Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+:1].[Na+].[Na+].[Na+].[N+:5]([C:8]1[CH:9]=[C:10]([C:35]([NH:37][C:38]2[C:39]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:40][C:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[C:43]([S:48]([O-:51])(=[O:50])=[O:49])[CH:42]=3)=[O:36])[CH:11]=[C:12]([C:14]([NH:16][C:17]2[C:18]([S:31]([O-:34])(=[O:33])=[O:32])=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([S:27]([O-:30])(=[O:29])=[O:28])[CH:21]=3)=[O:15])[CH:13]=1)([O-])=O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>O>[Na+:1].[Na+:1].[Na+:1].[Na+:1].[NH2:5][C:8]1[CH:9]=[C:10]([C:35]([NH:37][C:38]2[C:39]([S:52]([O-:55])(=[O:54])=[O:53])=[CH:40][C:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[C:43]([S:48]([O-:51])(=[O:49])=[O:50])[CH:42]=3)=[O:36])[CH:11]=[C:12]([C:14]([NH:16][C:17]2[C:18]([S:31]([O-:34])(=[O:33])=[O:32])=[CH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[C:22]([S:27]([O-:30])(=[O:29])=[O:28])[CH:21]=3)=[O:15])[CH:13]=1
Reactant: O=C(Nc1cc2ccc(S(=O)(=O)[O-])cc2cc1S(=O)(=O)[O-])c1cc(C(=O)Nc2cc3ccc(S(=O)(=O)[O-])cc3cc2S(=O)(=O)[O-])cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Product: Nc1cc(C(=O)Nc2cc3ccc(S(=O)(=O)[O-])cc3cc2S(=O)(=O)[O-])cc(C(=O)Nc2cc3ccc(S(=O)(=O)[O-])cc3cc2S(=O)(=O)[O-])c1
Temperature: 57 °C

Procedure:
A mixture of 4.35 g of 3,3'-[(5-nitro-1,3-phenylene)bis(carbonylimino)]bis[2,7-naphthalenedisulfonic acid] tetrasodium salt in 100 ml of water is heated to 57° C. A 2.07 g portion of sodium sulfide nonahydrate is added and the reaction is allowed to cool. The reaction is reheated to 67° C. and allowed to cool. The mixture is filtered and the filtrate is acidified to pH 4 using acetic acid. The mixture is heated and then filtered with added diatomaceous earth. Upon cooling the filtrate yields a solid which is filtered, washed with 50% ethanol, absolute ethanol and finally with ether giving 3,3'-[(5-amino-1,3-phenylene)bis(carbonylimino)]bis[2,7-naphthalenedisulfonic acid] tetrasodium salt.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]1([NH2:6])[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>O1CCOCC1>[O:24]=[C:18]([NH:6][C:3]1([C:2]([F:8])([F:7])[F:1])[CH2:5][CH2:4]1)[CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C1CCC(=O)O1
Reactant: NC1(C(F)(F)F)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCC(=O)NC1(C(F)(F)F)CC1
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
Slowly, 800.7 mg (4.96 mmol) of 1-(trifluoromethyl)cyclopropanamine and 0.85 ml (4.96 mmol) of diisopropylethylamine were added to a solution of 496 mg (4.96 mmol) of succinic anhydride in 10 ml of dioxane, with ice-cooling (10° C.). Stirring was continued for 20 min at room temperature, and the mixture was allowed to stand overnight at this temperature. Again, stirring was continued for 20 min at 80° C., the mixture was allowed to cool to room temperature, and the solution was concentrated. Repeatedly, the solution was washed alternately with ethyl acetate and with water. The combined organic phases were dried and concentrated. This gave 815.8 mg (73% of theory) of the desired compound.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[CH3:20].[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[OH:32])[O:28][CH2:27][CH2:26][CH:25]2[C:33]([O:35][CH2:36][CH3:37])=[O:34].CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu]Cl>[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][C:2]1[CH:19]=[CH:18][C:5]([C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:4][C:3]=1[CH3:20])[O:28][CH2:27][CH2:26][CH:25]2[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: Cc1cc(C(=O)NCCc2ccc(Cl)cc2)ccc1Br
Reactant: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Agent: Cl[Cu]
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3C)c(Cl)cc21
Temperature: 100 °C
Yield: 21.4 %

Procedure:
To a solution of 4-bromo-N-(4-chlorophenethyl)-3-methylbenzamide (0.0831 g, 0.236 mmol), ethyl 6-chloro-7-hydroxychroman-4-carboxylate (0.050 g, 0.195 mmol), and 2-(dimethylamino)acetic acid (0.0104 g, 0.101 mmol) in dioxane (1 ml) degassed with argon was added cesium carbonate (0.133 g, 0.409 mmol) and copper(I) chloride (0.0100 g, 0.101 mmol). The reaction was sealed in a screw-cap vial and heated to 100° C. for 16 hours. The reaction was cooled to ambient temperature, then loaded directly onto a Biotage SP1 system, eluting with a linear gradient of 5-70% EtOAc in hexanes to yield 22 mg of the title compound (21% yield).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[C:5]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C)ccc1-n1cccn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-n2cccn2)c(C(=O)O)n1

Procedure:
A solution of methyl 6-methyl-3-(1H-pyrazol-1-yl)-2-pyridinecarboxylate D37 (106 mg) and LiOH (17.53 mg, 0.732 mmol) in THF/water (2:1, 6 ml) was stirred overnight. The mixture was evaporated under reduced pressure; the residue was taken up in water (2 ml) and the pH was adjusted to pH=2 with 1 M HCl solution. The mixture was loaded onto a pre-conditioned C18 column (5 g, eluted with water and then MeOH). The methanol fractions were evaporated under reduced pressure to give the title compound D38 (98 mg) as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1.C[OH:15]>O.CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Br:6][C:7]1[CH:8]=[C:9]([C:12]([OH:15])=[O:13])[S:10][CH:11]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CO
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc(Br)cs1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a solution of chromium(VI)oxide (1.57 g, 15.70 mmol) in water (3 mL) was added dropwise concentrated sulfuric acid (1.3 mL, 23.55 mmol). The formed precipitate was re-dissolved by slow addition of the minimum required amount of water and the solution was cooled with an ice bath. This solution was then added dropwise to a solution of 4-bromo-2-thiophenecarboxaldehyde (2.0 g, 10.47 mmol) in acetone (20 mL) at about 5° C. The reaction mixture was stirred at about 5° C. for about 30 minutes and then at room temperature for about 2 hours. Methanol (30 mL) was added to the reaction mixture to destroy excess oxidant and the formed solids were collected by filtration. The filtrate was concentrated under vacuum and the residue was partitioned between diethyl ether and water. The organic extract was washed with water and brine, dried (MgSO4), filtered and concentrated under vacuum to provide the desired product. MS (DCI-NH3): m/z 206, 208 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]([CH3:10])=[C:4]([OH:11])[C:3]=1[CH3:12].[Na].C([Li])CCC.O1[C:21]([CH3:38])([CH2:22][CH2:23][CH2:24][CH:25]([CH3:37])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:36])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:20]1.Cl>O1CCCC1>[CH3:12][C:3]1[C:4]([OH:11])=[C:5]([CH3:10])[C:6]2[CH2:9][CH2:35][C@:33]([CH2:32][CH2:31][CH2:30][C@@H:29]([CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:24][CH2:23][CH2:22][CH:21]([CH3:38])[CH3:20])[CH3:37])[CH3:36])([CH3:34])[O:8][C:7]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C)c(O)c(C)c(C)c1O
Reactant: CC(C)CCCC(C)CCCC(C)CCCC1(C)CO1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 1 h
Yield: 78.1 %

Procedure:
10 g (66.7 mmol) of tetramethylhydroquinone are dissolved in 100 ml of dry tetrahydrofuran, 4 g (139 mmol) of sodium hydridge (80% in mineral oil) was added thereto at room temperature, 45 ml of butyllithium (1.6 molar in hexane) are subsequently added dropwise and the mixture is stirred for 1 hour. 10 g (44.3 mmol) of 1,2-epoxy-2,6,10,14-tetramethylpentadecane are now added dropwise; the mixture is left to react for 12 hours while stirring. 100 ml of 1N methanolic hydrochloric acid area added and the mixture is stirred at 50° C. for 2 hours. The mixture is subsequently concentrated at 50° C. and the residue is chromatographed on silica gel with toluene, whereby where are obtained 14.9 g (75%) of α-tocopherol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[C:7]2[OH:13].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18]>CN1CCCC1=O>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:9]2[N:8]=[C:7]([OH:13])[C:6]3[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: Oc1nc(Cl)nc2c(Br)cccc12
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CN1CCCC1=O
Product: Oc1nc(Nc2ccc(Cl)c(Cl)c2)nc2c(Br)cccc12
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A solution of 8-bromo-2-chloroquinazolin-4-ol (0.37 g) and 3,4-dichloroaniline (0.69 g) in 1-methyl-2-pyrrolidinone (8 mL) was heated at 140° C. for 3 h. The mixture was then cooled to room temperature and poured onto ice/water (100 mL). The precipitate which formed was isolated by filtration, washed sequentially with water and diethyl ether, then was dried in vacuo to afford the title compound (0.46 g). 1H NMR (300 MHz, DMSO-d6): δ11.14 (s, 1H), 9.22 (s, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.57-7.51 (m, 2H), 7.20-7.18 (m, 1H). HPLC Method B: 9.90 min. MS (APCI+): m/z 386, 388. (APCI−): m/z 384, 386. The starting material 8-Bromo-2-chloroquinazolin-4-ol was prepared as follows:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[CH:7]([C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1)[CH2:6]2.[CH2:32]([NH2:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:32]([NH:38][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[CH2:6][CH:7]1[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCN
Reactant: COc1ccc(C2Cc3cc(OC)ccc3C2CCCCCCCCCC(=O)O)cc1
Product: CCCCCCNC(=O)CCCCCCCCCC1c2ccc(O)cc2CC1c1ccc(O)cc1

Procedure:
The process described in Example 1 was repeated using 10-[(1RS, 2RS)-5-methoxy-2-p-methoxyphenylindan-1-yl]decanoic acid and n-hexylamine as starting materials. There was thus obtained as an oil N-n-hexyl-10-[(1RS, 2RS)-5-hydroxy-2-p-hydroxyphenylindan-1-yl]decanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:13]([C:12]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=2[Cl:10])=[O:14])[CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(=O)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-bromo-4-methoxy-benzene (7.48 g, 40 mmol), 2-chloro-4-nitro-benzoyl chloride (8.79 g, 40 mmol) and bismuth triflate (1.31 g, 2.0 mmol) under an atmosphere of argon was stirred at RT for 20 min. The temperature was raised to 80° C. and stirring was continued for 90 min. DCM was added to the reaction mixture and the organic phase was washed with aq. HCl (1 N, 0.5 mL) and NaHCO3 (aq.). The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was crystallised from a mixture of DCM and pentane to afford the title compound as yellow crystals
Reaction SMILES: [H-].[Na+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].O>CN(C=O)C>[C:3]1([O:13][CH2:15][CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O[C@@H](CCOc1cccc2ccccc12)c1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a mixture of 8 ml of DMF and 0.44 g of 60% sodium hydride in mineral oil at 5° C. in an ice bath was added dropwise a solution of 1.44 g of 1-naphthol in 8 ml of DMF. The reaction mixture was stirred at 5° C. for two hours and a solution of 1.71 g of (S)-(-)-3-chloro-1-phenyl-1-propanol in 5 ml of DMF was added. After stirring overnight at room temperature, the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate (3×50 ml). The combined extracts were combined and washed with water and 1N sodium hydroxide solution and dried over sodium sulfate. Yield: 2.56 g (92%). The crude product can be recrystallized from 95:5 hexane/ethyl acetate to give 1.5 g (54%) of purified (S)-(+)-3-(1-naphthalenyloxy)-1-phenyl-1-propanol, mp 76°-78° C.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[C:11]1=[N:12][NH:13][C:14](=[O:16])[CH2:15][CH:10]1[CH2:9]2)=O.OS(O)(=O)=O>>[NH2:5][C:6]1[CH:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[C:11]1=[N:12][NH:13][C:14](=[O:16])[CH2:15][CH:10]1[CH2:9]2
Reactant: O=C1CC2Cc3cc(NC(=O)C(F)(F)F)ccc3C2=NN1
Agent: O=S(=O)(O)O
Product: Nc1ccc2c(c1)CC1CC(=O)NN=C21

Procedure:
dl-7-trifluoroacetylamino-4,4a-dihydro-5H-indeno-[1,2-c]-pyridazin-3-one, m.p. 234° C., which is hydrolized with 1N H2SO4 to give dl-7-amino-4,4a-dihydro-5H-indeno[1,2-c]-pyridazin-3-one.
Reaction SMILES: O[C:2]1([C:18]2[C:27]([OH:28])=[CH:26][C:21]3[O:22][CH2:23][O:24][CH2:25][C:20]=3[CH:19]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[C:3]1=[O:17].OC1(C2C(O)=CC3ON=C(C)C=3C=2)C2C(=CC=CC=2)N(CC2C=CC(OC)=CC=2)C1=O>>[OH:28][C:27]1[C:18]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:11][C@H:12]3[CH2:16][CH2:15][CH2:14][O:13]3)[C:3]2=[O:17])=[CH:19][C:20]2[CH2:25][O:24][CH2:23][O:22][C:21]=2[CH:26]=1
Reactant: O=C1N(C[C@H]2CCCO2)c2ccccc2C1(O)c1cc2c(cc1O)OCOC2
Agent: COc1ccc(CN2C(=O)C(O)(c3cc4c(C)noc4cc3O)c3ccccc32)cc1
Product: O=C1C(c2cc3c(cc2O)OCOC3)c2ccccc2N1C[C@H]1CCCO1

Procedure:
Following the procedure as described in PREPARATION 9B, and making non-critical variations using 3-hydroxy-3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one to replace 3-hydroxy-3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one, 3-(7-hydroxy-4H-1,3-benzodioxin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one was obtained (84%) as a colorless solid: MS (ES+) m/z 368.2 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:30]5[CH2:31][CH2:32][O:28][C:29]5=[O:33])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1NCCO1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: O=C(c1ccc(N2CCOC2=O)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 84.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (473 mg) described in Preparation Example 95, oxazolidin-2-one (104 mg), the title compound (367 mg) was obtained.
Reaction SMILES: CS([C:4]1[O:5][C:6]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[CH:24]1([CH2:30][NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH:24]1([CH2:30][NH:31][C:4]2[O:5][C:6]3[CH:12]=[C:11]([O:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=4)[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCC1CCCCC1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)oc3c2)ccn1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Reaction time: 2 h

Procedure:
To a solution of 4-(2-(methylsulfinyl)benzo[d]oxazol-6-yloxy)-N-methylpyridine-2-carboxamide (1.40 g, 4.23 mmol, 1.0 eq) in 15 mL of THF was added cyclohexylmethanamine (955 mg, 8.46 mmol, 2.0 eq) at room temperature. The reaction mixture was stirred at that temperature for 2 hours. After the solvent was removed under reduced pressure, the residue was dissolved in 150 mL of ethyl acetate. The resulting mixture was washed with water (20 mL), brine (20 mL), then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by silica gel column eluted with ethyl acetate and hexane to give the titled compound. MH+=381.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[C:21]([F:24])([F:23])[F:22])[NH2:17]>C(O)C>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][C:20]=1[C:21]([F:23])([F:24])[F:22]
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc(C(F)(F)F)c(F)c2)C1=O
Yield: 34.8 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g; 1.45 mmol) and 3-fluoro-4-(trifluoromethyl)aniline (0.806 g; 4.36 mmol) in ethanol (3 mL). 1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxopyrrolidine-3-carboxylic acid 0.147 g (35%) was obtained as a solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH:2]1[CH2:10][C:11]([OH:13])=O.S(Cl)(Cl)=O.C[N:19]([CH:21]=O)C>C1(C)C=CC=CC=1>[S:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]1[CH2:10][C:11]([NH:19][C:21]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)=[O:13]
Reactant: O=C(O)CC1Sc2ccccc2S1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(CC1Sc2ccccc2S1)Nc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(benzo[1,3]dithiol-2-yl)acetic acid (1.35 g) in toluene (30 mL) were added thionyl chloride (0.600 mL) and DMF (catalytic amount) at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added acetonitrile (30 mL), and then was added dropwise a solution of aniline (1.54 g) in acetonitrile (10 mL) under ice-cooling. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 3 hours, and then concentrated under reduced pressure. To the residue was added 1N hydrochloric acid (50 mL), and the mixture was stirred at room temperature for 0.5 hour. The formed crystals were collected by filtration, washed with water, filtered, and then dried to obtain 2-(benzo[1,3]dithiol-2-yl)-N-(phenyl)acetamide (1.83 g) as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[N+:7]([O-])([O-:9])=[O:8].[K+].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1
Reactant: Cc1cc[nH]n1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: Cc1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-methylpyrazole (1.96 mL, 24.0 mmol) in sulfuric acid (15 mL) was cooled to −5° C. and potassium nitrate (1.1 eq) was added portion-wise. The reaction was warmed to rt and stirred for 16 h. The mixture was cooled to 0° C. and neutralized with ammonium hydroxide solution. The resulting solid was filtered and air-dried to give 3-methyl-4-nitro-1H-pyrazole. To a solution of 3-methyl-4-nitropyrazole (300 mg, 2.6 mmol), potassium carbonate (2 eq) and the alkylating reagent (1.1 eq) in acetonitrile (10 mL) was heated at 60° C. for 18 h. After cooling to rt the mixture was diluted with EtOAc and washed with water. The organic phase was collected, dried (MgSO4) and concentrated in vacuo. The crude residue was dissolved in methanol (10 mL), palladium on carbon (50 mg) was added and the reaction was stirred under a balloon of hydrogen for 18 h. The resulting mixture was filtered through Celite and the filtrate concentrated in vacuo to give the desired product.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[S:18][C:19]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:20]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:16][C:17]2[S:18][C:19]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
4-Bromomethylbenzoic acid (2.24 g, 10.4 mmol) was dissolved in toluene (80 mL), and thionyl chloride (7.59 mL, 104 mmol) was added thereto, followed by stirring under heating and reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in THF (50 mL), and 2-amino-4-(2-furyl)-5-morpholinothiazole (2.00 g, 7.97 mmol) obtained in Step 1 of Example 29, triethylamine (1.67 mL, 12.0 mmol) and N,N-dimethylaminopyridine (97.6 mg; 0.800 mmol) were added thereto, followed by stirring under heating and reflux for 1 hour. The reaction mixture was allowed to cool down to room temperature, and then a 10% aqueous solution of sodium carbonate was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:ethyl acetate=9:1) to afford the entitled Compound 59 (3.29 g, 92%).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.CN(/[CH:12]=[N:13]/[C:14]1[C:23]([C:24]([O:26]C)=O)=[CH:22][C:21]2[C:16](=[CH:17][C:18]([O:30][CH3:31])=[C:19]([O:28][CH3:29])[CH:20]=2)[N:15]=1)C.C(O)(=O)C>O1CCCC1>[CH3:29][O:28][C:19]1[C:18]([O:30][CH3:31])=[CH:17][C:16]2=[N:15][C:14]3[NH:13][CH:12]=[C:2]([C:1]#[N:3])[C:24](=[O:26])[C:23]=3[CH:22]=[C:21]2[CH:20]=1
Reactant: CC#N
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2nc1/N=C/N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3nc2cc1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
Acetonitrile (1.3 mL, 24.9 mmol) is added to a −78° C. solution of 9.0 mL of 2.5 M n-butyllithium (22.5 mmol) in 40 mL of tetrahydrofuran. After stirring at −78° C. for 15 min, a solution of 2.86 g (9.02 mmol) of methyl 2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinolinecarboxylate in 100 mL of tetrahydrofuran is added dropwise over 30 minutes. After stirring at −78° C. for 30 minutes, the reaction mixture is allowed to warm to room temperature and then stirred at room temperature for 1 hour. The reaction mixture is cooled to −78° C. and 3.0 mL of acetic acid is added. The mixture is then stirred at room temperature for 40 min. The solids are collected by filtration washing with water, methanol and ethyl acetate to provide 1.11 g (44%) of 7,8-dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitrile as a light yellow solid, mp>300° C. MS 281.9 (M+H)+ Analysis for C15H11N3O3.0.65H2O Calcd: C, 61.49; H, 4.23; N, 14.34. Found: C, 61.40; H, 4.40; N, 14.70.