Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=1[O:19][CH3:20])=[O:8])=[O:5].[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[O:19][CH3:20])=[O:8])=[O:5]
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.2 g (5.7 mmol) of 1-(2-chloro-4,5-difluorobenzoyl)-3-(2-methoxy-5-nitrophenyl)urea were heated to the boiling temperature in 50 ml of ethyl acetate and admixed with 6.4 g (28.5 mmol) of SnCl2 monohydrate. After 1 hour, the mixture was allowed to cool to room temperature and the pH was adjusted to 8 using 2 N sodium hydroxide solution. The precipitate which formed was filtered off and washed with methanol, and the mother liquor was washed twice with H2O, dried and concentrated under reduced pressure. The resulting product (1.4 g) was reacted in step d without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([CH:7]=O)[CH2:2]1.Cl.[NH2:10][OH:11].[OH-].[Na+]>O>[O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([CH:7]=[N:10][OH:11])[CH2:2]1
Reactant: NO
Reactant: O=CC1=CCCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ON=CC1=CCCOC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 5,6-dihydro-2H-pyran-3-carbaldehyde (10 g, 89 mmol) and hydrochloric acid salt of hydroxylamine (12.0 g, 178 mmol) in water (80 mL) was added a solution of sodium hydroxide (6.4 g, 160 mmol) in water (20 mL) dropwise. The cooling bath was removed and the mixture was allowed to stir at ambient temperature for 1 hour, the resulting solution was acidified with 2 N aqueous hydrochloric acid to pH 3-4, and then extracted with ethyl acetate (3×100 mL). All the organic solutions were washed with saturated NaHCO3 aqueous solution (2×50 mL), brine (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid, which was used in next step without further purification. 1H NMR (300 MHz, CD3OD) δ 7.76 (s, 1H), 6.15 (br, 1H), 4.35 (d, J=1.8 Hz, 2H), 3.86 (t, J=5.7 Hz, 2H), 2.32-2.31 (m, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[O:11]1[C:15]2[C:16]([CH2:20][OH:21])=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[CH:12]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]1[C:15]2[C:16]([CH:20]=[O:21])=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[CH:12]1
Reactant: OCc1cccc2ccoc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cccc2ccoc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
DMSO (2.87 ml, 40 mmol) was added slowly to a -78° C. solution of oxalyl chloride in methylene chloride (20 ml of 2M, 40 mmol). To this solution was added slowly a solution of benzofuran-7-methanol (4.03 g, 27 mmol) in methylene chloride, and the mixture was stirred 30 min at -78° C. Triethyl amine (30 ml) was added slowly to the reaction mixture, which was then allowed to warm to room temperature. The mixture was diluted with methylene chloride and washed with water and then with brine. The organic layer was concentrated in vacuo to an oil (3.16 g, 80%).
Reaction SMILES: [N:1]([CH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]1=[O:23])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]1=[O:23]
Reactant: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCCCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(N)CCCCc2ccccc21

Procedure:
A solution of 3-azido-1-ethoxycarbonylmethyl-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one (5.0 g) in ethanol (500 ml) is hydrogenated at atmospheric pressure using 10% palladium on charcoal (0.7 g) as catalyst. The catalyst is filtered off and the solvent removed under reduced pressure to give 3-amino-1-ethoxycarbonylmethyl-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A solution of 3-nitro-5-(trifluoromethyl)benzoic acid (5.4 g, 23 mmol) in MeOH (115 mL) was charged with 5% Pd/C, Degussa (1.09 g). The reaction vessel was purged with hydrogen and stirred under a hydrogen atmosphere (1 atm) for 3 h. The mixture was filtered and the filtrate was concentrated in vacuo to provide 3-amino-5-(trifluoromethyl)benzoic acid (4.25 g). This material was incorporated into procedure (80a) to provide 3-benzylamino-5-(trifluoromethyl)benzoic acid, a portion (17 mg, 0.06 mmol) of which was incorporated into procedure (91b). Purification by RP-HPLC afforded the title compound (S)-1.5 (R1=2,4-dimethylphenyl, R3=—C(O)NHt-Bu, Z=—C(O)—, R2=3-benzylamino-5-(trifluoromethyl)phenyl, all other R=H; 3 mg). Exact MS calcd for C33H41F3N5O3, the formula for (M+H)+=612.3161. Found: 612.3184.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:10]=[C:9]([CH3:19])[C:5]=1[C:6]([NH2:8])=[O:7])[CH3:2].[OH-].[Na+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>C1C=CC=CC=1.O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[CH2:1]([S:3][C:4]1[CH:12]=[C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:10]=[C:9]([CH3:19])[C:5]=1[C:6]([NH:8][CH2:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([F:22])[CH:24]=1)=[O:7])[CH3:2]
Reactant: CCSc1cc(N2CCOCC2)cc(C)c1C(N)=O
Reactant: Fc1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCSc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1cccc(F)c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 16 %

Procedure:
To a solution of 2-ethylsulfanyl-6-methyl-4-morpholin-4-yl-benzamide (0.26 g, 0.92 mmol) in benzene-tetrahydrofuran (1:1) (20 ml) are added tetrabutylammonium hydrogensulfate (0.031 g, 0.091 mmol) and 50% sodium hydroxide solution (8 ml) at RT. The reaction mixture is heated to 80° C. and 3-fluorobenzyl bromide (0.14 ml of a 2M solution in benzene, 0.28 mmol) is added. The reaction mixture is stirred at 80° C. for 15 min. After completion of the reaction (monitored by TLC), the reaction mixture is diluted with water (15 ml) and extracted with ethyl acetate (15×3 ml). The organic layer is washed with water (20 ml), brine (15 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 25% ethyl acetate/hexane) to yield 2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-6-methyl-4-morpholin-4-yl-benzamide (example 1) (0.06 g, 0.15 mmol, 16%). [M+H]+ 389.1.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22]CC)=[O:21])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:8]([CH3:19])=[C:7]([C:20]([OH:22])=[O:21])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(CCc2ccc(F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(=O)O)cc(C(C)(C)C)n1CCc1ccc(F)cc1
Reaction time: 8 h

Procedure:
A 15.91 g portion of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was dissolved in a mixture of 200 ml of ethanol and 20 ml of tetrahydrofuran at 80° C., and 96.01 ml of a 5 M sodium hydroxide aqueous solution was added thereto, followed by overnight stirring at the same temperature and then further stirring at 100° C. for 6 hours. The reaction liquid was concentrated to about 150 ml, and, under ice-cooling, 6 M hydrochloric acid was added thereto until pH became 1. The resulting solid was collected by filtration and washed with water to obtain 14.04 g of 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylic acid as a light brown solid.
Reaction SMILES: [F:1][C:2](=[C:11]([F:13])[F:12])[CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[F:1][C:2](=[C:11]([F:12])[F:13])[CH2:3][CH2:4][S:5]([C:6]1[O:7][CH:8]=[CH:9][N:10]=1)=[O:22]
Reactant: FC(F)=C(F)CCSc1ncco1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(CCC(F)=C(F)F)c1ncco1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.9 %

Procedure:
1.0 g of 2-(3,4,4-trifluoro-3-butenylthio)oxazole and 1.5 g of m-chloroperbenzoic acid (purity about 70%) were added to 50 ml of dichloromethane and stirred at room temperature for 20 hours. The reaction mixture was washed with 50 ml of 1N aqueous solution of sodium hydroxide and dried with magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (eluent: ethyl acetate:dichloromethane=1:4) to obtain 1.0 g of 2-(3,4,4-trifluoro-3-butenylsulfinyl)oxazole as colorless oil (yield 92.9%, n20D=1.4820).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].[Br:15][C:16]1[CH:20]=[N:19][N:18]([CH3:21])[C:17]=1[C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][C:31]([CH3:36])([N+:33]([O-])=O)[CH3:32])[NH2:25].C(N(CC)C(C)C)(C)C>ClCCl>[NH2:33][C:31]([CH3:36])([CH3:32])[CH2:30][O:29][C:28]1[CH:27]=[CH:26][C:24]([NH:25][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=2)=[CH:23][C:22]=1[C:17]1[N:18]([CH3:21])[N:19]=[CH:20][C:16]=1[Br:15]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2cccc(OC(F)(F)F)c2)ccc1OCC(C)(C)N
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
3-Trifluoromethoxybenzoyl chloride (12 mg, 0.06 mmol) was added to a solution of 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)aniline (18 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 μl, 0.06 mmol) in dichloromethane (0.5 mL) and the mixture was stirred at room temperature. After 1 h, the solution was diluted with dichloromethane, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried with sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved in methanol (0.5 mL). Acetic acid (0.1 mL) was added followed by zinc dust (33 mg) and the mixture was stirred at room temperature. After 4 h, the suspension was made basic with ammonium hydroxide and extracted twice with ethyl acetate. The combined extracts were evaporated to dryness, purified by preparative LCMS and lyophilized to give the product (21 mg, 81%) as a TFA-salt. LCMS m/z (%)=529.3 (M+H 81Br 76.1%), 527.5 (M+H 79Br 64.8%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 3 H), 1.18 (s, 3 H), 3.67 (s, 3 H), 3.84 (d, J=9.85 Hz, 1 H), 4.00 (d, J=9.85 Hz, 1H), 7.30 (d, J=9.09 Hz, 1 H), 7.60-7.65 (m, 1 H), 7.67 (s, 1 H), 7.68-7.73 (m, 2 H), 7.85-7.93 (m, 4 H), 7.95 (dd, J=8.97, 2.65 Hz, 1 H), 8.01 (d, J=7.83 Hz, 1 H), 10.48 (s, 1 H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:19](=[O:21])[NH2:20])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(C)(C)C.Br[CH2:24][C:25](=O)[CH2:26][CH3:27].C(OCC)C>CC#N>[CH2:26]([C:25]1[N:20]=[C:19]([C@@H:8]([NH2:7])[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[O:21][CH:24]=1)[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Reactant: CCC(=O)CBr
Solvent: CC#N
Solvent: CCOCC
Product: CCc1coc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C

Procedure:
A mixture of [1-(S)-carbamoyl-2-(4-nitrophenyl)ethyl-carbamic acid tert-butyl ester, 1, (10 g, 32.3 mmol) and 1-bromo-2-butanone (90%, 4.1 mL, 36 mmol) in CH3CN (500 mL) is refluxed for 18 hours. The reaction mixture is cooled to room temperature and diethyl ether is added to the solution and the precipitate which forms is removed by filtration and is used without further purification.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[O:11][CH2:12][C:13](F)([F:15])[CH:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl>[C:1]([Si:5]([O:8][CH2:9][C:10]1[O:11][CH:12]=[C:13]([F:15])[CH:14]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC(F)(F)CO1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc(F)co1
Reaction time: 8 h

Procedure:
tert-Butyl((4,4-difluoro-4,5-dihydrofuran-2-yl)methoxy)dimethylsilane was diluted with DCM and treated with silica gel (5 g SiO2/1 g of compound). The flask was swirled around to ensure an even mix, DCM was allowed to air dry and the flask left at rt overnight. The silica gel was transferred to a fritted funnel and eluted with DCM until no more product could be detected by TLC. The filtrate was concentrated to provide an orange oil tert-butyl((4-fluorofuran-2-yl)methoxy)dimethylsilane. 1H NMR (400 MHz, CDCl3) δ 0.09 (s, 6H), 0.91 (s, 9H), 4.55 (br s, 2H), 6.20 (m, 1H), 7.31 (dd, J=5.03, 0.63 Hz, 1H); 19F NMR (376.19 MHz, CDCl3) δ −170.53 (dd, J=4.95, 1.32, 1F).
Reaction SMILES: [CH:1]1([SH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[N:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:23][C:21]1[CH:20]=[CH:19][C:9]([C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:11])=[C:8]([S:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:22]=1
Reactant: SC1CCCC1
Reactant: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1SC1CCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
Cyclopentanethiol (7.84 mL, 73.22 mmol) was added in one portion to 2,6-dichloro-N-cyclohexylnicotinamide (20 g, 73.22 mmol) and sodium carbonate (23.28 g, 219.65 mmol) in DMF (150 mL). The resulting suspension was stirred at 60° C. for 3 hours. The mixture was cooled, evaporated, DCM (250 mL) was added and the mixture was washed with water (3×100 mL) and brine (50 mL), dried (MgSO4), filtered and evaporated to a sticky pale yellow solid. This was triturated with 4:1 hexane:ethyl acetate, filtered and dried to give 6-chloro-N-cyclohexyl-2-(cyclopentylthio)nicotinamide (13.8 g, 55.6%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].O1CCC[CH2:11]1.[OH-].[K+].CI>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:11])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: C1CCOC1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1ccc(Br)c(F)c1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
Into a 250-mL round-bottom flask, was placed 4-bromo-3-fluorophenol (5.0 g, 26.18 mmol, 1.00 equiv), tetrahydrofuran (50 mL). This was followed by the addition of potassium hydroxide (2.94 g, 52.40 mmol, 2.00 equiv) in portions. To this was added CH3I (5.6 g, 39.45 mmol, 1.51 equiv) dropwise. The resulting solution was stirred for 4 h at 30° C. TLC (Petroleum ether: EtOAc=1:4) controlled the reaction process. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. This resulted in 5.2 g (97%) of 1-bromo-2-fluoro-4-methoxybenzene as yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:9]=[C:8]([C:19]#[N:20])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.Br[CH2:22][CH2:23][CH2:24]Br.C(N(CC)CC)C>C(#N)C>[N:1]1([CH:2]2[CH:11]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10]3[CH:9]=[C:8]([C:19]#[N:20])[CH:7]=[CH:6][C:5]=3[CH2:4][CH2:3]2)[CH2:24][CH2:23][CH2:22]1
Reactant: BrCCCBr
Reactant: N#Cc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc2c(c1)C(Cc1ccccc1)C(N1CCC1)CC2
Temperature: 120 °C

Procedure:
7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (790 mg, 3.03 mmol), 1,3-dibromopropane (0.4 mL, 3.93 mmol) and triethylamine (0.914 mL, 6.56 mmol) were dissolved in acetonitrile (8 mL) and the reaction mixture heated to 120° C. in the microwave for 2 h. The solvent was evaporated in vacuo. Water (30 mL) and ethyl acetate (40 mL) were added. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloromethane, methanol). Yield: 346 mg (1.14 mmol, 37.6%).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Br[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:14]=O>CCO.C(Cl)Cl>[OH:10][C:6]1[CH:7]=[CH:8][N:9]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: O=CC(Br)c1ccccc1
Reactant: COc1ccnc(N)c1C#N
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1c(O)ccn2c(-c3ccccc3)cnc12
Temperature: 160 °C
Yield: 84 %

Procedure:
A mixture of compounds D3 (2 g, 13.41 mmol) and D4 (6.69 g, 33.5 mmol) in EtOH (10 ml) was subjected to microwave heating at 160° C. for 45 min. The reaction mixture was cooled to room temperature and then diluted with DCM, causing a solid to precipitate. The solid obtained was filtered off, washed thoroughly with DCM and dried in vacuo to yield compound D5 (2.65 g, 84%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)ccn1
Yield: 52.6 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (111 mg, 53%). MS (ISP) 423.0 [(M+H)+]; mp 243° C.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[F:6][CH:7]([F:22])[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]1.CC(OC)(C)C.[OH-].[Na+]>S(=O)(=O)(O)O>[F:22][CH:7]([F:6])[C:8]1([C:15]2[C:20]([N+:1]([O-:4])=[O:2])=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]1
Reactant: NC1=NC(c2ccccc2F)(C(F)F)COC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: NC1=NC(c2c(F)cccc2[N+](=O)[O-])(C(F)F)COC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Potassium nitrate (60.3 g, 596 mmol) was added portionwise to 600 ml sulfuric acid (Temperature<20° C.). This solution was added dropwise to a solution of 5-difluoromethyl-5-(2-fluoro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (112 g, 459 mmol) in 600 ml sulfuric acid, while keeping the reaction temperature<22° C. with an ice bath. After stirring for 1 h, the mixture was poured onto 10 Kg ice. TBME (6 L) was added and the pH was adjusted to 12-14 by the addition of about 5 L 30% aqueous NaOH. The phases were separated and the aqueous phase was extracted twice with TBME. The combined organic layers were dried with sodium sulfate and evaporated to give 130 g of a yellow solid that was used further without purification.
Reaction SMILES: Cl[C:2]1[C:3]([F:23])=[CH:4][C:5]2[C:6]([CH:22]=1)=[N:7][C:8]1[N:9]([CH2:19][CH2:20][F:21])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[F:23][C:3]1[C:2]([N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[CH:22][C:6]2=[N:7][C:8]3[N:9]([CH2:19][CH2:20][F:21])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: O=C(O)c1cn(CCF)c2nc3cc(Cl)c(F)cc3cc2c1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4CCF)CC1
Yield: 42.1 %

Procedure:
A suspension of 1.2 g of 8-chloro-7-fluoro-1-(2-fluoroethyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 12 cm3 of pyridine and 3.52 g of 1-methylpiperazine is heated, with stirring, at a temperature close to 110° C. for 6 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at about 60° C. The residue is taken up in 15 cm3 of water and 2 cm3 of acetic acid. A small amount of insoluble matter is removed by filtration through diatomaceous silica. 6 cm3 of 20% aqueous potassium hydroxide solution are added to the filtrate. A very small amount of insoluble matter is again removed by filtering through diatomaceous silica. 0.6 cm3 of acetic acid is added to the filtrate. The precipitate obtained is drained, washed with twice 5 cm3 of water and twice 5 cm3 of ethanol and recrystallized twice from 10 cm3 of dimethylformamide each time. 0.6 g of 7-fluoro-1-(2-fluoroethyl)-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 306°-308° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1.[CH2:24](I)[CH3:25].O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]([N:8]([CH2:24][CH3:25])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([N+:21]([O-:23])=[O:22])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 73.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in DMF (2.0 ml), 4′-chloro-2′-nitro-p-toluenesulfonanilide (0.30 g (0.92 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, ethyl iodide (0.50 ml (6.25 mmol)) was added dropwise. After one hour's heating at 100° C. with stirring, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, giving 0.24 g (74%) of the title compound as pale yellow crystals.