Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][O:31]C(OCC)C)C>CO>[CH3:13][O:15][C:16](=[O:37])[CH2:17][O:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C@@H:24]1[CH2:30][OH:31]
Reactant: CCOC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1COC(C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CO
Reaction time: 17 h
Yield: 64.4 %

Procedure:
p-Toluenesulfonic acid hydrate (620 mg, 3.26 mmol) was added to a solution of {(Z)-4-[(R)-2-(1-ethoxyethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-enyloxy}-acetic acid ethyl ester (1.10 g, 3.08 mmol) in MeOH (10 mL). After 17 h at rt, the reaction was quenched with saturated aqueous NaHCO3 (20 mL) and the mixture was extracted with CH2Cl2 (3×30 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (40% EtOAc/CH2Cl2→60% EtOAc/CH2Cl2, gradient, then 7% MeOH/CH2Cl2) afforded 538 mg (64%) of [(Z)-4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-enyloxy]-acetic acid methyl ester.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[N:13][C:14]([C:17]([CH3:22])([CH3:21])[C:18]([NH2:20])=[O:19])=[CH:15][CH:16]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:22])([CH3:21])[C:18]([NH2:20])=[O:19])=[N:13][CH:12]=1
Reactant: CC(C)(C(N)=O)c1ccc(NC(=O)OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C(N)=O)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.9 %

Procedure:
To a solution of the crude benzyl(6-(1-amino-2-methyl-1-oxopropan-2-yl)pyridin-3-yl)carbamate (880 mg) obtained in Step E of Example 153 in ethanol (30 mL) was added 10% palladium-carbon (90 mg), and the mixture was stirred overnight at room temperature under hydrogen atmosphere (at normal pressures). The palladium-carbon was removed by filtration through Celite, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (100 mg).
Reaction SMILES: O1CCCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.Cl>O.CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:9][C:8]([F:11])([F:10])[C:16]1([OH:20])[CH2:17][CH2:18][CH2:19][O:14][CH2:15]1
Reactant: O=C1CCCOC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCOC1
Temperature: 0 °C
Yield: 47.1 %

Procedure:
Tetrahydrofuran (50 mL) was added to a round bottom flask and placed under N2. trimethyl(trifluoromethyl)silane (1.033 mL, 6.99 mmol) was then added and stirred under N2 and then cooled to 0° C. Dihydro-2H-pyran-3(4H)-one (500 mg, 4.99 mmol) was then added via syringe and stirred for 5 minutes at 0° C. to ensure complete mixing. TBAF (0.050 mL, 0.050 mmol) was added dropwise slowly via syringe. The reaction was then allowed to warm up to RT for 30 min. The reaction was then cooled back down to 0° C. and added 1M HCl (50 mL) and then stirred at RT for overnight. The reaction was diluted with water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give the crude product 3-(trifluoromethyl)tetrahydro-2H-pyran-3-ol (400 mg, 47.1% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.01-3.93 (m, 1H), 3.82 (dd, J=11.8, 2.5 Hz, 1H), 3.60 (d, J=12.0 Hz, 1H), 3.41 (td, J=11.8, 2.5 Hz, 1H), 2.10-2.08 (m, 2H), 1.97-1.90 (m, 1H), 1.82 (dd, J=12.9, 4.4 Hz, 1H), 1.65-1.55 (m, 1H).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[NH:2]2.Cl.Br[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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:15]1[CH:16]=[CH:17][C:12]([N:2]2[C:3](=[O:9])[CH:4]3[CH2:7][CH2:8][CH:1]2[CH2:6][CH2:5]3)=[CH:13][CH:14]=1
Reactant: Brc1ccncc1
Reactant: O=C1NC2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Product: O=C1C2CCC(CC2)N1c1ccncc1
Temperature: 125 °C
Yield: 61.8 %

Procedure:
A mixture of 2-azabicyclo[2.2.2]octan-3-one (0.6 g, 4.8 mmol), 4-bromopyridine hydrochloride (1.17 g, 5.76 mmol), Cs2CO3 (2.36 g, 7.20 mmol) and xantphos (0.22 g, 0.38 mmol) was purged with argon gas for 10 min. Tetrakis(triphenylphosphine)palladium (0) (0.22 g, 0.19 mmol) was added and degassed for another 10 min. The reaction mixture was heated at 125° C. for 3 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and dried under reduced pressure to afford the crude compound. Purification by column chromatography over neutral alumina using 0.5% MeOH in CHCl3 as eluent afforded 600 mg (61.9%) of 2-(pyridin-4-yl)-2-aza-bicyclo[2.2.2]octan-3-one as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)(=[O:11])=[O:10])=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.Br[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41]3[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=3)[CH:39]=2)[C:34](=[O:47])[N:33]([CH3:48])[CH:32]=1.C(O[K])(C)=O.CC(=O)OCC>O1CCOCC1.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]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)(=[O:10])=[O:11])=[CH:5][C:4]=1[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:41]3[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=3)[CH:39]=2)[C:34](=[O:47])[N:33]([CH3:48])[CH:32]=1
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(Br)c3c2)cn1
Reactant: COc1ccc(S(=O)(=O)CCOC2CCCCO2)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[K]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)CCOC2CCCCO2)cc1-c1cn(C)c(=O)c2ccc(-c3cnn(C)c3)cc12
Yield: 23.3 %

Procedure:
The title compound of step 5 (325 mg, 0.76 mmol), the title compound of Example 41, step 2 (201 mg, 0.64 mmol), Pd(dppf)Cl2 (66 mg, 0.08 mmol) and AcOK (125 mg, 1.28 mmol) in 1,4-dioxane (6 mL) were heated at 70° C. for 12 h. After silica gel column chromatography (PE:EA=5:1-0:1) the title compound (80 mg, 23.6%) was obtained as a gray solid. 1H NMR: (CDCl3, 400 MHz) δ 8.48 (d, J=8.4 Hz, 1H), 8.03 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.58-7.69 (m, 2H), 7.14-7.18 (m, 2H), 7.06 (s, 1H), 4.50 (t, J=4.4 Hz, 2H), 4.06-4.15 (m, 1H), 3.93 (s, 3H), 3.84-3.90 (m, 1H), 3.84 (s, 3H), 3.71-3.80 (m, 2H), 3.65 (s, 3H), 3.49 (t, J=5.6 Hz, 2H), 3.41-3.47 (m, 1H), 1.25-1.67 (m, 6H). LCMS: 538.2 (M+H)+; 454.1 (M+H-THP)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]=[C:20]([C:22](O)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[OH:26][C:27]1[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]=[C:20]([C:22]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([CH3:37])[C:27]=4[OH:26])[CH2:32]3)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: CC(=O)NCc1ccc(-c2nc(C(=O)N3CCc4c(ccc(C)c4O)C3)c3ccccc3n2)cc1
Yield: 13 %

Procedure:
Reaction of 2-(4-(acetamidomethyl)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 69 (13% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.91 (s, 3H), 2.13 and 2.17 (2s, 3H), 2.66 and 2.92 (2t, 2H), 3.49 and 4.05 (2t, 2H), 4.35-4.37 (m, 2H), 4.40 and 4.93 (2s, 2H), 6.29 and 6.74 (2d, 1H), 6.79 and 7.00 (2d, 1H), 7.42-7.47 (m, 2H), 7.68-8.11 (m, 5H), 8.43-8.46 (m, 3H); MS (ESI) m/z 467 ([M+H]+).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].[Li+].CC([N-]C(C)C)C.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].P([O-])(O)(O)=O.[K+]>C1COCC1.C(O)(=O)C>[CH2:20]([O:19][C:17](=[O:18])[C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: C#CCCC(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C#CCCC(=O)O
Temperature: -78 °C
Yield: 18.8 %

Procedure:
4-pentynoic acid (2.01 g) and hexamethylphosphoamide (6.99 mL) were dissolved in 80 mL of THF, and LDA (20.1 mL) was added dropwise over 20 minutes while stirring at −78° C. After this solution was stirred at −78° C. for 1 hour, a solution of ethyl chloroformate (2.18 g) in 20 mL of THF was added dropwise over 15 minutes, and the mixture was stirred at that temperature for 30 minutes. Thereafter, acetic acid (1.15 mL) was added, a temperature was raised to room temperature, a 10% aqueous potassium dihydrogen phosphate solution was added, and extraction operation (THF once, tetrabutyl methyl ether two times) was performed. After the resulting organic layer was dried with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (A/B=30%→45%, A=ethyl acetate: acetic acid=30:1, B=n-hexane) to obtain the title compound (641 mg) having the following physical property values.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[CH:31][C:32](OC)=[O:33])[CH:27]([CH3:36])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)C>O1CCCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[CH:31][CH2:32][OH:33])[CH:27]([CH3:36])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)CCC1=CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
A solution of 1 M diisobutylaluminum hydride in toluene (13.9 mL, 13.9 mmol) was slowly dropped into a cooled (-78° C.) solution of 4-methoxycarbonylmethylene-3-methylpiperidine-1-carboxylic acid t-butyl ester (1.5 g, 5.6 mmol) obtained in the above 1) in tetrahydrofuran (30 mL) under an atmosphere of argon. After dropping, it was stirred for 2 hours at the same temperature. After the reaction was completed, ethanol (8 mL) was added thereto at 0° C. and allowed to warm to room temperature gradually. The reaction mixture was then concentrated under a reduced pressure, treated with an aqueous solution of 20% sodium potassium tartrate (20 mL), and stirred for 30 minutes. After stirring, the solution was extracted with ether, dried over anhydrous sodium sulfate. After drying, it was filtered, and the filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent; hexane:ethyl acetate=2:1) to obtain 1.2 g (yield 89.6%) of 4-(2-hydroxyethylidene)-3-methylpiperidine-1-carboxylic acid t-butyl ester. Its physical property is shown below.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4][NH:3]1.[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4]1
Reactant: CCOC(=O)c1ccc2nc[nH]c(=O)c2c1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2ncn(Cc3cccc(Br)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
Into a round-bottom flask was added ethyl 4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.14 g, 0.63 mmol), 3-bromobenzyl bromide (0.24 g, 0.95 mmol), cesium carbonate (0.25 g, 0.76 mmol), acetonitrile (12 mL) and DMF (3 mL). The reaction mixture was stirred at rt for 16 h. The mixture was then concentrated and to the residue was added EtOAc and water. After separation, the aqueous phase was extracted with EtOAc (2×). The combined organic phases were then washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. Flash column chromatography (25% to 50% EtOAc/hexanes) afforded ethyl 3-(3-bromobenzyl)-4-oxo-3,4-dihydroquinazoline-6-carboxylate (0.17 g, 68%) as a white solid. LC-MS: (FA) ES+ 388; 1H NMR (CDCl3, 300 MHz) δ 9.00 (d, J=1.70 Hz, 1H), 8.39 (dd, J=8.5, 1.9 Hz, 1H), 8.26 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.26 (m, 2H), 5.17 (s, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[N+:24]([O-])=O>[Pd].C(OCC)(=O)C.CO>[N:18]1([NH:17][C:15]2[CH:14]=[CH:13][C:11]3[NH:12][C:8]([C:5]4[CH:4]=[C:3]([NH2:24])[C:2]([NH2:1])=[CH:7][CH:6]=4)=[N:9][C:10]=3[CH:16]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(-c2nc3cc(NN4CCOCC4)ccc3[nH]2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc3cc(NN4CCOCC4)ccc3[nH]2)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-morpholin-4-yl-amine (0.5 g, 1.4 mmol) in 4:1 ethyl acetate/methanol (50 ml) under nitrogen, was added 5% palladium on carbon (100 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-[5-(morpholin-4-ylamino)-1H-benzoimidazol-2-yl]-benzene-1,2-diamine, as a thick oil that was used in the next step without any purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[NH:4][N:3]=1.[CH2:9]([O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@@H:17](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:16][CH2:15]1)=[O:13])[CH3:10].C([O-])([O-])=O.[K+].[K+].O1CCOCCOCCOCCOCCOCC1.CN(C=O)C>>[I:7][C:6]1[C:2]([CH3:1])=[N:3][N:4]([C@H:17]2[CH2:18][CH2:19][C@H:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:15][CH2:16]2)[C:5]=1[CH3:8]
Reactant: Cc1n[nH]c(C)c1I
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(=O)(=O)c2ccc(C)cc2)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(I)c2C)CC1
Temperature: 80 °C

Procedure:
A mixture of 3,5-dimethyl-4-iodopyrazole (300.0 mg, 1.351 mmol), cis-4-(toluene-4-sulfonyloxy)-cyclohexanecarboxylic acid ethyl ester (573.4 mg, 1.756 mmol), K2CO3 (373.5 mg, 2.702 mmol), 1,4,7,10,13,16-hexaoxacyclooctadecane (71.43 mg, 0.2702 mmol) and DMF (6 mL, 70 mmol) was heated to 80° C. overnight. The material was extracted with EtOAc, and washed with water (3×). The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 10-20% EtOAc in hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. MS (ES+): m/z=377.03 (100) [MH+]. HPLC: tR=3.74 min (polar—5 min, ZQ3).
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NCCF)c3)ccn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NCCF)c2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
After dissolving 160 mg of N1-(2-fluoroethyl)-5-[(2-{[(1-tert-butyloxycarbonyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide in 10 ml of trifluoroacetic acid, the solution was stirred at room temperature for 10 minutes. Ethyl acetate and sodium bicarbonate water were added to alkalinity for liquid separation. The ethyl acetate layer was washed once with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 86 mg of a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC#N.N1C=CC=CC=1.[C:19]1([O:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH3:9][O:8][C:5]1[N:4]=[N:3][C:2]([NH:1][C:26](=[O:27])[O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(N)nn1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)Oc2ccccc2)nn1
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A solution of 3-amino-6-methoxypyridazine (1.25 g, 10.0 mmol) in a mix of 1:1 THF:MeCN (20 mL), and pyridine (0.83 g, 1.5 mmol) was treated dropwise with phenylchloroformate (1.65 g, 10.5 mmol) in THF (10 mL). After stirring for 3 h, the resulting solid was collected and dried to provide the title compound (2 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[N:16]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=[O:7].S(Cl)([Cl:28])=O>>[F:1][C:2]1[CH:13]=[C:12]([O:14][C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:25])[CH:21]=3)[N:16]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([Cl:28])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F)C(=O)O
Product: CC(Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F)C(=O)Cl
Reaction time: 5 h

Procedure:
2-[2-Fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]propionic acid (1.73 g; 4.77 mmole) was treated with thionyl chloride and the mixture was heated under reflux with stirring for a period of 5 hours. The excess thionyl chloride was removed by distillation under reduced pressure to give 2-[2-fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]propionyl chloride as a straw coloured oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1)=[C:5]2[Cl:24].C[O-].[Na+].[C:28](=O)(O)[O-:29].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:29][CH3:28])[C:6]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1)=[C:5]2[Cl:24]
Reactant: FC(F)(F)c1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cn1
Reactant: O=C([O-])O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C

Procedure:
6-bromo-2,4-dichloro-3-(6-(trifluoromethyl)pyridin-3-yl)methyl)quinolone (1.0 g, 2.3 mmol, Intermediate 65: step b) and sodium methoxide (1.2 g, 22 mmol) in dry toluene (12 mL) were heated to 80° C. and refluxed under a positive pressure of nitrogen overnight. The mixture was allowed to cool to ambient temperature. Aqueous saturated sodium bicarbonate solution was added to the mixture and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was purified by flash column chromatography (silica gel, 0-20% EtOAc-Hex) to provide the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][S:11]([CH3:10])(=[O:13])=[O:12])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1ncc(Br)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4, 573 mg, 3.06 mmol) in pyridine (6 ml) was added dropwise methanesulfonyl chloride (Aldrich, Buchs, Switzerland, 0.286 ml, 3.68 mmol). The reaction mixture was stirred for 18 h at rt then are added methanesulfonyl chloride (0.03 ml, 0.39 mmol). The reaction mixture was stirred 4 h at rt before being evaporated to dryness. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (DCM/MeOH 0%-5%) to give the title compound as a pinkish solid. (HPLC: tR 2.05 min (Method A); M+H=265, 267 MS-ES).
Reaction SMILES: [ClH:1].[C:2]([CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9][CH:8]([NH:17][CH:18]([C:20]([O:22]CC)=[O:21])[CH3:19])[C:7]1=[O:25])([OH:4])=[O:3].[OH-].[Na+].Cl>O>[ClH:1].[C:2]([CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9][CH:8]([NH:17][CH:18]([C:20]([OH:22])=[O:21])[CH3:19])[C:7]1=[O:25])([OH:4])=[O:3]
Reactant: CCOC(=O)C(C)NC1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(NC1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Yield: 80.8 %

Procedure:
200 mg of the 5-carboxymethyl-3-(1-ethoxycarbonylethylamino)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride obtained in Example 12 was dissolved in 5 ml of water and 1.5 ml of a 1N aqueous solution of sodium hydroxide and then reacted at room temperature for an hour. Thereafter, the solution was adjusted to pH 1-2 with hydrochloric acid and concentrated to dryness under reduced pressure. Ethanol was added to the residue and the insoluble matter was removed by filtration. After the filtrate was concentrated, ether was added thereto so as to cause crystallization. Thus, there was obtained 150 mg of the desired compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Reactant: COCCN
Product: CCOc1cc(NCCOC)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Yield: 31 %

Procedure:
The same reaction procedure as in Example 27 was performed, except that the compound obtained in Example 85 was used in place of the compound obtained in Example 26, and 2-methoxyethylamine was used in place of N-methylpiperazine. In this manner, 46 mg (31%) of the captioned compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30]([O:32]C)=O)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:30](=[O:32])[CH2:29][O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2
Reactant: CN
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: CNC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 76 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (250 mg, 0.55 mmol) was reacted with methylamine to give the title compound as a white solid (185 mg, 76%), except that the residue was purified by chromatography on silica gel (eluant: 5% to 6% methanol in DCM). NMR Spectrum 2.73 (d, 3H), 4.88 (s, 2H), 5.77 (s, 2H), 6.97 (m, 2H), 7.29 (m, 1H), 7.37 (d, 1H), 7.76-7.69 (m, 3H), 7.84 (m, 1H), 8.16 (s, 1H), 8.32 (m, 1H), 8.54 (m, 3H), 10.84 (br s, 1H); Mass spectrum MH+ 440.