Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)[C:5](=[O:15])[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:36][C:37]1[CH:38]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:41][CH:42]=1>ClCCl.CN(C)C=O>[F:44][C:43]([F:45])([F:46])[C:39]1[CH:38]=[C:37]([NH:36][C:10](=[O:12])[C:9]([N:6]2[C:5](=[O:15])[C:4]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:3]([CH:2]([F:1])[F:22])[O:8][CH2:7]2)([CH3:13])[CH3:14])[CH:42]=[CH:41][CH:40]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C(=O)O)N1COC(C(F)F)=C(c2ccccc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C(=O)Nc1cccc(C(F)(F)F)c1)N1COC(C(F)F)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.1 %

Procedure:
To a stirred suspension of 2-(6-difluoromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoic acid (0.70g) in dichloromethane was added oxalylchloride (0.22 ml) followed by 1 drop of dimethylformamide. The reaction mixture was stirred at ambient temperature for 30 minutes and then cooled to 0° C. To the solution was added in turn triethylamine (0.36 ml), 3-aminobenzotrifluoride (0.34 g) and then triethylamine (0.36 ml). The reaction mixture was stirred at 0° C. for 30 minutes and at ambient temperature for 2 hours then washed in turn with water, 2M hydrochloric acid, water, 1M sodium carbonate and water. The organic solution was dried (magnesium sulphate) and evaporated under reduced pressure to give N-(3-trifluoromethylphenyl)-2-(6-difluoromethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 2, 0.25 g) as a beige solid, m.p. 58-60° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([Cl:10])=[C:4]([C:11]([Cl:14])([Cl:13])[Cl:12])[N:3]=1.[CH3:15][OH:16].[CH3:17][O-:18].[Na+]>CS(C)=O>[Cl:8][C:7]1[C:2]([O:18][CH3:17])=[N:3][C:4]([C:11]([Cl:14])([Cl:13])[Cl:12])=[C:5]([Cl:10])[C:6]=1[O:16][CH3:15]
Reactant: C[O-]
Reactant: CO
Reactant: Clc1nc(C(Cl)(Cl)Cl)c(Cl)c(Cl)c1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1nc(C(Cl)(Cl)Cl)c(Cl)c(OC)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 50.0 g portion (0.15 mol) of 2,3,4,5-tetrachloro-6-(trichloromethyl)pyridine was dissolved in 50 ml of warm dimethyl sulfoxide and 100 ml of methanol was added. Sodium methoxide (68.5 ml of 25 percent solution in methanol, 0.30 mol) was added, with stirring, over a 30 minute period and the resulting mixture was heated to reflux, with stirring, for two hours. After cooling, the mixture was poured into ice water and the aqueous mixture was extracted twice with methylene chloride. The extract was washed with water and evaporated to remove the methylene chloride. Traces of dimethyl sulfoxide remained. The residue was dissolved in ether and the ethereal solution was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to obtain 39.4 g of white solid product (81 percent of theory) melting at 67°-69° C. The proton nmr spectrum was consistent with the structure given.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4](Cl)[N:3]=1.[OH-].[Na+]>CO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nc(Cl)cc(-c2cccc3ccccc23)n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nccc(-c2cccc3ccccc23)n1
Yield: 54.4 %

Procedure:
2-Amino-6-chloro-4-(naphth-1-yl)-pyrimidine (170 mg) was dissolved in 10 mL of methyl alcohol at 0° C. 10% Palladium on activated carbon (70 mg) and approximately 1 mL of 20% sodium hydroxide were added to the solution, and the mixture was hydrogenated (1 atmosphere) for 1 hour to give solid 2-amino-4-(naphth-1-yl)-pyrimidine (80 mg). Treatment of the solid with hydrochloric acid/ethyl alcohol yielded 2-amino-4-(naphth-1-yl)-pyrimidine hydrochloride (25 mg), m.p. 181°-184° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:26])[CH:3]=1.[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=3[N:11]=[C:12]([NH:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30])[N:13]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2C(C)C
Reactant: NC(CO)CO
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2C(C)C

Procedure:
The product of Example 56, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one 1H-NMR: δ 1.61 (m, 6H), 2.15 (m, 3H), 3.45 (br s, 2H), 3.85 (m, 5H), 5.74 (m, 1H), 6.21 (d, 1H, J=9.8 Hz), 6.36 (br s, 1H), 6.91-7.20 (m, 4H). LC MS (m/e)=387 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1.[C:22](=O)([O-])[O-].[Na+].[Na+].CI>CN(C)C=O>[CH3:22][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1
Reactant: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCOC(CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 134A (158 mg) in anhydrous N,N-dimethylformamide (4 mL) was added sodium carbonate (64 mg) and methyl iodide (78 mg). After stirring overnight at room temperature, the mixture was evaporated to dryness. The crude product was then absorbed on silica gel (6 g) and purified on a silica gel column eluting with 10% methanol in dichloromethane to give the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][S:10][CH2:9][C@@H:8]([C:18]([O:20]C)=[O:19])[NH:7][C:6]1=[O:22])=[O:4].[OH-].[Na+]>CO>[C:3]([CH:5]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][S:10][CH2:9][C@@H:8]([C:18]([OH:20])=[O:19])[NH:7][C:6]1=[O:22])([OH:4])=[O:2]
Reactant: COC(=O)C1CCCCCCCSC[C@@H](C(=O)OC)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl (3R)-6-methoxycarbonyl-5-oxo-1-thia-4-azacyclotridecane-3-carboxylate (2.39 g, 7.21 mmol) is suspended in methanol (75 ml) and 1N sodium hydroxide (22.0 ml, 22.0 mmol) is added. The mixture is stirred for 4 hours at room temperature. The solvent is evaporated and the residue is dissolved in water (150 ml). The aqueous solution is adjusted to pH 1 by addition of 1 N hydrochloric acid and extracted with ethyl acetate (3×100 ml). The combined extracts are washed with brine (1×100 ml), dried (MgSO4) and the solvent is evaporated to give (3R)-6-carboxy-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid, m.p. 167°-170° C.
Reaction SMILES: C(NCCO)C1C=CC=CC=1.Cl.ClCCNCC1C=CC=CC=1.S(Cl)(Cl)=O.Cl.[CH2:29]([NH:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.NC1C(C)=CC=CC=1.Br[CH:56]([CH2:60]Br)[C:57]([NH2:59])=[O:58]>>[CH2:29]([N:36]1[CH2:37][CH2:38][N:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH3:46])[CH2:60][CH:56]1[C:57]([NH2:59])=[O:58])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)C(Br)CBr
Reactant: Cc1ccccc1NCCNCc1ccccc1
Agent: Cl
Agent: ClCCNCc1ccccc1
Agent: OCCNCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1N
Product: Cc1ccccc1N1CCN(Cc2ccccc2)C(C(N)=O)C1

Procedure:
2-Benzylaminoethanol (18.8 ml, 20 g, 0.13 mol) was converted to N-(2-chloroethyl)-N-benzylamine hydrochloride with thionyl chloride (19 ml, 31 g, 0.26 mol) according to the procedure described in J. Chem. Soc. 1955, 896. N-(2-chloroethyl)-N-benzylamine hydrochloride (4.0 g, 19 mmol) was converted to N-benzyl-N'-(2-methylphenyl)-1,2-diaminoethane hydrochloride by the procedure of Syn. Comm. 18, 45-50 (1988), using o-toluidine (6.1 ml, 6.1 g, 57 mmol) in place of aniline. 1-benzyl-4-(2-methylphenyl)piperazine-2-carboxamide was prepared from 2,3-dibromopropionamide (7.9 g, 34 mmol) by the procedure of J. Med. Chem. 35, 743-750 (1992) using N-benzyl-N'-(2-methylphenyl)-1,2-diaminoethane hydrochloride (4.95 g, 18 mmol) in place of N-benzyl-N'-phenyl-1,2-diaminoethane hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([C:8]([NH:22][C:23]2[CH:44]=[CH:43][CH:42]=[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=4)[CH:32]=3)[CH:24]=2)=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cn1cc(Cl)c(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cn1cc(Cl)c(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n1
Yield: 45.2 %

Procedure:
In the same manner as in Example 18-4 and using 4-chloro-1-methyl-1H-pyrazole-3-carboxylic acid (156 mg, 0.970 mmol), tetrahydrofuran (7 mL), oxalyl chloride (93.0 μL, 1.07 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (132 mg, 45%) was obtained as a white solid.
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([S:16][CH3:17])[C:10]=1[CH3:18].[CH3:19][S:20]SC>[Cu]>[CH3:18][C:10]1[C:11]([S:16][CH3:17])=[C:12]([S:20][CH3:19])[CH:14]=[CH:15][C:9]=1[Br:8]
Reactant: CSc1c(N)ccc(Br)c1C
Reactant: CSSC
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1ccc(Br)c(C)c1SC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
14.8 g (129 mmol) of tert-butyl nitrite and 20 g of copper powder are initially charged in 50 ml of dimethyl disulfide, and a solution of 20 g (86 mol) of 4-bromo-3-methyl-2-methylthioaniline in 100 ml of dimethyl disulfide is added dropwise at from 50 to 55° C. The mixture is subsequently stirred at 50° C. for 4 hours. For work-up, the solid is filtered off with suction and the filtrate is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with saturated aqueous NaHCO3 solution, dried over sodium sulfate, filtered off and concentrated. Excess dimethyl disulfide is removed under oil pump vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH:17]=[CH:16][N:15]=1>CN(C=O)C>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:19]=1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Reactant: COc1ccccc1-c1ccnc(Cl)c1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccnc(Nc2cccc(CS(N)(=O)=O)c2)c1
Yield: 1.8 %

Procedure:
G2 was prepared from (3-aminophenyl)methanesulfonamide (85 mg, 0.46 mmol) and A1 (100 mg, 0.46 mmol) following the procedure reported for G1 by heating in DMF for 3 hours, and it was obtained as a colorless amorphous solid (3.1 mg, 2%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 3.79 (s, 3H), 4.15 (s, 2H), 6.73 (bs, 2H), 6.84 (dd, J=5.3 Hz, J=1.5 Hz, 1H), 6.96-6.98 (m, 1H), 7.04 (dt, J=1.0 Hz, J=8.0 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.21-7.25 (m, 2H), 7.33 (dd, J=7.6 Hz, J=1.8 Hz, 1H), 7.36-7.42 (m, 1H), 7.64-7.68 (m, 2H), 8.14 (d, J=5.3 Hz, 1H), 9.08 (s, 1H). MS (ES) C19H19N3O3S requires: 369. found: 370 (M+H)+.
Reaction SMILES: CON(C)[C:4](=[O:18])[C@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].[CH3:20][Mg]Br.C1COCC1.C1(C)C=CC=CC=1.O>C1COCC1>[O:18]=[C:4]([CH3:20])[C@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:6]
Reactant: CON(C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, 1000 mg of benzyl {(2R)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (Example 149A, 3.8 mmol, 1 equivalent) were dissolved in 19.5 ml of THF and cooled to −78° C. At this temperature, 4 ml of 1.4 M methylmagnesium bromide solution in 1:3 THF/toluene (6 mmol, 1.5 equivalents) were added slowly. The mixture was then stirred at −78° C. for 5 min and at RT for 1 h and then allowed to stand at RT overnight. 0.27 ml of water was then added with ice cooling, and the mixture was then concentrated. The residue was diluted with water and 1 N aqueous hydrochloric acid solution and extracted four times with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. This gave 888 mg (97% of theory) of the title compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:16][CH2:17][Cl:18].C(N(CC)CC)C>>[Cl:18][CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: ClCCBr
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Solvent: CCN(CC)CC
Product: ClCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 35.4 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-piperazine (0.05 mol), 1-bromo-2-chloroethane (0.1 mol) and triethylamine (0.05 mol) was stirred for 30 minutes at 100° C. The mixture was cooled, then partitioned between CH2Cl2 and water. The layers were separated. The organic phase was filtered over dicalite. The organic filtrate was dried, filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 5.2 g (35%) of 4-(2-chloroethyl)-1-(3,4-dichlorophenyl)-piperazine (interm. 9).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:10]=[C:11]2[C:34](=[CH:35][CH:36]=1)[C:15]1=[N:16][O:17][C:18]([C:19]3[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:21][N:20]=3)=[C:14]1[CH2:13][CH2:12]2)[CH2:3][CH2:4][C:5]([O:7]C)=[O:6].C1COCC1.CO.[OH-].[Na+]>O>[O:1]=[C:2]([C:9]1[CH:10]=[C:11]2[C:34](=[CH:35][CH:36]=1)[C:15]1=[N:16][O:17][C:18]([C:19]3[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:21][N:20]=3)=[C:14]1[CH2:13][CH2:12]2)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(=O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 70 h
Yield: 93.2 %

Procedure:
A mixture of methyl 4-oxo-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 109A, 22 mg, 0.044 mmol), THF (2 mL), MeOH (0.5 mL), water (0.5 mL) and 2N aqueous sodium hydroxide (0.2 mL, 0.400 mmol) was stirred at room temperature under nitrogen for 70 h. The reaction mixture was concentrated and the residue was acidified with 10% citric acid (1.5 mL) and extracted with dichloromethane (4×2 mL). The combined dichloromethane extracts were dried (sodium sulfate) and concentrated under reduced pressure to give 4-oxo-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoic acid (20 mg, 0.041 mmol, 94% yield) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].Cl.[OH:13][CH2:14][CH2:15][N:16]1[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=[C:17]1[NH2:23].[O-]CC.[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([CH:7]=[N:23][C:17]2[N:16]([CH2:15][CH2:14][OH:13])[C:20]([CH2:21][CH3:22])=[CH:19][N:18]=2)=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: CCc1cnc(N)n1CCO
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1cnc(N=Cc2cnc([N+](=O)[O-])n2C)n1CCO
Reaction time: 8 h

Procedure:
To a solution of 0.4 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde dissolved in 25 ml. of ethanol, 0.494 g. of 1-(2-hydroxyethyl)-2-amino-5-ethylimidazole hydrochloride and 0.175 ml. of sodium ethoxide in 2.89 ml. of ethanol are added. After standing overnight, the solid which precipitates is collected on the filter and washed with water. Yield: 0.269 g., m.p. 185°-187° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.I[CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17].[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(O)cc(C(C)=O)c1
Reactant: CC(C)(C)CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OCCC(C)(C)C)cc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
1-(3-Hydroxy-5-methoxyphenyl)ethanone (O3.033; 1.12 g) and 1-iodo-3,3-dimethylbutane (1.57 g) were dissolved in DMF, and sodium hydride (194 mg) was added. After stirring at RT for 2 h, the DMF was drawn off. The residue was taken up in EA, washed with water, dried, filtered and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA 0-50% within 30 min). 850 mg of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][C:9]=2[O:19][CH3:20])=[CH:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.C(O)CCC>CCOC(C)=O>[CH3:20][O:19][C:9]1[CH:10]=[C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)=[CH:7][CH:6]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2cccn2)ccc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nn1
Temperature: 120 °C

Procedure:
Following GENERAL METHOD 6-1 for SNAr, Intermediate 2-1 (50 mg, 0.174 mmol), tert-butyl piperazine-1-carboxylate (59 mg, 0.314 mmol), DIPEA (0.06 mL, 0.349 mmol), and n-butanol (0.1 mL) were combined in a 4 mL reaction vial and heated at 120° C. overnight. The reaction was cooled to RT and EtOAc was added. The white solid that formed was filtered off and washed with EtOAc, dissolved in DCM and washed with H2O. The organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo to afford the desired product.
Reaction SMILES: [CH3:1][O:2][CH:3](O)[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[CH:15]=[CH:14][N+:13]([O-:16])=[C:12]([CH3:17])[CH:11]=1.[OH2:18]>CS(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:18][C:10]1[CH:15]=[CH:14][N+:13]([O-:16])=[C:12]([CH3:17])[CH:11]=1
Reactant: O
Reactant: CCC(O)OC
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCCOc1cc[n+]([O-])c(C)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
5.85 g (0.065 mol) of methoxypropanol was dissolved in 60 ml of dimethyl sulfoxide to obtain a solution. 2.6 g (0.065 mol) of sodium hydride was added to this solution at a room temperature in a nitrogen atmosphere. The obtained mixture was stirred at 60° C. for 0.5 hour. A solution of 4.66 g (0.0325 mol) of 4-chloro-2-methylpyridine 1-oxide in 20 ml of dimethyl sulfoxide was dropwise added to the mixture under cooling with ice. The mixture was stirred at 40° C. for one hour. After the completion of the reaction, the reaction mixture was concentrated under a reduced pressure to obtain a solid. 200 ml of water was added to this solid. The obtained mixture was extracted with chloroform and the obtained extract was dried over magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and purified by silica gel column chromatography (ethyl acetate/methanol) to obtain 4.09 g of the title compound.
Reaction SMILES: [ClH:1].[C:2]([NH2:7])(=[NH:6])[CH2:3][CH2:4][CH3:5].[OH-:8].[Na+].[OH2:10]>>[ClH:1].[CH3:2][C:3]1([OH:10])[C:4]([CH3:5])([OH:8])[NH:7][C:2]([CH2:3][CH2:4][CH3:5])=[N:6]1
Reactant: [OH-]
Reactant: CCCC(=N)N
Reactant: O
Agent: Cl
Agent: [Na+]
Product: CCCC1=NC(C)(O)C(C)(O)N1

Procedure:
A 112.7 gm. portion of butyramidine hydrochloride is dissolved in 200 ml. of water. A 107 gm. portion of freshly distilled diacetyl is added and the mixture is stirred. The pH is adjusted to 6.5-7.0 with 2 N NaOH and the solution is chilled. The desired product is collected as a solid, m.p. 104°-170° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[C:5]([CH3:8])=[N:6][CH:7]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([CH:3]=1)[CH:9]=[O:10]
Reactant: Cc1ncc(F)cc1CO
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1ncc(F)cc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a solution of 32 mg of (5-fluoro-2-methylpyridin-3-yl)methanol in 2 mL of dichloromethane, 80 mg of molecular sieves 3A and 40 mg of 4-methylmorpholine N-oxide were added, and the mixture was stirred at room temperature for 30 minutes. Thereto was added 6.0 mg of tetrapropyl ammonium perruthenate, and the mixture was stirred at room temperature for 1 hour 30 minutes. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 20 mg of 5-fluoro-2-methylnicotinaldehyde as a colorless oily substance.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C(O)(=O)C.Br>O>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2cc(O)ccc21

Procedure:
A mixture of 50 g of 6-methoxy-1-tetralone, 200 ml of acetic acid and 400 ml of hydrobromic acid (47% HBr) was heated under reflux for 24 hours. After cooling, the reaction mixture was poured into 3 liters of water, solid matter was filtered out, and the resulting filtrate was extracted three times with ethyl acetate. The extracts were washed with an aqueous solution of sodium carbonate, dried over sodium sulfate and evaporated. The resulting residue together with the filtered solid matter was recrystallized from ethyl acetate to yield 40.75 g (89.5% of the theoretical yield) of 6-hydroxy-1-tetralone in the form of reddish-brown crystals melting at 153°-155° C.