Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[N+:11]([O-:13])=[O:12].[OH-:14].[Na+].Cl>CS(C)=O.O>[F:8][C:6]1[CH:5]=[C:4]([O:9][CH3:10])[C:3]([N+:11]([O-:13])=[O:12])=[C:2]([OH:14])[CH:7]=1
Reactant: COc1cc(F)cc(F)c1[N+](=O)[O-]
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(F)cc(O)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 1,5-difluoro-3-methoxy-2-nitro-benzene (20 g, 105 mmol) in dimethylsulfoxide (50 ml) is added a 10N aqueous solution of sodium hydroxide (31.5 ml) and the mixture is stirred at room temperature for 18 h and at 60° C. for 3 h. After completion of reaction (monitored by TLC), the mixture is diluted with water (50 ml), acidified with 2N hydrochloric acid to pH 3 and extracted with ethyl acetate (3×100 ml). The combined organic layers are washed with water (50 ml), brine (50 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (15% ethyl acetate/hexane) to yield 5-fluoro-3-methoxy-2-nitro-phenol (12.0 g, 63.5 mmol, 60%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])[NH:13][C:12](=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][C:12](=[O:17])[NH:13][C:14](=[O:16])[CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)N1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C2CC(=O)NC(=O)C2)cc1
Yield: 61.7 %

Procedure:
A solution of 197 mg (0.841 mmol) of 4-(4-nitro-phenyl)-piperidine-2,6-dione (as prepared in the previous step) in methyl alcohol (MeOH) (15 mL) was hydrogenated over 10% Pd/C at 20 psi for 5 h at RT. The mixture was filtered through Celite, the filter cake was washed with MeOH, and the solvents were evaporated in vacuo to afford 106 mg (62%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C11H12N2O2, 205.1 (M+H). found 205.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:31])=O>CN(C=O)C>[Cl:31][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[N:9]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(Cl)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1

Procedure:
Distilled THF (10 mL) was added to 3-(4-chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)isoindolin-1-one (200 mg, 0.52 mmol), thionyl chloride (136.8 mg, 1.15 mmol, 0.08 mL) and catalytic DMF (3 drops) as for general procedure B1. 3-Chloro-3-(4-chlorophenyl)-2-(4-nitrobenzyl)isoindolin-1-one was produced as a viscous yellow oil (208.5 mg, 0.52 mmol) which was used immediately without further purification. Distilled THF (3 mL) was added to 3-chloro-3-(4-chlorophenyl)-2-(4-nitrobenzyl)isoindolin-1-one (208.5 mg, 0.52 mmol) and the resultant solution added dropwise to cis-cyclopentene diol (260 mg, 2.6 mmol) and dried potassium carbonate (359 mg, 2.6 mmol) in distilled THF (3 mL) as for general procedure B1. Removal of the solvent yielded the crude product as a yellow oil (262 mg). The sample was purified by flash column chromatography (EtOAc:Petrol, 40:60) to yield the title product as a yellow viscous oil. (211 mg, 44.4 mmol, 85%). 1H NMR: (300 MHz, DMSO) δ ppm 1.34, (m, 1H, H15/H16) 1.74, 2.2 (m, 1H, H15/H16) 4.22 (dt, 1H, H16) 4.40 (d, 1H, J=15.99 Hz, H9/H9′), 4.63 (d, 1H, J=16.02 Hz, H9/H9′), 4.93, 4.98, (dd, 1H, H17/H18), 5.15, 5.29 (dd, 1H, H17/H18), 5.76 (m, 1H, H14) 7.26 (m, 7H, H1-H5, H10, H13), 7.66 (m, 2H, H6-H7), 7.88 (d, 1H, H8), 8.00 (m, 2H, H11, H12).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[O:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14]1.Cl>CCOCC>[F:9][C:2]([F:1])([F:8])[C:3]([CH:14]1[C:15](=[O:22])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13]1)=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1COc2ccccc21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C1c2ccccc2OC1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 86.5 %

Procedure:
Ethyl trifluoroacetate (1.90 g, 14 mmol) was dissolved in ether (15 mL) and treated with sodium methoxide (25%) (3.67 g, 17 mmol). To the stirred solution was added 3-coumaranone (1.50 g, 11 mmol). The reaction was stirred at room temperature overnight (19 hours) and treated with 3N HCl (8 mL). The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo to give a reddish brown solid (2.19 g, 85%): mp 108°-111° C.; 1H NMR (CDCl3) 300 MHz 7.84 (d, J=8.1 Hz, 1H) 7.66 (m, 1H) 7.52 (d, J=8.7 Hz, 1H) 7.37 (m, 1H). Mass spectrum: M+H=231.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[NH:11]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)CCCN
Agent: Cl
Product: CCOC(=O)CCCNCC(=O)OC(C)(C)C
Yield: 55 %

Procedure:
By a method substantially equivalent to that described in Example 2-A; 13.6 g (55%) of N(CH2CH2CH2COOEt)Gly-O-t-Bu were prepared from t-butyl bromoacetate and ethyl 4-amino-butyrate hydrochloride.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([NH:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=O)=[CH:5][CH:4]=1)#[CH:2]>C(OC(=O)C)(=O)C>[C:1]([C:3]1[S:7][C:6]([C:8]2[O:13][C:12](=[O:14])[C:11]([CH3:16])([CH3:15])[N:10]=2)=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(C(=O)NC(C)(C)C(=O)O)s1
Solvent: CC(=O)OC(C)=O
Product: C#Cc1ccc(C2=NC(C)(C)C(=O)O2)s1

Procedure:
Prepared analogously to Example 3-a from 2-[(5-ethynyl-thiophen-2-yl)-carbonylamino]-2-methyl-propionic acid in acetic anhydride at 65° C. with subsequent purification by chromatography on silica gel with the eluant (petroleum ether/ethyl acetate=2:1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([O:22][CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[N:16]=1.O>CN(C)C(=O)C>[Cl:21][C:19]1[CH:20]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:17]([O:22][CH2:23][C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[CH:18]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Clc1cc(Cl)nc(OCc2ccsc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccc(Oc2cc(Cl)cc(OCc3ccsc3)n2)c1

Procedure:
To a solution of meta-trifluoromethylphenol (0.28 g, 0.0018×1.0 mol) in 10 ml of dry N,N-dimethylacetamide, sodium hydride (0.077 g, (ca.60% in mineral oil), 0.0018×1.1 mol) was added. After the bubbling ceased, a solution of 2,4-dichloro-6-(3-thienylmethyloxy)pyridine (0.46 g, 0.0018 mol) in 10 ml of dry N,N-dimethylacetamide was added dropwise and the resultant solution was stirred for about 7 hours at the temperature of 160° to 170° C. After allowed to cool, water was added to the reaction solution, then the mixture was partitioned by using ethyl acetate. The obtained organic layer was washed with aqueous saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off, then the residue was purified successively on silica gel column chromatography and on reversed phase column chromatography (Lobar column, Lichroprep RP-18, 40-63 μm, elution solvent: CH3CN/H2O=7/3(v/v)), whereby the end product was obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]([CH3:25])[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[NH:22][CH:23]=[CH:24][C:17]=23)[CH2:9]1)C1C=CC=CC=1.C(O)C>Cl.O.[Pd]>[CH3:25][N:15]([C@@H:10]1[C@H:11]([CH3:14])[CH2:12][CH2:13][NH:8][CH2:9]1)[C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][CH:23]=[CH:24][C:17]=12
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc2[nH]ccc12
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: C[C@@H]1CCNC[C@@H]1N(C)c1ccnc2[nH]ccc12
Reaction time: 8 h
Yield: 236.5 %

Procedure:
A degassed mixture of N-[(3R,4R)-1-benzyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (0.030 g, 0.000090 mol) and palladium (0.028 g, 0.000026 mol) in ethanol (2 mL, 0.03 mol) and 3.0 M of hydrogen chloride in water (0.2 mL) was stirred under an atmosphere of hydrogen overnight. The reaction mixture was filtered and washed with MeOH. The solvent was removed under vacuum to give 52 mg of an orange viscous oil. The oil was partitioned between ethyl acetate and sat. NaHCO3. The aqueous phase was extracted with ethyl acetate and THF. The combined organic phases were washed with sat. NaCl. Solvents were removed under vacuum to give 47 mg of an orange solid.
Reaction SMILES: COC1C=CC([CH2:7][C:8]([O:13][C:14](=[O:30])[C@H:15]([CH:27]([CH3:29])[CH3:28])[NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])(C)[C:9]([O-:11])=[O:10])=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C@H:15]([C:14]([O:13][CH:8]([CH3:7])[C:9]([OH:11])=[O:10])=[O:30])[CH:27]([CH3:28])[CH3:29])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: COc1ccc(CC(C)(OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)C(=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methoxybenzyl-2-(N-CBZ-L-valyloxy)-propionate (7.8 g, 17.5 mmole) in dichloromethane (100 ml) was added trifluoroacetic acid (10 ml) and the solution was stirred for one hour at room temperature. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography. Yield: 5.0 g
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.O[CH:12]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:13][CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>>[CH3:21][C:18]([O:17][C:16](=[O:22])[N:15]([CH2:14][CH2:13][CH:12]([O:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH2:24][CH:25]([CH3:26])[CH3:27])[CH3:23])([CH3:19])[CH3:20]
Reactant: CC(C)CC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)cc1O
Product: CC(C)CC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1C#N

Procedure:
The title compound was prepared according to the method of Example 2 step (b) but using 4-chloro-2-hydroxybenzonitrile and (3-hydroxy-5-methylhexyl)methylcarbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][C@H:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[CH:12]=[CH:11][C:3]=1[NH:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)[C@@H](C)Nc1ccc(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)C(C)Nc1ccc(F)c(F)c1F
Temperature: 95 °C
Reaction time: 19 h
Yield: 89.5 %

Procedure:
Methyl (2R)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 57% ee) was dissolved in dimethylacetamide (DMAc; 3 ml) and potassium carbonate (474.1 mg) was added thereto at room temperature. Then the liquid reaction mixture was stirred at 95° C. for 19 hours. After adding water to the liquid reaction mixture, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to thereby give the title compound (179 mg) as colorless crystals. The optical purity of this product was 0% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1COCC1.S(Cl)(Cl)=O.[CH3:24][N:25](C=O)[CH3:26]>>[CH3:24][N:25]([CH3:26])[C:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[CH:11]=1)=[O:14]
Reactant: O=C(O)c1cc(Cl)nc2ccccc12
Reactant: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1cc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-chloroquinoline-4-carboxylic acid (5.0 g) and THF (48 mL) was added a small amount of DMF, followed by addition of thionyl chloride (1.8 mL) with ice cooling. The mixture was stirred at room temperature for 1 h and then at 60° C. for 1 h. The mixture was cooled to room temperature and then concentrated under reduced pressure, and the residue was diluted with chloroform (30 mL). The mixture was ice-cooled, followed by addition of 50% aqueous dimethyl amine (20 mL), and the mixture was stirred for 10 min. 1 M aqueous sodium hydroxide was added, the mixture was extracted with chloroform, the organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to obtain the title compound (4.6 g).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)([CH3:3])[CH3:2].C(O)(=O)C.[I:14]Cl>C(Cl)Cl>[I:14][C:8]1[S:7][C:6]([NH2:9])=[N:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: ClI
Reactant: CC(C)c1csc(N)n1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1nc(N)sc1I
Reaction time: 0.5 h

Procedure:
The above prepared 4-isopropyl-thiazol-2-ylamine (1.020 g, 7.17 mmol) was dissolved in 14 mL of CH2Cl2 and 2.8 mL of acetic acid and treated at 0° C. with iodine monochloride (7.53 mL of 1M in CH2Cl2, 1.05 eq.) and kept at this temperature for 0.5 h. Pouring onto crashed ice/Na2CO3, twofold extraction with ethyl acetate, washing with water and brine, drying over sodium sulfate, and evaporation to dryness yielded 1.922 g of the title compound as dark brown viscous oil, sufficiently pure to be used for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-])=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([N:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]3)=[CH:25][CH:26]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:20][CH2:19][N:18]([CH3:17])[CH2:23][CH2:22]3)=[CH:32][CH:31]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: CN1CCN(c2ccc(C(=O)[O-])cc2)CC1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: CN1CCN(c2ccc(C(=O)Nc3ccc(C(=O)c4ccc(NC(=O)c5ccc(N6CCN(C)CC6)cc5)cc4)cc3)cc2)CC1

Procedure:
Compound 316 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-(4-methylpiperazino)benzoate. [M+H]+ calcd for C37H41N6O3: 617.32; found: 617.12.
Reaction SMILES: C([NH:9][C:10]1([C:19]([OH:21])=[O:20])[CH:15]2[CH2:16][CH2:17][CH2:18][CH:11]1[CH2:12][CH2:13][CH2:14]2)(=O)C1C=CC=CC=1>CC(O)=O.Cl>[NH2:9][C:10]1([C:19]([OH:21])=[O:20])[CH:15]2[CH2:16][CH2:17][CH2:18][CH:11]1[CH2:12][CH2:13][CH2:14]2
Reactant: O=C(NC1(C(=O)O)C2CCCC1CCC2)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: NC1(C(=O)O)C2CCCC1CCC2
Yield: 98.3 %

Procedure:
Dissolve 3 g (10.44 mmol) of 9-benzoylamino bicyclo[3.3.1]nonane-9-carboxylic acid in 200 mL of AcOH and 50 mL of 6N HCl aqueous solution, reflux the mixture for 18 h and then concentrate partially by distillation of 150 mL of solvent. After cooling, filter the reaction mixture and distribute in 150 mL of a 1:2 mixture of 1N HCl aqueous solution/ether. After extraction, concentrate the aqueous phase and then treat it dropwise with a 12N aqueous solution of soda (NaOH) to adjust the pH to 5-6. Filter the amino acid thus precipitated, wash with 3×50 mL of water and dry under reduced pressure, which gives 1.88 g of 9-aminobicyclo[3.3.1]nonane-9-carboxylic acid in the form of white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[CH3:33][NH:34][CH2:35][CH3:36]>>[CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:34]([CH2:35][CH3:36])[CH3:33]
Reactant: CCNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(Cl)c(NCc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C24H25ClN6O2, 464.9
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:8]([C:17]([OH:19])=[O:18])=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]2=O)=[CH:4][CH:3]=1>CO.O>[F:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[CH:13]2)[CH:11]=[CH:10][CH:9]=[C:8]3[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2c(=O)c3cc(F)ccc3[nH]c12
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2cc3cc(F)ccc3nc12
Yield: 95 %

Procedure:
Reduction of the known [Atwell et al., J. Med. Chem., 1987, 30, 658] 7-fluoro-9-oxoacridan-4-carboxylic acid as above gave 7-fluoroacridine-4-carboxylic acid (95%), mp (MeOH/H2O) 267-268° C. 1H NMR [(CD3)2SO] δ 7.87 (dd, J=8.4, 7.0 Hz, 1 H, H-2), 8.01 (ddd, J=9.5, 8.5, 2.3 Hz, 1 H, H-6), 8.13 (dd, J=9.3, 2.8 Hz, 1 H, H-8), 8.45 (dd, J=9.6, 5.3 Hz, 1 H, H-5), 8.54 (dd, J=8.5, 1.3 Hz, 1 H, H-1), 8.73 (dd, J=6.9, 1.4 Hz, 1 H, H-3), 9.47 (s, 1 H, H-9), 16. 53 (br s, 1 H, COOH). Anal. (C14H8FNO2) C, H, N, F.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5](N)=[CH:4][C:3]1=2.[H+].[B-](F)(F)(F)[F:23]>>[CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([F:23])=[CH:4][C:3]1=2
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1cc2c(cc1N)C(C)(C)CCC2(C)C
Agent: [H+]
Product: CCOC(=O)c1cc2c(cc1F)C(C)(C)CCC2(C)C

Procedure:
Reaction Schemes 1 and 2 provide examples for the synthesis of derivatives of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene-2-carboxylic acid, which are within the scope of Formula 6 and which are reacted with an amine of Formula 7 to provide (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-naphthalene-2-yl)carbamoyl derivatives within the scope of Formula 1. Thus, as is shown in Reaction Scheme 1, ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxylate (Compound A) is nitrated to provide the corresponding 3-nitro compound (Compound B). The nitro group of Compound B is reduced to provide the corresponding 3-amino compound (Compound C) which is described in the publication Lehmann et al. Cancer Research, 1991, 51, 4804. Ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylate (Compound C) is brominated to yield the corresponding 4-bromo derivative (Compound D), which is converted by treatment with isoamylnitrite and reduction with H3PO2, to ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-bromonaphthalene-2-carboxylate (Compound E). Saponification of Compound E yields 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-4-bromonaphthalene-2-carboxylic acid (Compound F) which is used as a reagent in accordance with Formula 6. Ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylate (Compound C) is also diazotized and reacted with HBF4 to provide ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetra-methyl-3-fluoronaphthalene-2-carboxylate (Compound G) which serves either per se or after saponification as a reagent in accordance with Formula 6.
Reaction SMILES: [Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=O)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21].C(=O)(O)[O-].[Na+]>COCCOCCOC>[Cl:1][C:2]1[S:19][C:5]2[NH:6][C:7](=[S:21])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1CN=C(c2ccccc2F)c2cc(Cl)sc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOCCOC
Product: Fc1ccccc1C1=NCC(=S)Nc2sc(Cl)cc21

Procedure:
10 g of 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one are dissolved in 150 ml of diethyleneglycol dimethyl ether at 55° C. and stirred with a mixture of 15 g of finely triturated phosphorus pentasulphide and 10 g of sodium bicarbonate for 40 minutes. The solvent is distilled off and the residue washed with water, filtered under vacuum and dried. The 7-chloro-5-(o-fluorophenyl)-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione thus obtained is refluxed in 200 ml of methanol with 15 g of acetyl hydrazine for 30 minutes. On cooling, 2-(2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-thieno[2,3-e]-1,4-diazepine precipitates. The methanol is distilled off and the residue partitioned between methylene chloride and water. The solvent is evaporated under reduced pressure and the residue crystallized from methanol to yield a second crop of 2-(2-acetylhydrazino)-7-chloro-5-(o-fluorophenyl)-3H-thieno[2,3-e]-1,4-diazepine, melting point 207° -209° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N.CO>C1COCC1.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][C@H:19]([C:23]([O:25][CH3:26])=[O:24])[CH:20]([CH3:21])[CH3:22])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(C#N)c2)cc1)C(C)C
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(CN)c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
A suspension of methyl N-[(3′-cyanobiphenyl-4-yl)sulfonyl]valinate obtained in Reference Example 93 (5.00 g, 13.4 mmol), Raney-nickel (5.00 g) and 28% aqueous ammonia (50 mL) in THF (50 ml)-methanol (50 mL) was stirred at room temperature for 15 hr under hydrogen atmosphere (1 atm). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. A mixed solvent of ethyl acetate-hexane was added to the residue, and the precipitated insoluble material was filtered off. The filtrate was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and diethyl ether was added to the residue. The precipitated solid was collected by filtration to give the title compound as a white powder (3.84 g, 76%).
Reaction SMILES: [S:1](=NC1C=CC=CC=1)=O.[CH:10]1[CH:15]=[C:14]([F:16])[C:13]([NH2:17])=[C:12]([NH2:18])[CH:11]=1>>[F:16][C:14]1[C:13]2[C:12](=[N:18][S:1][N:17]=2)[CH:11]=[CH:10][CH:15]=1
Reactant: O=S=Nc1ccccc1
Reactant: Nc1cccc(F)c1N
Product: Fc1cccc2nsnc12
Temperature: 110 °C

Procedure:
4-Fluoro-2,1,3-benzothiadiazole was synthesized according to the method in which N-thionylaniline (0.49 g, 3.5 mmol) was added to a solution of the 3-fluoro-O-phenylene diamine (200 mg, 1.6 mmol) in foluen (2 ml) The reaction mixture was heated at 100-120° C. for 4 hr. After the solvent was filtered off, the residue was dissolved in dichloromethane and the solution was washed with 10% HCl solution and water, successively. The organic layer was dried and evaporated to dryness. Purification by chromatography on a silica gel column with chloroform as an eluent gave 4-fluoro-2,1,3-benzothiadiazole as pal yellow oil. Confirmed data of the obtained chemical compound is shown as follows.