Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:9]([C:24]([F:27])([F:26])[F:25])[CH:8]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:22]=[CH:23][C:7]([B:28]([OH:33])[OH:29])=[CH:8][C:9]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1cc(Br)ccc1OCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCCCOC2CCCCO2)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
BuLi (2.5M, 19.1 ml) was added dropwise to a solution of 2-(3-(4-bromo-2-(trifluoromethyl)phenoxy)propoxy)tetrahydro-2H-pyran (16.6 g) in THF at −78° C. under N2 during 3 minutes. After stirring at −78° C. for another 10 minutes, triisopropyl borate (11 ml) was then added dropwise during 3 minutes at −78° C. The mixture was stirred at −78° C. for further 20 minutes, then warmed up to room temperature slowly and stirred at room temperature for 30 minutes. The mixture was then quenched with acetic acid (10% in water, 20 ml), extracted with EtOAc (200 ml), washed with brine (100 ml×5), dried over sodium sulphate, solvent removed under reduced pressure, the residue was taken in to toluene and then solvent removed under vacuum to take out trace of acetic acid (repeat 3 times, until no acetic acid smell). The product, as shown by NMR, contains 3 sets of product peaks assumed to be monomer, dimer and trimer.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([OH:9])[CH:3]=1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][Si:14]([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15])[CH:3]=1
Reactant: Cc1cc(Br)cc(O)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cc(O[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-6-methylpyridin-2-ol (376 mg, 2 mmol) in dry DMF (20 mL) is stirred under N2. TBDMS-Cl (600 mg, 4 mmol) is added, followed by triethylamine (0.97 mL, 7.00 mmol), and the mixture is stirred at rt for 1 h. The solution is poured into ice-water (170 mL) and extracted with diethyl ether (5×50 mL). The combined extracts are dried over Na2SO4 and the solvent is evaporated under reduced pressure. The residue is taken up in pentane (50 mL), dried over Na2SO4 and the solvent evaporated again, to afford the crude title compound as a yellow oil. This is used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].O1CCCC1>[C].[Pd].CO>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:20])[CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc([N+](=O)[O-])cc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(N)cc32)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 69.9 %

Procedure:
To a solution of 4-(3-cyano-6-nitroindol-1 yl)benzoic acid ethyl ester (0.11 g) in a mixed solvent of tetrahydrofuran (2 mL) and methanol (2 mL) was added palladium-carbon powder (0.04 g) under an argon atmosphere, and this mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.070 g).
Reaction SMILES: [NH:1]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:16](N(C)C)N(C)C>>[N:4]12[PH:16]34[N:10]([CH2:9][CH2:8][N:7]3[CH2:6][CH2:5]1)[CH2:11][CH2:12][CH2:13][N:1]4[CH2:2][CH2:3]2
Reactant: CN(C)P(N(C)C)N(C)C
Reactant: C1CNCCNCCNCCNC1
Product: C1CN2CCN3CCN4CCN(C1)[PH]234

Procedure:
A mixture of 4.00 g (21.5 mmol) of 1,4,7,10-tetraazacyclotridecane and 3.50 g (21.5 mmol) of hexamethylphosphorous triamide is heated for 2 hr under nitrogen at 125° and then distilled under vacuum to give 3.84 g (83%) of clear, colorless, viscous liquid 1,4,8,11-tetraaza-14-phosphatetracyclo[6.5.1.04,14.011,14 ]tetradecane, bp 92° (0.30 mm).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][NH:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: c1ccc(-c2n[nH]c3c2CCNC3)cc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(-c3ccccc3)n[nH]c2C1
Reaction time: 8 h

Procedure:
To a solution of Intermediate 58 (433 mg, 1.38 mmol) in DCM (5 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (310.3 mg, 1.38 mmol), triethylamine (1.15 mL, 8.29 mmol) and BOP (611.03 mg, 1.38 mmol). The solution was allowed to stir overnight. Following dilution with water, the mixture was extracted with DCM three times. The combined organic layers were dried over Na2SO4 and conc. The resulting residue was purified by basic HPLC (0-99% acetonitrile). (356 mg, 56%). MS (ESI): mass calcd. for C20H15ClF3N3O, 405.81. m/z found, 406.2 [M+H]+. 1H NMR (CDCl3): 7.76 (ddd, J=12.1, 7.8, 1.4 Hz, 1H), 7.56-7.33 (m, 7H), 5.17-4.97 (m, 1H), 4.52-4.33 (m, 1H), 4.28 (dt, J=12.9, 5.4 Hz, 1H), 3.99-3.83 (m, 1H), 3.54-3.41 (m, 1H), 2.97 (t, J=5.8 Hz, 1H), 2.79-2.68 (m, 1H).
Reaction SMILES: CO[C:3]([C:5]1C(=O)[N:9]([C:12]2[C:13](=[O:33])[O:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([N:22]2[C:26](=[O:27])[C:25]([C:28](OC)=O)=[CH:24][C:23]2=O)=[CH:17][CH:16]=3)[C:7](=[O:8])[CH:6]=1)=O.[CH2:34]([SH:36])[CH3:35].C[S:38]([CH3:40])=O>>[CH2:5]([CH:6]1[C:7](=[O:8])[N:9]([C:12]2[C:13](=[O:33])[O:14][C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([N:22]2[C:26](=[O:27])[CH:25]([CH2:24][CH3:23])[CH2:28][C:40]2=[S:38])=[CH:17][CH:16]=3)[C:34](=[S:36])[CH2:35]1)[CH3:3]
Reactant: COC(=O)C1=CC(=O)N(c2ccc3oc(=O)c(N4C(=O)C=C(C(=O)OC)C4=O)cc3c2)C1=O
Reactant: CCS
Reactant: CS(C)=O
Product: CCC1CC(=S)N(c2ccc3oc(=O)c(N4C(=O)C(CC)CC4=S)cc3c2)C1=O
Yield: 83 %

Procedure:
The reaction of 54 mg (0.12 mmol) of compound 5 in 3 mL dry DMSO with 27 μL ethanethiol (0.36 mmol) was carried out according to the same protocol used to obtain compound 7, giving compound 8 in 83% yield (58 mg, 0.1 mmol). FTIR (KBr) (cm−1): 3000, 1727, 1622, 600. 1H-NMR (DMSO-d6): δ (ppm) 8.24 (s, 1H), 7.53 (d, J=2.63, 1H), 7.36 (dd, J=9.24 Hz, J=2.67 Hz, 1H), 7.24 (d, J=9.24 Hz, 1H), 4.38 (d, 1H), 4.32 (s, 1H), 4.00 (s, 3H), 3.98 (d, J=5.6 Hz, 3H), 3.92 (d, J=5.4 Hz, 1H), 3.87 (d, J=5.6 Hz, 1H), 2.80 (m, 4H), 1.30 (t, J=7.24 Hz, 6H). 13C-NMR (DMSO-d6): δ (ppm) 175.06, 172.67, 168.06, 158.44, 150.63, 137.28, 128.83, 128.32, 124.22, 119.69, 118.47, 117.21, 50.01, 46.23, 42.16, 39.12, 14.24, 12.02. HRMS expected for C25H24N2O10S2: 576.087238; found: 576.087413.
Reaction SMILES: [C:1]1([C@H:7]([NH2:10])[CH2:8]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].ClC[C@@H]([NH3+])C1C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[N:32]=[C:33]=[S:34].[Cl-].ClC[C@@H]([NH3+])CC1C=CC=CC=1>>[CH3:22][C:23]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:24]=1[N:32]=[C:33]1[NH:10][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][S:34]1
Reactant: N[C@H](CO)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Agent: [NH3+][C@H](CCl)Cc1ccccc1
Agent: [NH3+][C@H](CCl)c1ccccc1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](c2ccccc2)CS1

Procedure:
(1S)-1-Phenyl-2-hydroxyethylamine was converted to (1S)-2-chloro-1-phenylethylammonium chloride according to Method B7b. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-2-chloro-1-benzylethylammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-phenyl-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[OH-:12].[K+]>CO.O>[OH:12][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:9]=1[C:8]([OH:7])=[O:11]
Reactant: Cc1ccc2c(c1)C(=O)OC2
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(CO)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
A colorless, homogeneous solution of 6-methylisobenzofuran-1(3H)-one (0.95 g, 6.41 mmol), KOH (0.576 g, 10.26 mmol) in methanol (20.52 mL) and water (5.13 mL) was refluxed. After two hr, the reaction was cooled to room temperature, concentrated in vacuo, and acidified with 1 M aqueous KHSO4 to pH ˜3. The mixture was extracted with EtOAc (4×50 mL). The combined extract was dried over MgSO4 and concentrated in vacuo to give the desired product (0.632 g, 3.81 mmol, 59.4% yield) as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)O)[C:11]#[N:12].O=P(Cl)(Cl)[Cl:22]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13]([Cl:22])[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[C:11]#[N:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CC(=C(O)c1ccco1)c1nc2ccccc2s1
Product: N#CC(=C(Cl)c1ccco1)c1nc2ccccc2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
2-Benzothiazol-2-yl-3-furan-2-yl-3-hydroxyacrylonitrile (474 mg, 1.77 mmol) was suspended in POCl3 (5 mL). The suspension was first stirred at 50° C. for 1 hr then refluxed for 30 min until the solid dissolved completely. The resulting brown solution was poured over crushed ice (200 mL). The resulting solids were isolated by filtration, washed with water until the pH of the wash water became neutral, and air-dried to yield 477 mg (94%) of 2-benzothiazol-2-yl-3-chloro-3-furan-2-ylacrylonitrile. MS (m/z, ES+): 287.0 (Cl35M+1, 100%), 289.0 (Cl37M+1, 45%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:23](=[O:24])[N:5]2[C:6]([C:20]([O-:22])=[O:21])=[C:7]([CH2:10][N+:11]3[N:12]([CH2:17][CH2:18][OH:19])[C:13]([NH2:16])=[CH:14][CH:15]=3)[CH2:8][S:9][C@H:4]12.C(=O)(O)[O-].[Na+].Cl.[NH2:31][C:32]1[S:36][N:35]=[C:34](/[C:37](=[N:41]/[O:42][CH2:43][CH3:44])/[C:38](Cl)=[O:39])[N:33]=1>C(#N)C.O>[NH2:31][C:32]1[S:36][N:35]=[C:34]([C:37](=[N:41][O:42][CH2:43][CH3:44])[C:38]([NH:2][C@@H:3]2[C:23](=[O:24])[N:5]3[C:6]([C:20]([O-:22])=[O:21])=[C:7]([CH2:10][N+:11]4[N:12]([CH2:17][CH2:18][OH:19])[C:13]([NH2:16])=[CH:14][CH:15]=4)[CH2:8][S:9][C@H:4]23)=[O:39])[N:33]=1
Reactant: CCO/N=C(\C(=O)Cl)c1nsc(N)n1
Reactant: Nc1cc[n+](CC2=C(C(=O)[O-])N3C(=O)[C@@H](N)[C@H]3SC2)n1CCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(N)n3CCO)CS[C@H]12)c1nsc(N)n1
Temperature: 5 °C
Yield: 71.6 %

Procedure:
A solution of 7β-amino-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate hydrochloride (50 g) in a mixture of acetonitrile (500 ml) and water (500 ml) was adjusted to pH 6.0 with aqueous sodium bicarbonate solution. To the resulting solution was added (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride hydrochloride (40 g) under stirring at 5° C. and the mixture was stirred at the same temperature for 1.5 hours, keeping pH 5.0-6.5 with aqueous sodium bicarbonate solution. The reaction mixture was evaporated to remove the containing organic solvent. The water solution was subjected to column chromatography on Sepabeads SP-205 (Trademark: Mitsubishi Kasei Corporation) (1.3 l). The column was washed with water (5 l) and the object compound was eluted with 15% isopropyl alcohol, and the eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamido]-3-[3-amino-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (syn isomer) (51.2 g).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[NH:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH:8]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(OC(=O)C1CCNCC1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, ice-cooled, solution of ethyl isonipecotate (78.5 g, 0.50 mole) and triethylamine (200 ml, 1.4 mole) in CHCl3 (1000 ml), triphenylmethyl chloride (15.33 g, 0.55 mole) was added. After stirring overnight at room temperature, the reaction mixture was washed with H2O, dried (Na2SO4) and the solvent evaporated. The oily residue was crystallized from MeOH--CHCl3, yielding 108.19 (96 percent) of 4-piperidine carboxylic acid, 1-(triphenylmethyl)ethyl ester as a white solid; mp 154°-155° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:15])([O-])[CH3:13].[K+].ClCC1CC1>CS(C)=O>[CH2:11]1[CH2:13][CH:12]1[CH2:15][O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OCCc1ccc(O)cc1
Reactant: CC(C)(C)[O-]
Agent: ClCC1CC1
Agent: [K+]
Solvent: CS(C)=O
Product: Oc1ccc(CCOCC2CC2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A reaction flask was charged with 4-Hydroxyphenethyl alcohol (1) (100 g, 0.72 mol), Potassium tert-butoxide (243 g, 2.17 mol), and 500 mL of DMSO. The mixture was stirred under nitrogen at 50° C. for 30 minutes. A solution of (Chloromethyl)cyclopropane (100 g, 1.10 mol) in 500 mL of DMSO was added dropwise to the reaction mixture. The mixture was then stirred at 50° C. for one hour and then cooled to room temperature.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.S([O-])([O-])(=O)=[O:15].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O.O>[O:15]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][C:11](=[O:13])[CH3:12])[CH2:1][CH2:2]1
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(=O)Nc1cccc2c1CCC2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1cccc2c1C(=O)CC2
Temperature: 0 °C

Procedure:
147 mg (0.84 mmol) N-indan-4-yl-acetamide are dissolved in 10 ml acetone and combined with 770 μl of a 15% aqueous magnesium sulphate solution. The solution is cooled to 0° C. and 397 mg (2.490 mmol) potassium permanganate are added batchwise. After 2 h the mixture is diluted with 50 ml of water, and extracted three times with 20 ml chloroform. The organic phase is dried with magnesium sulphate and the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (85:15).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1I.C([Mg]Br)(C)C.CN(C)[CH:23]=[O:24]>C(OCC)C.O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH:23]=[O:24]
Reactant: Clc1ccc(-c2ccc(Br)c(I)c2)cc1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Temperature: -75 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 4-bromo-4′-chloro-3-iodobiphenyl (4.80 g, 0.012 mol) (described in WO 2008/071405) in anhydrous diethyl ether/tetrahydrofuran (120 ml, 1:1 ratio) at −75° C. is added isopropyl magnesium bromide (18.96 ml, 15% solution in tetrahydrofuran) dropwise such as to maintain an internal temperature below −70° C. Once addition is complete the reaction mixture is stirred at −75° C. for 2 hours, then warmed to −45° C. Anhydrous N,N-dimethylformamide (1.71 g, 0.0184 mol) is next added dropwise, maintaining temperature below −40° C., followed by warming to room temperature and quenching with 2M hydrochloric acid (60 ml). The reaction mixture is further diluted with diethyl ether, the two phases separated, and the aqueous phase extracted with additional diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography (2% ethyl acetate in hexane eluant) to afford 4-bromo-4′-chloro-biphenyl-3-carbaldehyde (2.7 g, 75%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][CH:29]=[C:6]2[C:7]([N:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10](=[O:11])[C:5]=12)=[O:8])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:31]=[CH:30][CH:29]=[C:6]2[C:7]([N:9]([CH:12]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=3)[CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:10](=[O:11])[C:5]=12)=[O:8]
Reactant: CCOc1cc(C(CC(=O)OC)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CC(=O)OC)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Yield: 55.4 %

Procedure:
To a solution of methyl 3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate (2.5 g, 5.8 mmol) in 25 mL of ethyl acetate was added 0.25 g of 10% palladium on carbon catalyst. The mixture was hydrogenated in a Parr-Shaker apparatus at 55-60 psi of hydrogen overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to afford a yellow solid. The crude product was purified by flash column chromatography (silica gel, 7% ethyl acetate/methylene chloride). The resulting solid was recrystallized (60 mL ethyl acetate/20 mL hexane) and was then dried in vacuo (60° C., <1 mm) to afford 1.28 g (55%) of methyl 3-(3-aminophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propionate as a yellow solid: mp 134-136° C.; 1H NMR (CDCl3) δ7.40-7.26 (m, 1H); 7.16-7.01 (m, 3H), 6.86-6.72 (m, 2H), 5.71 (dd, J=6,98 Hz, 1 H), 5.28 (br s, 2H), 4.10 (q, J=7 Hz, 2H), 3.83 (s, 3H), 3.73 (dd, J=9.8, 16.5 Hz, 1 H), 3.64 (s, 3H), 3.24 (dd, J=6, 16.5 Hz, 1H), 1.44 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ171.1, 169.8, 168.3, 148.9, 148.1, 145.3, 134.9, 132.3, 131.3, 120.9, 120.0, 112.5, 112.4, 111.1, 110.8, 64.2, 55.8, 51.8, 50.2, 36.0, 14.6; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 50/50, acetonitrile/0.1% aqueous phosphoric acid) 5 min, 100%; Anal. Calcd. for C21H22N2O6. Theoretical: C, 63.31, H, 5.57, N, 7.03. Found: C, 63.11; H, 5.50; N, 6.99.
Reaction SMILES: C(#N)C([CH2:4][C:5]#[N:6])O.[H-].[Na+].[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:34]=[C:27]3[C:28](O[C:31](=O)[NH:32][C:26]3=[CH:25][CH:24]=2)=[O:29])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[N:36](C)C=O>O>[NH2:36][C:31]1[C:4]([C:5]#[N:6])=[C:28]([OH:29])[C:27]2[C:26](=[CH:25][CH:24]=[C:23]([N:20]3[CH2:21][CH2:22][N:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:18][CH2:19]3)[CH:34]=2)[N:32]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]c2ccc(N3CCN(Cc4ccccc4)CC3)cc2c(=O)o1
Reactant: N#CCC(O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#Cc1c(N)nc2ccc(N3CCN(Cc4ccccc4)CC3)cc2c1O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
6.1 g of malonitrile is dissolved in 100 mL of dimethylformamide. To the solution, in several portions, 3.6 g of 60% oily dispersion of sodium hydride are added. To the clear solution 18 g of 5-(4-benzylpiperazin-1-yl)isatoic anhydride is added and the mixture is stirred at room temperature for 10 hours. The reaction mixture is diluted with 100 mL of water and extracted with 2×50 mL of ethyl acetate. The aqueous phase is evaporated in vacuum, the solid residue is dissolved in 50 mL of water, the pH is adjusted to 6 with acetic acid and refluxed for 5 hours. After cooling the precipitated material is filtered off, washed with water. After drying 14.3 g of the title compound is obtained, m.p.: 291° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH2:16].N1C=CC=CC=1.CO[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1OC)[C:29](Cl)=[O:30].[CH2:37]([Cl:39])Cl>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[NH:16][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([CH2:37][Cl:39])[CH:27]=1
Reactant: COC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(N2CCCCC2)ccc1NC(=O)c1cccc(CCl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Amino-5-piperidin-1-yl-benzoic acid methyl ester (compound A) (2.1 g) produced by the above reaction was dissolved in anhydrous methylene chloride (20.0 ml). Subsequently, pyridine (900 μl) and 3-(chloromethyl)benzoyl chloride (compound B) (740 μl) were added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. After the completion of the reaction, distilled water was added thereto, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate and was then concentrated. The residue was purified by column chromatography using a chloroform-acetone system to give 2-(3-chloromethyl-benzoylamino)-5-piperidin-1-yl-benzoic acid methyl ester as a useful intermediate (1.8 g, yield 50%).
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)C#N.[CH3:13][OH:14]>O1CCCC1>[Cl:4][C:5]1[CH:12]=[C:11]([C:13]([CH3:1])=[O:14])[CH:10]=[CH:7][CH:6]=1
Reactant: N#Cc1cccc(Cl)c1
Reactant: CO
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, 36.7 mL (0.11 mole) of methylmagnesium bromide (3.0M in diethyl ether) is stirred, and a solution of 13.8 grams (0.10 mole) of 3-chlorobenzonitrile in 50 mL of dry tetrahydrofuran is added slowly dropwise. Upon completion of addition, the reaction mixture is warmed to reflux where it is stirred for about 18 hours. After this time the reaction mixture is cooled to ambient temperature, and about 40 mL of methanol is added dropwise. Upon completion of addition, the reaction mixture is stirred for two hours and then filtered. The filtrate is then stirred for about 18 hours with 35 grams of silica gel and 100 mL of water. The mixture is filtered, and the filtrate is diluted with ethyl acetate. The mixture is then washed with water, and the organic layer is dried with magnesium sulfate. The mixture is filtered, and the filtrate is concentrated under reduced pressure, yielding methyl 3-chlorophenyl ketone.