of p-bromobenzaldehyde, and 0.50 g (3.62 mmol) of K2CO3 were placed in a hardened-steel vial in a glove box under helium. The vial was sealed, and the sample was ball-milled for eight hours. The formed powder was first analyzed by solid state 31P{1H} CP MAS NMR spectroscopy, then loaded on a silica gel chromatography column, and the mixture of (E)- and (Z)-1-(p-bromophenyl)-2-(naphthyl)ethylenes (VII) (E:Z ratio ca. 3.5:1 by 1H NMR in CDCl3) was isolated in 93% yield, (0.54 g ) by eluation with hexane and toluene. Triphenylphosphine oxide was further obtained from the same column in 92% yield (0.53 g) using a hexane-acetone mixture as an eluant. The separation and purification of the E-isomer was performed according to the previously described procedure (Brooks et al., J. Am. Chem. Soc. 121, 5444 (1999)) by the column chromatography on silica gel.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13]>>[CH:2]1([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=[O:13])[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: O=Cc1cccc(O)c1
Reactant: BrC1C=CCCC1
Product: O=Cc1cccc(OC2C=CCCC2)c1

Procedure:
3-Bromo-1-cyclohexene and 3-hydroxybenzaldehyde were processed as described in Example 58A to provide the title compound.