Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22]Cl)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:25]=[CH:24][C:11]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][SH:3])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: SCCCN1CCN(CCc2ccc(Cl)cc2)CC1
Yield: 176.1 %

Procedure:
The procedure described in Example 1(b) was followed, using 1.3 g of thiourea, 6.4 g of 1-(4-chlorophenethyl)-4-(3-chloropropyl)piperazine dihydrochloride, 1.6 g of triethylamine and 150 ml of reagent ethanol. The hydrolysis was effected with 3.5 g of sodium hydroxide and 40 ml of water. Work-up, as described above, gave 5.6 g (89% of theory) of 3-[4-(4-chlorophenethyl)piperazin-1-yl]propanethiol dihydrochloride as a white crystalline solid, M.p. 279°-281° C.
Reaction SMILES: [OH:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1>[CH3:24][S:25]([O:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]#[N:10])[CH:5]=[CH:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=C1C=CC(=NO)S1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C1C=CC(=C(C#N)c2ccccc2)S1
Yield: 77.2 %

Procedure:
5 g (22 mmol) of (5-Hydroxyimino-5H-thiophen-2-ylidene)-phenyl-acetonitrile are dissolved in 50 ml of THF and cooled in an ice bath. After adding 4.6 ml (33 mmol) of triethylamine to the solution, 1.9 ml (24 mmol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred while cooling in an ice bath for 30 min. The reaction mixture is poured into 200 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 5.2 g (77%) of (5-Methylsulfonyloxyimino-5H-thiophen-2-ylidene)-phenyl-acetonitrile are obtained in the form of greenish brown crystals having a melting point of 160-162° C. (dec.).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH2:9](Cl)[C:10](=[CH2:12])[CH3:11]>>[CH3:9][C:10]1([CH3:12])[CH2:11][C:8]2[CH:7]=[CH:6][CH:5]=[C:3]([OH:4])[C:1]=2[O:2]1.[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2]
Reactant: C=C(C)CCl
Agent: Oc1ccccc1O
Product: CC1(C)Cc2cccc(O)c2O1

Procedure:
The reaction of catechol and methallyl chloride may be illustrated as follows: ##STR1## In accordance with existing processes the reaction mixture, I, would have been filtered to remove sodium chloride, then subjected to Claisen rearrangement and cyclization to form 2,3-dihydro-2,2-dimethyl-7-hydroxybenzofuran resulting in the loss of unreacted or excess catechol employed in the reaction.
Reaction SMILES: [CH:1]1([C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)[Cl:24].[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>O>[ClH:24].[CH:1]1([C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([O:10][C:27](=[O:30])[CH2:28][CH3:29])[CH2:5][CH2:6][N:7]([CH3:8])[CH3:9])[CH2:3][CH2:2]1
Reactant: ClC(Cl)Cl
Reactant: CCC(=O)Cl
Reactant: CN(C)CCC(O)(c1ccccc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(=O)OC(CCN(C)C)(c1ccccc1)C1CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred mixture of 6 g. (0.027 mole) of 1-cyclopropyl-3-dimethylamino-1-phenyl-1-propanol and 20 g. (0.14 mole) of potassium carbonate in 25 ml. of chloroform was treated at 0° C. with 3 g. (0.032 mole) of freshly distilled propionyl chloride in 25 ml. of chloroform over a ten-minute period. The mixture was allowed to warm to room temperature and stirring was continued for 24 hours. The reaction mixture was treated with 50 ml. of water and stirring was continued another 30 minutes. The chloroform layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to an oil. An ether solution of the oil was treated with ethereal hydrogen chloride. The salt was recrystallized from isopropanol-isopropyl ether mixture (yield was 4.2 g. (50%); m.p. 162°-164° C.). The analytical sample melted at 166°-168° C.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].CCN(CC)CC.S([N:25]=[N+:26]=[N-])(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[N+:25](=[C:1]1[C:2](=[O:3])[CH2:4][O:5][C:6]1=[O:7])=[N-:26]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: O=C1COC(=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [N-]=[N+]=C1C(=O)COC1=O
Reaction time: 2 h

Procedure:
To tetronic acid (5.00 g, 49.9 mmol) in CH2Cl2 (250 mL) at 0° C. were added Et3N (8.3 mL, 59.6 mmol) and tosyl azide (7.37 g, 37.4 mmol). After a period of 2 h at r.t., the reaction mixture was partitioned between NH4OAc (25%) and CH2Cl2. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting mixture was purified by flash chromatography (20% to 35% EtOAc in Hexane) to provide 1.4 of the title compound as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[C:9]2=[C:10]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[Br:20][C:21]1[CH:29]=[C:28]([Cl:30])[C:24]([C:25](Cl)=[O:26])=[C:23]([Cl:31])[CH:22]=1.CO>ClCCl>[Br:20][C:21]1[CH:22]=[C:23]([Cl:31])[C:24]([C:25]([C:7]2[C:8]3[C:9](=[C:10]([NH:14][C:15]([CH:17]4[CH2:18][CH2:19]4)=[O:16])[N:11]=[CH:12][CH:13]=3)[NH:5][CH:6]=2)=[O:26])=[C:28]([Cl:30])[CH:29]=1
Reactant: O=C(Nc1nccc2cc[nH]c12)C1CC1
Reactant: O=C(Cl)c1c(Cl)cc(Br)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: O=C(c1c(Cl)cc(Br)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
Aluminium chloride (4.3 g, 32.2 mmol) was added to a solution of N-(1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (0.65 g, 3.2 mmol) in dichloromethane (100 mL) under Argon atmosphere. The mixture was stirred at room temperature under inert atmosphere for about 1 hour, followed by drop wise addition of 4-bromo-2,6-dichlorobenzoyl chloride (4.6 g, 15.9 mmol) in dichloromethane (20 mL). After complete addition the reaction mixture was stirred at room temperature for about 16 hours. Methanol (100 mL) was poured in the reaction mixture and stirred well. Solvent was evaporated under vacuum, water (250 mL) was added and extracted with ethyl acetate (3×200 mL). The organic layer was washed with aqueous sodium bicarbonate (10%) solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel (100-200 mesh) column chromatography using 2% methanol in dichloromethane as an eluant to afford N-[3-(4-bromo-2,6-dichlorobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]cyclopropanecarboxamide (0.8 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]3[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][CH3:19])[C:13](=[O:20])[C:9]3=[C:10]([O:11][CH3:12])[C:6]=2[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[N:3]=1.CO[C:33](OC)([N:35]([CH3:37])[CH3:36])[CH3:34]>CN(C=O)C>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[CH2:22][N:4]1[C:5](=[O:21])[C:6]2[C:10]([O:11][CH3:12])=[C:9]3[C:13](=[O:20])[N:14]([CH2:18][CH3:19])[CH2:15][C@H:16]([CH3:17])[N:8]3[C:7]=2[C:2]([N:1]=[C:33]([N:35]([CH3:37])[CH3:36])[CH3:34])=[N:3]1
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N)c32)C1=O
Reactant: COC(C)(OC)N(C)C
Solvent: CN(C)C=O
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)nc(N=C(C)N(C)C)c32)C1=O

Procedure:
A solution of (6S)-4-amino-2-(3-chloro-4-fluorobenzyl)-10-methoxy-8-ethyl-6-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.20 g, 0.46 mmol; Example 120, step 3) and N,N-dimethylacetamide dimethyl acetal (0.37 mL, 2.51 mmol) in anhydrous DMF (50 mL) was stirred in an oil bath at 40° C. overnight. The reaction mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0-5% methanol in chloroform gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].II.[O:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[OH:8][CH:9]([CH2:2][CH2:3][CH2:4][CH3:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCCCBr
Reactant: CCOC(=O)C(CCCCCCCCCCCC=O)C(=O)OCC
Agent: II
Solvent: C1CCOC1
Product: CCCCC(O)CCCCCCCCCCCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
1-Bromobutane (0.92 ml, 8.512 mmol) in dry THF (5 ml) was slowly added to a stirred suspension of Mg metal (0.25 g, 10.059 mmol) and a catalytic amount of Iodine in dry THF (10 ml) at reflux temperature, and the reaction mixture stirred for 30 min after the completion of the addition. The prepared Grignard reagent was cooled to room temperature, then added dropwise over 15 min to a stirred solution of diethyl 2-(12-oxododecyl)malonate (2.65 g, 7.738 mmol) in THF (30 ml) at −10 to −15° C. and stirred at this temperature for 30 min. The reaction mixture was slowly warmed to room temperature and stirring continued for another one hour. The reaction was quenched with saturated ammonium chloride solution (10 ml), diluted with water (20 ml), extracted with diethyl ether (3×50 ml), dried on anhydrous MgSO4 and concentrated. The crude product was purified by silica gel column (4-6% EtOAc in hexane) and provided diethyl 2-(12-hydroxyhexadecyl)malonate (1.94 g, 62.5%) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].C[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:26](OC(O)C)C>N1C=CC=CC=1>[CH3:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: CCOC(C)O
Reactant: CNc1ccccc1
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccccc3C)c2cc1OC

Procedure:
A mixture of 0.86 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.86 g of N-methylaniline, 0.32 ml of pyridine, and 12 ml of ethoxyethanol was stirred, under nitrogen, at reflux temperature for 24 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexanes to give 0.54 g of 4-[(methylphenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile as a solid, mp 137-141° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:4]=[C:5]([CH2:12][C:13]([OH:15])=O)[N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]=3[CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][N:29]([C:13](=[O:15])[CH2:12][C:5]4[N:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]5=[C:3]([C:2]([F:1])([F:17])[F:16])[N:4]=4)[C:28]=3[CH:27]=[N:26]2)=[CH:23][CH:24]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1nc(C(F)(F)F)c2ccccn12
Product: O=C(Cc1nc(C(F)(F)F)c2ccccn12)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 72 %

Procedure:
The title compound was prepared from 2-(1-(trifluoromethyl)imidazo[1,5-a]pyridin-3-yl)acetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method A. The reaction slurry was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to provide 32 mg (72%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.36 (d, J=6.6 Hz, 1H), 8.35 (s, 0.9H), 8.06 (s, 0.1H), 7.63 (d, J=9.0 Hz, 1H), 7.50 (m, 0.3H), 7.42 (m, 1.7H), 7.12-7.22 (m, 2H), 7.01 (m, 1H), 6.79 (t, J=6.6 Hz, 1H), 4.51 (s, 0.2H), 4.38 (s, 1.8H), 4.08 (m, 1.7H), 3.90 (m, 0.3H), 2.86 (t, J=6.6 Hz, 0.3H), 2.80 (t, J=6.6 Hz, 1.7H), 2.02 (m, 2H); MS: (ES) m/z calculated for C22H18F4N5O [M+H]+ 444.1, found 444.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([NH:20][CH2:19][C:17]2[O:18][C:14]([CH3:13])=[CH:15][CH:16]=2)=[N:7]3)=[CH:24][CH:23]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1ccc(CN)o1
Reactant: Oc1cccc2nc(Cl)ccc12
Product: Cc1ccc(CNc2ccc3c(OCc4ccc(F)cc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=363.3 (M+H+), was prepared in accordance with the general method of example 63 from 5-hydroxy-2-chloroquinoline (CAS 124467-35-2), 5-methyl-2-furanmethanamine and 4-fluoro-benzyl bromide.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[N+:23]([C:22]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]2[O:10][C:9]([CH:15]([Cl:20])[C:16]([F:19])([F:17])[F:18])([C:11]([F:12])([F:13])[F:14])[O:8][C:7]=2[CH:21]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
352 g of 5-nitro-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole of Example 16a were introduced and treated with a mixture of 250 ml of 100% strength by weight nitric acid and 350 ml of concentrated sulphuric acid. The mixture was stirred for 2 hours at 60° C. After cooling, the mixture was poured into ice-water and extracted using methylene chloride. The methylene chloride phase was washed with sodium hydrogencarbonate solution and dried and then evaporated on a rotary evaporator. The yield was 392 g (91% of theory), and the melting point was 125° C. The NMR spectra showed the following characteristic absorptions: 19F-NMR: -68.5 and -81.0 ppm. 1H-NMR: 4.86 ppm.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][N:13]([CH:15]([N:19](C)C)[N:16](C)C)C.C(=O)(O)O.NC(N)=N>C1(C)C=CC=CC=1>[N:16]1[C:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:12]=[N:13][C:15]=1[NH2:19]
Reactant: O=C1CCCc2ncccc21
Reactant: CN(C)C(N(C)C)N(C)C
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: Cc1ccccc1
Product: Nc1ncc2c(n1)-c1cccnc1CC2
Yield: 11.2 %

Procedure:
To a refluxing solution, under nitrogen, of 45.0 g (0.306 mol) of 7,8-dihydro-5(6H)-quinolinone, (Example 1), in 750 ml of toluene is added dropwise a solution of 49.8 g (0.343 mol) of tris(dimethylamino)-methane in 250 ml of toluene. The solution is refluxed for 2 hours, cooled and concentrated. The residue is dissolved in 1 l of methanol and treated with 66.2 g (0.367 mol) of guanidine carbonate. The reaction mixture is refluxed, under nitrogen, for 2 hours. The mixture is concentrated to a green solid, the solid is washed with 500 ml of water, filtered and vacuum dried to give 69.1 g of crude product. Recrystallization from acetonitrile affords 6.8 g (77%) of the title compound as a light brown solid; mp 220°-226° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([O:8][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.7 %

Procedure:
Resorcinol monoacetate (6.10 g, 40 mmol) in DMF (10 mL) was added dropwise to a mixture of NaH (95%, 0.92 g, 40 mmol) in DMF (50 mL). The reaction mixture was stirred at room temperature for 10 min. Benzyl bromide (6.85 g, 40 mmol) in DMF (10 mL) was added dropwise and stirring was continued at room temperature for 2 h. The reaction was quenched carefully with water (100 mL) and then extracted with ethyl acetate (3×100 mL). The organic phase was washed with brine (2×50 mL), dried over Na2 SO4, and concentrated in vacuo. The residue was then purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a white solid (5.30 g, 55%). 1H-NMR (300 MHz, CDCl3) δ 2.28 (s, 3H), 5.03 (s, 2H), 6.72 (m, 2H), 6.85 (dd, 1H), 7.27 (t, 1H), 7.41 (m, 5H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.F[C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([CH3:26])=[N:20]2.CS(C)=O>O>[CH3:26][C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][C:23]([F:25])=[CH:24][C:15]=2[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:20]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc2c(F)cc(F)cc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c(N3CCNCC3)cc(F)cc2n1
Temperature: 120 °C
Yield: 20.7 %

Procedure:
A stirred mixture of piperazine (20 g), potassium carbonate (32 g), 5,7-difluoro-2-methylquinoline hydrochloride (WO2002034754, 20 g) and dimethylsulfoxide (390 mL) was heated to 120° C. for 15 hours. The mixture was cooled to room temperature, diluted with water (600 mL) and extracted with 6×500 mL portions of a mixture of DCM-ether (15:85). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried (sodium sulfate) and the solvent was partially evaporated under vacuum. The precipitate formed during the evaporation was filtered-off, washed with ether (50 mL) and dried under vacuum to give the title compound (4.7 g, 21%).
Reaction SMILES: [CH2:1]([C:13]1[NH:17][N:16]=[N:15][N:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1NN=NN=1)CCCCCCCCC.[CH2:33]([O:35][C:36](=[O:42])[CH:37](Br)[CH:38]([CH3:40])[CH3:39])[CH3:34].BrC1C=CC=CC=1CC(OCC)=O>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([CH:37]([CH:38]([CH3:40])[CH3:39])[C:36]([O:35][CH2:33][CH3:34])=[O:42])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1nnn[nH]1
Reactant: CCOC(=O)C(Br)C(C)C
Agent: CCCCCCCCCCc1nnn[nH]1
Agent: CCOC(=O)Cc1ccccc1Br
Product: CCCCCCCCCCCCc1nnn(C(C(=O)OCC)C(C)C)n1

Procedure:
When in the general procedure of Example 71 an appropriate amount of 5-dodecyl-1H-tetrazole was substituted for 5-decyl-1H-tetrazole and an appropriate amount of ethyl-2-bromo-3-methylbutyrate was substituted for ethyl 2-bromophenylacetate, the title compound was obtained. 1H NMR (CDCl3): δ5.26-5.23 (d, 1H); 4.29-4.19 (q, 2H); 2.94-2.77 (m, 3H); 1.82-1.70 (m, 2H); 1.31-1.20 (m, 21H); 1.08-1.05 (d, 3H); 0.97-0.95 (d, 3H) and 0.90-0.85 (t, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16].[OH-].[Na+]>C1C=CC=CC=1.O>[C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)(=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)Cc1ccc(NC(=O)C(C)C)cc1
Reaction time: 3 h
Yield: 88.4 %

Procedure:
10 g of ethyl 4-aminophenylacetate was dissolved in 100 ml of benzene and to this was added 25 ml of water. To the solution were added dropwise a solution of 6 g of isobutyryl chloride in 20 ml of benzene and a solution of 2.4 g of 93% NaOH in 25 ml of water simultaneously under stirring over 15 minutes. After completion of the dropwise addition, the reaction mixture was stirred for 3 hours and allowed to stand at room temperature overnight. After separating the benzene layer, washing it with 1N-HCl solution and further washing with a saturated solution of sodium chloride, the benzene layer was dried over anhydrous sodium sulfate. After separating sodium sulfate by filteration, the solvent was distilled off under reduced pressure and the residue was dissolved in 30 ml of benzene and crystallized from 90 ml of n-hexane. The formed crystals were separated by filteration and were dried at a temperature below 60° C. under reduced pressure to give 12.3 g of ethyl 4-(isobutyrylamino)phenylacetate (Yield: 88.3%). M.P. 92.5°-93.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[C:5]([N+:17]([O-:19])=[O:18])[CH:4]=2
Reactant: O=[N+]([O-])O
Reactant: Nc1c2c(nc3ccccc13)CCCC2=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1c2c(nc3ccc([N+](=O)[O-])cc13)CCCC2=O
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To 100ml of cold H2SO4 was added 5.00 g of 9-amino-3,4-di-hydroacridin-1(2H)-one. The mechanically stirred solution was cooled to 20° C. and 2.1ml (1 eq) of concentrated HNO3 (70 wt % solution) was added dropwise. Stirring was continued for 15 minutes after the addition, whereupon the reaction was complete. The reaction mixture was poured into excess crushed ice and made basic with a slight excess of 50% NaOH solution. More ice was added during the neutralization to keep the solution cool. The resulting precipitate was filtered and chromatographed over silica gel (EtOAc). The fractions containing the product were evaporated to a solid which was triturated with pentane to yield 4.77 g (79%) of a solid after drying, melting point 254° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][N:6]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[CH:10][CH:9]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:42][N:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH:48]=O>CO>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][N:6]([CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH3:32])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH2:16][C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)[CH2:48][C:44]2[N:43]([CH3:42])[CH:47]=[CH:46][N:45]=2)=[CH:12][CH:13]=1
Reactant: CCCN(CCC)CCCCN(CCC(=O)OC)Cc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(CCC(=O)OC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.5 %

Procedure:
The compound (48.2 mg) obtained in Example 34-2 was dissolved in anhydrous methanol (1.0 ml) and added with sodium cyanoborohydride (9.90 mg), acetic acid (100 μl), and 1-methyl-2-imidazole carboxaldehyde (12.8 mg) and the whole was stirred at room temperature for 3 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution, and the whole was stirred for a while. The solution was subjected to extraction with chloroform, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (56.1 mg) of the subject compound as a white solid.