Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CS(C)=O.C(OCC)(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCCCCCBr
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCCCOc1ccc(N2CCN(C(C)=O)CC2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a suspension of 1-acetyl-4-(4-hydroxyphenyl) piperazine (20 g) and potassium bicarbonate (12.55 g) in dimethylsulfoxide (200 ml) was added 1-bromohexane (19.12 ml) and stirred for 24 hours at 80° C. The reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over is magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-acetyl-4-(4-hexyloxyphenyl)piperazine (14.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I.CS[C:17]1[NH:18][CH2:19][CH2:20][N:21]=1.CO>C(OCC)C>[NH:21]1[CH2:20][CH2:19][N:18]=[C:17]1[N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1
Reactant: CSC1=NCCN1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: I
Solvent: CCOCC
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)CN(C1=NCCN1)CC2

Procedure:
A mixture of 10 g of 7-nitro-1,2,3,4-tetrahydroisoquinoline, 13.7 g of 2-methylsulphanyl-4,5-dihydro-1H-imidazole hydriodide and 100 ml of methanol is heated at reflux for 12 hours. The addition of diethyl ether causes the separation of a precipitate, which is taken up in water, neutralised using sodium hydroxide and extracted with dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:15][CH2:13][C:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:9])[F:10])=[CH:5][N:4]=1)=[O:14]
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Cl
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 16.6 g (0.074 mol) of 1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethanone in 150 ml of dry tetrahydrofuran, were added portionwise at room temperature 27.8 g (0.074 mol) of phenyltrimethylammonium tribromide. The solution was stirred for 3-hours at room temperature. The formed solid was removed by filtration and the mother liquors were concentrated under vacuum. The resulting orange oil (32.7 g) was purified by flash chromatography on silica gel (eluent: heptane/dichloromethane 3:1) to give 2-bromo-1-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethanone: 10.4 g (46%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]([CH:16]([O:18][CH3:19])[CH3:17])=[CH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:5].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.[CH3:29][C:30]1([CH3:38])[CH2:35][C:34](=[O:36])[CH2:33][C:32](=O)[CH2:31]1.N1CCCC1C(O)=O>C(O)C>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]2[C:33]3[C:34](=[O:36])[CH2:35][C:30]([CH3:38])([CH3:29])[CH2:31][C:32]=3[NH:1][C:2]([CH:16]([O:18][CH3:19])[CH3:17])=[C:3]2[C:4](=[O:5])[C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:8][CH:7]=2)=[CH:23][CH:22]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(C)C(N)=CC(=O)c1ccc(C(F)(F)F)cc1
Agent: O=C(O)C1CCCN1
Solvent: CCO
Product: COC(C)C1=C(C(=O)c2ccc(C(F)(F)F)cc2)C(c2ccc(F)cc2)C2=C(CC(C)(C)CC2=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6.4 g 3-Amino-4-methoxy-1-(4-trifluoromethyl-phenyl)-pent-2-en-1-one are dissolved in 25 ml of ethanol, 2.51 ml 4-fluorobenzaldehyde and 3.28 g 5,5-dimethyl-cyclohexane-1,3-dione and 270 mg DL-proline are successively added and the mixture is stirred for 30 minutes at room temperature. Then the mixture is heated for 24 hours to reflux at a dean-stark trap. After cooling to room temperature the solvents are evaporated in vacuo. The residue is chromatographed on silica gel.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:27]3[N:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]4=[N:30][C:26]=3[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:35])=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C=O)C>[Br:1][C:22]1[CH:21]=[C:20]2[C:25]([C:26]3[N:30]=[C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][N:28]4[C:27]=3[N:18]([C:15]3[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=3)[C:19]2=[O:35])=[CH:24][CH:23]=1
Reactant: O=c1c2ccccc2c2nc3ccccn3c2n1-c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cc(Br)ccc2c2nc3ccccn3c2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
N-Bromosuccinimide (1.2 equiv., 0.358 mmol, 0.061 g) was added to a solution of 1 (1.0 equiv., 0.295 mmol, 0.105 g) in DMF (3 ml). The reaction mixture was stirred at room temperature for 4 h. Water was added, the resulting precipitate was isolated by filtration and washed with water, isopropanol and isopropyl ether successively to give 3-bromo-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (101) (0.050 g, yield=36%, purity (LC)=93%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1C.[Br:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1.C(Cl)[Cl:29]>CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[O:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:29]
Reactant: ClCCl
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1ccc(CC#N)cc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: N#CCc1ccc(Cl)c(Oc2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a flask was charged with 3-hydroxy-4-methylphenylacetonitrile (32a; 0.92 g; 6.2 mmol), Cu(OAc)2 (1.3 g; 6.9 mmol), 3-bromobenzeneboronic acid (1.1 g; 5.5 mmol) and powdered 4 Å molecular sieves, was added CH2Cl2 (62 mL) followed by pyridine (2.5 mL; 31 mmol). The reaction was stirred at rt for 3 days. The suspension was filtered through a bed of CELITE®/silica gel and the solid washed with CH2Cl2. The combined filtrates were washed sequentially with 2N HCl (2×25 mL), NaHCO3 (25 mL), water and brine. The extracts were dried (MgSO4), filtered and evaporated. The crude product 76 was sufficiently pure to use in the next step.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:12][CH:13]1[CH2:18][NH:17][CH2:16][CH:15]([CH3:19])[NH:14]1>C(OCC)(=O)C>[CH3:12][C@H:13]1[NH:14][C@@H:15]([CH3:19])[CH2:16][N:17]([C:8]2[C:7]([F:11])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=2)[CH2:18]1
Reactant: O=Cc1cc(F)c(F)cc1F
Reactant: CC1CNCC(C)N1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2cc(F)c(C=O)cc2F)C[C@H](C)N1
Reaction time: 8 h

Procedure:
To a solution of 2,4,5-trifluorobenzaldehyde (1 eq) in ethyl acetate at room temperature was added 2,6-dimehtylpiperazine (2 eq). After being stirred overnight, the solution was washed with water, aqueous sodium bicarbonate, brine and dried, and purified on silica gel to give 4-(cis-3,5-dimethylpiperazinyl)-2,5-difluorobenzaldehyde.
Reaction SMILES: C[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH3:11].[CH3:12]CO>>[CH2:8]([O:7][C:5](=[O:6])/[C:4](/[CH3:12])=[C:3](\[NH2:11])/[CH3:2])[CH3:9]
Reactant: CCO
Reactant: CCOC(=O)CC(=O)CC
Reactant: N
Product: CCOC(=O)/C(C)=C(/C)N
Temperature: 80 °C

Procedure:
10 kg ethyl methylacetoacetate and 4 l abs. etanol was mixed in an autoclave and 3.4 kg of liquid ammonia was added. The mixture is stirred and the temperature gradually increased to 80° C. during 4 hrs. This temperature is maintained over night. The temperature is decreased to 40° C. and the excess ammonia is evaporated. Toluene (10 l) is added and the water is separated. The organic layer is dried by evaporation of toluene and alcohol. The yield is quantitative. The product is low melting solid.
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-:3])=[O:2].C(N)CCC.[Br:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>C(O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH3:5])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CC[N+](=O)[O-]
Solvent: CCCCN
Solvent: CCO
Product: COc1ccc(C=C(C)[N+](=O)[O-])cc1Br
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Nitroethane (0.800 mL, 836 mg, 11.1 mmol) and n-butylamine (0.050 mL, 37 mg, 0.51 mmol) were added to a solution of 3-bromo-4-methoxybenzaldehyde (2.00 g, 9.30 mmol) in 2.0 mL of absolute ethanol. The solution was heated in a 95° C. oil bath for 8 h and then stirred overnight at room temperature. The ethanol was evaporated, the residue was stirred with 12 mL of 8% ether in hexane, and the supernatant was decanted. The undissolved material was stirred with 12 mL of 8% ether in hexane, and sufficient toluene was added to bring it into solution at 60° C. The crystals which separated at room temperature were recrystallized again from a solution of hexane (7 mL) and toluene (1.8 mL) at 55° C. cooled to room temperature to give 1-(3-bromo-4-methoxyphenyl)-2-nitropropene as 598 mg of yellow needles. All of the mother liquors were combined and evaporated, and the residue was purified by flash column chromatography on 85 g of silica gel eluting with 25% dichloromethane in hexane to give an additional 791 mg of 1-(3-bromo-4-methoxyphenyl)-2-nitropropene (total isolated yield of 55%). 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.68 (d, 1H, J=2 Hz),7.40 (dd, 1H, J=9, 2 Hz),6.97(d, 1H, J=9Hz), 3.96 (s, 3H), 2.47 (s, 3H). Mass spectrum (NH3CI): m/e=272 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:6]=[C:5]([C:16](OCC)=[O:17])[CH:4]=1.[NH3:22]>CO>[CH3:1][N:2]([CH3:21])[C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[N:6]=[C:5]([C:16]([NH2:22])=[O:17])[CH:4]=1
Reactant: CCOC(=O)c1cc(N(C)C)n(Cc2ccccc2F)n1
Reactant: N
Solvent: CO
Product: CN(C)c1cc(C(N)=O)nn1Cc1ccccc1F
Temperature: 50 °C
Reaction time: 72 h

Procedure:
1.34 g of ethyl 5-(dimethylamino)-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate 1-9-1 (4.60 mmol, 1.0 eq.) were dissolved in 120 mL of methanol. 60 mL of a 7 N solution of ammonia in methanol were added and the solution was stirred for three day at 50° C. bath temperature. 60 mL of a 7 N solution of ammonia in methanol were added again and stirred for further 24 hours at 50° C. bath temperature. 60 mL of a 7 N solution of ammonia in methanol were added again stirred for 24 hour at 65° C. bath temperature. The solution was concentrated in vacuo to provide 1.33 g (5.07 mmol, quantitative) of analytically pure target compound.
Reaction SMILES: [C:1]([N:4]([CH3:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:1]([N:4]([CH3:20])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:30]3[S:29][N:28]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:31]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CC(=O)N(C)c1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N(C)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1

Procedure:
A solution of 2,2,2-trichloroethyl {4-[acetyl(methyl)amino]phenyl}carbamate (200 mg, 0.589 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (145 mg, 0.589 mmol), diisopropylethylamine (0.103 ml, 0.589 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (47.3 mg, 18.3%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.C([Li])CCC.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14].O>C1COCC1.[Cl-].[Na+].O.CCOC(C)=O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[Si:13]([CH3:15])([CH3:14])[CH3:12]
Reactant: Clc1ccsc1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)c1sccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-chlorothiophene (7.00 g, 59.0 mmol) in 60 mL anhydrous THF under nitrogen was added n-butyllithium, 2.5 M in hexanes (23.6 ml, 59.0 mmol) dropwise from a plastic syringe over 15 min. The reaction became cloudy with a white ppt. The reaction was allowed to stir for 40 min, at which point trimethylsilyl chloride (8.24 ml, 64.9 mmol) was added dropwise via syringe over 5 min. The mixture was allowed to stir for 10 min, and was then warmed to 0° C. for 10 min, and 7 mL water and 35 mL brine were added. The mixture was diluted with EtOAc, and the layers separated. The aqueous layer was extracted once with EtOAc. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give (3-chlorothiophen-2-yl)trimethylsilane as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH2:9])[N:6]([CH3:8])[N:7]=1)[CH3:2].[C:10](=O)([O-])[O-].[K+].[K+].C1COCC1.[C:21]1([O:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([O:27][C:28](=[O:29])[NH:9][C:5]2[N:6]([CH3:8])[N:7]=[C:3]([CH:1]3[CH2:10][CH2:2]3)[CH:4]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1cc(N)n(C)n1
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nc(C2CC2)cc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 5-Ethyl-2-methyl-2H-pyrazol-3-ylamine (10 g, 79.8 mmol) (500 ml) and potassium carbonate in THF (12.14 g, 87.8 mmol) is cooled to 0° C. Phenylchloroformate (10.15 ml, 80.6 mmol) is added dropwise over 20 minutes. The reaction mixture is stirred for 40 minutes at 0° C. then allowed to warm to ambient temperature and stirred for a further 2.5 hours. The reaction mixture is partitioned between ethylacetate and water. The organic phase is washed with 5% aqueous citric acid solution and brine. The organic phase is treated with MgSO4 and charcoal then filtered and evaporated to afford (5-Cyclopropyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester. [M+H] 246.21
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])[C:5](O)=[O:6].Cl.[CH3:30][NH:31][CH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[N:31]([CH3:32])[CH3:30])[CH:8]=[CH:9][C:10]=1[N:11]([CH3:28])[C:12]([C:14]1[S:27][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(C(=O)O)cc1Cl
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)benzoic acid and dimethylamine hydrochloride were reacted by a procedure similar to Example 47 to give 249. MS: (ESI+) 441.0
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.C[I:30].[CH3:31]N(C)C=O>CC(C)=O>[I-:30].[C:23]1([CH:20]2[CH2:19][CH2:18][N+:17]([CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:6]=3[CH2:7][CH2:8][C:9](=[O:15])[NH:10]4)([CH3:31])[CH2:22][CH2:21]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1CCc2c(cccc2OCC(O)CN2CCC(c3ccccc3)CC2)N1
Reactant: CI
Reactant: CN(C)C=O
Solvent: CC(C)=O
Product: C[N+]1(CC(O)COc2cccc3c2CCC(=O)N3)CCC(c2ccccc2)CC1
Product: [I-]
Reaction time: 5 h

Procedure:
2.0 Grams of 5-[2-hydroxy-3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril and 3 g of methyl iodide were mixed with 30 ml of dimethylformamide and the mixture was stirred at 50°-60° C. for 5 hours. The reaction mixture was concentrated under a reduced pressure and to the residue thus obtained was added 50 ml of acetone and stirred. The precipitates thus formed were collected by filtration and washed with acetone, then recrystallized from methanol-ethanol to obtain 1.7 g of 4-phenyl-1-[2-hydroxy-3-(2-oxo-1,2,3,4-tetrahydroquinolin-5-yloxy)propyl]-1-methylpiperidiniumiodide as in the form of colorless powdery substance. Melting point: 242°-243° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][CH3:22])[C:9]1[C:14]2[N:15]([CH3:19])[C:16](Cl)=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([CH3:32])[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[C:24]=1[NH2:31]>C(OCC)(=O)C>[CH2:1]([N:8]([CH2:20][CH2:21][CH3:22])[C:9]1[C:14]2[N:15]([CH3:19])[C:16]([NH:31][C:24]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[CH3:32])=[N:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCCN(Cc1ccccc1)c1cccc2nc(Cl)n(C)c12
Solvent: CCOC(C)=O
Product: CCCN(Cc1ccccc1)c1cccc2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Reaction time: 24 h
Yield: 79.4 %

Procedure:
A solution of 0.56 g (1.8 mmol) of N7-benzyl-2-chloro-1-methyl-N7-propyl-1H-benzimidazol-7-amine in 0.75 mL (5.4 mmol) of mesityl amine was heated to 130° C. After stirring for 24 h, the mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated to give a tan solid. The solid thus obtained was purified by flash chromatography eluting with a 1.3% methanol/dichloromethane mixture to give 0.59 g (80%) of the title compound as a cream colored solid.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:23]4[CH:28]=[C:27]([NH2:29])[C:26]([F:30])=[CH:25][C:24]=4[CH3:31])[C:15](=[O:22])[N:16]3[CH:19]([CH3:21])[CH3:20])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C:27]1[C:26]([F:30])=[CH:25][C:24]([CH3:31])=[C:23]([C:14]2[C:15](=[O:22])[N:16]([CH:19]([CH3:20])[CH3:21])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:28]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2C)c(=O)n3C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1C)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.8 %

Procedure:
To a solution of 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one (1.0 g, 2.2 mmol) in DCM (10 mL) was added TFA (3 mL) at RT. The resulting mixture was stirred at RT for 6 h, then washed with H2O (6×). The combined aqueous layers were neutralized with NH3.H2O, extracted with DCM (3×) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give 3-(5-amino-4-fluoro-2-methylphenyl)-1-isopropyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.5 g, 66.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.60 (s, 1H), 6.95 (m, 1H), 6.90 (d, J=12.4 Hz, 1H), 6.65 (d, J=9.2 Hz, 1H), 6.50 (s, 1H), 5.21 (br s, 1H), 4.95 (s, 2H), 2.92 (d, J=4.8 Hz, 3H), 2.02 (s, 3H), 1.58 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 341.2[M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[CH:19]=[CH:18][C:11]3[N:12]=[C:13](S(C)=O)[S:14][C:10]=3[CH:9]=2)[CH:6]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[OH:27].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[CH:19]=[CH:18][C:11]3[N:12]=[C:13]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[OH:27])[S:14][C:10]=3[CH:9]=2)[CH:6]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc(Br)c3)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc(Br)c3)cc2s1
Temperature: 110 °C
Yield: 66.4 %

Procedure:
To a suspension of 6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (130 mg, 0.37 mmol) from Step 6 of this Example and (1R,2R)-2-aminocyclohexanol (126 mg, 1 mmol) in anhydrous DMA (1.0 mL) was added DIEA (320 μL, 1.8 mmol). The mixture was heated in a sealed tube at 110° C. for 7 h. The mixture was cooled to rt and water was slowly added while stirring to give a precipitate. The mixture stirred for 10 min and the solid was collected by filtration to afford (1R,2R)-2-((6-((4-bromo-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 68%) as a tan solid. The material was used in the next step without further purification. LCMS (ESI) m/z 407 and 409 (M+H)+.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].[CH:5](=O)[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15]O>>[CH2:5]([CH:2]=[N+:3]([CH3:15])[O-:4])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNO
Reactant: O=CC=Cc1ccccc1
Reactant: CO
Agent: Cl
Product: C[N+]([O-])=CCC=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A mixture of 5 g (60 mmole) of methylhydroxylamine hydrochloride and 8 g (61 mmole) of cinnamaldehyde were combined in 25 mL of anhydrous methanol and stirred for 15 minutes at room temperature. The solvent was then removed at reduced pressure and replaced with 50 mL of methylene chloride. The solution was washed with 75 mL of saturated aqueous sodium bicarbonate followed by washing with a brine solution. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The solid residue was titurated with ether, filtered and dried. There was obtained 7.2 g (45 mmole or 74% yield) of α-cinnamyl-N-methylnitrone having a melting point of 85-6° C.
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]([CH3:15])=[O:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[H][H].[CH2:20](Br)/[CH:21]=[C:22](\[CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])/[CH3:23]>C1COCC1>[C:1]([O:4][C:5]([C:13](=[O:14])[CH3:15])([CH2:20]/[CH:21]=[C:22](/[CH3:23])\[CH2:24][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28])[C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Reactant: CC(C)=CCC/C(C)=C\CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC(C/C=C(/C)CCC=C(C)C)(C(C)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-butyl 2-acetoxyacetoacetate (B1) (19.5 g, 90 mmol) was added dropwise to a stirred suspension of NaH (2.59 g, 108 mmol) in THF (180 mL) at 0° C. After the liberation of hydrogen gas stopped, nerylbromide (19.6 g, 90 mmol) was added dropwise at 0° C. Afterwards the ice bath was removed and the mixture stirred at room temperature for 16 hours. The resulting mixture was diluted with ether (750 mL), washed with water (3 200 mL) and brine (1 200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was used without further purification.