Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:18])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:17]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1.Cl.C(O)(C)C.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>O1CCOCC1>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:18][C:4]2[C:3]([O:2][CH3:1])=[CH:17][C:7]3[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][CH3:16])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:21][CH:22]=1
Reactant: COCCN1CCc2cc(N)c(OC)cc2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COCCN1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2CC1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
8-Methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (165 mg, 0.000659 mol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (220 mg, 0.00066 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (200 uL) and Isopropyl alcohol (6.6 mL, 0.086 mol) were combined in a microwave vessel. Heat at 130° C. for 20 min. The mixture was treated with 500 mgs of MP-carbonate resin and stirred for 20 min. The mixture was filtered and concentrated and put on high vac overnight. The crude solid was dissolved in DCM and purified on an ISCO column (40 g, SiO2, 100% DCM to MeOH/DCM gradient) to afford N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonam (99 mg, 48%). MP: 92-94° C. 1H-NMR (CDCl3, 400 MHz): 1H-NMR (CDCL3) δ 7.96 (s, 1H), 7.32 (s, 1H), 6.67 (s, 1H), 5.37-5.31 (m, 2H), 3.99-3.95 (broad m, 1H), 3.88 (s, 1H), 3.56 (br s, 2H), 3.38 (s, 1H), 3.28-3.24 (m, 1H), 2.99-2.70 (complex series of m, 11H), 2.26-2.20 (m, 2H), 1.88-1.80 (m, 2H), 1.41-1.28 (m, 6H), 0.92-0.85 (m, 2H). LC/MS: 552.92 (M+H).
Reaction SMILES: C[O-].[Na+].[O:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5]1.[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:5]2[C:6](=[O:14])[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:4]2)=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=C1COc2ccccc2N1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C=C2Oc3ccccc3NC2=O)cc1
Temperature: 25 °C

Procedure:
Sodium methoxide (0.65 g, 0.012 mol) was added in one portion to a mixture of 2H-1,4-benzoxazin-3(4H)-one (1.49 g, 0.01 mol) and 4-dimethylamino benzaldehyde (2.38 g, 0.016 mol) in dry DMF (10 ml). The reaction mixture was refluxed overnight, then cooled to room temperature and poured into crushed ice. The precipitated solid was collected by filtration, washed with water and dried. The crude product was purified by recrystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:13](=[O:18])[C:14]([F:15])([F:16])[F:17])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])(=[O:21])[CH3:20]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1N
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1NC(C)=O

Procedure:
N-[2-(3-Amino-4-methoxyphenyl)ethyl]-2,2,2-trifluoro acetamide (5.24 g., 0.02 moles) in acetic anhydride (20 ml) was boiled at reflux for 2 hr. The anhydride was removed under reduced pressure and the syrupy residue added to water. The grey solid was collected and recrystallised from toluene using charcoal to give the sub-title compound as cream crystals (4.0 g) mp 105°-106°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:12])[CH3:11])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH3:27]>[Cu]Br>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH3:27])[C:10](=[O:12])[CH3:11])[CH3:2]
Reactant: CCc1ccccc1NC(C)=O
Reactant: CCc1ccccc1Br
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccccc1N(C(C)=O)c1ccccc1CC
Temperature: 200 °C
Yield: 67 %

Procedure:
The mixture of the N-(2-ethylphenyl)acetamide (7.35 g, 45.03 mmol), anhydrous K2CO3 (6.22 g, 45.03 mmol), copper(I)bromide (452.2 mg, 3.15 mmol) in 1-bromo-2-ethylbenzene was stirred and heated to 200° C. under argon for 48 h. After cooling the reaction mixture was poured into ice-H2O and extracted with ethyl acetate (2×500 mL), the combined organics were washed with brine, dried over anhydrous K2CO3), filtered and concentrated to dryness. The crude obtained was purified on the ISCO machine using the ethyl acetate-hexane gradient to afford the N,N-bis(2-ethylphenyl)acetamide (8.1 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:29]=1[NH2:30].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:30][C:29]3[CH:31]=[CH:32][C:33]([CH3:35])=[CH:34][C:28]=3[F:27])=[O:21])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: Cc1ccc(N)c(F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: C[Al](C)C
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(C)cc1F
Yield: 38.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 2-fluoro-4-methyl aniline (0.050 g, 0.39 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.047 g of desired product. 1H NMR (DMSO-d6): δ 2.30 (s, 3H), 4.03 (s, 3H), 7.02 (d, J=8.1 Hz, 1H), 7.14 (d, J=11.7 Hz, 1H), 7.51 (t, 1H), 7.58 (d, 1H), 7.65-7.75 (m, 2H), 7.85 (s, 1H), 8.04-8.10 (m, 2H), 10.07 (br s, 1H), 12.65 (br s, 1H); MS (m/z): 469.16 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S:8]2)[CH:2]=1.[OH:13]O>C(O)C.C(OCC)(=O)C.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][S@:8]2=[O:13])[CH:2]=1
Reactant: c1cncc([C@@H]2CCCCS2)c1
Reactant: OO
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[S@@]1CCCC[C@H]1c1cccnc1

Procedure:
A solution of (S)-2-(3-pyridyl)tetrahydro-2H-thiopyran (0.6 g) and copper (II) acetylacetonate (0.8 g) in ethanol (15 ml) is treated with hydrogen peroxide (2 ml; 27.5%), in 0.5 ml portions during a 20 hour period. Two hours after the final addition the reaction mixture is diluted with ethyl acetate (30 ml) and washed with saturated brine (2×30 ml). The combined brine washes are then extracted with ethyl acetate (3×30 ml), the combined ethyl acetate phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure, to give (1R,2S)-2-(3-pyridyl)tetrahydro-2H-thiopyran 1-oxide (0.5 g), in the form of a white solid, m.p. 131° C. [NMR (CDCl3): 8.7(s,2H), 7.7(d,1H); 7.3(s,1H); 3.6(dd,2H); 2.8(t,1H); 2.3-1.5(m,6H). Elemental analysis: C,61.3; H,6.7; N,6.9; S,16.5.%; calculated: C,61.5; H,6.7; N,7.1; S,16.4%.]
Reaction SMILES: [CH2:1]([C:3]12[CH2:29][CH2:28][C:25]3([CH2:27][O:26]3)[CH2:24][CH:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2].[CH3:30][O-:31].[Na+]>>[CH2:1]([C:3]12[CH2:29][CH2:28][C:25]([CH2:27][O:31][CH3:30])([OH:26])[CH2:24][CH:4]1[CH2:5][CH2:6][O:7][C:8]1[C:9]2=[CH:10][C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:23])[CH:18]=3)[C:15]=2[CH:16]=1)[CH3:2]
Reactant: CCC12CCC3(CO3)CC1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Reactant: C[O-]
Agent: [Na+]
Product: CCC12CCC(O)(COC)CC1CCOc1cc3c(cnn3-c3ccnc(C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 50 mL round-bottom flask equipped with rubber septum and nitrogen inlet needle was charged with rac-(2′R,4aS,12bR)-12b-ethyl-9-(2-methylpyridin-4-yl)-1,2,4,4a,5,6,9,12b-octahydrospiro[benzo[4,5]oxepino[3,2-f]indazole-3,2′-oxirane] (93, R1=2-Methylpyridin-4-yl, R2=Ethyl) (0.200 g, 0.513 mmol) and NaOMe (0.5 M in MeOH) (5.1 mL, 2.57 mmol). The resulting solution was allowed to stir at rt for about 16 h, after which the reaction solution was concentrated under reduced pressure. The residue was partitioned between a mixture of water (20 mL) with sat. aq. NH4Cl (5 mL) and EtOAc (25 mL). After separating the layers, the aqueous phase was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The sample was purified on silica gel (4 g, EtOAc). Collection and concentration of the appropriate fractions gave rac-(3R,4aS,12bR)-12b-ethyl-3-(methoxymethyl)-9-(2-methylpyridin-4-yl)-2,3,4,4a,5,6,9,12b-octahydro-1H-benzo[4,5]oxepino[3,2-f]indazol-3-ol (94, R1=2-methylpyridin-4-yl, R2=Ethyl, R3=Methoxymethyl) (198 mg, 92%). LC/MS, method 2, Rt=2.04 min, MS m/z 422 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=5.8 Hz, 1H), 8.20 (s, 1H), 7.86-7.72 (m, 2H), 7.64 (s, 1H), 7.53 (s, 1H), 4.39-4.30 (m, 1H), 3.81-3.71 (m, 1H), 3.33 (s, 3H), 3.19-3.02 (m, 2H), 2.87-2.70 (m, 3H), 2.53-2.45 (m, 1H), 2.38-2.20 (m, 3H), 1.96-1.85 (m, 1H), 1.82-1.65 (m, 2H), 1.63-1.36 (m, 4H), 1.34-1.22 (m, 1H), 0.60 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[C:11](Cl)(Cl)=[O:12].[CH3:15][C:16]([OH:19])([CH3:18])[CH3:17].N1C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[C:16]([O:19][C:11]([N:6]1[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[N:8]=[N:7]1)=[O:12])([CH3:18])([CH3:17])[CH3:15]
Reactant: Brc1ccc2[nH]nnc2c1
Reactant: CC(C)(C)O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nnc2cc(Br)ccc21
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of Example 248B (770 mg; 5 mmol) in THF (5 mL) was added to a solution of 20% phosgene in toluene (10 mL) at −20° C., stirred for 1 hr. at −20° C. then 2 hrs. at r.t., evaporated and dissolved in THF (4 mL). This solution was added to a solution of tBuOH (1 mL), and pyridine (426 mg; 5.4 mmol) in THF (3 mL) at −20° C. then stirred overnight at r.t. The solids were removed by filtration and rinsed with EtOAc. The filtrate was rinsed with water and brine, dried (MgSO4), concentrated, and isolated by flash chromatography (1:1 Et2O:hexane) to provide the desired product (970 mg; 76%).
Reaction SMILES: S(S([O-])=O)([O-])(=O)=[O:2].[Na+].[Na+].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=NO)[CH3:22])=[CH:16][CH:15]=1)([O:12][CH3:13])=[O:11].Cl>O.CO>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=[O:2])[CH3:22])=[CH:16][CH:15]=1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(CC(C)=NO)cc1
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CC(C)=O)cc1

Procedure:
Sodium metabisulphite (131 g) in water (300 ml) was added to 1-(4-carbomethoxyphenyl)propan-2-one oxime (37.5 g) in methanol (200 ml) and the mixture refluxed for 6 hours. The reaction mixture was cooled, concentrated hydrochloric acid (100 ml) added, the mixture extracted with chloroform and the combined chloroform extracts washed with water followed by sodium bicarbonate solution. The chloroform layer was dried (MgSO4) and evaporated to give the title compound as an oil (bp 126°-129°/0.7 mm) which crystallised on standing, (mp 40°-47°). τ (CDCl3) 7.88 (3H, s), 6.28 (2H, s), 6.14 (3H, s), 2.77 (2H, d, J=8 Hz), 2,04 (2H, d, J=8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCCCCCCCBr
Reactant: CCOC(=O)c1csc(S)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCSc1nc(C(=O)OCC)cs1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of 2-mercaptothiazole-4-carboxylic acid ethyl ester (Zhelyazkov, L.; Todorova, N.; Manolova, P. Tr. Nauchnoizsled. Khim.-Farm. Inst., 9, 59-67 (1974); Chem. Abstr., 83, 58706 q) (3.0 g) in DMF (20 ml) is added sodium hydride (0.70 g of 60% dispersion). After 10 min, 1-bromooctane (3.0 ml) is added, and the mixture is stirred at 60° for 30 min. The mixture is poured into water and extracted with ether, and the extracts are dried, filtered, and concentrated. The residue is recrystallized from hexane to provide 2-(octylthio)thiazole-4-carboxylic acid ethyl ester as a colorless solid (3.7 g, 78%). This material is reduced in the usual fashion with lithium aluminum hydride in THF, providing 2-(octylthio)thiazole-4-methanol (2.12 g, 67%) as a colorless oil after chromatography. This is combined with DDQ (1.8 g) in 1,4-dioxane (25 ml) and stirred for 48 hr at room temperature. The reaction mixture is filtered, and the filtrate is concentrated and chromatographed with dichloromethane to provide 2-(octylthio)thiazole-4-carboxaldehyde as a tan solid (1.67 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].CN(C(ON1N=N[C:36]2C=CC=N[C:35]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50](O)(=O)CC.C(N(CC)C(C)C)(C)C.[Cl-].[Cl-].[Ca+2]>CN(C=O)C>[CH2:35]([C:25]1[N:24]([CH3:50])[C:3]2[CH:4]=[C:5]([N:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[CH:10][C:9]3=[O:23])[CH:6]=[CH:7][C:2]=2[N:1]=1)[CH3:36]
Reactant: CCC(=O)O
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (90 mg), HATU (106 mg), propionic acid (0.040 ml), N,N-diisopropylethylamine (0.136 ml) and DMF (2 ml) was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was dissolved in AcOH (2 ml), and the mixture was stirred at 90° C. for 1 h. After evaporation of the solvent, the residue was purified by NH silica gel column chromatography (hexane/EtOAc). The resulting solid was recrystallized from EtOAc/MeOH to give the title compound (44.9 mg) as an off-white solid.
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=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[N:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:20]2[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccncc3)c12

Procedure:
The title compound, white solid (44 mg, 63%), MS (ISP) m/z=282.3 [(M+H)+], mp 323.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available pyridine-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: Cl.[N:2]1([C:11]2[CH:12]=[C:13]([CH2:17][NH:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>C(Cl)Cl>[CH2:31]([O:30][C:28]([N:18]([CH3:19])[CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:12]=1)=[O:29])[CH3:32]
Reactant: CNCc1cccc(N2CCc3ccccc32)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N(C)Cc1cccc(N2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
An ice cold rapidly stirred solution of 7.73 g (28.18 mmole) of 3-(1-indolinyl)-N-methyl benzenemethanamine hydrochloride of Example 8b in 150 ml CH2Cl2 was treated dropwise with a solution of 9.9 ml (70.45 mmole, 2.5 equivalents) of triethylamine in 10 ml CH2Cl2. After stirring for three minutes, a solution of 4.0 ml (42.27 mmole, 1.5 equivalents) ethyl chloroformate in 10 ml CH2Cl2 was added dropwise. At the end of the addition the reaction mixture was permitted to warm to room temperature, stirred for 1 hour and stand about 64 hours. Water (200 ml) was added and the organic layer was separated and washed with 2 N HCl (200 ml), water (300 ml), brine (300 ml), dried (Na2SO4), and concentrated to give 7.64 g (87.3%) of crude product. Chromatography on silica gel (85 g) using ether-methylene chloride afforded 6.73 g (76.9% overall) of an oil of N-ethoxycarbonyl-3-(1-indolinyl)-N-methylbenzenemethanamine, bp>240° C./0.1 mm.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])(=[O:16])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 3,3,3-trifluoropropan-1-ol (618 ml) and pyridine (224 ml). Cool to between 0° C. and 10° C. and add portion-wise p-toluenesulfonylchloride (147 g). Allow to warm to ambient temperature and stir overnight. Add HCl 0.5N (1.6 L), extract with ethyl acetate, combine the organic layers, dry over MgSO4, filter, and evaporate to give the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[N:16]([C:40]2[CH:41]=[N:42][C:43]([O:46][CH:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[CH:44][CH:45]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]1[N:16]([C:40]2[CH:41]=[N:42][C:43]([O:46][CH:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[CH:44][CH:45]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCOCC3)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCOCC3)nc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 270.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogen carbonate (0.32 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C. for 30 min, 4′-({2-ethyl-6-oxo-4-propyl-1-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.2 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (4 mL) N,N′-carbonyldiimidazole (0.09 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.6 g, 27%).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([O:29][C:30]([NH:32][C@H:33]([C:37]([NH:39][C@@H:40]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C@H:41]([OH:56])[CH2:42][C@@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][C@H:44]1[C:49]([NH:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([O:29][C:30]([NH:32][C@H:33]([C:37]([NH:39][C@@H:40]([CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[C:41](=[O:56])[CH2:42][C@@H:43]1[CH2:48][CH2:47][CH2:46][CH2:45][C@H:44]1[C:49]([NH:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[O:50])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C[C@@H]1CCCC[C@H]1C(=O)NC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)C[C@@H]1CCCC[C@H]1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
220 mg (0.59 mmol) of pyridinium dichromate were added to a solution of 48 mg (0.08 mmol) of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide in 1 ml of dimethylformamide and the mixture was stirred at room temperature for 18 hours. 10 ml of water were added and the mixture was extracted with two 10 ml portions of ethyl acetate. The combined extracts were washed with two 10 ml portions of water, dried over anhydrous magnesium sulphate and evaporated. The crude product was chromatographed on a column of silica gel using 4% methanol in dichloromethane for the elution to give 31 mg of 2(S)-[3(S)-[[N-(benzyloxycarbonyl)-L-valyl]amino]-2-oxo-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a white solid of melting point 186°-188° C.; MS m/e 578 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22]([C:28]#[N:29])=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[CH2:30]=[O:31]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[C:22]([C:28]#[N:29])=[N:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH2:30][OH:31])[N:10]=1
Reactant: C=O
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)n[nH]c1=O
Solvent: O
Solvent: CO
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Temperature: 100 °C
Yield: 92.1 %

Procedure:
A solution of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (2.0 g, 4.60 mmol) in methanol (30 mL) was treated with a solution of 37% aqueous formaldehyde (7.5 mL, 100.72 mmol). The resulting mixture was heated to 100° C. for 18 h. At this time, the reaction mixture was cooled to 25° C. and was diluted with water. The resulting precipitate was collected by filtration, was washed with water and was dried in vacuo to afford 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (1.97 g, 92%) as a light yellow solid. ES+-HRMS m/e calcd for C18H14N6O5Cl2 (M+H+) 465.0476, found 465.0475.