Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.[Br:10]P(Br)Br>ClCCl>[BrH:10].[Br:10][CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: OCc1ccncc1Cl
Solvent: ClCCl
Product: Br
Product: Clc1cnccc1CBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (3-chloropyridin-4-yl)methanol (1.0 g, 7.2 mmol) in anhydrous dichloromethane (35 mL) was added dropwise tribromophosphane (750 uL, 7.9 mmol). The mixture was stirred at room temperature for 5 hours. Dichloromethane was evaporated, and the residue was dried in vacuo, affording 4-(bromomethyl)-3-chloropyridine hydrobromide. The product was used for the next step without further purification.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([CH3:22])=[O:21]>O.C(#N)C>[C:20]([C:16]1[O:15][C:19]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)(=[O:21])[CH3:22]
Reactant: CC(=O)c1ccco1
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(-c2ccc(C#N)cc2)o1
Reaction time: 0.75 h
Yield: 18 %

Procedure:
A mixture of 50 g (0.42 mole) of p-aminobenzonitrile, 146 ml of concentrated hydrochloric acid, and 106 ml of H2O was heated at 80° for for 20 minutes and then cooled to 0°. A solution of 29 g (0.42 mole) of sodium nitrite in 105 ml of H2O was added dropwise while maintaining the temperature at 0°-5° by means of an ice bath. The reaction was kept at 0° for 45 minutes. A solution of 47 g (0.42 mole) of methyl 2-furyl ketone in 43 ml of acetonitrile was added followed by a solution of 10 g of CuCl2 .2H2O in 50 ml of water. The reaction became exothermic and was controlled below 40°. The reaction was allowed to stand overnight. The aqueous layer was decanted and the residual semisolid was extracted with 6000 ml of refluxing hexane. The hexane was cooled and the resulting precipitate was filtered and air dried to yield 16 g (18%) of p-(5-acetyl-2-furyl)benzonitrile. An analytical sample was prepared by recrystallizing a sample from hexane/charcoal, m.p. 115°-116°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9]CC(C)(C)N=2)=[CH:4][CH:3]=1.[Mg].[CH2:16]([CH:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)[CH2:17][CH3:18].[Cl-].[NH4+].[O:28]1CCCC1>>[CH2:16]([CH:19]1[CH2:24][CH2:23][C:22]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:9])=[O:28])=[CH:6][CH:7]=2)=[CH:21][CH2:20]1)[CH2:17][CH3:18]
Reactant: C1CCOC1
Reactant: CCCC1CCC(=O)CC1
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CCCC1CC=C(c2ccc(C(=O)O)cc2)CC1

Procedure:
A solution of 50 g of 2-(4-bromophenyl)-4,4-dimethyl-2-oxazoline in 600 ml of tetrahydrofuran is added dropwise to a boiling suspension of 6 g of magnesium in 100 ml of tetrahydrofuran and the reaction mixture is subsequently heated to the boil for another 2 hours. A solution of 2.8 g of 4-n-propylcyclohexanone in 50 ml of tetrahydrofuran is then added dropwise and the reaction mixture is heated to the boil for 4 hours with stirring. After cooling, 500 ml of 10% strength aqueous ammonium chloride solution is added to the reaction mixture which is then extracted three times with 600 ml of diethyl ether. The combined extracts are dried over sodium sulphate and evaporated. The residue is dissolved in 120 ml of ethanol and, after the addition of 2 ml of concentrated sulphuric acid, the solution is heated to the boil for 16 hours. Subsequently, the reaction mixture is concentrated to 25 ml and subjected to chromatography on a neutral alumina column. 28 g of ethyl 4-(4-n-propylcyclohexen-1-yl)-benzoate is eluted with diethyl ether. This material is heated to the boil for 3 hours with 200 ml of 10% strength aqueous sodium hydroxide solution and 4-(4-n-propylcyclohexen-1-yl)-benzoic acid is isolated from the reaction mixture after acidification with dilute hydrochloric acid, extraction of the mixture with diethyl ether, drying of the extract and evaporation; yield 24 g of colorless crystals, m.p. 93°.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][N:6]([CH3:8])[CH2:5][NH:4][C:3]1=[N:9][N+:10]([O-:12])=[O:11].[H-].[Na+].[H][H].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][N:19]=1>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:4]2[CH2:5][N:6]([CH3:8])[CH2:7][N:2]([CH3:1])[C:3]2=[N:9][N+:10]([O-:12])=[O:11])=[CH:20][N:19]=1
Reactant: [H][H]
Reactant: CN1CNC(=N[N+](=O)[O-])N(C)C1
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CN(C)C(=N[N+](=O)[O-])N(Cc2ccc(Cl)nc2)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
1 g of 1,5-dimethyl-2-nitroiminohexahydro-1,3,5-triazine was dissolved in 20 ml of dried DMF. To the solution, 0.27 g of 60% sodium hydride was added with cooling. The mixture was stirred for 1 hour at room temperature until evolution of hydrogen was ceased and then the mixture was heated with stirring further for 1 hour at 50° C. To the mixture, a solution of 0.9 g of 2-chloro-5-pyridylmethylchloride in 8 ml of dried DMF was added dropwise at 40-50° C. After this addition, the reaction mixture was heated with stirring it for two hours at 70-80° C. The mixture was poured into ice-water and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and dichloromethane was distilled off. The residue was purified by a column chromatography to obtain 1.3 g of the title compound. This compound is No.5 in Table 1. m.p.: 116-117° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:24]1[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[S:27][C:28]=1[Cl:29]>COCCOC.O.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:29][C:28]1[S:27][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=1[C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Reactant: CCn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CCn1nccc1-c1cc(C(=O)OC)sc1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a 100 mL sealed flask was added 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.61 g, 11.74 mmol), potassium carbonate (3.25 g, 23.48 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (2 g, 7.83 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.4 g, 0.78 mmol) in 1,2-dimethoxyethane (DME) (50 mL) and H2O (10 ml). After stirring for 3 h at 70° C., the reaction solution was diluted with DCM (100 mL) and washed with H2O. The organic layer was dried Na2SO4, filtered and concentrated. The residue was purified on silica gel [EtOAc/hexanes, 10-30%] to give the product [1.8 g, 85%] as an off white solid: LC-MS (ES) m/z 271 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[C:15]([O:14][C:12]([N:10]1[CH2:11][CH:8]([C:3]2[C:2]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:9]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N1CC(c2nccnc2N2CCOCC2)C1
Temperature: 160 °C
Yield: 94 %

Procedure:
A mixture of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (7) (269 mg, 1.0 mmol) in morpholine was heated by microwave at 160° C. for 2 h. The mixture was concentrated to give the crude compound and which was purified by column chromatography to afford pure product (11) (300 mg, yield 94%) as solid. ESI-MS (M+1): 321 calc. for C16H24N4O3 320.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15](O)=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18].S(Cl)([Cl:26])=O>C1C=CC=CC=1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([Cl:26])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)[CH3:18]
Reactant: O=S(Cl)Cl
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Solvent: c1ccccc1
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)Cl)c(Cl)c(Cl)c2C1=O

Procedure:
A solution of (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid (3.57 g., 0.01 mole) and thionyl chloride (2.38 g., 0.02 mole) in benzene (50 ml.) is refluxed for 1 hour. The excess thionyl chloride and benzene are evaporated at reduced pressure as is a subsequent 50 ml. portion of benzene affording (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetyl chloride as a yellow oil which is used in step B without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6]([O:8]C(C)(C)C)=[O:7])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:16]=[C:15]([CH2:17][C:18]([NH:20][C@H:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
200 mg (0.395 mMol) of tert.butyl (S)-2-ethoxy-4-[N-(1-(2-piperidino-phenyl)-3-methyl-1-butyl)-aminocarbonylmethyl]-benzoate (melting point: 122°-123° C.; [α]D20 =+8.7°; c=1 in methanol) are stirred into 2 ml of methylene chloride together with 0.45 g (3.95 mMol) of trifluoroacetic acid overnight at ambient temperature. The mixture is evaporated down in vacuo and the evaporation residue is distributed between aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic extract is dried, filtered and evaporated down in vacuo. The evaporation residue is crystallised from ethanol/water (2/1).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25](I)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([O-:31])=[O:30].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:29]([OH:31])=[O:30])[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[O-]
Reactant: Ic1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1
Yield: 17.6 %

Procedure:
(1-Benzyl-1H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine (0.48 g) in DMF under CO was treated with sodium formate (0.1 g) and catalytic quantities of triphenyl phosphine and bistriphenylphosphine palladium (II) chloride at 110° C. The mixture was cooled, added to 5% sodium hydroxide and extracted with ethyl acetate. The aqueous phase was treated with 2N HCl and the precipitated solid filtered and dried to give the title compound (0.07 g); δH [2H6]DMSO 13.35(1H,bs), 10.40(1H,s), 9.30(1H,s), 8.60(1H,s), 8.30(1H,d), 8.17(2H,d), 7.84(1H,d), 7.72(1H,s), 7.30(5H,m,), 5.70(2H,s); m/z (M+1)+396.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[C:4]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13][C:3]=12.[Br-:16].[Br-].[Br-].[C:19]1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.CO>[Br:16][CH2:19][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH2:10][C:4]=12)=[O:9]
Reactant: C[N+](C)(C)c1ccccc1
Reactant: Cc1sc(C(=O)O)c2c1CC(C)(C)CC2
Reactant: [Br-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1sc(C(=O)CBr)c2c1CC(C)(C)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of 1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (1.18 g, 5.31 mmol, Example C) in THF (60 mL) and methanol (6 mL), phenyltrimethylammonium bromide dibromide (2.0 g, 5.31 mmol) is added in portions. Upon complete addition, the mixture is stirred at rt for 30 min before the solvent is evaporated. The crude product is purified by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 μm, 20-95% acetonitrile in water containing 0.5% formic acid) to give 2-bromo-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (1.28 g) as a colourless oil; 1H NMR (CDCl3): δ 4.24 (s, 2H), 3.03 (t, J=7.0 Hz, 2H), 2.36 (s, 3H), 2.30 (s, 2H), 1.54 (t, J=7.0 Hz, 2H), 0.98 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:12])[C:5](=O)[CH2:6][C:7](OC)=[O:8].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[C:16]([CH3:22])[CH:15]=1.Cl.O.[NH2:25][NH2:26]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:6]2[C:7]([OH:8])=[N:25][NH:26][C:5]=2[CH:4]([CH3:12])[CH3:3])=[C:16]([CH3:22])[CH:15]=1
Reactant: NN
Reactant: COC(=O)CC(=O)C(C)C
Reactant: Cc1cc(Br)ccc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1Cc1c(O)n[nH]c1C(C)C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Add sodium hydride (8.29 g, 0.21 mol, 60% dispersion in oil) to a solution of methyl 4-methyl-3-oxovalerate (27.1 mL, 0.19 mol) in tetrahydrofuran at 0° C. After 30 min at room temperature, add a solution of 4-bromo-1-chloromethyl-2-methyl-benzene (35.0 g, 0.16 mol) in tetrahydrofuran (50 mL). Heat the resulting mixture at 70° C. overnight (18 hours). Add 1.0 M HCl (20 mL) to quench the reaction. Extract with ethyl acetate (200 mL), wash extract with water (200 mL) and brine (200 mL), dry over Na2SO4, filter and concentrate under reduced pressure. Dissolve the resulting residue in toluene (200 mL) and add hydrazine monohydrate (23.3 mL, 0.48 mol). Heat the mixture at 120° C. for 2 hours with a Dean-Stark apparatus to remove water. Cool and remove the solvent under the reduced pressure, dissolve the residue with dichloromethane (50 mL) and methanol (50 mL). Pour this solution slowly to a beaker with water (250 mL). Collect the resulting precipitated product by vacuum filtration. Dry in vacuo in an oven overnight at 40° C. to yield the title compound as a solid (48.0 g, 0.16 mol). MS (m/z): 311.0 (M+1), 309.0 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1/[CH:11]=[CH:19]\[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)c1OCc1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1cccc(/C=C\C(=O)O)c1OCc1ccccc1

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(benzyloxy)-3-methylbenzaldehyde (20 g, 88.39 mmol, 1.00 equiv), propanedioic acid (27.6 g, 265.23 mmol, 3.00 equiv), piperidine (1.5 g, 17.62 mmol, 0.20 equiv) and pyridine (200 mL). The resulting solution was heated to reflux for 2 h in an oil bath. The reaction was then quenched by the addition of 1.5 L of water/ice. The pH value of the solution was adjusted to 2-3 with hydrogen chloride. The solids were collected by filtration. The filter cake was washed with 2×500 mL of water and 2×500 mL of hexane. This resulted in 21 g (89%) of (2Z)-3-[2-(benzyloxy)-3-methylphenyl]prop-2-enoic acid as a white solid. MS (ESI) m/z 269 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[C:11]([CH3:12])=[CH:10][C:9](=[O:13])[C:4]([C:5]([O:7]C)=[O:6])=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>[OH-].[Na+]>[CH3:1][N:2]1[C:11]([CH3:12])=[CH:10][C:9](=[O:13])[C:4]([C:5]([OH:7])=[O:6])=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1c(-c2ccccc2)n(C)c(C)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(C(=O)O)c(-c2ccccc2)n1C
Yield: 86.4 %

Procedure:
6.0 gms of crude methyl 1,6-dimethyl-2-phenyl-4-oxonicotinate is suspended in 66 gms of 5% aqueous sodium hydroxide solution. The reaction mixture is heated on a steambath (85°) for two hours. The resulting homogeneous solution is cooled and acidified with dilute HCl. The resulting solid is collected by filtration yielding 4.9 gms of 1,6-dimethyl-2-phenyl-4-oxonicotinic acid. mp (acetonitrile/methylene chloride)=246-9 (dec.).
Reaction SMILES: [I-].[CH:2]([NH:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[CH3:15])=[O:3].[I-].[N+](C1C=CC=CC=1C=CC1C=CC=C[N+]=1C)([O-])=O>>[CH3:15][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[CH2:8][CH2:7][C:6]1[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=1[NH:4][CH:2]=[O:3]
Reactant: C[n+]1ccccc1CCc1ccccc1NC=O
Agent: C[n+]1ccccc1C=Cc1ccccc1[N+](=O)[O-]
Agent: [I-]
Product: CN1CCCCC1CCc1ccccc1NC=O

Procedure:
Reduction of 2-(o-formamidophenethyl)-1-methylpyridinium iodide as described in Example 1 for 2-(o-nitrostyryl)-1-methylpyridinium iodide provides 2'-[2-(1-methyl-2-piperidyl)ethyl]formanilide which is purified by crystallization from isopropyl ether, (79% yield) m.p. 81°-84.5°C. (corr.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:24])[CH2:22][CH3:23])=[CH:19][C:12]=3[O:11]2)=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc(OC)cc1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml once, saturated sodium bicarbonate solution 50 ml, and a saturated salt solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The crude extract was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 4 ml/hexane 10 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 251.6 mg.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][C:6]=1[CH:15]=[N:16][OH:17])(=[O:3])[CH3:2].[OH-].[Na+]>>[OH2:3].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[CH:15]=[N:16][OH:17])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)c(C=NO)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(C(=O)O)cc1C=NO
Product: O
Temperature: 25 °C
Reaction time: 4 h
Yield: 131.8 %

Procedure:
A mixture of methyl 4-acetylamino-3-[(hydroxylimino)methyl]benzoate (142 mg, 0.6 mmol) and 1N sodium hydroxide (1.0 mL, 1.0 mmol) was stirred at room temperature for 4 h. The mixture was filtered through a pad of cotton and neutralized with dil. hydrochloric acid. The precipitate obtained was collected by filtration, washed with water, and dried under vacuum over acetone for 24 h to give 95 mg (71%) of the title compound as a white powder, mp 215°-218° C. (dec).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:23]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:26][CH:27]=1>ClCCl.N1C=CC=CC=1>[F:31][C:28]([F:29])([F:30])[C:24]1[CH:23]=[C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)=[O:13])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccccc1SSc1ccccc1C(=O)Nc1cccc(C(F)(F)F)c1
Yield: 15.1 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 3-aminobenzotrifluoride (1.87 g, 11.6 mmol) in 15 mL of pyridine. The crude product was recrystallized from ethanol, then ethyl ether to yield 0.519 g of the title compound, mp 167-168° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](C(=O)C)[CH:5]=[CH:4][N:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22]([OH:24])[CH3:23]>O>[C:22]([C:2]1[N:3]2[N:11]=[N:12][N:13]=[C:4]2[CH:5]=[CH:6][CH:7]=1)(=[O:24])[CH3:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1ccnc(Cl)c1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cccc2nnnn12

Procedure:
A solution of 11.42 g of 2-chloro-4-acetylpyridine, 9.51 g of sodium azide and 9.2 ml of 12 N HCl in 86 ml of a 1:1 ethanol:water mixture was heated at reflux for three hours. An additional 9.2 g of sodium azide was added and the reaction mixture heated at reflux overnight. An aqueous solution of sodium carbonate (3.92 g) was added and the mixture repeatedly extracted with methylene chloride. The combined extracts were washed with water and saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 10.2 g of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[N:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[S:23](=[O:32])(=[O:31])[N:22]=3)[C:11]2=[O:33])=[CH:4][CH:3]=1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[S:23](=[O:31])(=[O:32])[N:22]=3)[C:11]2=[O:33])=[CH:6][CH:7]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=Cc1ccc(Br)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 264A (0.049 g, 0.094 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.008 mL, 0.188 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.134 mL, 0.268 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (6.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.92 (brs, 2 H) 7.09 (t, J=6.99 Hz, 1 H) 7.28 (m, 3 H) 7.54 (m, 5 H) 7.68 (d, J=8.09 Hz, 2 H) 8.09 (dd, J=8.09, 1.47 Hz, 1 H) 16.25 (brs, 1 H). MS (ESI−) m/z 524 (M−H)−.