Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15]([N:23]=[C:24]=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.[H-].[Na+].Cl>CN(C)C=O.O>[F:11][C:12]([F:26])([F:27])[C:13]1[CH:14]=[C:15]([NH:23][C:24]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CC(=O)C2CCC1C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O

Procedure:
A solution of bicyclo[3,2,1]octane-2,4-dione (0.34 g, 2.5 mmole), 3,5-bis(trifluoromethyl)phenyl isocyanate (0.86 ml, 5.0 mmole), and 60% sodium hydride in mineral oil (0.11 g, 2.75 mmole) in dimethylformamide (100 mL) was stirred at 0° C. for 1 hour and heated at 45–50° C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N aqueous HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (30% dichloromethane/hexane) to give a clear oil as the expected product. The oily product was crystallized by triturated with hexane in a dry ice bath and collected at room temperature to give the title compound as a white solid, mp=88–90° C.; (−) ESI m/z=392 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O.C1COCC1.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>O>[CH2:23]([N:25]([CH2:26][CH3:27])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:24]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCNCC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-methyl-3-nitrobenzoic acid (1.97 g) and thionyl chloride (6 mL) was heated under reflux for 18 hours. The reaction liquid was concentrated under reduced pressure, followed by an azeotropic process with toluene to give a red-brown oil. To a mixture of the red-brown oil and THF (25 mL), diethylamine (2.6 mL) was added under ice cooling and stirred at room temperature for 5 hours. The reaction liquid was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give N,N-diethyl-4-methyl-3-nitrobenzamide (2.61 g) as a brown oil.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][N:8]([CH3:14])[C:9](=O)[N:10]([CH3:12])[CH3:11].C(=O)=O.[C]=O>C(Cl)(Cl)(Cl)Cl>[Cl-:4].[CH3:7][N:8]([CH3:14])[C:9]([Cl:4])=[N+:10]([CH3:12])[CH3:11]
Reactant: CN(C)C(=O)N(C)C
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C=O
Agent: [C]=O
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)C(Cl)=[N+](C)C
Product: [Cl-]

Procedure:
A solution of 2.5 ml (0.027 mol) of oxalyl chloride in 15 ml of anhydrous carbon tetrachloride is poured dropwise into a solution of 3.4 ml (0.027 mol) of tetramethylurea in 10 ml of anhydrous carbon tetrachloride kept stirring under a nitrogen atmosphere. While the stirring is continued, the reaction medium is maintained at reflux until the evolution of carbon dioxide and carbon monoxide gases has ceased. The formamidinium chloride obtained in the form of a white solid is dissolved at 0° C. in 30 ml of anhydrous acetonitrile.
Reaction SMILES: [NH:1]=[C:2]([C:7]#[N:8])[C:3](=[NH:6])[C:4]#[N:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](N)=[C:12](N)[CH:11]=1.FC(F)(F)C(O)=O>O>[Cl:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[N:6]=[C:3]([C:4]#[N:5])[C:2]([C:7]#[N:8])=[N:1]2
Reactant: Nc1ccc(Cl)cc1N
Reactant: N#CC(=N)C(=N)C#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc2ccc(Cl)cc2nc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
A mixture of 0.5 g (4.7 mmols) of the diiminosuccinonitrile and 0.67 g (4.7 mmols) of 4-chloro-1,2-phenylenediamine was slowly added to 10 ml of trifluoroacetic acid at about 20° C. over a period of 30 minutes, and the resulting mixture was stirred at room temperature for 8 hours and then allowed to stand overnight. To the reaction mixture was added 50 ml water, and the solid precipitated was filtered and sufficiently washed with water. The solid thus obtained was dried under reduced pressure, followed by a silica gel column chromatography (eluent: hexane/ethyl acetate=75/25) and then recrystallization from chloroform/ethanol, whereby 0.6 g (59%) of 6-chloro-2,3-dicyanoquinoxaline was obtained as colorless crystals.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]([F:19])([F:18])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:21]1[NH:25][C:24]2[CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:23]=2[N:22]=1.C(N(CC)C(C)C)(C)C>>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:23]2[N:22]=[C:21]([N:15]3[CH2:16][CH2:17][N:12]([C:11]4[CH:10]=[CH:9][N:8]=[CH:7][C:6]=4[C:5]([F:4])([F:18])[F:19])[CH2:13][CH2:14]3)[NH:25][C:24]=2[CH:26]=1
Reactant: FC(F)(F)c1cnccc1N1CCNCC1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(N3CCN(c4ccncc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The piperazine from step (b) above (0.55 g, 1.81 mmol), 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.4 g, 1.81 mmol, Example 1c) and N,N-diisopropylethylamine (0.63 mL, 3.62 mmol, Aldrich) reacted under the conditions of Example 3c to give the title compound as a light-yellow solid. M.p. 220-224° C. MS (ESI, pos. ion) m/z: 416 (M+1).
Reaction SMILES: [Br:1][C:2]([CH3:10])([CH3:9])[C:3]([O:5][CH2:6][CH:7]=[CH2:8])=[O:4].[Cl:11][SiH:12]([CH3:14])[CH3:13]>C([Si](C)(C)O[Si](C=C)(C)C)=C.[Pt].C1(C)C=CC=CC=1>[Br:1][C:2]([CH3:10])([CH3:9])[C:3]([O:5][CH:6]([Si:12]([Cl:11])([CH3:14])[CH3:13])[CH2:7][CH3:8])=[O:4]
Reactant: C[SiH](C)Cl
Reactant: C=CCOC(=O)C(C)(C)Br
Agent: [Pt]
Agent: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: Cc1ccccc1
Product: CCC(OC(=O)C(C)(C)Br)[Si](C)(C)Cl
Reaction time: 72 h

Procedure:
To a round-bottomed flask, allyl 2-bromo-2-methylpropionate (2.5 mL) was mixed with dry toluene (30 mL) under nitrogen flow. Chlorodimethylsilane (12.2 mL) was added dropwise to the flask and subsequently Platinum(0)-1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (solution in xylene, Pt˜2%, 0.3 mL). The mixture was stirred under nitrogen for 3 days, after which the mixture was stripped under vacuum to remove toluene and unreacted chlorodimethylsilane. The product, 1-(chlorodimethylsilyl)propyl 2-bromoisobutyrate, was obtained as a yellow oil. 1.6 mL of this oil was then added via syringe to a silica/MEK (Methyl Ethyl Ketone) suspension (Nissan, 30 wt % suspended in MEK, particle size of SiO2˜15-20 nm, 13 g) in a round-bottomed flask under nitrogen flow. The mixture was stirred for 24 hours at 50° C., after which the mixture was cooled down and hexamethyldisilazane (1.5 mL) was added. The mixture was stirred at room temperature for 3 hours and heated to 40° C. for overnight, after which the mixture was cooled down. The precipitate was removed by centrifugation (5000 rpm for 0.5 hours), and the supernatant was added dropwise into hexane to precipitate colloids. The particles were washed with hexanes for several times and dried under vacuum. Solution NMR of the silica-bound initiator (Br-silica) showed no peaks for 1-(chlorodimethylsilyl)propyl 2-bromoisobutyrate or allyl 2-bromo-2-methylpropionate indicating that all free initiator was gone.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]1>>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C(O)C1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncccn2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2ncccn2)=NC1c1ccc(Cl)cc1Cl
Yield: 56.5 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-1,4-dihydro-[2,2′-bipyrimidine]-5-carboxylate (0.72 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-2-carboxylic acid hydrochloride (0.26 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.45 g, 56%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2](=[N:29][N+:30]([O-:32])=[O:31])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1)=[O:17])[NH:8]C(OC(C)(C)C)=O.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[OH-].[Na+]>>[NH2:1][C:2](=[N:29][N+:30]([O-:32])=[O:31])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:16]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH:25]=1)=[O:17])[NH2:8].[F:33][C:34]([F:39])([F:38])[C:35]([O-:37])=[O:36]
Reactant: CCOc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)OC(C)(C)C)cc1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc(CNC(=O)[C@H](N)CCCNC(N)=N[N+](=O)[O-])cc1
Product: O=C([O-])C(F)(F)F
Yield: 70 %

Procedure:
Prepared analogously to Example 5e) from (R)-N5 -[amino(nitroimino)methyl]-N2 -[(tert.-butyloxy)carbonyl]-N-[(4-ethoxyphenyl)methyl]-ornithinamide by the action of trifluoroacetic acid in a yield of 70% of theory. The base liberated from the salt by treatment with 1N sodium hydroxide solution melted at 182°-184° C. (ethyl acetate).
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1C(=O)C2=CC=CC=C2C1=O)[CH2:3][P:4]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=[O:8])[O:5][CH2:6][CH3:7].O.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C>[NH2:17][CH2:16][CH:2]([OH:1])[CH2:3][P:4]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=[O:8])[O:5][CH2:6][CH3:7]
Reactant: CCOC(OCC)P(=O)(CC(O)CN1C(=O)c2ccccc2C1=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(OCC)P(=O)(CC(O)CN)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.0 g of ethyl 2-hydroxy-3-phthalimido-propyl(diethoxymethyl)phosphinate in 23 ml of isopropanol is added 4 ml of water. To this mixture is added 0.47 g of sodium borohydride and this is stirred for a period of 24 hours at room temperature. After this time 2.6 ml of glacial acetic acid are carefully added and the reaction heated to 80° for a period of 2 hours. Afterthis time, the reaction is cooled to room temperature, the solvent evaporated under reduced pressure and the residue passed down a silica column using a mixture of one part ethyl acetate to one part ethanol as eluant. Ethyl 3-amino-2-hydroxy-propyl(diethoxymethyl)phosphinate is obtained as colourless oil, 31P=+45.8 and +45.2 ppm (CDCl3).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1.COC(=O)OC>CS(C)=O>[CH3:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[C:6]([C:19]([OH:21])=[O:20])[C:7](=[O:18])[C:8]3=[CH:9][C:10]=2[F:17])[CH2:28]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC1CNCCN1
Solvent: CS(C)=O
Solvent: COC(=O)OC
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 55 °C
Yield: 70 %

Procedure:
Forty grams of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid and 28.4 g (2.1 eq) of 2-methyl piperazine were suspended in DMSO (800 mL) under nitrogen atmosphere. The mixture was heated to 55° C. during 24 hours. Thereafter, dimethylcarbonate (200 mL) was added, the reaction mixture was cooled to 5° C., and held at this temperature overnight. The mixture was then filtered under vacuum and the compound was then dried under vacuum to obtain 35.5 g after assay (70% yield) of gatifloxacin.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:12](=[O:24])(=[O:25])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[CH2:21][O:20][B:19]([OH:22])[C:18]=3[CH:23]=2)=[C:6]([CH2:8][C:9]([NH:29][CH2:26][CH2:27][CH3:28])=[O:10])[CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(CC(=O)O)c1
Reactant: CCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Cc1cc(N)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Reaction time: 16 h
Yield: 51.3 %

Procedure:
To a stirred solution of 2-(5-amino-2-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)acetic acid (360 mg, 1 mmol) and n-propylamine (0.6 mL, 6 mmol) in 10 mL of DMF was added PyBOP (780 mg, 1.5 mmol) and TEA (0.5 mL, 3.56 mmol). The reaction mixture was stirred for 16 hours. After water was added, the reaction mixture was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated. The crude residue was purified by prep HPLC (SunFire Prep C18 OBD 5 uM 30×50 mm column) to give the desired product as a white powder (207 mg, yield 51%). MS calcd for (C18H22BN3O5S): 403.1. MS found (ESI negative): (M−H)−=402.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.89 (s, 1H), 9.17 (bs, 1H), 7.99 (t, J=5.6 Hz, 1H), 7.42 (m, 2H), 7.22 (d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.46 (d, J=2 Hz, 1H)), 6.35 (d, J=8.8, 2.4 Hz, 1H), 4.87 (s, 2H), 3.78 (s, 2H), 3.05 (m, 2H), 1.43 (m, 2H), 0.85 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(O)C.C(O[C:7]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]2)=[O:8])C.CC[O-].[Na+].[OH:28][CH2:29][CH2:30][NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[OH:28][CH2:29][CH2:30][N:31]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:7]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH:17]=[CH:16]2)=[O:8]
Reactant: CCOC(=O)CCCOc1ccc2[nH]c(=O)ccc2c1
Reactant: OCCNC1CCCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1

Procedure:
Into 100 ml of ethanol were added 2.7 g of 6-(3-ethoxycarbonylpropoxy)carbostyril, 0.5 g of sodium ethylate and 5 ml of N-(2-hydroxyethyl)cyclohexylamine and reacted in an autoclave under a pressure of 110 atomospher at 140°-150° C. for 6 hours. After the reaction was completed, the reaction mixture was cooled and was concentrated under a reduced pressure. The residue thus obtained was dissolved in 200 ml of chloroform and washed with 1% K2CO3 aqueous solution, a diluted hydrochloric acid and water in this order, then dried with anhydrous sodium sulfate. Then the solvent was removed by distillation and the residue thus obtained was purified by a silica-gel column chromatography [the silica-gel used as Wako C-200, and the solvent used was a mixture of chloroform:methanol=20:1 (V/V)]. The crude crystals thus obtained was recrystallized from chloroform-petroleum ether to obtain 0.9 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyril as in the form colorless needle-like crystals. Melting point: 165°-166° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:18]([O:20]CC)=[O:19])[CH2:6][C:5]2=1.[Li+].[OH-]>C1COCC1.CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:18]([OH:20])=[O:19])[CH2:6][C:5]2=1
Reactant: CCOC(=O)C1CCc2[nH]c3c(C(N)=O)cc(Br)cc3c2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: NC(=O)c1cc(Br)cc2c3c([nH]c12)CCC(C(=O)O)C3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of ethyl 6-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylate (0.9 g, 2.464 mmol) and LiOH (0.177 g, 7.39 mmol) in THF/EtOH/H2O (3/1/1) (25 mL) was stirred at room temperature for 72 hours The reaction mixture was concentrated and the residue was dissolved in water. Aqueous 1M HCl was added to this solution until pH=5 whereupon a light yellow solid precipitated. The solid was collected by filtration, washed with water, air-dried and used as such in the next reaction. LCMS: RT=0.96 min, m/z (M+H) 337.0/339.0.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:32])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27](=[O:29])[CH3:28])[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:31])([CH3:30])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[C:27]([N:24]1[CH2:25][CH2:26][N:21]([C:17]2[CH:16]=[C:15]([CH:12]3[C:11]([CH3:31])([CH3:30])[CH2:10][C:9]4[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([Cl:32])[CH:8]=4)[NH:13]3)[CH:20]=[CH:19][CH:18]=2)[CH2:22][CH2:23]1)(=[O:29])[CH3:28]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(N3CCN(C(C)=O)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)N1CCN(c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 26 %

Procedure:
A mixture of 2-[3-(4-acetyl-piperazin-1-yl)-phenyl]-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (247 mg, 0.54 mmol), lithium hydroxide hydrate (230 mg, 5.4 mmol), water (1.0 mL) in methanol (2 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(4-acetyl-piperazin-1-yl)-phenyl]-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (62 mg, 26%) as a white solid: LC/MS m/e calcd for C24H28ClN3O3M+: 441.96, observed: 442.0.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7]
Reactant: C1CCNC1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (0.85 g, 12 mmol) and 2-nitro-7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (2.05 g, 10 mmol) were mixed in 1,2-dichloroethane (35 mL) and then treated with NaBH(OAc)3 (3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The mixture was stirred at ambient temperature under a N2 atmosphere overnight. The reaction mixture was quenched with saturated NaHCO3, and the product was extracted with EtOAc (3×30 mL). The organic layers were combined and dried over NaSO4. The solvent was evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2/DMA=1/1 (DMA=CH2Cl2/MeOH/30% NH3=80/19/1) to afford 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine, a yellow oil (2.2 g, 85%); MS (m/e): 261 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: BrCCOC1CCCCO1
Reactant: N#CCc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(CCOC1CCCCO1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A solution of 50 g of 3,4-difluorophenyl acetonitrile in 50 ml of THF is added dropwise at 20° C. to a suspension of 14.4 g of 60% sodium hydride in oil in 250 ml of THF, and the reaction mixture is left stirring for three hours at RT. It is cooled in an ice bath, a solution of 68.2 g of 1-bromo-2-(tetrahydro-2-pyranyloxy)ethane in 50 ml of THF is added dropwise and the reaction mixture is left stirring overnight at RT. It is acidified by adding a pH 2 buffer solution, and the THF is then evaporated off under vacuum. The aqueous phase is extracted with ether, the organic phase is washed twice with a pH 4 buffer solution, with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with toluene and then with a toluene/AcOEt (100:3; v/v) mixture. 50 g of the expected product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:2]1([NH:1][CH2:10][CH2:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C=CC(=O)OCC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)CCNc1ccccc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
According to the procedure of P. L. Southwick, J. Am. Chem. Soc. 75 3413 (1953), to a solution of aniline (31.86 g, 0.35 mol) and ethyl acrylate (35.0 g, 0.35 mol) in 200 ml of dry benzene (freshly distilled from CaH2) was added 0.5 ml of tin tetrachloride and the resulting solution was heated under reflux for 24 h. After cooling to room temperature the suspension was filtered to remove the inorganic solids and then concentrated in vacuo to give a dark green oil which was chromatographed on silica gel eluting with ethyl acetate/toluene (30/70) to give the title compound (40.7 g, 60%) as a light yellow oil. B.p. 95°-98° C. at 0.1 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].[OH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[CH:28][CH:27]=[CH:26]2>CC#N.O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH:16]([C:15]2[CH:18]=[CH:19][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[C:22]2[C:21]([OH:20])=[C:30]3[C:25]([CH:26]=[CH:27][CH:28]=[N:29]3)=[CH:24][CH:23]=2)[N:7]=1
Reactant: Cc1ccnc(N)n1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Oc1cccc2cccnc12
Solvent: CC#N
Solvent: O
Product: Cc1ccnc(NC(c2ccc([N+](=O)[O-])cc2)c2ccc3cccnc3c2O)n1

Procedure:
The title compound was prepared by method B presented for the compound of Example 1 with the change that 2-amino-4-methyl-pyrimidine (Sigma), 4-nitro-benzaldehyde and 8-hydroxy-quinoline were used as starting materials. Product obtained: C21H17N5O3, (MW: 387.1); yield: 344 mg, (49.6%); m.p.: 136-145° C.; HPLC (CH3CN/H2O 70:30 Phenomenex C18 282 nm): Tr =5.21 min. NMR 9 (DMSO) δ2.14 (3H, s, CH3), 6.35 (1H, d, J =5.8 Hz), 6.55 (1H, s), 7.00 (1H, d, J =8.0 Hz), 7.36-7.43(2H, m], 7.50-7.55 (1H, m), 7.56 (1H, d, J =7.5 Hz), 7.60 (1H, d, J =8.5 Hz), 7.79 (1H, d, J =5.5 Hz), 8.15 (2H, d, J =8.5 Hz), 8.28 (1H, d, J =8.5 Hz), 8.84 (s, 1H), 10.1 (s, 1H); 13C NMR 9 (DMSO) δ 20.6 (CH3), 51.6 (NHCH), 109.0 (CH), 114.2 (CH), 117.7 (CH), 121.9 (CH), 123.5 (2×CH), 124.6 (Cq), 126.7 (CH), 127.7 (Cq), 128.2 (2×CH), 136.1 (CH), 138.2 (Cq), 146.2(Cq), 147.1 (Cq), 147.2 (CH), 148.5 (CH), 149.8, 152.0 and 157.9 (3 Cq).