Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1)(=[O:27])[CH3:26]
Reactant: Nc1ccc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(CCN2CCC(NC(=O)c3ccccc3)CC2)cc1
Reaction time: 24 h

Procedure:
1-[2-(p-Aminophenyl)ethyl]-4-benzamidopiperidine (2.3 g.) was refluxed for 2 hours with acetic anhydride (22 ml.) in anhydrous pyridine (100 ml.). The solution was refrigerated for 24 hours and a crystalline product was filtered off, which after washing with ether yielded the title compound, m.p. 270°-275° C (dec.). Found: C, 72.6; N, 7.55; N, 11.6. C22H27N3O2 requires C, 72.3; H, 7.45; N, 11.5%).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[S:12][C:11]([CH2:13][O:14][CH3:15])=[N:10][C:9]=1[CH3:16])=[O:7])C>C(O)C>[CH3:15][O:14][CH2:13][C:11]1[S:12][C:8]([C:6]([OH:7])=[O:5])=[C:9]([CH3:16])[N:10]=1
Reactant: CCOC(=O)c1sc(COC)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCc1nc(C)c(C(=O)O)s1

Procedure:
6.7 g of 85% potassium hydroxide in 1130 ml of ethanol are added at room temperature to 22.1 g of 2-methoxymethyl-4-methylthiazole-5-carboxylic acid ethyl ester and the reaction mixture is then heated under reflux for 18 hours. After cooling, the ethanol is evaporated off and the residue is dissolved in 200 ml of water. After stirring with active carbon, the mixture is filtered over Hyflo and the filtrate is acidified with concentrated hydrochloric acid with vigorous stirring. The resulting yellowish crystals are filtered off, washed with water and dried. After recrystallisation from tetrahydrofuran/petroleum ether (30°-45° C.) (=10:1) the yellowish crystals melt at 168°-169.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C[O-].[Na+].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]>CO.C1C=CC=CC=1.[I-].[K+].C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8])[O:10][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: Oc1cc(Cl)c(Cl)c(Cl)c1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)C(Oc1cc(Cl)c(Cl)c(Cl)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 4.93 g of 3,4,5-trichlorophenol and 1.19 g of sodium methoxide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene and 50 mg of potassium iodide. The mixture is refluxed for 20 hours and the solvent removed in vacuo. To the residue is added water and the mixture is extracted with ether. The ether extracts are washed with 10% potassium carbonate and with water and dried (MgSO4). Evaporation of the solvent under vacuum gives a tan oil. The oil is dissolved in chloroform and filtered through a column of silica gel. Removal of the solvent from the second 200 ml cut gives the product as a tan oil.
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([NH:18][S:19]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])([CH3:17])[CH3:16].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:15]([NH:18][S:19]([C:22]1[NH:23][C:24]2[C:29]([C:30]=1[CH:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])=[O:20])([CH3:17])[CH3:16]
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CC(C)NS(=O)(=O)c1cc2ccccc2[nH]1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 84.8 %

Procedure:
To a solution of benzhydrol (0.58 g, 3.15 mmol) and N-isopropylindole-2-sulfonamide (0.7 g, 3.12 mmol) in 15 ml of methylene chloride was added a solution of methanesulfonic acid (0.2 ml, 3.12 mmol) in 4 ml of methylene chloride, followed by stirring at room temperature for 2.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution for neutralization and the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 1.4 g of a crude product. The obtained crude product was washed with ethanol to give 1.07 g (yield: 85%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][S:30]([NH:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([CH:40]([F:42])[F:41])[CH:39]=1)(=[O:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:36]2[CH:35]=[C:34]([NH:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH:39]=[C:38]([CH:40]([F:42])[F:41])[CH:37]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CS(=O)(=O)Nc1cc(B(O)O)cc(C(F)F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(C)(=O)=O)cc(C(F)F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 16.5 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.23 mmol) were added (3-(methylsulfonamido)-5-(difluoromethyl)phenyl)boronic acid (598 mg, 20% purity, 0.34 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 mg, 0.02 mmol) and 284 μl of a 2M aqueous solution of cesium carbonate in dioxane (3 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude was purified by flash chromatography (0 to 85%, hexane-ethyl acetate) using SP1® Purification System to give 22 mg (17% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH:17]=[CH:16][C:8]=2[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=3)[CH:17]=[CH:16][C:8]=2[C:9]([OH:11])=[O:10])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(/C=C/c2ccc(OC(F)(F)F)cc2)cc1Nc1ccc(F)cc1

Procedure:
Trifluoroacetic acid 10 mL solution of the obtained tert-butyl 2-(4-fluoroanilino)-4-((E)-2-(4-(trifluoromethoxy)phenyl)vinyl)benzoate was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 60-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-(4-fluoroanilino)-4-((E)-2-(4-(trifluoromethoxy)phenyl)vinyl)benzoic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]5)=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH2:44][CH2:45][O:46]C2CCCCO2)[N:15]=1)=[O:13])[CH3:2].[ClH:53]>CO.O1CCOCC1>[ClH:53].[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][CH2:21][C:22]3[C:23](=[N:24][C:25]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([N:35]5[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]5)=[CH:31][C:30]=4[O:42][CH3:43])=[N:26][CH:27]=3)[C:17]=2[N:16]([CH2:44][CH2:45][OH:46])[N:15]=1)=[O:13])[CH3:2]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(CCOC2CCCCO2)c2c1CCCc1cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc1-2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCc1cccc(CC)c1NC(=O)c1nn(CCO)c2c1CCCc1cnc(Nc3ccc(N4CCN(C)CC4)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2,6-diethylphenyl)-9-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,4,5,6-tetrahydropyrazolo[4′,3′:6,7]cyclohepta[1,2-d]pyrimidine-3-carboxamide (0.040 g, 0.056 mmol) in MeOH (0.6 mL), 4M HCl in dioxane (0.010 mL) was added. The mixture was stirred at room temperature for 1 h. The organic solvent was evaporated to dryness to give the title compound in quantitative yield.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][OH:10].[N+:11]([C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:17]1[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C[C@H]1CCCN1CCCO
Product: C[C@H]1CCCN1CCCOc1ccc([N+](=O)[O-])cc1

Procedure:
The target compound was obtained by the method according to Example 18, using 3-[(2S)-2-methylpyrrolidin-1-yl]propanol and 4-nitrophenol as starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:12][CH2:13][CH3:14])[C:10]=1[Cl:11])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)=[O:24])[N:8]=[C:9]([CH2:12][CH2:13][CH3:14])[C:10]=1[Cl:11])=[O:5])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CCCc1n[nH]c(C(=O)OCC)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1nn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)c(C(=O)OCC)c1Cl

Procedure:
Protocol T was followed using 4-Chloro-5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=3/7) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.94-7.0 (m, 2H), 6.82-6.90 (dd, 2H), 5.0 (s, 2H), 4.36-4.40 (q, 2H), 3.62-3.82 (m, 4H), 3.04-3.18 (m, 4H), 2.58-2.66 (t, 2H), 1.64-1.76 (m, 2H), 1.34-1.38 (t, 3H), 0.94-1.0 (t, 3H). 13C NMR (400 MHz, CDCl3): 165, 160.2, 156.2, 152.4, 147, 133, 118.4, 118.2, 115.8, 115.4, 112.2, 61, 53, 50.6, 50.2, 45, 42, 30, 22.8, 14.4, 14.2.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:35])[CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1.C(O)(=O)C>C1COCC1>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:28]([OH:35])([CH:11]([C:13]1[C:18]([F:19])=[CH:17][N:16]=[CH:15][N:14]=1)[CH3:12])[CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1
Reactant: CCc1ncncc1F
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(c1ncncc1F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: -65 °C
Reaction time: 3 h

Procedure:
To THF (20 ml) was added sodium bis(trimethylsilyl)amide (79 ml) of a 1.0M solution in THF) and the solution cooled to -65° C. under nitrogen. A solution of 4-ethyl-5-fluoropyrimidine (10 g) (see Preparation 8) in THF (100 ml) was added over 30 minutes. After stirring for 3 hours at -65° C. the thin slurry was treated with a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (17.7 g) in THF (100 ml), dropwise over 30 minutes. The solution was stirred for a further 1 hour at -65° C. and then treated with acetic acid (20 ml). After warming to -20° C. the solution was washed with water (200 ml) and the organic layer separated and combined with an ethyl acetate (200 ml) back extract of the aqueous phase. The combined organic layers were concentrated under reduced pressure to provide a solid that was triturated with diethyl ether (230 ml) and filtered. The filtrate was concentrated under reduced pressure and chromatographed on silica with 1:1 diethyl ether/ethyl acetate as the eluent. The fractions containing the title compound were combined, concentrated under reduced pressure and the residue chromatographed on silica with 1:1 ethyl acetate/hexane as the eluent. The appropriate fractions were combined and evaporated under reduced pressure to provide the purified title compound (0.82 g), m.p. 125°-127° C. Found: C,54.89; H,4.06; N,19.66; C16H14F3N5O requires: C,55.01; H,4.01; N,20.05%.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([C:36]3(O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>CCOC(C)=O.C(Cl)Cl>[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)=[CH:28]2)(=[O:25])=[O:26])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)n2cc(C3(O)CCCCC3)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C3CCCCC3)c3ccccc32)cc1
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Under N2, add triethylsilane (676 mg, 0.929 ml, 5.82 mmol, 2.6 eq) followed by trifluoroacetic acid (4.08 g, 2.7 ml, 35.79 mmol, 16.0 eq) to a CH2Cl2 solution (20 ml) of 4-[3-(1-Hydroxy-cyclohexyl)-indole-1-sulfonyl]-benzoic acid methyl ester (9.25 mg, 2.24 mmol, 1 eq). Stir for 1.5 hours and then remove volatiles on rotovap. Add EtOAc to crude mix and workup with sat aqueous sodium bicarbonate. Extract product into organics, separate organics, dry over MgSO4, and concentrate on rotovap to give crude product as a pink oil. Purify by silica gel chromatography to give 4-(3-Cyclohexyl-indole-1-sulfonyl)-benzoic acid methyl ester (775 mg, 87% yield) as a white solid. Mass Spectrum (m/e): 397.99 (MH+).
Reaction SMILES: [CH2:1]1[CH2:8][C:6](=O)[C:4](=O)[CH2:3][CH2:2]1.Cl.[C:10]1([N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)N)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(=O)C>[C:6]1([N:16]2[C:18]3[C:23](=[CH:22][CH:21]=[C:20]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[N:16]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:19]4=3)[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:4]=[CH:3][CH:2]=[CH:1][CH:8]=1
Reactant: O=C1CCCCC1=O
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: c1ccc(-n2c3ccccc3c3ccc4c5ccccc5n(-c5ccccc5)c4c32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
1,2-Cyclohexadione (98%; 5.0 g, 1 eq.) is dissolved in acetic acid (100%; 30 ml). 1,1-Diphenylhydrazine hydrochloride (98%; 19.68 g, 2 eq.) is slowly added thereto. The suspension is stirred at room temperature overnight. Subsequently, the reaction is stirred at reflux for 54 h. After cooling to room temperature, the suspension is filtered with suction and washed with a little acetic acid. The residue is suspended in hot distilled water, filtered off with suction and washed to neutrality. The solid is dried under reduced pressure overnight. Subsequently, the solid is dissolved in toluene (300 ml) and Pd/C (10%; 2 g) is added; the mixture is stirred at reflux overnight. The solution was filtered through Celite (super standard) and washed with toluene and methylene chloride. The clear solution is concentrated and the residue is dried at 100° C. under reduced pressure. This gives 5.11 g of compound 4, 57.2% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].CC(O)(CC)C.[NH:21]1[CH:25]=[CH:24][N:23]=[N:22]1.[I-].[K+].[OH-].[Na+].[CH3:30][S:31]([OH:34])(=[O:33])=[O:32]>C(OC(C)C)(C)C.C(OCC)(=O)C>[CH3:30][S:31]([OH:34])(=[O:33])=[O:32].[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Reactant: c1c[nH]nn1
Agent: CS(=O)(=O)O
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CCC(C)(C)O
Product: COc1ccc(C(=O)CCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.6 g (50 mmol) 4-Chloro-1-(4-methoxy-phenyl)-butan-1-one, 20 ml 2-methyl-2-butanol, 5.2 g (75 mmol) 1H-[1,2,3]-triazole, 9.5 g (57 mmol) potassium iodide and 3.0 g (75 mmol) NaOH were stirred at 100° C. for 4 h. After removal of solvents in vacuo, the residue was partitioned between toluene and water. Washing of the toluene phase twice with water, drying over sodium sulphate and evaporation gave an oily residue that was dissolved in 80 ml diisopropyl ether/ethyl acetate (1:2). The solution was kept at 20° C. during the addition of 2.8 ml methanesulfonic acid and stirred at room temperature for 2 h. The formed precipitate was isolated, washed with cold diethyl ether and dried at 40° C. in vacuo to give 1-(4-methoxy-phenyl)-4-[1,2,3]triazol-1-yl-butan-1-one methanesulfonate. Yield: 2.25 g (13%).
Reaction SMILES: [F:1][CH:2]([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[C:10](=[O:19])[C:11]([C:16](O)=[O:17])=[CH:12][NH:13][C:14]=2[CH3:15])[CH:6]=[CH:7][CH:8]=1.[CH3:21][N:22](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C>[CH3:21][NH:22][C:16]([C:11]1[C:10](=[O:19])[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]([F:20])[F:1])[CH:4]=2)=[C:14]([CH3:15])[NH:13][CH:12]=1)=[O:17]
Reactant: Cc1[nH]cc(C(=O)O)c(=O)c1-c1cccc(C(F)F)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c[nH]c(C)c(-c2cccc(C(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(3-difluoromethyl-phenyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 16a, 931 mg, 3.33 mmol), TBTU (1.17 g, 3.64 mmol), triethylamine (0.94 mL, 6.70 mmol) in DMF (3 mL) is stirred for 30 min. Then, methylamine (5.23 mL of 2M solution in THF, 10.5 mmol) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is concentrated under reduced pressure and purified by preparative reversed-phase HPLC (XBridge, gradient of acetonitrile in water, 0.3% NH4OH, 60° C.). Yield: 0.25 g (25% of theory); ESI mass spectrum: [M+H]+=293; Retention time HPLC: 0.59 min (Z011_S03).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[CH:69][C:70]([N:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)=[N:71][CH:72]=2)[C:56]=1[CH3:79].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[N:71][C:70]([N:73]5[CH2:74][CH2:75][O:76][CH2:77][CH2:78]5)=[CH:69][CH:68]=4)[C:56]=3[CH3:79])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(N3CCOCC3)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCOCC3)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.043 mmol), 2,5-dimorpholinopyridin-3-amine (0.084 g, 0.32 mmol), 4-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)morpholine (0.1 g, 0.27 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.079 g, 0.82 mmol) in toluene (2.7 mL) at 120° C. for 1.9 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(6-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (1H, dd, J=2.4, 0.7 Hz), 7.90 (1H, dd, J=8.8, 2.5 Hz), 7.75 (1H, d, J=5.9 Hz), 7.60 (1H, ddd, J=10.0, 2.5, 1.0 Hz), 7.55 (1H, d, J=2.5 Hz), 7.42 (1H, dd, J=4.0, 2.6 Hz), 6.98 (1H, d, J=8.6 Hz), 6.41 (1H, d, J=2.5 Hz), 3.69-3.78 (6H, m), 3.61-3.69 (6H, m), 3.52-3.61 (4H, m), 3.14 (2H, br. s.), 2.95-3.05 (4H, m), 2.83 (2H, br. s.), 2.12 (3H, s). Mass Spectrum (ESI) m/e=604.3 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.F[C:24]1[CH:29]=[CH:28][N:27]2[C:30]([C:33]([NH:35][C:36]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:37]=3[C:38]([CH3:53])=[N:39][N:40]4[CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=3)=[O:34])=[CH:31][N:32]=[C:26]2[CH:25]=1>C1COCC1.CN1C(=O)CCC1>[CH3:53][C:38]1[C:37]2[C:41](=[CH:42][CH:43]=[CH:44][C:36]=2[NH:35][C:33]([C:30]2[N:27]3[CH:28]=[CH:29][C:24]([O:7][CH2:8][CH2:9][N:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[CH:25][C:26]3=[N:32][CH:31]=2)=[O:34])[N:40]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([CH3:52])[N:47]=2)[N:39]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(F)ccn45)cccc32)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C(=O)OC(C)(C)C)CC6)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 0.4 M solution of potassium tert-butoxide (0.068 g, 0.606 mmol) in THF cooled in an ice-water bath was added tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate 0.278 g, 1.21 mmol). The reaction was stirred for 10 minutes before adding 7-fluoro-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 53; 0.100 g 0.241 mmol) in 2 mL of NMP. The reaction was warmed to ambient temperature and stirred for 1 hour, then heated to 60° C. and stirred for 12 hours. THF was removed by rotary evaporation and the mixture was heated to 120° C. for 5 hours. Another equivalent of potassium t-butoxide was added and the mixture was heated for another 3 hours. The reaction was quenched with water and extracted with EtOAc. The extracts were dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative thin layer chromatography and reverse phase chromatography gave the title compound. MS (APCI), positive scan, m/z=625.0 (M+H).