Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:16]=[CH:17][C:18]=3[Cl:22])[N:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]([O:23][CH:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)[CH:16]=[CH:17][C:18]=3[Cl:22])[N:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:6]
Reactant: O=C(O)c1ccc(Nc2ncc3c(Cl)ccc(OC4CCNCC4)c3n2)cc1Cl
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Nc2ncc3c(Cl)ccc(OC4CCNCC4)c3n2)cc1Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
A mixture of 2-chloro-4-(5-chloro-8-(piperidin-4-yloxy) quinazolin-2-ylamino) benzoic acid (1 eq), morpholine (3 eq), HATU (1.5 eq) and DIEA (4 eq) in NMP was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by semi-prep HPLC to provide pure product in 50% yield. ES/MS m/z 502.3 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]([CH2:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=2)([C:20](OCC)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(OCC)C>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]([CH2:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=2)([CH2:20][OH:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)C1(Cc2cc(C)ccn2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccnc(CC2(CO)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a slurry of lithium aluminum hydride (280 mg, 7.37 mmol) in anhydrous diethyl ether (30 mL) at 0° C., a solution of ethyl N-tert-butoxycarbonyl-4-(4-methylpyridin-2-ylmethyl)piperidine-4-carboxylate (2.7 g, 7.45 mmol) in diethyl ether (20 mL) was added dropwise with the temperature of the reacting mixture maintained below 10° C. The resulting mixture was stirred at 0° C. for 30 min, and quenched with successive addition of water (0.28 mL), 15% aqueous NaOH (0.28 mL), and water (0.84 mL). The resultant slurry was stirred at room temp. for 30 min., and filtered through a small plug of Celite. The filtrate was washed brine, dried over anhydrous magnesium sulfate, and filtered. Concentration of the filtrate under vacuum provided the title alcohol.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][Mg]Br>C1COCC1>[Br:1][C:2]1[C:7]([CH:8]([OH:9])[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cccnc1Br
Solvent: C1CCOC1
Product: CC(O)c1cccnc1Br
Temperature: 0 °C

Procedure:
To a solution of 2-bromo-pyridine-3-carbaldehyde (0.14 g, 0.75 mmol) in dry THF (10 mL) was dropwise added methylmagnesium bromide (1.4 M, 0.59 mL, 0.82 mmol) at −20° C. The reaction was allowed to warm to 0° C. for 20 min and then quenched with aqueous ammonium chloride solution. The usual work up gave a crude material, which was purified by chromatography (silica gel, 40% EtOAc/hexanes). 1H NMR (300 MHz, CDCl3) 8.30 (m, 1H), 7.96 (m, 1H), 7.34 (m, 1H), 5.21 (q, 1H), 1.54 (d, 3H).
Reaction SMILES: C1(C(C2C=CC=CC=2)([PH:15]([O-])([O-:17])[O-:16])C(CC)CCCC)C=CC=CC=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)([CH3:34])[CH3:33])=[CH:28][CH:27]=1.[Na]>>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([OH:25])=[CH:31][CH:30]=1)([C:35]1[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=1)([CH3:34])[CH3:33].[CH2:26]([O:25][P:15]([O-:17])[O-:16])[CH2:27][CH2:28][CH2:29][CH2:32][CH2:35][CH2:36][CH3:37]
Reactant: CCCCC(CC)C(c1ccccc1)(c1ccccc1)[PH]([O-])([O-])[O-]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na]
Product: CCCCCCCCOP([O-])[O-]

Procedure:
In a round bottom flask, 34.6 g (0.1 mol) of diphenyl-(2-ethylhexyl)phosphite, 22.8 g (0.1 mol) of bisphenol-A, and a catalytic quantity of metallic sodium (or alcoholate of an alkali metal) was heated at 180° C. under an atmosphere of nitrogen for one hour. The temperature was reduced to 90–100° C. The phenol was then removed under vacuum (10 mm) over 2.5 hours. When the residual pressure dropped to 1 mm, the reaction mass was subjected to vacuum for two more hours. The yield was quantitative. The phosphorus-31 NMR showed a series of peaks from 126 to 131 ppm.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[C:7](=[O:22])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[CH2:9][CH:10]=1.Cl>C1COCC1>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[CH2:9][CH:10]=[C:6]([CH2:5][CH2:4][C:3]([OH:23])=[O:2])[C:7]1=[O:22]
Reactant: COC(=O)CCC1=CCN(Cc2ccc(OC)cc2OC)C1=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(CN2CC=C(CCC(=O)O)C2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
10.8 mg of LiOHH2O solution (0.25 mM) was added to 0.86 ml of THF solution containing 55 mg of 3-[1-(2,4-dimethoxy benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (0.17 mM) in a dropwise manner at 0° C. The reaction mixture was stirred for 2 hrs at 0° C. adjust pH 1 with 5% HCl was added to the mixture to pH 1. Then the mixture was extracted three times with 10 ml of ethyl acetate, the organic layer was washed with 15 ml of saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 41 mg of 3-[1-(2,4-dimethoxy-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid (160 (yield: 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][C@H:11]2[CH2:15][CH2:14][N:13]([C:16]3[C:17]4[N:18]([CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:20][N:21]=3)[CH2:12]2)=[O:9])=[N:6][CH:7]=1.[CH:25]1(B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:25]1([C:2]2[CH:3]=[N:4][C:5]([C:8]([NH:10][C@H:11]3[CH2:15][CH2:14][N:13]([C:16]4[C:17]5[N:18]([CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:20][N:21]=4)[CH2:12]3)=[O:9])=[N:6][CH:7]=2)[CH2:27][CH2:26]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(Br)cn1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CCN(c2nccn3cccc23)C1)c1ncc(C2CC2)cn1
Temperature: 120 °C
Yield: 4 %

Procedure:
To a solution of (S)-5-bromo-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.25 g, 0.65 mmol, 1 eq) in 2 mL of toluene was added 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.16 g, 1.86 mmol, 2.8 eq), followed by PCy3 (0.033 g, 0.11 mmol, 0.2 eq), K3PO4 (0.48 g, 2.3 mmol, 3.5 eq) in 0.1 mL of H2O and Pd(OAc)2 (0.013 g, 0.06 mmol, 0.1 eq). After heating for 1 h at 120° C. the mixture was filtered and purified by HPLC to afford (S)-5-cyclopropyl-N-(1-(pyrrolo[1,2-a]pyrazin-1-yl)pyrrolidin-3-yl)pyrimidine-2-carboxamide (0.009 g, 0.026 mmol, 4%). 1H NMR (400 MHz, CD3OD) δ 8.64 (s, 2 H), 7.76 (m, 1 H), 7.71 (d, J=5.4 Hz, 1 H), 7.54 (s, 1 H), 6.92 (dd, J=2.6, 4.4 Hz, 1 H), 6.84 (d, J=5.5 Hz, 1 H), 5.00-3.60 (br, 5 H), 2.65-2.30 (br, 2 H), 2.07-2.02 (m, 1 H), 1.23-1.18 (m, 2 H), 0.96-0.91 (m, 2 H); MS: (ES) m/z calculated for C19H20N6O [M+H]+ 349.2, found 349.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[Cl:36][CH2:37][C:38](Cl)=O.[OH-].[Na+]>C(Cl)Cl.O>[Cl:36][CH2:37][C:38]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)[C:3]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:10][CH:11]=[CH:12][C:2]=2[N:1]=1
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cccc2nc(CCl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Temperature: 0 °C
Reaction time: 13 h
Yield: 76 %

Procedure:
To an ice-cooled solution of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (1.0 g) and triethylamine (0.3 g) in methylenechloride (10 ml) was added chloroacetyl chloride (0.24 ml) in portions. The mixture was allowed to stir for 13 hours and then evaporated to dryness to give a residue. The residue was washed with H2O, dried and dissolved in EtOH (10 ml). To the solution was added conc-HCl (1 ml) and the solution was refluxed for 6 hours. The reaction solution was evaporated to dryness to give a residue and the residue was dissolved in methylene chloride and water. The solution was made basic with 1N-NaOH and the organic layer was washed with water, dried and evaporated to dryness to give crystals Recrystallization from ethyl acetate-isopropylether gave colorless crystals (0.88 g, 76%) 1H-NMR(200 MHz, CDCl3) δ: 1.21(3H,t), 4.21(2H,q), 4.83(2H,s), 6.02(2H,s), 7.02(2H,d), 7.29- 7.49(5H,m), 7.58-7.79(3H,m), 8.00 (1H,dd).
Reaction SMILES: [CH:1]([C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8])=[CH:5][CH:4]=1)=O.[O:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C(C1C=CC=CC=1)(=O)C.[OH-].[Na+]>CO>[N:29]1([C:32]2[CH:33]=[CH:34][C:35]([C:38](=[O:40])[CH:39]=[CH:1][C:3]3[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:8])=[CH:24][CH:25]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27][O:26][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(N2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)c1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=CC(=O)c2ccc(N3CCOCC3)cc2)cc1
Reaction time: 72 h
Yield: 90 %

Procedure:
To a stirred solution at room temperature of XI (210 mg, 0.62 mmol), 4′-morpholino acetophenone (227 mg, 1.11 mmol) or acetophenone derivative (1.5–2.0 equiv.) in MeOH (10 ml) was added a solution of NaOH (1.9 ml, 1N in H2O). A precipitate appeared. After 3 days, the reaction mixture was filtered off, rinsed with MeOH, air-dried and dried under vacuum to afford the title compound XXVf (295 mg, 0.56 mmol, 90% yield) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.Cl.CN(C)CCCl>>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)c(OCCN(C)C)c1
Agent: CN(C)CCCl
Agent: Cl
Product: CN(C)CCOc1cc(C(=O)O)ccc1-c1ccc(F)cc1

Procedure:
Using the procedure outlined in Description 77, the title compound was prepared from methyl 2-(2-dimethylaminoethoxy)-4′-fluoro-1,1′-biphenyl-4-carboxylate (D78) (200 mg, 0.61 mmol)) and 2-(dimethylamino)ethylchloride hydrochloride (114 mg, 0.79 mmol) as a solid (122 mg). MS(ES): MH+ 304, M-H+ 302.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:33]([O:35][CH3:36])=[O:34])=[N:11][N:12]([CH:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][NH:20][C:21]([O:23]C(C)(C)C)=O)[C:13]=1C(OC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:10]([C:33]([O:35][CH3:36])=[O:34])=[N:11][N:12]2[CH:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:19][NH:20][C:21](=[O:23])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CNC(=O)OC(C)(C)C)n1nc(C(=O)OC)c(OCc2ccccc2)c1C(=O)OC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CNC(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl 4-(benzyloxy)-1-{2-[(tert-butoxycarbonyl)amino]-1-(ethoxycarbonyl)ethyl}-1H-pyrazole-3,5-dicarboxylate (6.97 g, 13.78 mmol) in CHCl3 (150 mL) was added TFA (30 mL). The reaction was allowed to stir at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between saturated aqueous NaHCO3 solution and CHCl3. The aqueous layer was extracted three times with CHCl3, and the combined organic extracts were dried over Na2SO4. Concentration in vacuo afforded a yellow oil which was dissolved in EtOAc (30 mL) and sonicated. The resulting precipitate was collected by filtration to afford the title product as a white solid. The filtrate was further purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA), and collection and concentration of the appropriate fractions afforded additional title product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.38 (d, J=5.2 Hz, 1H), 6.45-7.43 (m, 2H), 7.38-7.30 (m, 3H), 5.55 (d, J=4.0 Hz, 1H), 5.26 (dd, J=11.2, 40.0 Hz, 2H), 4.23-4.14 (m, 2H), 3.97 (dd, J=5.0, 13.8 Hz, 1H), 3.79 (s, 3H), 3.71 (dd, J=5.4, 13.8 Hz, 1H), 1.18 (t, J=7.0 Hz, 3H); ES MS (M+H)=374.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:22])=[C:5]2[C:18](=[CH:19][C:20]=1[CH3:21])[C:8]1[NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][C:15]=3[C:7]=1[CH2:6]2.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+].N1C2C(=CC=CC=2)C=C1>FC(F)(F)C(O)=O.O>[CH3:1][O:2][C:3]1[C:4]([CH3:22])=[C:5]2[C:18](=[CH:19][C:20]=1[CH3:21])[C@H:8]1[NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][C:15]=3[C@H:7]1[CH2:6]2
Reactant: COc1ccc2[nH]c3c(c2c1)Cc1c-3cc(C)c(OC)c1C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc2c(c1)[C@H]1Cc3c(cc(C)c(OC)c3C)[C@H]1N2
Reaction time: 4 h

Procedure:
5,10-Dihydro-2,8-dimethoxy-1,3-dimethylindeno[1,2-b]indole (1.04 g, 3.55 mmol) was dissolved in trifluoroacetic acid (5 cm3) and triethylsilane (0.6 cm3) added with vigorous stirring. Stirring was continued for 4 hours, and the reaction worked up incomplete due to the appearance by t.l.c. of impurities. The solution was poured into water, stirred, and brought to pH 7.0 with solid sodium bicarbonate. The organic material was extracted into DCM, which was washed with sodium bicarbonate solution, and filtered through phase separating filter paper. The product and starting material were separated by column chromatography eluting with 20% EtOAc/60°-80° petrol to yield starting indole (0.06 g, 6%) and a colourless solid. Yield: 0.57 g, 58% .M.p. 149-50° C. (from EtOAc/petrol). 1H NMR (CDCl3) δ: 6.99 (1H, s), 6.79 (1H, m), 6.57 (2H, m), 5.18 (1H, d, J=8.5 Hz), 4.18 (1H, dd(br)), 3.74 (3H, s), 3.65 (3H, s), 3.35 (1H, dd, 3J=8.4 Hz), 3.06 (1H, d(d)), 2.25 (3H, s), 2.15 (3H, s).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21](O)=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH:25]=1)[C:15]([CH3:38])([CH3:37])[CH2:14]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)[CH:25]=1)[C:15]([CH3:38])([CH3:37])[CH2:14]2
Reactant: CN1CCN(c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)CC1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(C3Nc4c(cc(Cl)cc4C(=O)NS(=O)(=O)C4CC4)CC3(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a suspension of 60% sodium hydride (114 mg, 2.8 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (350 mg, 2.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-chloro-3,3-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (120 mg, 0.3 mmol) and 1,1′-carbonyldiimidazole (118 mg, 0.8 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {6-chloro-3,3-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carbonyl}-amide (62 mg, 40%) as a white solid: LC/MS m/e calcd for C26H33ClN4O3S (M+H)+: 517.0, observed: 517.1.
Reaction SMILES: N1C=CC=C(C)C=1.Cl.C(C(CCCC)CO)C.[CH:18](=[C:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28])[CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+]>>[CH2:18]([C:23]1[C:24](=[O:28])[CH2:25][CH2:26][CH:27]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC=C1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC(CC)CO
Solvent: Cc1cccnc1
Product: CCCCCC1=CCCC1=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
5.44 g (0.058 mol) of 3-picoline and 5.54 g (0.053 mol) of a 35% hydrochloric acid were mixed with 100.0 g of 2-ethylhexanol and heated to 140° C. Then, 100.0 g (0.53 mol) of 2-pentylidene cyclopentanone were added dropwise thereto for 2 hours at the same temperature. After this dropping addition was finished, the resultant mixture was stirred for 2 hours under heating at the same temperature. After the reaction was finished, the mixture was cooled to the room temperature and neutralized with an aqueous solution of sodium hydroxide. Then, the resultant organic layer was analyzed in the same manner as in Example 1. As the result, 69.2 g of 2-pentyl-2-cyclopentenone were obtained (yield: 86.0%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14](C3CCN(C)CC3)=C[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:24]([C:28]1[CH:29]=[C:30]2[C:35](=[C:36](F)[CH:37]=1)[C:34](=[O:39])[N:33]([C:40]1[N:47]=[CH:46][CH:45]=[C:44](I)[C:41]=1[CH:42]=[O:43])[N:32]=[CH:31]2)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:39])[N:33]([C:40]1[C:41]([CH2:42][OH:43])=[C:44]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[C:15]5[CH2:14][N:6]([CH3:8])[CH2:5][CH2:4][N:10]5[N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[CH:45]=[CH:46][N:47]=1)[N:32]=[CH:31]2)([CH3:27])([CH3:26])[CH3:25]
Reactant: CN1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(I)c3C=O)ncc2c1
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)ccc6c5=O)c4CO)nn(C)c3=O)cc2C1

Procedure:
Preparation by a similar procedure to example 1 (Step 5-6), except substituting 6-chloro-2-methyl-4-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridazin-3(2H)-one for 6-chloro-2-methyl-4-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one and substituting 2-(6-tert-Butyl-1-oxo-1H-phthalazin-2-yl)-4-iodo-pyridine-3-carbaldehyde for 2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-iodonicotinaldehyde in step 5 afforded 72 mg of the title compound as a white solid. (M+H)+=568 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9 H) 2.54 (s, 3 H) 2.97 (br. s., 2 H) 3.68 (s, 2 H) 3.90 (s, 3 H) 4.08 (t, J=6.99 Hz, 1 H) 4.17 (t, J=5.48 Hz, 2 H) 4.47-4.56 (m, 2 H) 5.86 (s, 1 H) 7.62 (d, J=4.91 Hz, 1 H) 7.77 (d, J=1.89 Hz, 1 H) 7.86-8.01 (m, 3 H) 8.38 (s, 1 H) 8.44 (d, J=8.31 Hz, 1 H) 8.72 (d, J=4.91 Hz, 1 H).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH2:78][C:79]2[CH:84]=[CH:83][C:82]([O:85][CH3:86])=[CH:81][CH:80]=2)[C:63]=1[N:64]1[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][C@@H:65]1[CH3:77].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])=[N:44][C:43]=1[C:55]([NH:58][C:59]1[CH:60]=[N:61][N:62]([CH2:78][C:79]2[CH:84]=[CH:83][C:82]([O:85][CH3:86])=[CH:81][CH:80]=2)[C:63]=1[N:64]1[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:75])([CH3:76])[CH3:74])=[O:71])[CH2:66][C@@H:65]1[CH3:77])=[O:57])=[O:40])([CH3:36])([CH3:37])[CH3:35]
Reactant: COc1ccc(Cn2ncc(N)c2N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncc(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)c2N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 45.1 %

Procedure:
A solution of PyBOP (328 mg, 0.63 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (176 mg, 0.50 mmol) in DCM (5 mL) was stirred at room temperature for 30 min. A solution of Intermediate 33 (S)-tert-butyl 4-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate (181 mg, 0.45 mmol) and DIPEA (0.13 mL, 0.72 mmol) in DCM (5 mL) was added and the mixture stirred at room temperature for 65 hr. The mixture was diluted with DCM (40 mL) and washed with water (15 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (S)-tert-butyl 4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a yellow solid (150 mg). This solid was re-dissolved in DCM (10 mL) and TFA (2 mL) was added before being heated at 65° C. for 2.5 hr. The mixture was concentrated under reduced pressure before being re-dissolved in 7 N ammonia in MeOH (20 mL) and heated in a sealed pressure vessel behind a blast shield at 55° C. for 16 hr. The mixture was concentrated under reduced pressure, re-dissolved in MeOH and passed through an SCX column, washing with DCM and MeOH and eluting with 3-10% 7 N ammonia in MeOH/DCM to give 174 as an off-white solid (60 mg, 32% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.03 (s, 1H), 7.51-7.41 (m, 1H), 7.16 (t, J=8.9 Hz, 2H), 3.20-3.14 (m, 1H), 3.08-2.98 (m, 5H), 2.64 (dd, J=12.7, 9.4 Hz, 1H), 0.93 (d, J=6.2 Hz, 3H). LCMS (ES+) m/z 420 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[C:5]2[N:11]=[CH:10]N=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[N:7]=1.[C:27]1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCCC)CC>O.CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([N:20]([CH2:21][CH2:22][CH3:23])[CH2:24][CH2:25][CH3:26])[C:5]2[N:11]=[CH:10][CH:27]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCN(CCC)c1nc(C)nc2c(-c3ccc(Cl)cc3Cl)ncnc12
Solvent: CCOC(C)=O
Solvent: CCCNCCC
Solvent: O
Product: CCCN(CCC)c1nc(C)nc2c(-c3ccc(Cl)cc3Cl)ccnc12
Temperature: 195 °C

Procedure:
A mixture of 4 (10 mg), p-toluenesulfonic acid (20 mg) and dipropylamine (50 ml) is stirred and heated to 195° C. in a sealed tube for 1.5 h. The solution is then allowed to cool to r.t., and dissolved in a mixture of water and EtOAc. This is extracted with EtOAc, the organic phase washed with brine, dried and concentrated. The product is purified by prep. TLC (SiO2) using ethyl acetate/hexane.