Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=1)#[N:2].[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH2:16][C:5]3[CH:6]=[CH:7][C:8]([C:9]4[CH:14]=[CH:13][N:12]=[C:11]([F:15])[CH:10]=4)=[C:3]([C:1]#[N:2])[CH:4]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: N#Cc1cc(CC(=O)O)ccc1-c1ccnc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(F)c4)c(C#N)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetic acid 206-6 (50 mg, 0.20 mmol) was dissolved in DMF (2 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (52 mg, 0.23 mmol) and DIEA (170 uL, 0.98 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (111 mg, 0.29 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-cyano-4-(2-fluoropyridin-4-yl)phenyl)acetamide 211. MS m/z 459.2 (M+1)); 1H NMR 400 MHz (DMSO-d6) δ 10.64 (s, 1H), 8.41 (d, 1H), 8.05 (d, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.81 (dd, 1H), 7.71 (d, 1H), 7.62 (dt, 1H), 7.49 (s, 1H), 7.42 (dd, 1H), 3.85 (s, 2H), 3.59-3.54 (m, 4H), 3.15 (t, 2H), 3.08 (t, 2H), 2.04 (s, 3H).
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.[N+:9]([C:12]1[CH:22]=[CH:21][C:15]([CH2:16][O:17][C:18](Cl)=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10].[OH-].[Na+].Cl>O.O1CCCC1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]([N:3]2[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]2)=[O:19])=[CH:21][CH:22]=1)([O-:11])=[O:10]
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 116.2 %

Procedure:
To a solution of (R)-thiazolidine-4-carboxylic acid (20.0 g) in a mixture of water (100 ml) and tetrahydrofuran (100 ml) was added a solution of 4-nitrobenzyloxycarbonyl chloride (32.4 g) in tetrahydrofuran (60 ml) under ice-cooling with stirring, keeping the pH between 8.5 and 9.0 with 4N aqueous sodium hydroxide. After stirring for 30 minutes, the mixture was adjusted to pH 1 with concentrated hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, and evaporated under reduced pressure to give (R)-3-(4-nitrobenzyloxycarbonyl)thiazolidine-4-carboxylic acid (54.5 g) as a crude syrup.
Reaction SMILES: O.[CH:2]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N+:14]([O-])([OH:16])=[O:15].N([O-])=O.[Na+]>CCOCC>[CH:2]1([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(C2CCCC2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(C2CCCC2)ccc1O
Reaction time: 120 h

Procedure:
To a stirred mixture of 50 ml of water, 50 ml of ether and 4-cyclopentylphenol was added dropwise 2.1 ml of 61% nitric acid and further was added a catalytic amount of sodium nitrite, then the mixture was reacted with stirring at room tempeature for 5 days. The reaction mixture was extracted with 200 ml of ethyl acetate and dried wih anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent:chloroform-n-hexane (1:1)] to give 3.60 g of 4-cyclopentyl-2-nitrophenol.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.Cl.[CH3:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C>C(#N)C.CN(C)C=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:28]2[CH2:29][CH2:30][CH2:31][CH:26]([NH:25][CH3:24])[CH2:27]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CNC1CCCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC1CCCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC)C1
Yield: 29.5 %

Procedure:
A suspension of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.039 g), 3-methylaminopiperidine hydrochloride (1.5 g) and triethylamine (2.5 g) in acetonitrile (30 ml) and N,N-dimethylformamide (10 ml) was refluxed overnight. Concentration of thereaction mixture followed by purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=15:5:1) gave a yellow crystalline substance [MS m/e: 404 (M+)]. The crystalline substance thus obtained was recrystallized from ethanol to afford 5-amino-7-(3-methylaminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg) as yellow needles. m.p. 265°-275° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[CH2:11][NH:12][O:13][CH:14]=[C:15]=[O:16])[CH2:4][CH2:3]1.[Cl:22][C:23]1[C:24](=[O:30])[NH:25][N:26]=[CH:27][C:28]=1Cl.C(N(CC)CC)C.C(O)C>O>[Cl:22][C:23]1[C:24](=[O:30])[NH:25][N:26]=[CH:27][C:28]=1[N:12]([O:13][CH:14]=[C:15]=[O:16])[CH2:11][C:10]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:9]=1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: COc1ccc(CNOC=C=O)cc1N1CCN(C)CC1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(CN(OC=C=O)c2cn[nH]c(=O)c2Cl)cc1N1CCN(C)CC1
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A mixture comprising 1.16 g of 3-(4-methylpiperazin-1-yl)-carbonylmethoxy-4-methoxybenzylamine, 0.5 g of 4,5-dichloro-3(2H)-pyridazinone, 0.46 g of triethylamine, 10 ml of ethanol and 10 ml of water, was refluxed under heating with stirring overnight. The solvent was distilled off under reduced pressure, and an aqueous potassium carbonate solution was added to the residue. The mixture was extracted with chloroform. The extract solution was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography and then crystallized from chloroform/diethyl ether to obtain 0.61 g of the above-identified compound as white crystals.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1([C:15](=N)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=[O:20])C>>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:15]1[C:9]1[CH:14]=[CH:13][C:12]([OH:20])=[CH:11][CH:10]=1
Reactant: Nc1ccccc1N
Reactant: CC(=O)O
Reactant: N=C(O)c1ccccc1
Product: Oc1ccc(-c2nc3ccccc3[nH]2)cc1
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 324 g (0.3 mol) of o-phenylenediamine, 67.5 g (0.36 mol) of benzene carboximidoic acid, 4 hydroxy-, methyl ester hydrochloride and 450 ml of glacial acetic acid was stirred at reflux for two hours. After standing overnight at room temperature the hydrochloride salt of the benzimidazole was collected by filtration, washed with acetic acid, and finally ether. The hydrochloride salt of the product was suspended in 450 ml of dilute ammonium hydroxide, stirred for one hour at room temperature, and chilled briefly. The product was collected and the filter cake was treated with charcoal during recrystallization from a 2:1 water-alcohol mixture. Filtration gave 45.9 g (73%) of 4-(1H-benzimidazol-2-yl)phenol (mp 286°-289° C.) and a second crop of 2.8 g on standing.
Reaction SMILES: O[C:2]1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[NH2:32][C@@H:33]1[C:39](=[O:40])[N:38]([CH:41]2[CH2:43][CH2:42]2)[C:37]2[CH:44]=[CH:45][CH:46]=[CH:47][C:36]=2[N:35]([CH3:48])[CH2:34]1.[C:49]([OH:54])(=O)[C@H:50]([CH3:52])[OH:51]>C1COCC1>[CH:43]1([CH2:41][N:38]2[C:39](=[O:40])[C@@H:33]([NH:32][C:49](=[O:54])[C@@H:50]([OH:51])[CH3:52])[CH2:34][N:35]([CH3:48])[C:36]3[CH:47]=[CH:46][CH:45]=[CH:44][C:37]2=3)[CH2:42][CH2:2]1
Reactant: CN1C[C@H](N)C(=O)N(C2CC2)c2ccccc21
Reactant: C[C@H](O)C(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)C(=O)N[C@H]1CN(C)c2ccccc2N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydroxybenzotriazole (121 mg, 1 mmol), diisopropylethylamine (23 2 mg, 2 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (172 mg, 1 mmol) were added to a cooled (0° C.) solution of (S)-3-amino-1-cyclopropyl-5-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one (220 mg, 1 mmol) and L-(+)-lactic acid (81 mg, 1 mmol) in THF (2 ml) and stirred overnight at r.t. The solvent was evaporated, the residue was taken up in dichloromethane and washed with water. The organic phase was dried over Na2SO4 and evaporated. Upon chromatographic purification (silica gel, dichloromethane/methanol=1:0−9:1) the title compound (347 mg, quant.) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[NH:13][CH:12]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:11]3[CH2:23][CH2:24][CH2:25][O:26][CH:10]3[C:9]=2[CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:27]([N:20]1[CH2:21][CH2:22][CH:17]([CH:12]2[CH:11]3[CH2:23][CH2:24][CH2:25][O:26][CH:10]3[C:9]3[CH:8]=[C:7]([O:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH:16]=[CH:15][C:14]=3[NH:13]2)[CH2:18][CH2:19]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)CCOc1ccc2c(c1)C1OCCCC1C(C1CCNCC1)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CCOc1ccc2c(c1)C1OCCCC1C(C1CCN(Cc3ccccc3)CC1)N2
Temperature: 90 °C
Yield: 38.5 %

Procedure:
A Microwave vial was charged with (4aSR*,5RS*,10bSR*)-9-(isopentyloxy)-5-(piperidin-4-yl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (80 mg, 0.22 mmol, 1 equiv.), benzaldehyde (24 mg, 22 μL, 0.22 mmol, 1 equiv.), NaBH(OAc)3 (95 mg, 0.44 mmol, 2 equiv.) followed by DCE (2.5 mL) under argon atmosphere. This reaction mixture was heated under microwave heating at 90° C. for 10 min. After cooling back to r.t., the reaction mixture was quenched with sat. NaHCO3 solution and diluted with CH2Cl2. The phases were separated and the organic phase additional extracted with CH2Cl2 twice. The combined organic phases were dried over MgSO4 and the solvent removed under reduced pressure after filtration. The residue was purified by Combiflash chromatography (SiO2, c-Hexane/AcOEt) to afford (4aSR*,5RS*,10bSR*)-5-(1-benzylpiperidin-4-yl)-9-(isopentyloxy)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (38 mg, 38%). The compound was prepared as hydrochloride salt following the method described in example 1.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 71 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 4-methylbenzenesulfonyl chloride under the conditions used in example 2 giving 71% of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][O:23][C:19](=[O:22])[CH:20]=[CH:21][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2=CCCCc3ccccc32)cc1
Reactant: C=CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C2=CCCCc3ccccc32)cc1
Temperature: 100 °C
Yield: 91.3 %

Procedure:
To a solution of 9-(4-bromophenyl)-6,7-dihydro-5H-benzocycloheptene (2a, compound III, R3=H, X=Br, n=2) (12.38 g, 41 mmol) in DMF (30 mL) was added methyl acrylate (38.2 g, 444 mmol), triethylamine (29.0 g, 286 mmol), and bis(triphenylphosphine)palladium(II) chloride (7.0 g, 10.0 mmol). The mixture was placed in a pressure bottle and heated at 100° C. for 4 days. The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 7.5 to 15% EtOAc/hexanes) to give the ester (2b) as a white solid (11.4 g, 90%): 1H NMR (CDCl3) δ 7.69 (d, J=15.7 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.24 (m, 5H), 6.98 (m, 1H), 6.52 (t, J=7.3 Hz, 1H), 6.43 (d, J=15.7 Hz, 1H), 3.81 (s, 3H), 2.65 (t, J=7.0 Hz, 2H), 2.17 (m, 2H), 1.98 (m, 2H); APcI m/z: 346 (M+H+CH3CN+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.C(NC(C)C)(C)C.C[Li].COCN[C:22](=O)[CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].C[CH2:35][O:36]CC>O1CCCC1>[CH3:31][C:28]([O:27][C:26](=[O:32])[NH:25][CH2:24][CH2:23][CH2:22][C:35]([C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:36])([CH3:29])[CH3:30]
Reactant: COCNC(=O)CCNC(=O)OC(C)(C)C
Reactant: COc1ccccn1
Reactant: CCOCC
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ncccc1C(=O)CCCNC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
2-Methoxypyridine (1.9 ml) and then diisopropylamine (0.1 ml) were added to a solution of methyl lithium (10 ml of a 1.6M solution in ether) in tetrahydrofuran (20 ml) at −78° C. and the solution was stirred at 0° C. for 18hand then re-cooled to −78° C. A solution of 1,1-dimethylethyl [3-(methoxymethylamino)-3-oxopropyl]-carbamate (1.6 g) in tetrahydrofuran (5 ml) was added slowly and the resultant solution was allowed to warm to −30° C. over 3.5 h, quenched with aqueous ammonium chloride and extracted with ether (three times). The combined organic extracts were dried (sodium sulphate), evaporated and purified by chromatography on silica eluting with petrol-ether gave the sub-title compound as a colourless oil (0.572 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[CH:24]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:51]=[CH:50][CH:49]=[CH:48][C:29]=1[CH2:30][NH:31][CH2:32][C:33](=[O:47])[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Na].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:24][N:31]([CH2:30][C:29]1[CH:48]=[CH:49][CH:50]=[CH:51][C:28]=1[O:27][CH3:26])[CH2:32][C:33](=[O:47])[CH:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1CNCC(=O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1CN(CC(=O)C(c1ccccc1)c1ccccc1)C[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
Under nitrogen atmosphere, to a solution of (2R)-2-formylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (2.64 g) and 3-(2-methoxybenzylamino)-1,1-diphenylpropan-2-one (3.66 g) in dichloromethane (30 ml) was added acetic acid (0.607 ml) and sodium tritacetoxyborohydride (4.82 g) under ice-cooling, and then it was stirred at room temperature for 3 hours. The reaction mixture was poured into aqueous sodium hydrogen carbonate (100 ml) and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (82 g) using a mixed solvent of hexane and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-2-[[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.24 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.[K+].[Br-].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[Br-:10].[CH2:24]([C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([CH3:11])[C:21]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Clc1nc[nH]c1Cl
Reactant: BrCc1ccccc1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc2ccccc2c(Cc2ccccc2)c1-[n+]1c[nH]c(Cl)c1Cl
Temperature: 85 °C
Reaction time: 2.5 h

Procedure:
4,5-dichloroimidazole (10.0 mmol, 1.370 g) and KOH (11.0 mmol, 0.617 g) were placed in a 50 mL round bottom flask with 10 mL acetonitrile. The mixture was brought to reflux (85° C.) and stirred 1 h until KOH was consumed. 2-Bromomethylnapthalene (10.00 mmol, 2.211 g) was added and the solution was stirred 2.5 hours. KBr was removed by vacuum filtration and benzyl bromide (10 mmol) was added to the filtrate. The mixture was stirred at reflux for 1.5 hours. The white precipitate was collected by filtration and analyzed. 1H NMR (500 MHz, d6-DMSO): δ 5.51 (2, 2H), 5.65 (s, 2H), 7.94-8.02 (m, 8H), 7.95-8.06 (m, 4H), 9.63 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:22])[C:5]([S:11][C:12]2[S:13][C:14]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=3[N:16]=2)=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([NH:1][S:34]([C:25]2[CH:26]=[CH:27][C:28]([C:30]([F:31])([F:32])[F:33])=[CH:29][C:24]=2[Cl:23])(=[O:36])=[O:35])[CH:3]=[C:4]([Cl:22])[C:5]=1[S:11][C:12]1[S:13][C:14]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:15]=2[N:16]=1)(=[O:10])[CH3:9]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: CC(=O)c1cc(N)cc(Cl)c1Sc1nc2cc(Cl)ccc2s1
Solvent: c1ccncc1
Product: CC(=O)c1cc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)cc(Cl)c1Sc1nc2cc(Cl)ccc2s1
Temperature: 90 °C
Yield: 72 %

Procedure:
To a 1M solution of 1-[5-Amino-3-chloro-2-(5-chloro-benzothiazol-2-ylsulfanyl)-phenyl]-ethanone, (265) (4.12 g, 11.19 mmol) in pyridine, obtained from Aldrich, was added 2-chloro-4-trifluoromethyl-benzenesulfonyl chloride (3.75 g, 13.43 mmol) and heated to 90° C. for 1.5 hours. The crude reaction mixture was concentrated under vacuum, partitioned between 2M aqueous HCl (100 mL) and EtOAc (100 mL), and extracted 3 times with EtOAc (100 mL). The combined organic layers were washed twice with saturated aqueous brine (100 mL), dried over Na2SO4, concentrated under vacuum, purified by column chromatography (0-5% Et2O in CH2Cl2), and triturated with CH2Cl2/hexane mixture with 0.5 mL of MeOH added to yield compound 277 (4.9 g, 72%) as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[ClH:1].[ClH:1].[ClH:1].[CH:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[CH:24]=3)=[N:7][CH:6]=2)[CH2:10][CH2:11]1)([CH3:17])[CH3:16]
Reactant: CC(C)N1CCN(Cc2ccc(Cl)nc2)CC1
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc(CN3CCN(C(C)C)CC3)cn2)ccn1
Product: Cl

Procedure:
1-(6-Chloropyridin-3-ylmethyl)-4-isopropylpiperazine (0.2 g, 0.788 mmol) and 2-methylpyridin-4-boronic acid (0.119 g, 0.867 mmol) were mixed with catalyst and reacted in the same manner as in example 18. The title compound was isolated as yellow crystals of the trihydrochloride. Yield: 295 mg (73%).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>CCOCC>[Br:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:4]
Reactant: C1COCCN1
Reactant: O=C(Br)CBr
Solvent: CCOCC
Product: O=C(CBr)N1CCOCC1
Reaction time: 8 h

Procedure:
Bromoacetylbromide (20.1 g) was added dropwise to a rapidly stirred solution of morpholine (17.4 g) in ether (200 ml). After stirring overnight, the mixture was washed with water (2×50 ml), dried (MgSO4) and evaporated to afford a colourless oil. 1H NMR (360 MHz, CDCl3) δ3.46 (2H, m, 2×CHHN), 3.63 (2H, m, 2×CHHN), 3.69 (4H, m, 2×CH2O), 3.75 (2H, s, CH2Br).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[H-].[Na+].[H][H].[CH2:16]([N:23]1[C:29](=O)[O:28]C(=O)[C:25]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:24]12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([N:23]1[C:24]2[C:25](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:3]([OH:5])=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[C:29]1=[O:28])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ccccc12
Reactant: [H][H]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O
Temperature: 80 °C
Yield: 68.7 %

Procedure:
In a solution of 4.50 g of diethyl malonate in 20 ml of N,N-dimethylformamide was gradually added 1.10 g of 62.4% sodium hydride at room temperature, and stirring was continued at room temperature until hydrogen evolution ceased. The reaction solution was heated to 80° C., and a solution of 6.70 g of N-benzylisatoic anhydride in 20 ml of N,N-dimethylformamide was added dropwise. After the addition, the reaction mixture was stirred under heating at 120° C. for 7 hours. After cooling to room temperature, the reaction mixture was poured into ice water and washed with ethyl acetate. The aqueous phase was made acidic with 1 N hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was crystallized from ethanol to give 5.88 g of ethyl 1-benzyl-4-hydroxy-1,2-dihydro-2-oxoquinoline-3-carboxylate.