Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.Cl.[CH3:27][N:28]([CH3:39])[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH2:34][CH2:33][CH2:32]2>CN1C(=O)CCC1.O>[CH3:27][N:28]([CH3:39])[C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([C:2]1[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:34][CH2:33][CH2:32]2
Reactant: CN(C)c1ccc2c(c1)CCCN2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(N(C)C)ccc43)nc2c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (420 mg, 1.76 mmol,) in NMP (3 mL) was added DIEA (343 mg, 2.65 mmol), N,N-dimethyl-1,2,3,4-tetrahydroquinolin-6-amine hydrochloride (400 mg, crude) and the reaction was stirred for 2 h at 130° C. in an oil bath. The resulting solution was diluted with water (100 mL), and the solids were collected by filtration to give methyl 3-[6-(dimethylamino)-1,2,3,4-tetrahydroquinolin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a red solid (260 mg, 39%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH2:16][CH:10]([CH2:11][N:12]([C:17]([O:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:18])[CH2:13]2)[CH2:9]1)C1C=CC=CC=1.[O:25]1C[CH:26]1[CH2:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([O:29][CH2:28][CH:26]([OH:25])[CH2:1][N:8]2[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][N:12]([C:17]([O:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=[O:18])[CH2:11]3)[CH2:15]2)=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: CC(C)(CO)OC(=O)N1CC2CC(CN(Cc3ccccc3)C2)C1
Product: CC(C)(CO)OC(=O)N1CC2CC(CN(CC(O)COc3ccc(C#N)cc3)C2)C1
Yield: 88 %

Procedure:
2-Hydroxy-1,1-dimethylethyl 7-benzyl-3,7-diazabicyclo[3.3.1]-nonane-3-carboxylate (from step (c) above) was debenzylated according to the method described in Example E(b) above and subsequently reacted with 4-(2-oxiranylmethoxy)benzonitrile (see Example A above) in accordance with the method described in Example 2 above to give the title compound in an overall yield of 88%.
Reaction SMILES: [Sn](CC)(CC)(CC)[CH2:2][CH3:3].N#N.[Si:12]([O:19][CH2:20][CH:21]1[CH2:35][C:34]2[C:23](=[CH:24][C:25]3[N+:30]([O-:31])=[N:29][C:28](I)=[N:27][C:26]=3[CH:33]=2)[CH2:22]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>O1CCOCC1.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>[Si:12]([O:19][CH2:20][CH:21]1[CH2:35][C:34]2[C:23](=[CH:24][C:25]3[N+:30]([O-:31])=[N:29][C:28]([CH2:2][CH3:3])=[N:27][C:26]=3[CH:33]=2)[CH2:22]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CC[Sn](CC)(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCC1Cc2cc3nc(I)n[n+]([O-])c3cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1COCCO1
Product: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CO[Si](C)(C)C(C)(C)C)C3
Yield: 87.9 %

Procedure:
Et4Sn (1.47 mL, 7.5 mmol) and Pd(PPh3)4 (154 mg, 0.99 mmol) were added to a N2-purged, stirred solution of iodide 133 (2.27 g, 4.97 mmol) in dry dioxane (30 mL) at 20° C. and the reaction mixture was stirred at reflux temperature under N2. After 5 h more Et4Sn (1.5 mL, 7.5 mmol) and Pd(PPh3)4 (150 mg, 0.98 mmol) were added and the mixture stirred at reflux temperature for 5 h. The mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of EtOAc/pet. ether, to give 1-oxide 135 (1.57 g, 88%) as a yellow solid: mp (EtOAc/pet. ether) 63-65° C.; 1H NMR δ 8.23 (s, 1H, H-9), 7.72 (s, 1H, H-5), 3.59-3.66 (m, 2H, CH2O), 3.14-3.24 (m, 2H, CH2), 2.92-3.06 (m, 4H, H-6, H-8), 2.72-2.83 (m, 1H, H-7), 1.43 (t, J=7.5 Hz, 3H, CH3), 0.87 [s, 9H, SiC(CH3)3], 0.04 [s, 6H, Si(CH3)2]. Anal. calcd for C19H29N3O2Si: C, 63.5; H, 8.1; N, 11.7. Found: C, 63.3; H, 8.2; N, 11.4%.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:8][C:7]1[C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)=[N:3][C:4]([S:9][CH3:10])=[N:5][CH:6]=1
Reactant: OB(O)c1cccnc1
Reactant: CSc1ncc(C)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: CSc1ncc(C)c(-c2cccnc2)n1
Yield: 83 %

Procedure:
A mixture of 4-chloro-5-methyl-2-methylsulfanyl-pyrimidine (1.24 g, 7.1 mmol), pyridine-3-boroni acid (1.04 g, 8.46 mmol), Na2CO3 (863 mg, 7.76 mmol), PPh3 (186 mg, 0.71 mmol) and Pd(OAc)2 (40 mg) in n-PrOH (50 ml) was refluxed for 2 hours. The solvent was then evaporated under vacuum and the crude was partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (1-1) to afford 1.28 g of the title compound as a white solid (83% yield)
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.[CH2:13]([NH2:15])[CH3:14]>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH:15][CH2:13][CH3:14])=[O:7]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Reactant: CCN
Product: CCNC(=O)c1cc(Cl)cc(Cl)c1O

Procedure:
Prepared from 3,5-dichloro-2-hydroxybenzoic acid and ethylamine using the method of preparation 57 to give the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[CH:15]=[CH:14][S:13][C:4]3=[N:5][CH:6]=2)=[O:10])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnc2sccc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sccc2c1O
Temperature: 190 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of ethyl 4-hydroxythieno[2,3-b]pyridine-5-carboxylate (J. Heterocyclic Chem. 1977, 14, 807) (0.447 g) and 4-chlorobenzylamine (2.43 mL) is stirred at 190° C. for 1 h. The reaction is then allowed to cool to rt and is diluted with toluene (5 mL). The resulting precipitate is filtered off and washed with toluene followed by hexanes to yield an off-white solid. This material is recrystallized from acetic acid/water then ethanol to yield 0.285 g (45%) of the title compound as a white solid.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[C:2]=[S:3].Cl.[NH2:15][CH2:16][C:17]#[N:18]>C(N(CC)CC)C>[NH2:15][C:16]1[N:1]([CH:4]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)[C:2](=[S:3])[NH:18][CH:17]=1
Reactant: S=C=NC1CCc2ccccc2C1
Reactant: N#CCN
Agent: Cl
Solvent: CCN(CC)CC
Product: Nc1c[nH]c(=S)n1C1CCc2ccccc2C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-isothiocyano-1,2,3,4-tetrahydronaphthalene (1.92 g, 10.1 mmol), prepared as in Example 10, and aminoacetonitrile hydrochloride (0.94 g, 10.1 mmol) in 1.41 mL of triethylamine was heated at 60° C. for 1 hour. The solvent was evaporated and the residue was purified by flash chromatography (elution: methylene chloride followed by 3% methanol in methylene chloride). The purified residue was recrystallized from ethyl acetate/hexane. The residue (1.06 g) and 44 mL of 0.1N potassium hydroxide was stirred under nitrogen for 15 minutes. The residue was isolated by filtration, washed with water, air dried and then stirred with methylene chloride. Filtration and drying gave 5-amino-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione, m.p. 169°-171° C.
Reaction SMILES: [N:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)C=C[CH:2]=1.N1C2C=CC=CC=2NC=1.[Br:24][C:25]1C=CC(I)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cu](I)I>[Br:24][C:25]1[CH:9]=[CH:10][C:11]([N:12]2[C:13]3[CH:8]=[CH:7][CH:6]=[CH:5][C:14]=3[N:1]=[CH:2]2)=[CH:27][CH:26]=1
Reactant: Brc1ccc(I)cc1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc(-n2cnc3ccccc32)cc1
Temperature: 110 °C
Reaction time: 40 h
Yield: 64 %

Procedure:
To a mixture of copper iodide (0.16 g, 0.85 mmol) and 1,10-phenanthroline (0.31 g, 1.7 mmol) in anhydrous DMF (4.2 mL) was added benzimidazole (1.00 g, 8.5 mmol), 1-bromo-4-iodobenzene (2.88 g, 10.1 mmol), and cesium carbonate (5.53 g, 17 mmol) and the reaction mixture was heated to 110° C. and allowed to stir for 40 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between water and dichloromethane and the organic layer was separated, dried (Na2SO4) and the solvent removed under reduced pressure. Purification by flash column chromatography (silica, petroleum ether:ethyl acetate 1:1) provided the title compound (64%). LCMS (ESI+) 274.2 (MH+).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15]([OH:17])=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O[C:19]1[CH:35]=[CH:34][C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH:31]([N:28]1[CH2:29][CH2:30][N:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([O:16][C:15](=[O:17])[CH:14]=[C:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:35][CH:34]=2)[CH2:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: O=C(O)C=C1c2ccccc2-c2ccccc21
Reactant: CC(C)N1CCN(C(=O)c2ccc(O)cc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc(OC(=O)C=C3c4ccccc4-c4ccccc43)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 20 ml chloroform solution containing 2.67 g (12 mmol) of 9-fluorenylidene acetic acid, 2.48 g (10 mmol) of 1-(4-hydroxybenzoyl)-4-isopropylpiperazine and 122 mg (1 mmol) of 4-dimethylaminopyridine was added 2.48 g (12 mmol) of dicyclohexyl carbodiimide, and the mixture was stirred at room temperature for 3 hours. Any insoluble matter which had formed was removed by filtration, and the filtrate was concentrated under reduced pressure. Thereafter, any insoluble matter was removed by filtration using 20 ml of ethyl acetate, and the filtrate was extracted up to 60 ml of 1N hydrochloric acid. After being washed with ethyl acetate, the extract was neutralized with sodium hydrogen carbonate and extracted up to 60 ml of chloroform. After being washed twice with water, the extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain yellow crystals. Recrystallization of the crystals from ethyl acetate-petroleum ether gave yellow prismatic crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].P(Br)(Br)[Br:22].C([O-])(O)=O.[Na+]>C(OCC)C>[Br:22][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[C:3]([C:17]([F:20])([F:19])[F:18])[CH:4]=2)=[CH:8][CH:9]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: FC(F)(F)c1cc(Oc2ccc(CBr)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
To the solution of (4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl)methanol (4.5 g, 14.87 mmol) in Diethyl ether (100 mL) was added PBr3 (1.402 mL, 14.87 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 5 h. The mixture was poured into ice water and neutralized with sat. NaHCO3 solution to pH-7, then extracted with Et2O. The organic was dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (3.2 g, 7.88 mmol, 53.0% yield) as a light yellow solid. LCMS: rt=2.01 min, [M+H+]=365, 367.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1)=[O:4].O.O.O.[O-:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+].O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(S(C)(=O)=O)nc1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(Oc2ccccc2)nc1
Temperature: 100 °C
Yield: 65.7 %

Procedure:
To a solution of 2-methanesulfonyl-pyrimidine-5-carboxylic acid methyl ester (0.8 g, 3.7 mmol) in NMP (3 mL) is added sodium phenoxide trihydrate (0.68 g, 4 mmol). The mixture is heated at 100° C. in Biotage Microwave for 60 sec. The reaction is poured into water and the precipitate is collated by filtration and dried to afford 2-phenoxy-pyrimidine-5-carboxylic acid methyl ester (0.56 g, 66%) as a solid. MS: 231 (M+H); 1H NMR (300 MHz, CDCl3): δ 4.75 (s, 3H), 7.19-7.33 (m, 3H), 7.46 (t, 2H) 9.10 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.CCCCCC>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:40])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine (62.7 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.6 ml) at room temperature, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure. The resultant residue was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate) to provide the titled compound (48.0 mg, 54%) as white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.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>[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:2]2[N:7]=[C:6]([CH2:8][N:9]3[C:17](=[O:18])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]3=[O:19])[CH:5]=[C:4]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[N:3]=2)[CH:31]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)N1Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccnc2)n1
Temperature: 80 °C
Yield: 33.2 %

Procedure:
To a solution of 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-ylmethyl]-isoindole-1,3-dione (0.30 g, 0.72 mmol) in DME (4 mL) and H2O (1 mL) was added 3-pyridine boronic acid (0.09 g, 0.72), Pd(PPh3)4 (0.04 g, 0.04 mmol), and K3PO4 (0.21 g, 1.01 mmol) at rt. The resulting mixture was heated to 80° C. for 12 hours then allowed to cool to rt. At which time the mixture was partitioned between H2O (5 mL) and EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×5 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated and purified by FCC to afford the title compound as a colorless solid (0.11 g, 33%). MS (ESI): mass calcd. for C25H15F3N4O2, 460.1; m/z found, 461.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([OH:5])=O.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:26])=[CH:10][CH2:11][CH2:12][C:13]([CH3:25])=[CH:14][CH2:15][CH2:16][C:17]([CH3:24])=[CH:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[C:3]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:5]
Reactant: C1CCNC1
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCC1

Procedure:
Starting materials: 2,6,10,14-tetramethyl-18-oxo-2,6,10,14-nonadecatetraenoic acid and pyrrolidine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C:9]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:10][CH:11]([OH:14])CO)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:33])[N:7]([C:9]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[CH2:18][C:19]([F:20])([F:21])[F:22])[CH2:10][CH:11]=[O:14])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(CC(O)CO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C)C(=O)CC(F)(F)F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(CC=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C)C(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
tert-Butyl(1-(3,4-dichlorophenyl)-3,4-dihydroxy-1-{[methyl-(3,3,3-trifluoro-propionyl)-amino]-methyl}-butyl)-methyl-carbamate (1.95 g) was dissolved in a mixture solvent of tetrahydrofuran (20 mL) and water (10 mL). Sodium periodate (1.61 g) was added thereto, and the mixture was stirred for 1 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (1.79 g, 98%). The compound was used in the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:37]([CH2:40][CH3:41])=[C:38]=[O:39]>C1COCC1.O>[CH2:40]([NH:37][C:38]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]([CH:16]2[CH2:25][C:24]3[CH:23]=[C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH:35][CH3:36])=[O:34])[CH:28]=4)[CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1)=[O:39])[CH3:41]
Reactant: CCN=C=O
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CN)cc(C(F)(F)F)c2)CC3)ccn1
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C(=O)NC)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[7-({[3-(aminomethyl)-5-(trifluoromethyl)phenyl]amino}-carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide (0.411 g, 0.824 mmol) and TEA (0.23 mL, 1.65 mmol) in THF (10 mL) was added isocyanatoethane (0.10 mL, 1.26 mmol) in THF (5 mL) dropwise. The reaction mixture was allowed to stir at rt overnight. The reaction mixture was diluted with water and extracted with DCM. The organic solutions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography and then converted to the HCl salt of 4-{[7-({[3-({[(ethylamino)carbonyl]amino}methyl)-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide I-420. 1H NMR (400 MHz, d6-DMSO; HCl salt) δ: 10.42 (s, 1H), 8.84 (dd, 1H), 0.51 (dd, 1H), 8.03 (s, 1H), 7.68 (s, 1H), 7.41 (dd, 1H), 7.22-7.26 (m, 2H), 7.17 (dd, 1H), 7.01 (dd, 1H), 7.96 (dd, 1H), 4.23 (s, 2H), 3.01 (dd, 2H), 2.94 (dd, 2H), 2.80-2.90 (m, 3H), 2.77 (dd, 3H), 2.08-2.14 (m, 1H), 1.75-1.86 (m, 1H), and 0.98 (dd, 3H). LCMS: (FA) ES+ 570.7, ES− 568.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([CH2:14][NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[C@H:10]([CH2:14][NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2ccc(Cl)s2)[C@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)[C@H](CNC(=O)c2ccc(Cl)s2)C1
Reaction time: 3 h
Yield: 72.9 %

Procedure:
81.1 To a solution of (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, prepared according to example 79.5) in 10 ml of CH2Cl2 was added at 5° C. 2.30 ml of NEt3 and 1.59 g of SO3-pyridine complex, the solution was warmed to 22° C. and stirring was continued for 3 h. The mixture was washed with aqueous NH4Cl, the organic layer was dried and evaporated. The residue was chromatographed on silica (heptane/AcOEt, 2:1) to give 435 mg of (R)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale yellow solid. MS 303.0 ([M-isobutene+H]+)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])O1.[CH3:20][CH:21]([O:23][C:24](=[O:41])[NH:25][C@H:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)[N:29]([C:37](=[O:39])[CH3:38])[C@@H:28]([CH3:40])[CH2:27]1)[CH3:22].C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[C:37]([N:29]1[C:30]2[C:35](=[CH:34][C:33]([C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:32][CH:31]=2)[C@H:26]([NH:25][C:24]([O:23][CH:21]([CH3:22])[CH3:20])=[O:41])[CH2:27][C@@H:28]1[CH3:40])(=[O:39])[CH3:38]
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A flask was charged with methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.355 g, 1.354 mmol), 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 100) (0.5 g, 1.354 mmol), a saturated NaHCO3 aqueous solution (1.5 mL, 1.354 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.111 g, 0.135 mmol) then filled with 1,4-dioxane (7 mL) and the resulting mixture was degassed by bubbling nitrogen into it then stirred at 100° C. for 1 h under microwave irradiation before being cooled to room temperature, filtered through celite and concentrated in vacuo. The residue was partioned between EtOAC (30 mL) and water (30 mL) and the layers were separated. The organic phase was washed with brine (30 mL), dried under MgSO4 and concentrated in vacuo. Purification of the residue on Sp4 using a 50 G silica cartridge (gradient:20 to 80% AcOEt in Hexanes) gave methyl 3-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (319 mg, 55%).