Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[CH:23](=O)[CH2:24][CH2:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:23]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC=O
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (300 mg, 1.00 mmol) prepared in Example (8b) in tetrahydrofuran (20 mL) were added butyraldehyde (107 mg, 1.49 mmol), sodium triacetoxyborohydride (420 mg, 1.99 mmol) and acetic acid (60 mg, 0.99 mmol) in that order, the mixture was stirred at room temperature for 13 hours and 30 minutes. After the reaction completed, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 270 mg of 1-butyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a light yellow oil.
Reaction SMILES: [OH-].[Na+:2].[N:3]1([C:9]2[N:10]=[C:11]([CH2:16][C:17]([O:19]CC)=[O:18])[NH:12][C:13](=[O:15])[CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>O1CCCC1>[N:3]1([C:9]2[N:10]=[C:11]([CH2:16][C:17]([O-:19])=[O:18])[NH:12][C:13](=[O:15])[CH:14]=2)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1.[Na+:2]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
18.7 ml of 2M sodium hydroxide are added to a solution of 10 g of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 300 ml of tetrahydrofuran. The reaction mixture is stirred for 48 hours at ambient temperature. The precipitate formed is filtered off through sintered glass, washed with ethyl acetate and rinsed several times with ethyl ether. The solid obtained is then dried in a rotary evaporator, so as to give 8.7 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:46])[CH:41]=2)[O:36]1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH:35]1[CH2:44][CH:43]([OH:45])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:46][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)C(O)CC(c1cc(F)ccc1F)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)C(O)CC(c2cc(F)ccc2F)O3)nc1

Procedure:
2-(2,5-Difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 200 mg of 2-(2,5-difluorophenyl)chroman-4,6-diol (Example 14(b)). The product was purified on preparative TLC-plate covered with silica gel using toluene-ethyl acetate (4:1) as an eluant. 1H NMR (400 MHz, CDCl3) δ: 9.03 (d, 1H, J 2.8 Hz), 8.50 (dd, 1H, J 9.1, 2.8 Hz), 7-36-7.33 (m, 2H), 7.08-6.95 (m, 5H), 5.50 (d, 1H, J 11.1 Hz), 5.09 (m, 1H), 2.53 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[NH:7][N:6]=1)=[O:4].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:13][O:12][C:10]([C:8]1[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]([CH3:14])[N:7]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(=O)OC)[nH]n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1cc(C(=O)OC)n(C)n1
Reaction time: 0.67 h

Procedure:
1H-Pyrazole-3,5-dicarboxylic acid dimethyl ester (639, 9.1 g, 49.0 mmol) was combined with acetone (400 mL) and potassium carbonate (10.2 g, 74.1 mmol). The mixture was stirred for 40 minutes under an atmosphere of nitrogen. To the stirring suspension, methyl iodide (3.4 mL, 54.0 mmol) was added dropwise. The reaction was stirred at room temperature overnight and then the solvent was evaporated under reduced pressure. The resulting solid was washed with water and filtered. After toluene was added, the solvent was removed under reduced pressure. The resulting compound 640 was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([N:8]([CH2:13][C:14]2[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[C:16]([CH3:27])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH2:9]([N:8]([CH2:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16]([CH3:27])[CH:15]=1)[C:4]1[C:3]([CH3:28])=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:10][CH2:11][CH3:12]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(F)cc2)c1C

Procedure:
Prepared from ethyl (4-{[(3-bromo-2-methylphenyl)(butyl)amino]methyl}-2-methylphenoxy)acetate and 4-fluorophenylboronic acid using the procedure described for Example 25 (Method A).
Reaction SMILES: [CH2:1]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[S:27]1[CH:31]=[N:30][N:29]=[C:28]1[NH2:32].Cl>N1C=CC=CC=1>[CH2:1]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:32][C:28]2[S:27][CH:31]=[N:30][N:29]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46 %

Procedure:
To a solution of p-hexadecylbenzenesulfonyl chloride (600 mg, 1.50 mmol) in pyridine (8 mL) was added 1,3,4-thiadiazol-2-amine (228 mg, 2.25 mmol). The reaction mixture was stirred at room temperature for 6 hours, then 2 M HCl (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL), the organic layer was washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with methanol:DCM 1:19 to give the product as a solid (320 mg, 0.69 mmol, 46% yield), mp 118-119° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=6.9 Hz), 1.25 (m, 26H), 1.59 (m, 2H), 2.64 (t, 2H, J=8.1 Hz), 7.29 (d, 2H, J=7.8 Hz), 7.84 (d, 2H, J=7.8 Hz), 8.23 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.7, 29.2, 29.3, 29.4, 29.6, 29.7, 31.1, 31.9, 35.9, 126.5, 128.9, 138.1, 142.5, 148.7, 167.5; MS (LCQ, ESI+) Calcd for C24H40N3O2S2 466.3, found 466.3 (M+H)+; HRMS (ESI+, m/z) Calcd for C24H40N3O2S2 466.2556, found 466.2558 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([C:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:40])[CH2:38][OH:39])=[N:35][CH:36]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:29][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:40])[CH2:38][OH:39])=[N:35][CH:36]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:27])[CH3:28])=[O:4]
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1ccc(Br)cn1
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(C)(CO)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 80 °C
Yield: 24 %

Procedure:
To a solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (200 mg, 0.48 mmol) in a mixture of toluene (3 ml) and ethanol (2 ml) is added tert-butyl 2-(5-bromopyridin-2-yl)-1-hydroxypropan-2-ylcarbamate (160 mg, 0.48 mmol), aqueous sodium bicarbonate solution (2M, 2 mmol, 1 ml), and [1,1′Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (18 mg, 0.024 mmol). The stirred reaction mixture is heated at 80° C. under a blanket of nitrogen for 1 hour. The reaction is concentrated to dryness and partitioned between methylene chloride (25 ml) and water (25 ml). The organic phase is washed with saturated brine (25 ml) and concentrated on to silica gel (1 g). Purification by column chromatography (12 g silica gel, ethyl acetate/heptane 0-100%, 16 cvs) affords the title compound (62 mg): m/z M+H 538.2. Retention time 2.75 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.C([Li])CCC.C([Sn](Cl)(CCCC)CCCC)CCC.[N+:32]([C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Br)([O-:34])=[O:33]>CCOCC.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH2:6][O:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[N+:32]([O-:34])=[O:33])=[N:3]1
Reactant: CC1(C)COC(c2cccs2)=N1
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [Pd]
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(C)COC(c2sccc2Cc2ccccc2[N+](=O)[O-])=N1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 72.1 %

Procedure:
To a solution of 4,5-dihydro-4,4-dimethyl-2-(2-thienyl)-oxazole (4.5 gms 25 mmol) in anhydrous ether at -70° C., n-butyl-lithium (2.5 molar solution in hexane, 11 ml) is added drop by drop under N2 atmosphere. The reaction mixture is stirred at -78° C. for 45 minutes and tri-n-butyltin chloride (8.3 gms 25 mmol) in dry ether is added drop by drop. The reaction mixture is stirred at room temperature for 1 hour and quenched with water. The reaction mixture is extracted with ether, washed well with water, dried and concentrated. The product obtain is pure enough for further transformation. The oil product, 4,5-dihydro-4,4-dimethyl-2-[(3-(tributylstannyl)-2-thienyl]-oxazole is mixed with 2-nitrobenzyl bromide (5.5 g 25 mmol) in toluene and refluxed in the presence of tetrakis (triphenylphosphine)-palladium (0) (200 mg) for 16 hours. At the end, reaction mixture is cooled to room temperature and filtered. Toluene is removed under reduced pressure and the product is isolated as brown oil by silica gel column chromatography by eluting it with 30% ethyl acetate:hexane to give 5.7 g of the desired product. Mass spectrum; M+ 316.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2>C(OCC)C>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Solvent: CCOCC
Product: COC(=O)Cc1ccc2c(c1)C(O)c1ccccc1CO2

Procedure:
The objective compound was obtained as light yellow crystals (recrystallized from diethyl ether) from Compound d obtained in Reference Example 4 in a manner similar to Reference Example 2.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:10]([CH2:13][CH2:14][CH3:15])([O-:12])=[O:11].C([O-])(=O)C.[NH4+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:13]([N+:10]([O-:12])=[O:11])[CH2:14][CH3:15]
Reactant: CCC[N+](=O)[O-]
Reactant: O=Cc1ccccc1F
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCC(=Cc1ccccc1F)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
30 ml of acetic acid were added to 4.73 g (38.11 mmole) of 2-fluorobenzaldehyde, 4.41 g (49.49 mmole) of nitropropane and 3.23 g (41.90 mmole) of ammonium acetate, and the resulting mixture was heated under reflux, whilst stirring, for 4 hours. At the end of this time, the reaction mixture was cooled to room temperature, neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and then xylene was added to the solution. The mixture was concentrated by evaporation under reduced pressure, to give 7.4 g of the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=O)[N:6]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[C:5]2=[O:22].[Sn].Cl>CCO>[NH2:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[NH2:1])[C:5](=[O:22])[N:6]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH2:7]2
Reactant: CN1CCC(N2C(=O)c3cc(N)c([N+](=O)[O-])cc3C2=O)CC1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: CN1CCC(N2Cc3cc(N)c(N)cc3C2=O)CC1
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A mixture of 5-amino-2-(1-methyl-piperidin-4-yl)-6-nitro-isoindole-1,3-dione (10.0 g, 32.9 mmol), tin powder (39.7 g, 329 mmol), EtOH (300 mL) and conc. HCl (100 mL) was stirred at 75° C. for 4 h. After cooling to RT excess of Tin was removed by filtration, the filtrate was evaporated. The residue was dissolved in CH2Cl2-MeOH (1:1) mixture, basified with NH4OH. Precipitate formed was removed by filtration, SiO2 was added to the filtrate, stirred for 1 h, the solvent was evaporated, the residue was loaded onto SiO2 (500 g) column. Eluted with CH2Cl2-MeOH—NH4OH (gradient from 100:0:0 to 100:10:1 v/v). Yield 7.86 g (30.2 mmol, 92%) as beige solid. LCMS [M+H]+ 261.4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C(Cl)Cl>CN(C=O)C>[N:19]([C:12]1[C:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:17][C:16]=2[N:15]=[CH:14][CH:13]=1)=[N+:20]=[N-:21]
Reactant: Clc1ccnc2c1CCN(Cc1ccccc1)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=Nc1ccnc2c1CCN(Cc1ccccc1)C2
Temperature: 70 °C
Yield: 55.1 %

Procedure:
7-Benzyl-4-chloro-5,6,7,8-tetrahydro-[1,7]naphthyridine (0.417 mmol) was treated with 5 equiv. of NaN3 (135 mg) in DMF (0.5 ml) and heated to 70° C. for 4 h. The residue was dissolved on 50 ml of DCM and washed with brine. The organic layer was concentrated to afford a black oil, which was purified by column chromatography to afford the desired azide (61 mg), which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([CH3:15])=[C:13]([OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:14]([CH3:15])=[C:13]([O:16][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccc(F)cc2c(O)c1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Yield: 93.8 %

Procedure:
To a mixture of 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid methyl ester (8.0 g, 34.2 mmol) and potassium carbonate (9.45 g, 68.4 mmol) was added benzyl bromide (4.5 mL, 37.6 mmol) in acetone (100 mL). The resulting mixture was vigorously stirred at reflux for 10 hours under a nitrogen atmosphere. The mixture was cooled, then filtered, and concentrated in vacuo to give 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (10.4 g, 94%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][N:7]1[C:15]2[N:14]=[CH:13][NH:12][C:11]=2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:8]1=[O:25])=[O:4].[Cl:28]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:28][C:13]1[NH:12][C:11]2[C:10](=[O:16])[N:9]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[C:8](=[O:25])[N:7]([CH2:6][O:5][C:3](=[O:4])[C:2]([CH3:27])([CH3:26])[CH3:1])[C:15]=2[N:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)C(=O)OCn1c(=O)c2[nH]cnc2n(COC(=O)C(C)(C)C)c1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1c(=O)c2[nH]c(Cl)nc2n(COC(=O)C(C)(C)C)c1=O
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
2,2-Dimethylpropionic acid [3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl ester (2.31 g) was dissolved in N,N-dimethylformamide (18 ml), and N-chlorosuccinimide (973 mg) was added to the solution while cooling on ice. Then, the mixture was stirred for 10 minutes on ice, and then at room temperature for 20 hours. The obtained reaction mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After removing the solvent by distillation from the organic layer, the residue was purified by silica gel column chromatography to give 1.61 g of the title compound from the elution fraction of hexane-ethyl acetate (1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[C:13]1([N:19]=[C:20]=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH:1][C:20]([NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21]
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(C(F)(F)F)cc1O
Product: O=C(Nc1ccccc1)Nc1ccc(C(F)(F)F)cc1O
Yield: 71.2 %

Procedure:
N -[2-Hydroxy-4-(trifluoromethyl) phenyl]-N′-phenyl urea was prepared from 2-amino-5-trifluoromethylphenol (150 mg, 1.09 mmol) and phenyl isocyanate (1.09 mmol) according to the procedure in General method A. The product was purified by precipitation from methylene chloride and filtering to afford the titled compound (230 mg, 87% ). mp: ° C.; 1H NMR (DMSO-d6): d 9.45 (s, 1H, NH), 8.50 (s, 1H, NH), 8.31 (d, 1H, J=10.0 Hz), 7.45 (d, 2H, J=10.0 Hz), 7.29 (t, 2H, J=6.67 Hz), 7.10 (m, 2H), 6.99 (t, 1H, J=6.67 Hz). EI-MS m/z 296 (M+). Anal. (C14H11N2O2F3)C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16]Cl)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[I-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[OH:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][O:29][C:22]3[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=3[Cl:20])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(O)c(Cl)c1
Reactant: ClCCCC1CCN(c2ccc(Cl)nn2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OCCCC2CCN(c3ccc(Cl)nn3)CC2)c(Cl)c1
Reaction time: 2 h
Yield: 41.3 %

Procedure:
To a stirred solution of 3.0 parts of 3-chloro-6-[4-(3-chloropropyl)-1-piperidinyl]pyridazine in 80 parts of acetonitrile were added 2.1 parts of sodium iodide. The reaction mixture was stirred for 2 hours at reflux temperature. After cooling, a mixture of 2.2 parts of 2-chloro-4-methoxyphenol and 3.8 parts of potassium carbonate was added to the mixture and the whole was stirred for 2 days at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried at 70° C., yielding 1.8 parts (41.3%) of 3-chloro-6-[4-[3-(2-chloro-4-methoxyphenoxy)propyl]-1-piperidinyl]pyridazine; mp. 101.0° C. (comp. 141).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH:14][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: NC1CCc2c([nH]c3ccccc23)C1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(=O)NC1CCc2c([nH]c3ccccc23)C1
Reaction time: 5 h

Procedure:
A solution of 0.05 mol of 2,3,4,9-tetrahydro-1H-carbazol-2-amine in 450 ml of CHCl3 and 185 ml of saturated aqueous NaHCO3 was stirred vigorously at room temperature and treated dropwise during 30 min with a solution of 0.15 mol of propanoyl chloride in an equal volume of CHCl3. After stirring vigorously for 5 hr, the CHCl3 layer was separated, washed in succession with 10% aqueous K2CO3, H2O, 0.1 N hydrochloric acid, H2O, and dried over anhydrous Na2SO4. The residue remaining after evaporation of the CHCl3 was recrystallized from ethyl acetate to give the title compound, mp 169°-170°.
Reaction SMILES: [CH:1]1([N:4]([CH3:28])[C:5]2[C:6]([CH:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)C3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[OH:29][Li].O.O>CO.C(Cl)(Cl)Cl>[O:29]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[CH:27]=[C:19]1[C:6]1[C:5]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH3:28])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=2)[N:7]=1
Reactant: COC(=O)c1ccc2nc(C3Cc4ccccc4C3)c(N(C)C3CC3)nc2c1
Reactant: [Li]O
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1cc2ccccc2o1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of methyl 3-(cyclopropyl(methyl)amino)-2-(2,3-dihydro-1H-inden-2-yl)quinoxaline-6-carboxylate (95.0 mg, 0.25 mmol) in methanol (15 mL) and CHCl3 (10 mL) was added LiOH.H2O (35.0 mg, 0.83 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (10 mL) and adjusted pH to 6 with hydrochloric acid (1N). The solids were collected by filtration to afford 2-(benzofuran-2-yl)-3-(cyclopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (43.6 mg, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][OH:6].[N+]([O-])(O)=O.[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=[O:6]
Reactant: OCc1ccc(F)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60.1 %

Procedure:
10.2 g (0.05 mol) of 3-bromo-4-fluoro-benzyl alcohol were added to a mixture of 10 g of nitric acid (density: 1.4) and 5 ml of water at 30°-35° C. and the mixture was then stirred at room temperature for 5 hours. After adding 30 g of ice, sodium hydroxide solution was added to the mixture until the pH value reached 13, and the mixture was then extracted by shaking with 200 ml of toluene. The organic phase was washed three times with 50 ml of water each time, dried over sodium sulphate and then evaporated. The residue was distilled. 6.1 g (60% of theory) of 3-bromo-4-fluoro-benzaldehyde were thus obtained in the form of an oil which slowly solidified and had a melting point of 29°-31° C.