Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:51][C:52]1[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][C:53]=1[NH2:54]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:54][C:53]1[CH:55]=[C:56]([CH3:59])[CH:57]=[CH:58][C:52]=1[F:51])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Reactant: Cc1ccc(F)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)c2cccc(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-benzyloxy benzoic acid (1.00 g, 4.38 mmol) in 20 ml of anhydrous DMF were added HATU (1.83 g, 4.82 mmol) and DIPEA (1.7 ml, 9.6 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 2-fluoro-5-methylaniline (657 mg, 5.25 mmol). The mixture was heated at 66° C. for 16 hours, cooled to room temperature, and partitioned between EtOAc (100 ml) and 0.5M HCl (200 ml). The organic phase was washed with 0.5M HCl (2×50 ml), saturated NaHCO3 (50 ml) and brine (50 ml), dried over Na2SO4, and evaporated to dryness to afford 3-(benzyloxy)-N-(2-fluoro-5-methylphenyl)benzamide as light brown solid. Yield: 1.5 g, 100%.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[CH3:10][C:11](O)([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1.CCCCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([O:8][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:7])[CH2:3]1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCC
Product: CC(C)(C)OC(=O)C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.9 %

Procedure:
3,3-difluorocyclobutanecarboxylic acid (1.0 g, 7.3 mmol) was dissolved in DCM (10 mL) and cooled in an ice bath. To the solution was added N,N-dimethylpyridin-4-amine (92 mg, 0.735 mmol) portionwise followed by 2-methylpropan-2-ol (1.1 g, 14.7 mmol) in one portion. A 1M solution of N,N′-dicyclohexylcarbodiimide in DCM (8.1 mL, 8.1 mmol) was added dropwise keeping the temperature below 10° C. The resulting slurry was warmed up to room temperature and stirred for 18 hours. The solid was removed by filtration and the filtrate was washed with 2N aqueous HCl solution (2×15 mL), water (2×15 mL), and then saturated aqueous NaHCO3 solution (2×15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to give 1.49 g of a crude product as a mixture of white solid and yellow oil. To the mixture was added pentane (30 mL) and the mixture as then filtered through a silica gel pad eluting with pentane to give the title compound (896 mg, 63%) as colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[N+:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)([O-:19])=[O:18]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc([N+](=O)[O-])c2)cc1-c1c(Br)cnn1C
Yield: 69.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.036 g, 0.13 mmol) was treated with 3-nitrophenyl isocyanate (0.023 g, 0.13 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.2 to afford Compound 15 (0.040 g, 0.09 mmol, 70%) as a yellow solid. LCMS m/z (%)=446 (M+H79Br, 100), 448 (M+H81Br, 89). 1H NMR (400 MHz, acetone-d6) δ: 8.63 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 7.80-7.86 (m, 2H), 7.72 (dd, J=2.7, 9.0 Hz, 1H), 7.55 (t, J=8.2 Hz, 1H), 7.50 (s, 1H), 7.45 (d, J=2.7 Hz, 1H), 7.16 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=O>[N+](C1C=CC=CC=1)([O-])=O.CCCCCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCCCCC
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A mixture of 4,5-dichlorophenylendiamine (4 g, 22.6 mmol) and methyl 4-formylbenzoate (3.68, 22.6 mmol) in nitrobenzene (35 ml) was heated at 140° C. for 30 h. After cooling, the mixture was diluted with n-hexane (150 ml) and stirred for 1 h. The solid was filtered obtaining 5 g of the title compound (yield 68.9%) as a brown powder, mp=240–250° C.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].I[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=1.Cl>COCCOC.C1COCC1>[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:4]([C:3]#[N:7])[C:5]#[N:6])=[CH:10][CH:11]=1)=[CH2:16]
Reactant: C=Cc1ccc(I)cc1
Reactant: N#CCC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C#N)C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To an ice-cooled suspension of NaH (0.792 g, 33.0 mmol) in anhydrous 1,2-dimethoxyethane (20 mL) was added dropwise via syringe a solution of malononitrile (0.99 g, 15 mmol) in anhydrous 1,2-dimethoxyethane (5 mL) under N2. The mixture was stirred for 1 h at room temperature under N2. Next, 1-iodo-4-vinyl-benzene (1.15 g, 5.00 mmol), dry THF (15 mL), and tetrakis(triphenyphophine)palladium(0) (0.58g, 0.50 mmol) were added to the resulting pink suspension under an N2 flow, and the reaction mixture stirred at 85° C. for 2 h. After cooling to room temperature, the reaction mixture was poured into ice, neutralized with 10% HCl, and extracted with CH2Cl2 (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel eluting with 1:1 hexane: CH2Cl2, to give 0.603 g (71.8%) of the title compound as pale yellow solid: mp 40-42° C. ° C; 1H NMR (400 MHz, CDCl3): δ 7.526 (d, 2H, J=7.6 Hz), 7.462 (d, 2H, J=7.6 Hz), 6.738 (d×d, 1H, J1=17.6 Hz, J2=10.8 Hz), 5.846 (d, 1H, J=17.6 Hz), 5.398 (d, 1H, J=10.8 Hz), 5.075 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 139.840, 135.372, 127.766, 127.556, 125.245, 116.619, 111.897, 28.050; Anal. Calcd. for C11H8N2: C, 78.55; H, 4.79; N, 16.66. Found; C, 78.76; H, 4.75; N, 16.02.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(OCC)C>[Cl:1][CH2:2][C:3]([O:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: OC1CCCCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCl)OC1CCCCC1
Yield: 98 %

Procedure:
Chloroacetyl chloride (40 mL, 500 mmol) was added dropwise to a solution of cyclohexanol (52 mL, 500 mmol) and triethylamine (77 mL, 550 mmol) in diethyl ether cooled to below 5° C. Upon completion of the addition, the mixture was filtered to remove triethylamine hydrochloride. The filtrate was washed twice with 1M HCl and twice with brine, and was then dried over MgSO4, filtered and evaporated to afford cyclohexyl chloroacetate (86.5 g, 490 mmol, 98%) as a colorless liquid, bp 100° C./5 mm. The chloroacetate (79.5 g, 450 mmol) was added dropwise to a suspension of sodium azide (36.6 g, 563 mmol) in dimethylformamide (60 mL) maintained below 20° C. The mixture was stirred at room temperature overnight, and then was poured into water (200 mL), and the solution was extracted with ether (4×200 mL). The combined organic extracts were washed with brine, then dried, filtered and evaporated to yield cyclohexyl azidoacetate (78.4 g, 428 mmol, 95%) as a colorless liquid, b.p. 85°-90° C. (0.1 mm). Catalytic reduction of the azide with hydrogen over 10% palladium on carbon in ethanol afforded cyclohexyl glycinate, treatment of which with dry HCl afforded glycine cyclohexyl ester HCl, m.p. 144°-145° C., in quantitative yield after crystallization from diethyl ether.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]3[NH:35][CH2:34][C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:30]3=[N:31][CH:32]=2)[CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:35]1[C:29]3[C:30](=[N:31][CH:32]=[C:27]([N:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH:28]=3)[C:33]3([CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:34]1)=[C:3]([CH3:20])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[N:5]2
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (58.1 mg, 0.20 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (55 mg, 0.20 mmol), XPhos pre-catalyst (14.8 mg, 0.02 mmol) and sodium tert butoxide (38.4 mg, 0.40 mmol) in toluene (4 mL) at 90° C. for 2 h. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1′-(5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]-pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, dt, J=4.8, 1.4 Hz), 7.86-7.95 (2H, m), 7.70 (1H, ddd, J=9.3, 2.5, 1.5 Hz), 7.55-7.60 (1H, m), 7.39-7.46 (1H, m), 6.96-7.06 (1H, m), 5.70-5.85 (1H, m), 4.07-4.21 (2H, m), 3.87-4.01 (2H, m), 3.71-3.81 (4H, m), 3.50-3.63 (2H, m), 2.96-3.06 (4H, m), 2.19-2.44 (5H, m), 1.68-1.86 (2H, m). Mass Spectrum (ESI) m/e=530.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CCN(C(C)C)C(C)C.Cl.[NH2:20][OH:21]>CCO>[OH:21][NH:20][C:5](=[NH:6])[C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=1
Reactant: N#Cc1cccc(F)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)c1cccc(F)c1
Temperature: 70 °C
Yield: 96 %

Procedure:
To a mixture of 3-Fluoro-benzonitrile (1.21 g, 10 mmol) and DIEA (5.20 ml, 30 mmol) in EtOH (20 ml) was added 2.08 g of Hydroxylamine hydrochloride (30 mmol) and the reaction was heated at 70° C. for 48 h. Half of the solvent was removed under reduced pressure. The mixture was poured in DCM (100 ml) and water (30 ml). 2.5 ml of NaOH 1N was added until pH=9-10. The organic layer was separated and the aqueous phase was extracted with DCM. The organics layers were combined, washed with water, dried over MgSO4, filtered and evaporated under reduced pressure to afford 1.48 g (96%) of N-Hydroxy-3-fluoro-benzamidine as a white solid which can be used without further purification.
Reaction SMILES: C[O:2][CH2:3][CH2:4][N:5]([CH2:26][CH2:27][O:28]C)[C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[C:20]([CH3:23])[CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:28][CH2:27][CH2:26][N:5]([CH2:4][CH2:3][OH:2])[C:6](=[O:25])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:24])[C:16]3[C:21]([CH:22]=2)=[C:20]([CH3:23])[CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:8]=1
Reactant: COCCN(CCOC)C(=O)c1ccc(-c2cc3c(C)cccc3c(=O)[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(CCO)CCO)cc3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
To a stirred solution of N,N-Bis-(2-methoxy-ethyl)-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzamide (40 mg, 0.10 mmol) in CH2Cl2 (2.5 mL) under N2 at −78° C. was added boron tribromide (1M in CH2Cl2, 2.54 mL, 2.54 mmol). The reaction was allowed to warm to RT and stirred for 16 h. The reaction mixture was quenched with H2O and extracted with EtOAc (5 mL) upon which a pale yellow solid precipitated and was filtered off. The aqueous phase was further extracted with CH2Cl2 (5 mL). The combined organics were evaporated to dryness. Product was found to be also present in the aqueous phase and was passed through an Isolute-103 cartridge (500 mg), washing with H2O (4× column volumes). The product was eluted from the column with MeOH (4× column volumes) and evaporated to dryness. The combined crude product was purified by reverse phase preparative HPLC-MS to obtain N,N-bis-(2-hydroxy-ethyl)-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzamide as a white solid (23 mg, 63%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[O:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1.[O:26]1[CH:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27]1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:32][CH2:31][C:28]2[CH:29]=[CH:30][O:26][CH:27]=2)=[C:3]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: OCc1ccoc1
Product: O=[N+]([O-])c1ccc(OCc2ccoc2)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1

Procedure:
Prepared by the method of Example 44a), from 2-(2-fluoro-5-nitrophenyl)-5-phenylbenzoxazole (400 mg, 1.2 mmol) in 3-furanmethanol (2 ml) the subtitle compound was obtained (392 mg, 79%). The product was used directly in the next step without purification.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].[OH-].[Na+].Br[CH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1>C(N(CC)CC)C>[CH2:2]([NH:4][CH2:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)[CH3:3]
Reactant: CC(=O)c1cccc(CBr)c1
Reactant: CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CCNCc1cccc(C(C)=O)c1
Yield: 66.6 %

Procedure:
The procedure described in Referential Example 4 was repeated, except that ethylamine hydrochloride (16.31 g; 200 mmol), sodium hydroxide (instead of triethylamine) (8 g; 200 mmol), and 3′-bromomethylacetophenone (4.26 g; 20 mmol) were used, to thereby yield 2.36 g of the target compound (yield: 66.7%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].[CH3:11][CH2:12][O-].[Na+].C(I)C>CCO>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:11][CH3:12])[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)CC(=O)CC
Agent: [Na+]
Solvent: CCI
Solvent: CCO
Product: CCOC(=O)C(CC)C(=O)CC
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.6 %

Procedure:
To a solution of 3-oxo-pentanoic acid ethyl ester (5.19 g, 36 mmol) in anhydrous EtOH (40 mL) was added NaOEt (21% wt. in EtOH, 11.7 mL, 36 mmol). he reaction mixture was heated to 80° C. Ethyl iodide (6.18 g, 39.6 mmol) was added dropwise at 80° C. Stirring was continued at 80° C. for 16 hours. The reaction mixture was concentrated and loaded onto a silica gel column and eluted with 1-2% EtOAc/heptane to give 4.38 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[C:14]=1[F:21])[CH:7]=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:25].[N+:26]([O-])([O-:28])=[O:27].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]([C:13]1[CH:18]=[C:17]([N+:26]([O-:28])=[O:27])[C:16]([F:19])=[C:15]([F:20])[C:14]=1[F:21])[CH:7]=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:25]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cn(-c2ccc(F)c(F)c2F)c2cc(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)c(F)c2F)c2cc(F)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 72 h
Yield: 74.9 %

Procedure:
To 10 ml of conc. sulfuric acid was added 830 mg of 6,7-difluoro-1,4-dihydro-4-oxo-1-(2,3,4-trifluorophenyl)-quinoline-3-carboxylic acid. Potassium nitrate (710 mg) was added in portions to the solution, which was stirred at 100° C. for 3 days. The reaction solution was allowed to cool, poured into ice water, and stirred overnight. The precipitated solid was collected by filtration, washed with water, ethanol and diethyl ether to give 700 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 75.1 %

Procedure:
Using 1.18 g of t-butyl N-{2-amino-5-[2-(morpholin-4-yl)phenoxy]-phenyl}-N-methylcarbamate, 0.92 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.53 g of diethyl cyanophosphonate, 0.33 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to Example (2-1), whereby 1.47 g of the desired compound were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[CH3:21][O+](C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[N:13]=[C:12]([O:14][CH3:21])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(C)(c2cccc(Br)c2)COC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.9 %

Procedure:
In a vacuum dried flask under an argon atmosphere, a solution of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (3.0 g, 11.1 mmol) in dichloromethane (145 ml) was treated with trimethyloxonium tetrafluoroborate (2.594 g, 17 mmol). The reaction mixture was stirred at room temperature for 17 hours. For the workup, the incomplete reaction was extracted with a saturated solution of sodium hydrogen-carbonate (70 ml). The organic layer was dried over sodium sulfate and evaporated. There were obtained 3.12 g of the title compound as light yellow oil containing about 17% of the starting lactam. Mass (calculated) C12H14BrNO2 [284.16]; (found) [M+H]+=284, [M+2-H]+=286.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[O:11])=[N:7][CH:8]=1.Br[CH2:25][C:26](=O)[CH3:27].C([O-])(O)=O.[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:25]=[C:26]([CH3:27])[C:9]=2[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[O:11])[CH:8]=1
Reactant: CC(=O)CBr
Reactant: COc1ccc(CC(=O)c2cc(OC)c(OC)c(OC)c2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(C)cn2c1
Yield: 95 %

Procedure:
A mixture of 2-(5-methoxypyridin-2-yl)-1-(3,4,5-trimethoxyphenyl)ethanone (0.200 g, 0.631 mmol), 1-bromo-2-propanone (0.171 g, 1.3 mmol), and NaHCO3 (0.212 g, 2.6 mmol) in acetone (5 mL) was refluxed for 20 h. The precipitate was removed by filtration. The filtrate was concentrated to give a residue, which was purified on a silica gel column eluting with CH2Cl2 to afford compound 5 (0.213 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:20](Cl)(=[O:22])=[O:21])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1.[OH-].[NH4+:27]>O1CCOCC1>[F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:20]([NH2:27])(=[O:22])=[O:21])=[CH:13]3)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1C(=O)c1ccc(F)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc2cc(S(N)(=O)=O)ccc2c1C(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
A solution of 5-(4-fluorobenzoyl)-6-methoxy-2-naphthalenesulfonyl chloride (5.39 g, 14.2 mmol), [prepared as described in step 2 above], in dioxane (100 ml), was cooled in an ice bath under nitrogen, and concentrated ammonium hydroxide (20 ml) was added dropwise. After 1 h, the dioxane was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (gradient elution, 20-60% ethyl acetate/hexane) and then recrystallized from ethyl acetatelhexane to afford 2.7 g of 5-(4-fluorobenzoyl)-6-methoxy-2-naphthalenesulfonamide as white crystals.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH2:20])[CH3:16]>C(Cl)(Cl)(Cl)Cl>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:20][CH2:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])=[S:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(CN)OCC
Reactant: CCOC(=O)c1ccc(N=C=S)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=S)NCC(OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
20 g of 4-carboethoxyphenyl isothiocyanate was dissolved in 50 ml of carbon tetrachloride, and 13 g of aminoacetaldehyde diethylacetal was dropwise added thereto in 5 minutes. Then, the resulting solution was stirred at room temperature for 1 hour. 50 ml of carbon tetrachloride was added to the reaction mixture, and crystals precipitated were collected by filtration, washed with 50 ml of carbon tetrachloride, then dried. Yield: 27.5 g (80.9 mol%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[OH:11]S(O)(=O)=O>[O-2].[O-2].[Mn+4]>[CH2:1]([C:4]1[C:5](=[O:10])[CH:6]=[CH:7][C:8](=[O:11])[CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccccc1O
Reactant: O=S(=O)(O)O
Agent: [Mn+4]
Agent: [O-2]
Product: CCCC1=CC(=O)C=CC1=O

Procedure:
Manganese dioxide (45 g) was stirred in 25% H2SO4 (1300 ml) at room temperature. 2-propylphenol (90 g) was added followed by managanese dioxide (270 g), added over 1 hr to maintain a reaction temperature below 50° C. After a further 11/2 hours the reaction mixture was steam distilled, the distillates extracted with chloroform and the chloroform evaporated to yield propyl-p-benzoquinone (7 g), delta H(CDCl3) 1.00 (3H, t, J8.0Hz), CH3), 1.57(2H, tq, J 8.0,8.0Hz, CH2), 2.42(2H,t,J 8.0Hz, CH2), 6.58-6.82 (3H, m, CH).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][C:11]1[N:12]=[C:13]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:21])[S:14][C:15]=1[C:16](O)=[O:17]>>[CH3:10][C:11]1[N:12]=[C:13]([NH:19][C:20](=[O:21])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[S:14][C:15]=1[C:16](=[O:17])[NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)O
Reactant: NCCc1ccccc1
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)NCCc1ccccc1
Yield: 34 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use phenethylamine in place of benzylamine to react with 4-methyl-2-[(pyridine-4-carbonyl)amino]thiazole-5-carboxylic acid, the title compound was obtained as a white solid in 34% yield; 1H NMR (DMSO-d6, 300 MHz) δ 13.2 (s, br, 1H), 8.89-8.66 (m, 2H), 8.16-7.88 (m, 3H), 7.29-7.14 (m, 5H), 3.47-3.32 (m, 2H), 2.81-2.65 (m, 2H), 2.46 (s, 3H); MS (ES+) m/z 367.2 (M+1).