Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:37][CH:27]([CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.9 %

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (1 g; 4.36 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.33 g; 4.38 mmol), triethylamine (1.22 mL; 8.75 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.92 g; 4.8 mmol) are added sequentially. The mixture is stirred for 18 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is diluted with ethyl acetate (150 mL) and washed successively with water (150 mL), 0.1 N HCl (100 mL), saturated aqueous sodium bicarbonate (50 mL), and saturated brine (50 mL). The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (5%→40% ethyl acetate in hexanes) affording the desired product (0.77 g) as a solid.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]O)[CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCNCC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(C(OCC2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a round bottom flask, benzhydrol (1.84 g, 10 mmol, 1.0 eq.), piperidin-4-yl-methanol (1.15 g, 10 mmol, 1.0 eq.), and p-toluenesulfonic acid monohydrate (2.09 g, 1.1 eq.) were suspended in toluene (400 ml). The mixture was refluxed with a Dean-Stark condenser for 3-4 hours. After cooling to room temperature, the solution was washed with 5% NaOH solution (2×20 ml), then with water (2×20 ml). The solution was then dried over anhydrous Na2SO4. The solvent was then removed under vacuum. The crude product 4-(1,1-diphenyl-methoxymethyl)-piperidine was obtained (2.33 g, 82.8% yield). ESMS 268.1 (M+1), 290.1 (M+23).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[S:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]([O-])=[O:20].[K+].CC(OC(C)=O)=O>CC#N>[O:17]=[C:10]1[NH:9][C:8]([C:4]2[CH:3]=[C:2]([O:1][C:19](=[O:20])[CH3:18])[CH:7]=[CH:6][CH:5]=2)=[N:13][C:12]2[CH:14]=[CH:15][S:16][C:11]1=2
Reactant: O=c1[nH]c(-c2cccc(O)c2)nc2ccsc12
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1

Procedure:
A mixture of 2-(3-hydroxy-phenyl)-3H-thieno[3,2-d]pyrimidin-4-one, 26, (10.95 g, 44.8 mmol), KOAc (6.6 g, 67.2 mmol) and Ac2O (16.5 mL, 0.175 mol) in MeCN (150 mL) were heated at reflux temperature for 24 h. The cooled reaction mixture was poured onto water (500 mL) and the resulting precipitate was collected by filtration. This was then washed with water and dried to furnish acetic acid 3-(4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidin-2-yl)-phenyl ester, 27, as a grey solid (10.87 g, 85%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10](OC)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([C:10](=[O:17])[CH2:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)c1ccccc1
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Yield: 89.2 %

Procedure:
A mixture containing 6.0 g (0.05 mol) of acetophenone, 40.8 g (0.30 mol) of methyl benzoate, and 3.73 g (0.06 mol) of 90% CaO is heated with stirring at 195°-200° C. for three and one-half hours while under nitrogen. The methanol (3.6 mL) that is distilled during the reaction is collected in a Dean Stark collector. The mixture is cooled, and 100 mL of toluene is added. The resulting mixture is cooled in cold water and acidified with 6N HCl. Stirring is continued until all of the solid is dissolved (ca 30 minutes). The toluene layer is separated and washed with aqueous Na2CO3 and water. Evaporation of the toluene solution gave 10 g of 1,3-diphenyl-1,3-propanedione as an oil representing an 89% yield based on acetophenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(Cl)Cl>[CH3:16][C:15]([NH:12][CH2:11][CH2:10][C:9]1[C:13]2[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[NH:7][CH:8]=1)=[O:17]
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a suspension, cooled in ice, of 5 g (26.3 moles) of 5-methoxytryptamine (in a raw condition) in 100 ml methylene chloride there is slowly added, under stirring, a cold solution of 5 ml (52.6 moles) of acetic anhydride in 50 ml of methylene chloride. Stirring and cooling are continued for 1 hour (the reaction progression can be controlled by TLC), so as to obtain a full solution; then the solution is washed by Na2CO3 2N×2, under strong stirring, and then by water. The organic phase, dried on anhydrous Na2SO4 and evaporated, provides 6 g of raw melatonine, which is purified by chromatography on column (4 cm; diameter/length ratio 1:5) of Merck silica gel (70-230 mesh) (120 g); the solution is eluted by methylene chloride in order to remove the scarcely polar products thereby providing pure melatonine by eluting with methylene chloride-acetone (8:2). There are obtained 4 g of product (purifying yield 65%) which are crystalized from acetone-water. Melting point 116°-7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:14]([NH2:16])=O.C([O-])(O)=O.[Na+]>>[N+:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[NH:16][CH:14]=[N:1]2)=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: NC=O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]cnc2cc([N+](=O)[O-])ccc12
Temperature: 150 °C
Yield: 70.4 %

Procedure:
A mixture of 2-amino-4-nitrobenzoic acid (5.0 g, 27.5 mmol) and formamide (8.0 ml, 201.5 mmol) in a microwave reaction vessel was heated in a microwave reactor at 150° C. for 1 hr. The slurry was cooled to rt, stirred with aq. NaHCO3, filtered, washed with water followed by ether and dried in vacuum oven to provide 3.7 g of 7-nitroquinazolin-4(3H)-one (compound 98-1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.[C:14]([OH:18])(=[O:17])[CH:15]=O.C(OCC)(=O)C>O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][N:10]=[CH:15][C:14]([OH:18])=[O:17])=[CH:7][CH:8]=1
Reactant: O=CC(=O)O
Reactant: NNc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C=NNc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
4-Trifluoromethylphenyl hydrazine (4.1 g, 23 mmol) was gradually added to a solution of concentrated hydrochloric acid (5 ml) in water (120 ml). 40% aqueous solution (4.3 g, 23 mmol) of glyoxylic acid was gradually added, and stirred at room temperature for 5 hours. After leaving it overnight, the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated brine, and dried on anhydrous sodium sulfate. The solvent was distilled off, and the resulting crystals were washed with hexane and a little amount of ethyl acetate to obtain (4-trifluoromethylphenyl hydrazono) acetic acid (4.7 g, 20 mmol, 88%).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([O:15][OH:16])([CH3:14])([CH3:13])[CH3:12].S(=O)(=O)(O)O>CCCCC>[CH3:10][C:4]1([O:16][O:15][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2](=[O:1])[CH2:3]1
Reactant: CC(C)(C)OO
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: O=S(=O)(O)O
Solvent: CCCCC
Product: CC1(C)CC(=O)CC(C)(OOC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A reaction mixture of 6.9 g. (0.05 mole) of isophorone, 23.20 g. (0.2 mole) of dry 81% t-butyl hydroperoxide and 25 ml. of pentane was cooled to 10° C. and 5.70 g. of 77% sulfuric acid added slowly over 45 minutes. The reaction mixture was allowed to warm to 25° C. and stirred at 25° C. for five hours. The pentane solution of the product was washed with water, and sodium bisulfite solution and then dried over anhydrous magnesium sulfate. The product weighing 9.35 g., was obtained by stripping under reduced pressure (60.4% recovery). The infrared spectrum had a strong absorption in the 880 cm-1 region usually associated with t-butylperoxy groups. Iodometric assay showed the presence of active oxygen and the GLC scan of the product showed a large peak for the expected product.
Reaction SMILES: [OH:1][CH:2]([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([NH:15][CH3:16])=[O:14])[CH:7]=[CH:6]2.CN(C)C(=O)C.[H-].[Na+].Cl>O>[CH3:16][NH:15][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:21]=3)=[O:1])[CH:4]=2)[CH:9]=1)=[O:14]
Reactant: CNC(=O)c1ccc2cc(C(O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: 0 °C
Reaction time: 60 h
Yield: 89.5 %

Procedure:
Under a nitrogen atmosphere, 6-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (1.0 g, 1.91 mmol) was added to N,N-dimethylacetamide (50 mL), and then sodium hydride (oil, 0.15 g, 3.85 mmol) was added at room temperature, and the mixture was stirred at the same temperature for about 60 hr. To the reaction mixture were added dropwise water (50 mL) and 1 mol/L hydrochloric acid (5 mL) at room temperature, and the mixture was stirred at the same temperature for 45 min. Then, the reaction mixture was cooled to 0° C., and stirred for 2 hr. The crystals were collected by filtration, and washed with water (30 mL). The obtained wet crystals were dried under reduced pressure to give N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (0.89 g, 1.71 mmol). yield 90%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:17][N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.O.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>[CH3:17][N:18]1[C:22]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:21][CH:20]=[N:19]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)cs1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)cs1
Temperature: 75 °C
Yield: 70.1 %

Procedure:
To a solution of methyl 4-bromo-2-thiophenecarboxylate (1.0 g, 4.5 mmol) in dioxane/H2O (5:1, 12 mL) was added K2CO3 (1.86 mg, 13.5 mmol), tetrakistriphenylphosphine Pd(0) (300 mg, 0.25 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.23 g, 5.9 mmol). The reaction mixture was heated to 75° C. in a sealed tube for 2 h. The reaction mixture was concentrated and purified on silica gel (EtOAc/Hex 10-40%) to give the title compound (701 mg, 70%) as a white solid: LC-MS (ES) m/z 223 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH3:7][C:8]1[CH:9]=[C:10]([S:15]C#N)[CH:11]=[CH:12][C:13]=1[OH:14]>O1CCCC1>[CH3:7][C:8]1[CH:9]=[C:10]([SH:15])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: Cc1cc(SC#N)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(S)ccc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 250 ml three-necked flask with a constant-pressure dropping funnel, to a stirred mixture of lithium aluminum tetrahydride (LiAlH4, 1.0 g, 26.3 mmol) and tetrahydrofuran (30 ml) was added dropwise at 0° C. a solution of 3-methyl-4-hydroxy-phenyl thiocyanic acid (1.7 g, 10.3 mmol) in tetrahydrofuran (THF, 30 ml). After 30 min of stirring at 0° C. and another 2 hours of stirring at room temperature, the reaction was quenched by addition of broken ice in an ice water bath. The value of pH of the mixture was adjusted to 3-4 by adding 6 M hydrochloric acid, and then the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with a saturated solution of sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtrated, and evaporated in vacuo to yield a crude product of 3-methyl-4-hydroxy-mercaptobenzene (yellow liquid).
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([CH:22]2[O:24][CH2:23]2)=[CH:20][CH:19]=1.[H-].[Na+].FC(F)(F)C([O-])=O>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:23][CH:22]([C:21]3[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=3)[OH:24])[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: Cc1ccc(C2CO2)cc1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: O=C([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccc(C)cc2)C1
Yield: 14.3 %

Procedure:
Preparation of the title compound was carried out according to General Method 6. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, 1 mmol), 4-methylstyrene oxide (1 mL, 7.5 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 mL) at 120° C. for 16 h (overnight) to obtain 50 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Br:24][CH2:25][CH2:26][OH:27]>CCOCC.O>[Si:1]([O:27][CH2:26][CH2:25][Br:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 101.1 %

Procedure:
A mixture of tert-butyldiphenylsilyl chloride (20.32 g, 74.03 mmol) and imidazole (6.25 g, 91.9 mmol) was treated dropwise with 2-bromoethanol (47, 5 mL, 8.87 g, 70.8 mmol). Stirring was continued for 12 h. The mixture was diluted with Et2O and water. The phases were separated, and the aqueous layer was extracted Et2O. The organic extract was washed with water and dried over Na2SO4. Concentration of the sample yielded a pale brown oil (26.01 g, 97%): 1H NMR δ 1.11 (s, 9H), 3.45 (t, J=6.3 Hz, 2H), 3.96 (t, J=6.3 Hz, 2H), 7.42-7.47 (m, 6H), 7.70-7.73 (m, 4H); 13C NMR δ 19.52, 27.03, 33.43, 64.24, 128.04, 130.10, 133.49, 135.84.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1.Cl.[NH2:18][OH:19]>C(O)C>[Cl:8][C:9]1[N:10]=[CH:11][C:12]([C:13](=[N:18][OH:19])[NH2:14])=[CH:15][CH:16]=1
Reactant: NO
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1ccc(Cl)nc1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
Triethylamine (68 mL, 498 mmol) was added to a solution of 6-chloronicotinonitrile (30.0 g, 217 mmol), hydroxylamine hydrochloride (33.0 g, 476 mmol) and ethanol (325 mL) and stirred for 12 hours at 75° C. The reaction mixture was cooled to room temperature, quenched with H2O (400 mL) and the partially concentrated in vacuo. The resulting slurry was filtered and dried to provide the title compound as a crude white solid (37.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O.C(OCC)(=O)C>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Bromophenol (2 g, 0.0116 mol) in acetone (40 mL) was treated with potassium carbonate anhydrous (1.91 g, 1.2 equivalents) and benzyl bromide (1.44 mL, 1.05 equivalents). The reaction was refluxed under a nitrogen atmosphere. After 5-6 hours reflux, the reaction was cooled to room temperature and diluted with an equal volume of ethyl acetate. This solution was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. A white fluffy solid was obtained. Yield=2.36 g (73%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([Br:8])=[CH:2][CH:1]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution composed of p-bromophenol (17.3 g, 0.1 mol) and dry DMF (100 mL), anhydride K2CO3 (8.28 g, 0.06 mmol) and benzyl bromide (25.6 g, 0.15 mmol) were added. The mixture was stirred at 80° C. under a nitrogen atmosphere for six hours. Then, the reaction mixture was charged into 500 mL of ice water.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]([N:19]=[C:20](OCC)[CH3:21])#[N:18]>N1C=CC=CC=1>[C:17]([N:19]=[C:20]([NH:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])[CH3:21])#[N:18]
Reactant: CCOC(C)=NC#N
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: c1ccncc1
Product: CC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of trans-4-amino-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (15.28 g) and ethyl N-cyanoacetimidate (9.42 g) in pyridine (70 ml) was refluxed under nitrogen atmosphere for 9 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 ml), washed with 5% hydrochloric acid (100 ml), water (100 ml), and brine (100 ml), successively. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give trans-4-[N-[1-(cyanoimino)ethyl]amino]-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (12.68 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:8][C:5]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1cc(Cl)ccc1C
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)c1cc(Cl)ccc1CBr

Procedure:
Reaction of ethyl 4-chloro-o-toluate with N-bromosuccinimide as described in Example 1a provides ethyl α-bromo-4-chloro-o-toluate as an oil.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[CH3:12].O.[OH-].[Li+]>O.O1CCCC1>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[C:5]([CH3:12])[CH:6]=1)#[N:11]
Reactant: COC(=O)c1ccc(C#N)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 4-cyano-2-methylbenzoic acid methyl ester (Example 3.6) (61 g, 348 mmol) in a mixture of water (0.360 ml) and tetrahydrofuran (1.4 l) was added lithium hydroxide hydrate (31.4 g, 748.2 mmol). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated. The residue was acidified by addition of aqueous hydrochloric acid (1N) and extracted with a mixture of methanol and chloroform (5:95). The organic phase was dried over sodium sulfate and concentrated. The residue was crystallized in a mixture of ethyl acetate andcyclohexane to give 4-cyano-2-methylbenzoic acid (55.5 g, 99% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:12]([CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([C:19]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.2 %

Procedure:
To a stirred solution of p-nitrobenzyl chloride (15 g) and diethyl benzylmalonate (22 g) in N,N-dimethylformamide (150 ml) was added Nail (60% in oil, 3.8 g). After stirring at room temperature for 2 days, the reaction mixture was concentrated under reduced pressure and the residue was suspended in ethyl acetate. The ethyl acetate layer was washed with aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and brine, and dried (MgSO4). The organic solvent was evaporated off and the residual oil was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:6, v/v) gave diethyl benzyl-4-nitrobenzylmalonate (24 g, 71%) as crystals. Melting point: 70°-71° C.