Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>[Pd](Cl)Cl.C(N(CC)CC)C>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 67.5 °C
Reaction time: 20 h

Procedure:
A stirred mixture of 3.05 g (14. 31 mmol) of 4-tert-butyl-bromobenzene (Compound 20), 1.41 g (14.39 mmol) of trimethylsilylacetylene (Compound 16), 139 mg (0.13 mmol) of cuprous iodide, 293 mg (0.42 mmol) of bis(triphenyophosphine) palladium (II) chloride and 3 ml of triethylamine was flushed with nitrogen and then heated under nitrogen at 65-70 degrees C. for 20 hours. The reaction mixture was stirred at room temperature for a further 4 hours and the triethylamine then removed under vacuum. The residue was purified by flash chromatography (silica; hexanes) to give the title compound as a colorless oil. PMR (CDCl3): & 0.26 (9H, s), 1.31 (9H, s), 7.32 (2H, d, J~8.2 Hz), 7.42 (2H, d, J~8.2 HZ).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[NH:19]1[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]1>>[O:25]=[S:22]1(=[O:26])[CH2:23][CH2:24][N:19]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)N3CCS(=O)(=O)CC3)s2)noc1C(F)(F)F
Yield: 80 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and thiomopholine 1,1-dioxide by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried to afford product as a colorless solid (157 mg, 80%). 1H NMR (DMSO-d6) 2.34 (d, J=1.7, 3H), 3.27 (obs m, 4H), 4.00 (m, 4H), 7.58 (d, J=3.5, 1H), 7.68 (d, J=4.0, 1H). 13C NMR (incomplete, F-coupled carbons obscured by baseline noise due to poor solubility) 8.0, ˜44 (br), 51.5, 116.6, 128.0, 130.0, 130.8, 139.6, 158.5, 162.7. 19F NMR −62.2. LC/MS 5.80 min, [M+1]+ 395.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[N:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25].N1C=CC=CC=1>ClCCl>[CH2:1]([O:5][C:6]1[CH:14]=[N:13][CH:12]=[CH:11][C:7]=1[C:8]([N:23]([O:24][CH3:25])[CH3:22])=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)COc1cnccc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccncc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-isobutoxyisonicotinic acid (2.2 g, 11.2 mmol) and oxalyl chloride (7 g, 55 mmol) in 25 mL of dichloromethane was stirred at room temperature for 1 h. The resulting solution was concentrated down under reduced pressure and the residue was re-dissolved in 50 mL of dichloromethane. To this solution were added N,O-dimethylhydroxyl-amine hydrochloride (4.5 g, 46.4 mmol) and pyridine (5 mL) at 0° C. The reaction was allowed to warm up to room temperature over 30 min period, and quenched with 2 mL of water. The resulting mixture was bacified with 1 mL 10% KOH solution (pH=10), the layers were separated, and the aqueous layer was washed twice with 20 mL portions of dichloromethane. The combined dichloromethane washes were dried over sodium sulfate, and concentrated down under reduced pressure, resulting in 1.8 g (67%) of 3-isobutoxy-N-methoxy-N-methylisonicotinamide. 1H-NMR (400 MHz, d6-DMSO): δ 8.46 (s, 1H), 8.25 (d, 1H), 7.45 (d, 1H), 3.96 (d, 2H), 3.43 (s, 3H), 2.76 (d, 3H), 2.05 (m, 1H), 0.94 (d, 6H). MS (EI) for C12H18N2O2: 239 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:20][OH:21])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH2:18][CH3:19])=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(O)(=O)C>C1C=CC=CC=1>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:21][CH2:20]1)=[CH:9][C:10]([O:17][CH2:18][CH3:19])=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3
Reactant: O=Cc1ccccc1
Reactant: CCOc1cc2c(cc1OCC)C(C(CO)CO)NCC2
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOc1cc2c(cc1OCC)C1C(CO)COC(c3ccccc3)N1CC2
Yield: 70 %

Procedure:
10 mmoles (2.8 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline and 11 mmoles (1.17 g) of freshly distilled benzaldehyde are refluxed in 50 ml of absolute benzene, in the presence of a catalytic amount of hydrochloric acid or acetic acid for 4 hours. The solvent is distilled off and the residual pale-yellow oil is crystallized by trituration with ether. The aimed compound is obtained in a yield of 70%.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCN=[N+]=[N-])cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a stirred solution of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-4-phenyl-1H-imidazole (1.1 g, 3.4 mmol) and KI (566 mg, 3.4 mmol) in DMF (7 mL) was added sodium azide (443 mg, 6.8 mmol), and then the resulting mixture was stirred overnight at 100° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried (MgSO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 960 mg (89%) of the title compound as pale yellow amorphous: MS (ESI) m/z 318 [M+H]+, 1H-NMR (CDCl3)δ1.26 (2H, t, J=7.5 Hz), 2.72 (3H, q, J=7.7 Hz), 2.98 (2H, t, J=6.6 Hz), 3.59 (2H, t, J=6.6 Hz), 7.20-7.41 (9H, m), 7.79 (2H, dd, J=7.1, 1.3 Hz).
Reaction SMILES: [Cl:1][CH:2]([F:16])[C:3]([F:15])([F:14])[O:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=1.[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C1(C)C=CC=CC=1>[Cl:13][C:7]1[CH:6]=[C:5]([O:4][C:3]([F:15])([F:14])[CH:2]([Cl:1])[F:16])[C:10]([Cl:11])=[CH:9][C:8]=1[NH:12][C:23]([NH:22][C:20](=[O:21])[C:19]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:18]=1[F:17])=[O:24]
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)Cl)cc1Cl
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)Cl)cc1Cl

Procedure:
A solution of 5.9 g (0.02 mole) of the above prepared 4-(2-chloro-1,1,2-trifluoroethoxy)-2,5-dichlorobenzeneamine in 100 ml toluene was placed in a 500 ml 3-necked round bottom flask fitted with a mechanical stirrer, thermometer and reflux condenser and 5.5 g (0.03 mole) of 2,6-difluorobenzoyl isocyanate was added while stirring. The temperature rose from 23° to 34° C. in a few minutes. The mixture was heated under reflux while stirring for one hour giving a clear solution which was cooled in an ice water bath. The toluene was removed by evaporation in a rotary evaporator and 25 ml acetic acid and 5 ml water were added to the residue. The resulting mixture was heated to boiling, giving a clear solution, cooled in an ice water bath and suction filtered. The filter cake obtained was washed with a little cold aqueous acetic acid and dried at room temperature. Weight, 8.5 g of white solid. m.p. 177°-179° C. The structure was verified by NMR.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C@@H:6]([O:11][C@H:12]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N+:21]([CH2:25][CH2:26][O:27][CH3:28])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].C(O)(=O)C>[Pt]=O.C(O)C>[CH3:28][O:27][CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:12]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[O:11][C@@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O:3][CH3:2])=[O:5])=[CH:14][CH:15]=2)[CH2:20]1
Reactant: COCC[n+]1cccc(-c2ccc([C@H](O[C@@H](CC(C)C)C(=O)OC)c3ccccc3)cc2)c1
Agent: O=[Pt]
Agent: [Br-]
Solvent: CCO
Solvent: CC(=O)O
Product: COCCN1CCCC(c2ccc([C@H](O[C@@H](CC(C)C)C(=O)OC)c3ccccc3)cc2)C1
Reaction time: 18 h

Procedure:
A mixture of 3-{4-[(R)-{[(1S)-1-(methoxycarbonyl)-3-methylbutyl]oxy}(phenyl)methyl]phenyl}-1-(2-methoxyethyl)pyridinium bromide from example 41 step 1 (870 mg, 1.64 mmol), ethanol (50 mL), acetic acid (197 mg, 3.28 mmol) and platinum oxide (hydrated) 79-84% (63 mg) was hydrogenated at 60 psi for 18 hours. The mixture was filtered, concentrated and then concentrated twice with n-heptane. The residue was chromatographed on silica gel using 10% methanol in dichloromethane to obtain the title compound as a thick oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1F.C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][NH:27][CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[N:27]([CH2:26][CH2:25][CH2:24][N:23]([CH3:29])[CH3:22])[CH3:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: CNCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCCN(C)c1c(N)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A heterogeneous mixture of 1-chloro-2-fluoro-3-nitro-5-(trifluoromethyl)benzene (1.25 mL, 8.2 mmol), K2CO3 (3.44 g, 24.6 mmol), N1,N1,N3-trimethylpropane-1,3-diamine (1.26 mL, 8.61 mmol)and THF were allowed to stir at room temperature for 45 min. The THF was removed under reduced pressure and reconstituted in EtOAc (50 ml). The organic layer was washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated to an oil. The concentrated oil was taken up in EtOH (20 ml) to which Raney nickel (2.5 g wet, washed) was added. The reduction was monitored and after 1 h, another portion of Raney nickel (3.8 g, wet, washed) was added. The reaction was allowed to stir for an additional 30 min., and filtered through Celite, washed with EtOH (10 ml) and concentrated. The crude residue was purified via flash chromatography (silica gel, gradient elution 0 to 25% MeOH in CH2Cl2) to afford 6-chloro-N1-(3-(dimethylamino)propyl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine as a yellow oil. MS m/z=310.1 [M+H]+. Calc'd for C13H19ClF3N3: 309.8.
Reaction SMILES: [OH:1][C@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1.[C:18](O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:18]([O:1][C@@H:2]1[CH2:17][N:5]2[CH2:6][CH2:7][N:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)[CH2:9][C@@H:4]2[CH2:3]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O[C@@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
A solution of 0.595 g (2.35 mmol) of (7R,8aS)-7-hydroxy-2-(5-chloropyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 17), 0.430 g (3.52 mmol) of benzoic acid and 0.738 g (2.81 mmol) of triphenylphosphine in 25 mL of dry THF was treated with 0.44 mL (2.8 mmol) of diethyl azodicarboxylate, and the mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue purified by flash silica gel chromatography with 10:1 methylene chloride:acetone. A second chromatography of the major fraction with the same system gave 0.63 g (75%) of the title compound. mp (.HCl) 202°-205° C. HRMS calcd for C19H21 ClN3O2 (MH+): 358.1322, found: 358.1320.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[CH:10]([OH:13])([CH3:12])[CH3:11]>>[CH3:11][C:10]([OH:13])([CH2:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1])[CH3:12]
Reactant: CC(C)O
Reactant: C=C(C)c1ccccc1
Product: CC(CC(C)(C)O)c1ccccc1

Procedure:
By reaction of α-methylstyrene with isopropanol under the conditions described in example 1, after multistage distillation, a mixture which 2-methyl-4-phenyl-2-pentanol (90.3 GC area %) was obtained. In a 300 mL autoclave, 27.7 g of this mixture were dissolved in 132.3 g of tetrahydrofuran, and 1.6 g of a catalyst according to preparation example 1 were initially charged in a catalyst basket. The autoclave was purged three times with nitrogen. This was followed by hydrogenation at 160° C. and hydrogen pressure 160 bar for 10 hours. The output was analyzed by means of gas chromatography (30 m column material DB1 ID: 0.25 mm, FD: 0.25 μm, 50° C.—5 min isothermal, −6° C./min 290° C.—219 min isothermal). The composition of the output after 10 h is reported in the table below.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:37]1[CH:42]2[CH2:43][NH:44][CH2:45][CH2:46][N:41]2[CH2:40][CH2:39][O:38]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:44]3[CH2:45][CH2:46][N:41]4[CH:42]([CH2:37][O:38][CH2:39][CH2:40]4)[CH2:43]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C1CN2CCOCC2CN1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCOCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 57.1 %

Procedure:
A 8 ml sealed vial was charged with 124 mg (0.233 mmol) of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide (WO 2005/002577); 83 mg (0.584 mmol) of octahydropyrazino[2,1-c][1,4]oxazine (EP 472826), 90 mg (0.701 mmol) of potassium carbonate; the reagents were dissolved in 0.5 ml of DMSO. The crude product was purified by flash chromatography (silica, cyclohexane/EtOAc 90/10-30/70) affording the title compound as a white solid 85 mg (0.133 mmol).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>N1C=CC=CC=1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:23]([C:19]2[O:18][CH:22]=[CH:21][CH:20]=2)=[O:24])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccc(-c2cnc3ccccc3n2)c1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 0.01 mol) in pyridine (10 mL) was cooled to 0° C. and 2-furoyl chloride (1 mL, 0.01 mol) was added dropwise over 10 min. The reaction mixture was stirred overnight at room temperature, diluted with water (50 mL), and stirred until precipitate formed. The solid was filtered, dried, and recrystallized from toluene to afford N-[3-(quinoxalin-2-yl)phenyl]furan-2-carboxamide (2.4 g, 76%). LCMS calculated for C19H13N3O2 (M+H): 316.10. found 316. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.45 (1H, s), 9.51 (1H, s), 8.68 (1H, s), 8.22-7.80 (7H, m), 7.61 (1H, m), 7.40 (1H, m), 6.81 (1H, m).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.[NH:34]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:34]4[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: OCC1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(CO)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and pyrrolidin-3-ylmethanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (1H), 7.75 (m, 1H), 7.55 (2H), 7.05 (1H), 4.73 (1H), 3.65 (m, 2H), 3.50 (m, 3H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 438 [M+H]
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:27]([C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][N:9]=2)[CH2:4]1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:34]([NH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:27]([C:28]3[CH:33]=[N:32][CH:31]=[N:30][CH:29]=3)=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:23])[F:24])=[CH:17][CH:16]=3)=[O:13])=[CH:10][N:9]=2)[CH2:4]1)(=[O:36])[CH3:35]
Reactant: NC[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncnc2)C1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2cncnc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-6-(3-(Aminomethyl)pyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-5-(pyrimidin-5-yl)nicotinamide (Example 177, 30 mg, 0.063 mmol) was dissolved in dioxane (0.5 mL), acetic anhydride (7.09 mg, 0.069 mmol) was added and the RM was stirred for 3 h at RT. The RM was poured into 15 mL of Na2CO3 10%, then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and evaporated to dryness under reduced pressure, dissolved in MeOH, evaporated and dried under HV to afford the title compound as an off-white solid. HPLC (Condition 4) tR=4.95 min, UPLC-MS (Condition 3) tR=0.93 min, m/z=517.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.60 (m, 1H) 1.75 (s, 3H) 1.79-1.93 (m, 1H) 2.15-2.31 (m, 1H) 2.86-3.02 (m, 3H) 3.04-3.20 (m, 2H) 3.23-3.36 (m, 1H) 7.33 (d, J=8.21 Hz, 2H) 7.77-7.93 (m, 3H) 8.08 (d, J=2.35 Hz, 1H) 8.77 (d, J=0.78 Hz, 1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.16 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH2:20]([C:22]1([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].C(=O)([O-])[O-].[Ca+2]>CN(C)C(=O)C>[CH2:20]([C:22]1([CH3:28])[CH2:27][CH2:26][N:25]([C:2]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCC1(C)CCNCC1
Reactant: O=C(c1ccc(Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)N(C)C
Product: CCC1(C)CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccc(Cl)cc2)CC1
Yield: 57.4 %

Procedure:
Proceeding as indicated in example 2 with 0.0734 mole (21.7 g) of 2,4'-dichloro-5-nitro-benzophenone, 0.11 mole (18 g) of 4-ethyl4-methylpiperidine and 0.22 mole (30.4 g) of calcium carbonate in 100 cm3 of N,N-dimethyl acetamide, 16.3 g (Yield: 57%) of the expected product are obtained after re-crystallization in isopropyl ether. M.P.: 105° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:5]([C:6](OCC)=[O:7])=[C:4]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]=1[CH3:21].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[NH2:1][C:2]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:5]2[C:6](=[O:7])[O:17][C:16]([O:18][CH2:19][CH3:20])=[N:15][C:4]=2[C:3]=1[CH3:21]
Reactant: CCOC(=O)Nc1c(C)c(N)cc(CC)c1C(=O)OCC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOc1nc2c(C)c(N)cc(CC)c2c(=O)o1
Temperature: 0 °C
Yield: 59.3 %

Procedure:
A solution of ethyl 4-amino-2-ethoxycarbonylamino-6-ethyl-3-methyl-benzoate (20 mg) in concentrated sulphuric acid (3 ml) was stirred at room temperature for 4 hrs. The solution was added dropwise to an ice-cold stirred mixture of ethyl acetate and saturated sodium bicarbonate solution. After neutralization, the mixture was extracted with ethyl acetate. The organic extract was dried over magnesium sulphate and evaporated to give a solid. This material is further purified by thick layer chromatography (25% ethyl acetate: pet,. ether 30-60) to yield 7-amino-2-ethoxy-5-ethyl-8-methyl-4H-3,1-benzoxazin-4-one (10 mg). IR (CHCl3): 3500, 3420, 1740, 1650, 1610, 1565 cm-1. H--NMR (CDCl3): 1.20 (t, 3H, CH3), 1.40 (t, 3H, CH3), 2.20 (s, 3H, CH3 --Ar), 3.05 (q, 2H, CH2Ar), 4.50 (q, 2H, CH2O), 6.50 (s, 1H, ArH).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=1[O:14][CH3:15].[C:16](O)(=[O:21])[CH2:17][C:18](O)=[O:19]>O>[Br:6][C:7]1[CH:13]=[C:12]2[C:10](=[CH:9][C:8]=1[O:14][CH3:15])[NH:11][C:18](=[O:19])[CH:17]=[C:16]2[OH:21]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(N)ccc1Br
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cc2[nH]c(=O)cc(O)c2cc1Br
Temperature: 105 °C
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
POCl3 (5.07 mL, 54.4 mmol) was added to a mixture of 4-bromo-3-methoxyaniline (10 g, 49.5 mmol) and malonic acid (5.15 g, 49.5 mmol) with thorough mixing, and the mixture was then heated to 105° C. After 5 minutes, the reaction began to bubble vigorously, and eventually formed a hard foam; heating was continued for 1 hour. After cooling, water (200 mL) was added, and the mixture was stirred for 30 minutes. The solid was filtered off and washed with water. 2N NaOH (300 mL) was added to the solid, and stirring was continued overnight. The remaining solid was filtered off; EtOH (5 mL) was then added to the filtrate; and the basic layer was then acidified with concentrated HCl to pH 2. The resulting solid was then filtered off, washed with water. The solid was then transferred to a flask, and the remaining water was removed by stripping off EtOH (200 mL×2). The solid was then further dried under high vacuum for 15 hours to yield 8.75 g (66%) of the title compound as an off-white solid. LRMS ESI+ (M+H)+ 270.2/272.2.