Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.CO[CH:13](OC)[CH2:14][CH:15](OC)OC.C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:15]=[CH:14][CH:13]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(CC(OC)OC)OC
Reactant: NNc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(-n2cccn2)cc1

Procedure:
A solution of 4-chlorophenylhydrazine hydrochloride (2.02 g, 11.3 mmol), 1,1,3,3-tetramethoxypropane (2.00 mL, 12.1 mmol) and sodium acetate (1.00 g, 12.2 mmol) in acetic acid (25 mL) is heated to gentle reflux overnight. The solution is cooled and poured into water (125 mL). Solid sodium bicarbonate is added in portions until the pH of the mixture is slightly basic. This is then extracted twice with ethyl acetate (125 mL), and the extracts are washed with brine, combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 1-(4-chlorophenyl)pyrazole in two crops (1.13 g+0.24 g, 7.65 mmol, 68%). m.p. 50-53° C. TLC RF 0.19 (10:90 ethyl acetate-hexane), 1H NMR (300 MHz, CDCl3): δ 7.89 (1H, dd, J=2.4, 0.6 Hz), 7.72 (1H, d, J=1.5 Hz), 7.64 (2H, d, J=8.7 Hz), 7.42 (2H, d, J=8.7 Hz), 6.47 (1H, dd, J=2.4, 1.8 Hz). MS (ES+): m/e 182 (3), 181 (34), 180 (6), 179 (100).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.CO.Cl.[O-:16][C:17]#[N:18].[K+]>O>[CH3:1][N:2]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[C:17]([NH2:18])=[O:16]
Reactant: CNC1CCCc2ccccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN(C(N)=O)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 8.05 grams (0.05 mole) of 1,2,3,4-tetrahydro-N-methyl-1-naphthylamine in 10 ml. of methanol is added a solution of 4.2 ml. of 12N hydrochloric acid (0.05 mole) in 35 ml. of water. The mixture is cooled in an ice-water bath while a solution of 4.46 grams (0.055 mole) of potassium cyanate in 15 ml. is added dropwise. After the addition is complete, the reaction mixture is stirred at room temperature for 45 minutes and then at 70° to 75° C. for 30 minutes. The mixture is cooled to 25° C., and the solid product filtered off, washed with water and then with cold ethyl acetate. The dried product weighs 7.1 grams and has melting point 160°-163° C. Recrystallization from acetone-hexane gives the analytical sample, melting point 161° to 163° C. Recrystallization from acetone-hexane gives the analytical sample, melting point 161° to 163° C. Analysis Calculated for C12H16N2O: C, 70.56; H, 7.90; N, 13.72. Found: C, 70.60; H, 7.94; N, 13.75.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:10]([C:13]1[C:21]2[O:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=2[CH:16]=[CH:15][C:14]=1[O:26][CH2:27][CH2:28][CH2:29]Br)[CH2:11][CH3:12]>>[CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[N:4]([CH2:29][CH2:28][CH2:27][O:26][C:14]2[CH:15]=[CH:16][C:17]3[C:18]([C:22]([F:24])([F:25])[F:23])=[N:19][O:20][C:21]=3[C:13]=2[CH2:10][CH2:11][CH3:12])[C:3]1=[O:8]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)NC(C)(C)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
5,5-Dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from 5,5-dimethylimidazolidine-2,4-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][C:15]=1[NH:29][NH:30]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:20][C:18]1[CH:19]=[C:14]([Cl:13])[C:15]([N:29]2[C:9](=[O:10])[NH:8][C:6]([C:5]3[CH:11]=[CH:12][C:2]([I:1])=[CH:3][CH:4]=3)=[N:30]2)=[CH:16][C:17]=1[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: O=C=NC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)c(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1Cl
Yield: 34.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-iodobenzoyl isocyanate (Intermediate-67, 0.300 g, 0.800 mmol), tert-butyl 2-(2,4-dichloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazine carboxylate (Intermediate-83, 0.397 g, 1.6 mmol), DCM (20 mL), trifluoro acetic acid (5.0 mL) to afford 0.150 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.09 (s, 9H), 4.31 (d, J=4.2 Hz, 2H), 7.40-7.58 (m, 2H), 7.61-7.78 (m, 2H), 7.93-8.02 (br d, 2H), 8.17 (m, 1H).
Reaction SMILES: C(C1COC(=O)N1[C:14](=[O:49])[CH:15]([C:20]1[CH:21]=[C:22]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=2)[CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[C:35]([F:38])([F:37])[F:36])[CH:25]=1)[CH2:16][CH:17]([CH3:19])[CH3:18])C1C=CC=CC=1.O[Li].O.OO.[O-:55]S([O-])=O.[Na+].[Na+]>C1COCC1.O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][O:26][C:24]2[CH:25]=[C:20]([C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([OH:55])=[O:49])[CH:21]=[C:22]([C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:47])([F:46])[F:48])=[CH:43][CH:44]=3)[CH:23]=2)=[C:29]([C:35]([F:37])([F:38])[F:36])[CH:30]=1
Reactant: O=S([O-])[O-]
Reactant: CC(C)CC(C(=O)N1C(=O)OCC1Cc1ccccc1)c1cc(OCc2ccc(F)cc2C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)c1cc(OCc2ccc(F)cc2C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
To a solution of 4-benzyl-3-{2-[5-(4-fluoro-2-trifluoromethyl-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one (0.535 g, 0.78 mmol) in THF (9 mL) was added water (3 mL). The system was cooled to 0° C. To this cold solution was added LiOH.H2O (33 mg, 0.78 mmol) and 30% H2O2 (0.354 mL, 3.12 mmol,) and stirred at 0° C. for 20 min. The excess H2O2 was quenched by adding 1.5 M aqueous Na2SO3 solution (2.08 mL, 3.12 mmol) and stirred at room temperature for 5 min. The organic solvent was removed in vacuo. The resulting liquid was acidified to pH 2 by adding 1 N aqueous HCl solution. The aqueous layer was extracted with EtOAc (3×50 mL) and dried (MgSO4). The mixture was concentrated in vacuo to receive a crude mixture which was purified by ISCO silica gel column chromatography to yield (R)-2-[5-(4-Fluoro-2-trifluoromethyl-benzyloxy)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid (310 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:21]1[CH:25]=[C:24]([CH2:26][OH:27])[O:23][N:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>ClCCl>[CH2:11]([C:21]1[CH:25]=[C:24]([CH:26]=[O:27])[O:23][N:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCc1cc(CO)on1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCCCCCCc1cc(C=O)on1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of oxalyl chloride (31.7 ml) in dry dichloromethane (100 ml) cooled to -60° C., was added a solution of dimethylsulfoxide (9.8 ml) in dichloromethane (30 ml) followed by a slurry of 3-(1-decyl)-5-isoxazolemethanol (13.8 g) in dry dichloromethane (100 ml). The reaction mixture was stirred at -60° C. for 0.5 hr, quenched with triethylamine (40 ml), and allowed to warm to ambient temperature. The solution was poured into water (300 ml) and extracted with dichloromethane. The organic phases were washed with dilute citric acid, dried, and evaporated. The residue was flash chromatographed (silica, 50:1-dichloromethane:methanol). The appropriate fraction were collected and evaporated. The residue was recrystallized from ether-hexane to give 11.2 g (82%) of product, mp 46°-48° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](CO)[C:5]([OH:10])=[C:4](CO)[CH:3]=1.C(O)(=O)C(O)=O.[C:19]1([C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22])[OH:20]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][CH:3]=1.[C:19]1([C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:22])[OH:20]
Reactant: OCc1cc(Cl)cc(CO)c1O
Agent: O=C(O)C(=O)O
Agent: Oc1ccccc1O
Solvent: O
Product: Oc1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
To a 1 liter, 3 necked round bottomed flask equipped with a paddle stirrer, condenser, thermometer and heating source, were added 188.6 g (1 mole) of the 4-chloro-2,6-dimethylolphenol, followed by 10 g (0.11 moles) of oxalic acid and 220 g (2 moles) of catechol. To this were added 400 g of water. The reaction mixture was stirred and heated to 70° C. Solution occurred when the temperature reached approximately 60° C. Then, the reaction mixture was heated to reflux and held at reflux for 4 hours. After 1 hour at reflux, the product began to separate.
Reaction SMILES: [OH-].[Na+].[C:3]1([CH:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH:16]=3)=[C:11]([NH2:25])[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(OC)(O[CH3:30])(=O)=O>O.C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:3]1([CH:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH:16]=3)=[C:11]([NH:25][CH3:30])[O:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cccc(C2=C(N)OC(c3ccccc3)C2=O)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CNC1=C(c2cccc(C(=O)OC)c2)C(=O)C(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
In this example, 0.60 g of solid sodium hydroxide in 4.0 ml of water was added to a mixture of 4.1 g of 2-phenyl-3-oxo-4-(3-methoxycarbonylphenyl)-5-amino-2,3-dihydrofuran in 70 ml of methylene chloride at room temperature followed by the addition of 1.73 g of dimethyl sulfate and 0.30 g of benzyltriethyl ammonium chloride. The two-phase mixture was then stirred at room temperature for about 18 hours and then washed one time with water, dried over magnesium sulfate and then concentrated by evaporation under vacuum to yield an oil. The oil was triturated with 1:1 diethyl ether:methanol to afford 2.3 g of the title compound as a white powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:18])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][CH:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cccn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3cccn3)c1)=N2

Procedure:
The title compound was prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M55) (438 mg, 0.82 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (238 mg).
Reaction SMILES: F[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.[NH2:14][C@@H:15]([C:19]([OH:21])=[O:20])[C@H:16]([CH3:18])[OH:17].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:14][C@H:15]([C@@H:16]([OH:17])[CH3:18])[C:19]([OH:21])=[O:20])=[CH:3][CH:4]=1)#[N:13]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)O
Temperature: 75 °C
Reaction time: 24 h
Yield: 69.7 %

Procedure:
4-fluoro-1-naphthonitrile (13916-99-9) (1.0 g, 5.84 mmol) was mixed together with H-D-Thr-OH (835 mg, 7.01 mmol) in DMSO (20 mL). K2CO3 (1.61 g, 11.68 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane/EtOAc and then with EtOAc, 100% to get the pure final product (1.1 g):1H NMR (500 MHz, acetone-d6, δ in ppm) 8.25 (d, J=9 Hz, 1H), 8.09 (d, J=9 Hz, 1H), 7.84 (d, J=9 Hz, 1H), 7.75 (t, J=9 Hz, 1H), 7.65 (t, J=9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 6.32 (d, J=9 Hz, 1H), 4.53 (m, 1H), 4.38 (m, 1H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][N:11]([CH:18]([CH3:35])[C:19]([NH:21][C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:24][CH:23]=3)=[O:20])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH:15]([F:17])[F:16])=[CH:12][N:11]([CH:18]([CH3:35])[C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:33][CH:34]=3)=[O:20])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OC(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
99 mg (0.18 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-(difluoromethoxy)-2-oxopyridin-1(2H)-yl]propanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 75 mg (84% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[C:21]3([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1NCCN1c1ccnc(Cl)c1
Reactant: OC1(c2ccncc2Br)CCCC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccnc(Cl)c2)CCN1c1cnccc1C1(O)CCCC1
Yield: 11.1 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(2-chloro-pyridin-4-yl)imidazolidin-2-one (I-33b: 100 mg, 0.5 mmol) was reacted with 1-(3-bromo-pyridin-4-yl)-cyclopentanol (I-34a: 135 mg, 0.558 mmol), copper iodide (9.6 mg, 0.05 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (21.62 mg, 0.15 mmol), potassium phosphate (322.87 mg, 1.52 mmol) and 1,4-dioxane (5 mL) to yield the crude product. Purification by preparative HPLC afforded 20 mg of the product (11% yield).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:21]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:9]1)=O)(C)(C)C.[ClH:28].CO>>[ClH:28].[NH:8]1[CH2:9][CH:10]([C:12]2[C:21]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3nc2N2CCCCC2)C1
Agent: Cl
Solvent: CO
Product: c1ccc2nc(N3CCCCC3)c(C3CNC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 3-(3-piperidin-1-yl-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (92) (139 mg, 0.38 mmol) in 4 M HCl/MeOH solution (10 mL) was stirred at RT for 30 min. Then the solvent was evaporated at 40° C. to give 2-azetidin-3-yl-3-piperidin-1-yl-quinoxaline hydrochloride (93) (115 mg, 0.38 mmol, 100% yield) as a yellow solid. ESI-MS (M+1): 269 calc. for C16H20N4 269
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:15][C:16]([CH2:19][O:20][CH3:21])=[CH:17][N:18]=3)=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH:1]1([C:5]2[C:13]([C:14]3[NH:15][C:16]([CH2:19][O:20][CH3:21])=[CH:17][N:18]=3)=[CH:12][C:8]([C:9]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COCc1cnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COCc1cnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
To a round-bottom flask was added a solution of 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoic acid (compound 246.4, 50.0 mg, 0.150 mmol, 1.00 equiv, 90%) in N,N-dimethylformamide (3 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 41.0 mg, 0.170 mmol, 1.10 equiv), EDC.HCl (64.0 mg, 0.330 mmol, 2.00 equiv), and 4-dimethylaminopyridine (41.0 mg, 0.340 mmol, 2.00 equiv) were added to the reaction. The resulting solution was stirred for 3 h at 25° C., then quenched with water and extracted with 2×30 mL of ethyl acetate. The combined organic layers were concentrated in vacuo. The crude product (˜50 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (26.0% CH3CN up to 42.0% in 7 min, up to 100.0% in 2 min, down to 26.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 18 mg (25%) of the title compound as a white solid. m/z (ES+) 469 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.73-7.64 (m, 3H), 7.52-7.32 (m, 4H), ˜4.9 (1H partially obscured by water peak), 4.60 (s, 2H), 3.81-3.68 (m, 1H), 3.68-3.52 (m, 1H), 3.46 (s, 3H), 3.35-3.22 (m, 1H partially obscured by methanol solvent peak), 3.09-2.95 (m, 2H), 2.52 & 2.41 (2 singlets, amide rotamers, Ar—CH3, 3H), 2.16-1.97 (m, 6H), 1.94-1.58 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([C:24]2[C:33]([OH:34])=[C:32]3[C:27]([CH:28]=[CH:29][CH:30]=[N:31]3)=[C:26]([Cl:35])[CH:25]=2)[NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1)C.[OH-].[Na+].Cl>C1COCC1>[Cl:35][C:26]1[CH:25]=[C:24]([CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:36])=[O:3])[CH:11]=[CH:10][CH:9]=2)[C:33]([OH:34])=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[N:31]2
Reactant: CCOC(=O)Cc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(C(NC(=O)COc2ccccc2)c2cc(Cl)c3cccnc3c2O)c1
Yield: 42.4 %

Procedure:
The solution of 100 mg of ethyl(3-{(5-chloro-8-hydroxyquinolin-7-yl) [(phenoxyacetyl)amino]methyl}phenyl)acetate in THF and Sodium hydroxide (aqueous, 5 eq.) were stirred at room temperature for 48 h. The reaction mixture was acidified to pH 3 with 2N aq. HCl, then concentrated. The residue was diluted with methylene chloride, washed with water, dried over sodium sulfate and concentrated. Solids were triturated with ether and filtered to give 40 mg (43%) of (3-{(5-chloro-8-hydroxyquinolin-7-yl)[(phenoxyacetyl)amino]methyl}phenyl)acetic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=1.C(N(C(C)C)C(C)C)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>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:13])[C:10]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C(O)c1ccc(Cl)c(Cl)c1
Reactant: COc1cc(CCN)ccc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CCNC(=O)C(O)c2ccc(Cl)c(Cl)c2)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (3,4-dichloro-phenyl)-hydroxy-acetic acid (3 g), 4-(2-amino-ethyl)-2-methoxy-phenol hydrochloride (2.7 g) and ethyl-diisopropyl-amine (7 ml) in dimethylformamide (60 ml) is added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (6 g) in one portion. The mixture is stirred at room temperature for 3 hours. Then water (400 ml) is added. The mixture is extracted with ethyl acetate (2×400 ml) and washed with brine (2×200 ml). The organic layers are collected, dried with MgSO4 and evaporated. 2-(3,4-dichloro-phenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-acetamide is obtained which is purified by flash column chromatography on silica gel (ethyl acetate/hexane 2:1); the product is an oil.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH3:35])=[C:21]([CH:34]=1)[C:22]([NH:24][C:25]1[N:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1)=[O:23].C(N(CC)CC)C>ClCCl>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][N:11]([C:31]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22](=[O:23])[C:21]4[CH:34]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=4[CH3:35])=[N:30][CH:29]=3)=[O:32])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1cccnc1N2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Nc3ncccc32)cn1

Procedure:
As described for Example 1, 6,11-dihydro-5H-pyrido[2,3-b][1,4]benzodiazepine (2 mmol) is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride (2.1 mmol) in the presence of triethylamine (4 mmol) in dichloromethane to give the product as a solid, m.p. 102° C.-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4].[NH2:25][C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:25][C:26]([C:27]([OH:29])=[O:28])([CH3:31])[CH3:30])[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH2:10]2)=[O:4]
Reactant: CC(C)(N)C(=O)O
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(NC(C)(C)C(=O)O)c1)C(C)(C)C2
Temperature: 120 °C
Yield: 23.7 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (1.2 g, 2.94 mmol), 2-aminoisobutyric acid (1.20 g, 12 mmol), copper (I) iodide (0.34 g, 1.76 mmol), N,N-dimethylglycine hydrochloride (0.33 g, 2.35 mmol) and potassium carbonate (1.22, 8.82 mmol) in DMSO (10 mL) was heated for 4 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. 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-(1-carboxy-1-methyl-ethylamino)-phenyl]-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (300 mg, 24%) as a white solid: LC/MS m/e calcd for C23H27ClN2O4 (M+H)+: 431.9, observed: 431.1.