Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([CH3:22])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:19]=[C:20]([CH3:22])[CH:21]=[C:16]([CH3:15])[CH:17]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)cc(-c2nc3cc(F)ccc3c(Cl)c2C)c1
Temperature: 120 °C

Procedure:
Prepared according to procedure F using 2,4-dichloro-7-fluoro-3-methylquinoline (500 mg, 2.173 mmol), 3,5-dimethylbenzeneboronic acid (326 mg, 2.173 mmol), sodium carbonate (1.15 g, 10.87 mmol) and Pd(PPh3)4 (251 mg, 0.217 mmol) in toluene/water (4 mL:1 mL) and heating in the microwave for 90 min at 120° C. After purification 4-chloro-2-(3,5-dimethylphenyl)-7-fluoro-3-methylquinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=300 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:7].[BH4-].[Na+]>C(O)C.C1COCC1>[CH3:1][N:2]([CH3:3])[CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14])[OH:7]
Reactant: COC(=O)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: CNC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(C(O)CN(C)C)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dimethylamine (33% in ethanol, 156 ml) was added to a stirred suspension of methyl 5-(bromoacetyl)-2-(phenylmethoxy)benzoate (105.8 g) in absolute ethanol (1 l) and THF (1 l). The resulting solution was stirred at RT for 2 h, treated with NaBH4 (25 g) and stirred at RT overnight. The solvent was removed in vacuo and H2O (500 ml) was added to the residue. The mixture was extracted with EA (2×500 ml), the combined extracts were washed with H2O and BR, dried (Na2SO4) and concentrated in vacuo. The product was purified twice by [FCS] eluted with EA-methanol-triethylamine (80:20:1) to give the title compound as a fawn solid (59.8 g) m.p. 79°-81°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1.C(=O)(O)[O-].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][CH2:6][N:7]([C:16]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=1)[CH:8]1[CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)CCNC1CCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Reaction time: 2.5 h
Yield: 47 %

Procedure:
A solution of 1.9 g (0.011 mole) of 3-cyclobutylaminopropanoic acid ethyl ester in 7 mL of acetonitrile was added dropwise to a mixture of 1.74 g (0.09 mole) of 2,4-dichloro-5-nitro-pyrimidine and 2.07 g (0.021 mole) of potassium bicarbonate and 20 mL of acetonitrile at ambient temperature over 45 mins. The mixture was stirred for 2.5 hours, then diluted with 45 mL of ethyl acetate. The mixture was filtered, concentrated under reduced pressure and the residue purified by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-90:10) to give 1.7 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-propanoic acid ethyl ester (IV-23).
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:15][S:16]([O:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 3 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
In a 4 neck 5 L flask was added (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 719 mmol) in 2.5 L of THF. The material was cooled to 3° C. and methanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portions over 10 minutes. N-ethyl-N-isopropylpropan-2-amine (126 ml, 719 mmol) was added through an addition funnel over 12 minutes. The reaction was stirred in the ice bath for 30 minutes and then at ambient temperature for 1 hour. The reaction was filtered and the solids washed with MTBE (about 3 L). The filtrate was concentrated and the residue was purified over silica gel (7:1 to 3:1 Hexanes/EtOAc) to afford an oil that slowly solidified under vacuum. The solids were ground using a mortar and pestle, washed with hexanes (about 1000 mL) and dried to afford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 531 mmol, 73.8% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Oc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: O
Product: NS(=O)(=O)Oc1ccc(Cl)c(Cl)c1
Yield: 82.2 %

Procedure:
A solution of 16.3 g (0.1 mole) of 3,4-dichlorophenol in 100 ml of toluene was heated at reflux utilizing a Dean-Stark trap to remove any water that may have been present. The solution was cooled in an ice bath, treated with 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate, and heated at reflux overnight. The solution was cooled in an ice bath, vigorously stirred, and treated dropwise with water until gas evolution ceased. The solid which precipitated was collected by filtration, washed with water and benzene, dried, and recrystallized from benzene to yield 19.9 g (82%) of a white solid, mp 121°-123° C.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].O[CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=1
Reactant: CC(C)(C)OC(=O)n1cnc(CO)c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1cnc(CON2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (2.70 g, 16.6 mmol), tert-butyl 4-(hydroxymethyl)-1H-imidazole-1-carboxylate 120 (Bull. Chem. Soc., Japan, 2002, Vol 75, No 11, 2517-2526, 1.64 g, 8.27 mmol) and triphenylphosphine (4.34 g, 16.6 mmol) in THF (100 mL) was added DIAD (3.52 mL, 18.2 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 121 (1.7 g, 61.96) as a white foam.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[O:6][CH2:5]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1.C1(C)C(C)=CC=CC=1>[CH2:17]([O:3][CH:4]1[CH2:9][O:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[O:6][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: OC1COC(c2cccc(F)c2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1C
Product: Fc1cccc(C2OCC(OCc3ccccc3)CO2)c1
Yield: 71.2 %

Procedure:
A slurry of sodium hydride (3.7 g of 62%, 0.096 mole) in benzene (100 ml) and xylene (100 ml) was stirred at ambient temperature while 5-hydroxy-2-(3-fluorophenyl)-1,3-dioxane (18.9 g, 0.096 mole) was added dropwise during 1 hour. This mixture was stirred 1 additional hour, then to it was added benzyl chloride (12.2 g, 0.096 mole) during 1/2 hour. The mixture was heated under reflux for 18 hours, cooled, filtered and the filtrate washed with water (2 × 200 ml). The washed solution was dried over magnesium sulfate and concentrated to give 19.7 g of oil which was distilled under 2 × 10-4 mm pressure to give three fractions distilling at bath temperature of 98°-119° C (cut 1); 119°-139° C (cut 2); and 139°-143° C (cut 3). Cut 2 (9.1 g) was found by nmr analysis to be a mixture of cis and trans-dioxanes and the corresponding dioxolane. Cut 3 (1.5 g, m.p. 70°-71° C) was found by nmr to be 100% cis-5-benzyloxy-2-(3-fluorophenyl)-1,3-dioxane and this cut was used in further studies.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:53])[CH:15]([C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH:47]2[CH2:49][CH2:48]2)(=[O:46])=[O:45])=[C:40]([CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)[CH2:16][C@H:17]1[CH2:37][CH2:36][C:19]2(O[C@H](C3C=CC=CC=3)[C@@H](C3C=CC=CC=3)[O:20]2)[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CC(C)=O.C(=O)([O-])O.[Na+]>O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:53])[C@@H:15]([C:38]1[CH:43]=[CH:42][C:41]([S:44]([CH:47]2[CH2:49][CH2:48]2)(=[O:46])=[O:45])=[C:40]([CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)[CH2:16][C@H:17]1[CH2:37][CH2:36][C:19](=[O:20])[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CC[C@H](C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)C1
Temperature: 25 °C
Yield: 41 %

Procedure:
A mixture of (4R)-4-benzyl-3-{2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]propanoyl}-1,3-oxazolidin-2-one (70 g), 4 M hydrochloric acid (140 mL), and acetone (560 mL) was stirred under heating and reflux for 2 hours. After leaving it to be cooled at room temperature, saturated aqueous sodium hydrogen carbonate solution/water (1/1, 200 mL) was added thereto, and the organic solvent was evaporated under reduced pressure, followed by extraction with ethyl acetate (200 mL×2). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70→50:50) to obtain (4R)-4-benzyl-3-{(2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoyl}-1,3-oxazolidin-2-one (21 g) as a colorless amorphous substance.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]2[C@@H:7]([CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10]2)[CH2:6][CH2:5]1)=[N+]=[N-].[H][H]>[Ni].C(O)C>[CH2:12]([N:9]1[CH2:10][C@@H:11]2[C@@H:4]([NH2:1])[CH2:5][CH2:6][C@@H:7]2[CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Agent: [Ni]
Solvent: CCO
Product: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reaction time: 24 h

Procedure:
(3aR,4S,6aS)-4-Azido-2-benzyloctahydrocyclopenta[c]pyrrole (1.70 g, 7.02 mmol), Raney®-nickel (0.46 g, 20% wt), and ethanol (47 mL) were combined in a Parr stirrer reactor. The reactor was pressured with hydrogen gas to 30 psi and the reaction mixture was agitated for 24 hours. The slurry was filtered to provide (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in ethanol.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][N:20]2[C:24]3[CH:25]=[C:26]([O:29][CH2:30][C:31]4[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=4)[CH:27]=[CH:28][C:23]=3[N:22]=[C:21]2[CH2:37][C:38]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:39]([OH:41])=[O:40])=[C:17]([F:48])[CH:16]=1>>[CH2:42]([C:38]([CH2:37][C:21]1[N:20]([CH2:19][C:18]2[CH:46]=[CH:47][C:15]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)=[CH:16][C:17]=2[F:48])[C:24]2[CH:25]=[C:26]([O:29][CH2:30][C:31]3[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=3)[CH:27]=[CH:28][C:23]=2[N:22]=1)([CH2:44][CH3:45])[C:39]([OH:41])=[O:40])[CH3:43]
Reactant: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(Br)cc1F)C(=O)O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCC(CC)(Cc1nc2ccc(OCc3ccn(C)n3)cc2n1Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1F)C(=O)O

Procedure:
The title compound was prepared in a manner analogous to that in Example 144 using (4-(trifluoromethyl)phenyl)boronic acid and 2-((1-(4-bromo-2-fluorobenzyl)-6-((1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)methyl)-2-ethylbutanoic acid and (4-(trifluoromethyl)phenyl)boronic acid. MS (ESI): mass calcd. for C33H32F4N4O3, 608.24; m/z found, 609.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=8.3, 2H), 7.73 (d, J=8.4, 2H), 7.57-7.54 (m, 1H), 7.54-7.52 (m, 1H), 7.49 (d, J=2.3, 1H), 7.41 (dd, J=8.0, 1.8, 1H), 7.03 (d, J=2.3, 1H), 6.93 (dd, J=8.8, 2.3, 1H), 6.88 (t, J=7.9, 1H), 6.28 (d, J=2.3, 1H), 5.61 (s, 2H), 5.01 (s, 2H), 3.81 (s, 3H), 3.12 (s, 2H), 1.90-1.73 (m, 4H), 0.88 (t, J=7.5, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13]1>ClCCCl>[O:22]=[C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]1[NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: Nn1cnc2ccccc2c1=O
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCCl
Product: O=C(Nc1ccc(F)cc1)Nn1cnc2ccccc2c1=O
Temperature: 0 °C

Procedure:
4-Fluorophenyl isocyanate (0.74 mL, 6.51 mmol) is added to a mixture of 3-amino-4(3H)-quinazolinone (1.00 g, 6.21 mmol) in 1,2-dichloroethane at reflux. The reaction mixture is heated at reflux for 18 hours, cooled to 0° C. and filtered. The filter cake is washed with ether and dried to give the title product as a white solid, 1.64 g (89%), mp 237°-238° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:34]=[CH:33][N:32]=[C:31]([C:30]([F:41])([F:40])[F:29])[CH:36]=1
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccnc(C(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 90 °C
Reaction time: 18 h
Yield: 46.5 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.14 mmol) were added 2-(trifluoromethyl)pyridin-4-ylboronic acid (39 mg, 0.20 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (11 mg, 0.01 mmol) and 204 μl of a 2M aqueous solution of cesium carbonate in dioxane (2.5 ml). The mixture was stirred under argon atmosphere at 90° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography using SP1® Purification System (0% to 70% hexane/AcOEt in 25 CV, 70% AcOEt in 10 CV) to give 33 mg (48% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.B(O)(O)[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1ccc(-c2cc(Cl)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light brown solid (72 mg, 89%), MS (ISP) m/z=325.5 [(M+H)+], mp 251.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available p-tolylboronic acid (44.2 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][N:19]1[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=2[C:21]2[CH:41]=[CH:42][CH:43]=[CH:44][C:20]1=2>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][N:19]2[C:25](=[O:26])[CH:24]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]3[CH:37]=[CH:38][CH:39]=[CH:40][C:22]=3[C:21]3[CH:41]=[CH:42][CH2:43][CH2:44][C:20]2=3)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2C2=C1CCC=C2

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (Ex. B) and 5-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7-K), the title compound was prepared. The reaction was monitored by tlc (Rf=0.35, 3% MeOH/CHCl3) and product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:24](=[O:25])[C:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:22][N:21]([CH3:33])[CH:20]=3)=[O:18])=[C:11]([F:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][N:36]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:34][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:39]3[CH:38]=[N:37][N:36]([CH3:35])[CH:40]=3)[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:24](=[O:25])[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][N:21]([CH3:33])[CH:20]=1)=[O:18]
Reactant: Cn1cc(C(=O)Nc2cc(F)c(Oc3ccnc(Cl)c3)cc2F)c(=O)c(-c2ccc(F)cc2)c1
Reactant: Cn1cc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(C(=O)Nc2cc(F)c(Oc3ccnc(-c4cnn(C)c4)c3)cc2F)c(=O)c(-c2ccc(F)cc2)c1
Temperature: 80 °C
Yield: 87.7 %

Procedure:
N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (0.125 g, 0.221 mmol) was combined with 1-methyl-pyrazole-4-boronic acid (0.058 g, 0.277 mmol) and K2CO3 (0.092 g, 0.664 mmol) in dioxane (2 mL) and H2O (0.333 mL), the mixture sparged with argon, treated with Pd(PPh3)4 (0.013 g, 0.011 mmol), sparged again with argon, and heated to 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, washed with H2O, then brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (103 mg, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.50 (s, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.57 (dd, J=12.7, 7.2 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J=2.3 Hz, 1H), 7.98 (s, 1H), 7.70 (dd, J=8.6, 5.6 Hz, 2H), 7.58 (dd, J=11.0, 7.4 Hz, 1H), 7.30-7.22 (m, 3H), 6.74 (dd, J=5.7, 2.5 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H); MS (ESI) m/z: 532.2 (M+H+).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:14])=O)C1C=CC=CC=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>[Pd]>[CH2:26]([O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:44]([C:41]2[CH:40]=[CH:39][C:38]([O:37][CH3:36])=[CH:43][CH:42]=2)(=[O:46])=[O:45])[CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:21][CH:20]=1)=[O:24])[CH3:27]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Product: CCOC(=O)Cc1ccc(NC(=O)C(COC2CCCCO2)NS(=O)(=O)c2ccc(OC)cc2)cc1
Yield: 2.6 %

Procedure:
The procedure described in Example 15 was repeated, except that (RS)-2-(benzyloxycarbonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(tetrahydropyran-2-yloxy)propanamide (0.68 g) was hydrogenolyzed in the presence of 10% Pd-C, and then, reacted with 4-methoxybenzenesulfonyl chloride (575 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-methoxybenzenesulfonylamino)-3-(tetrahydropyran-2-yloxy)propanamide (3 19 mg).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([NH:18][C@H:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:20][CH3:21])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:4])=[O:3].[C:34]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH3:34][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[C:6]1[C:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]([NH:18][C@H:19]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][CH3:21])=[O:17])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: O=C([O-])[O-]
Reactant: CC[C@H](NC(=O)c1c(NS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)c1c(N(C)S(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
A solution of 3-[(methylsulfonyl)amino]-2-phenyl-N-[(1S)-1-phenylpropyl]quinolin-4-carboxamide (1) (459 mg, 1.0 mmol) in 5 ml DMF was added Cs2CO3 (325.8 mg, 1.0 mmol) and CH3I (62.3 μL, 1.0 mmol). The reaction mixture was stirred at RT under N2 for 2 h. All solvent was removed in vacuo and the residue was partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution, dried over sodium sulfate and then concentrated in vacuo. The residue was purified by recrystallization from ether/CH2Cl2 to give the title compound (210 mg, 44.4%) as a solid. 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H), 1.97 (m, 2H), 2.71 (s, 3H), 3.43 (s, 3H), 5.10 (q, 1H), 5.14 (b, 1H), 7.32 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.42 (m, 2H). MS APCI, m/z=474 (M+1). LCMS: 2.32 min.