Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3cc4ccccc4o3)c(N(C)C(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (200 mg, 0.68 mmol, 1.00 equiv), benzofuran-2-ylboronic acid (220 mg, 1.36 mmol, 1.99 equiv), Pd(PPh3)4 (157 mg, 0.14 mmol, 0.20 equiv), K3PO4 (577 mg, 2.73 mmol, 4.01 equiv), 1,4-dioxane (4 mL). The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40). This resulted in 160 mg (63%) of methyl 2-(benzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24](O)=[O:25])[CH2:19][CH2:18]3)=[O:16])[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[NH:29]1[CH2:38][CH2:37][CH2:36][C@H:30]1[C:31]([N:33]([CH3:35])[CH3:34])=[O:32]>>[CH3:34][N:33]([CH3:35])[C:31]([C@@H:30]1[CH2:36][CH2:37][CH2:38][N:29]1[C:24](=[O:25])[CH2:23][N:20]1[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=3)[S:10][CH:11]=2)[CH2:18][CH2:19]1)=[O:32]
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Reactant: O=C(O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1
Product: CN(C)C(=O)[C@@H]1CCCN1C(=O)CN1CCN(C(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)CC1

Procedure:
In analogy to example 22.3, (4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetic acid (example 22.2) was coupled with H-Pro-NMe2, using general method C, to give (S)-1-[2-(4-{2-[2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetyl}-piperazin-1-yl)-acetyl]-pyrrolidine-2-carboxylic acid dimethylamide. Off-white solid. MS 547.5 ([M+H]+)
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=O)[O:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([N:19]1[CH2:20][CH2:21][CH2:22][C:23]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: O=C1CCCO1
Product: CCCCCCCC/C=C\CCCCCCCCN1CCCC1=O

Procedure:
Oleylamine (125 g, tech grade, 80% pure, 0.374 mole) was heated with γ-butyrolactone (27 ml, 0.35 mole) at 180° C. under nitrogen for 24 hours. The product was purified via vacuum distillation as a light yellow waxy solid. Mass Spectra: m/e (relative intensity) 335 (M+, 28.40).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=2)=[O:20])=[CH:7][CH:6]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:1][N:2]([CH3:3])[C:29](=[O:30])[CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])/[CH:18]=[CH:17]/[C:12]2[CH:13]=[N:14][N:15]([CH3:16])[C:11]=2[C:8]2[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=2)=[CH:23][CH:24]=1
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CC(=O)O)cc2)c1-c1ccc(F)cc1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49 %

Procedure:
A mixture of dimethylamine (2M tetrahydrofuran solution, 1.7 mL), [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)phenyl]acetic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.35 g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.44 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (2E)-N-{4-[2-(dimethylamino)-2-oxoethyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide as colorless crystals (0.36 g, yield 49%) from a fraction eluted with ethyl acetate-methanol (20:1, v/v). Recrystallization thereof from acetone-diisopropyl ether gave colorless prism crystals. melting point: 209-210° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH2:9])[CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][NH:9][C:37]([C:36]2[CH:40]=[CH:41][C:33]([N:30]3[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:28][CH2:29]3)=[N:34][CH:35]=2)=[O:38])[CH:7]=1
Reactant: NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methanamine 84-2 (53 mg, 0.195 mmol), 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)nicotinic acid 46-1 (16 mg, 0.195 mmol), and HATU (81.5 mg, 0.214 mmol) were added N,N-diisopropylethylamine (DIEA, 52 μL, 0.298 mmol) and DMF (1.0 mL). The solution was stirred overnight at room temperature and was subjected to silica gel column chromatography with 1:1 ethyl acetate/hexanes as eluent to give tert-butyl 4-(5-(((3-fluoro-2′-(trifluoromethyl)-[2,4′-bipyridin]-5-yl)methyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate 46-2.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1>[Si:15]([O:14][CH2:13][CH2:12][C:11]1[CH:10]=[CH:9][S:8][C:7]=1[CH:27]([C:26]1[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=1)[OH:28])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccsc1Br
Reactant: O=Cc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccsc1C(O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
n-Butyllithium in hexanes (12.7 mL, 1.6 M, 20.3 mmol) was added dropwise to a solution of (2-(2-bromothiophen-3-yl)ethoxy)(tert-butyl)dimethylsilane (5.9 g, 18.4 mmol) in anhydrous THF (15 mL) at −78° C. The resulting mixture was stirred at −78° C. for 30 min and 4-fluorobenzaldehyde (2.5 g, 20.3 mmol) in THF was added slowly. The mixture was stirred at −78° C. for 2 h and then warmed up to rt. After cooling again to 0° C. 50 mL of aqueous saturated ammonium chloride was added and the mixture was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo and the product was purified by flash chromatography eluting with ethyl acetate/hexane (1:3) to afford the title compound as a solid (3.8 g, 59%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[F:20])[CH:4]=1.[C:21]1([CH2:27][C:28]([N:30]=[C:31]=[S:32])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH3:1][S:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:31]([NH:30][C:28](=[O:29])[CH2:27][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[S:32])=[CH:15][C:14]=2[F:20])[CH:4]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CSc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Solvent: C1CCOC1
Product: CSc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 3 h
Yield: 26 %

Procedure:
To a suspension of 231 (61 mg) in THF (2 mL) was added 2-phenylacetyl isothiocyanate (42 mg, 0,199 mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and the residue was purified by column chromatography, eluent EtOAc/hexane (35:65), to produce yellow oil. Purification of this material by preparative HPLC (column C-18 Aquasil, gradient: 60% MeOH to 95% MeOH) afforded title compound 232a (25 mg, 26% yield) as a cream solid. Characterization of 232a is provided in the table 22.
Reaction SMILES: Br[CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1.[Cl:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[Cl:27].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[Cl:27])[O:28][CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a solution of 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 40 mg, 0.11 mmol) in dimethylsulfoxide (0.5 mL) was added 3,4-dichlorophenol (18 mg, 0.11 mmol) followed by addition of potassium carbonate (31 mg, 0.22 mmol). The reaction was left to stir at room temperature for 18 hours. The reaction mixture was poured into water (50 mL) and acidified with 2M HCl (2 mL), then extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (20 mL), then dried over magnesium sulfate and evaporated in vacuo to give a colourless glass (44 mg). The solid was then triturated with 1:1 ether:heptane (4 mL), sonicated and the supernatant decanted. The resulting solid was dried in vacuo to give an off-white solid as the title compound (47 mg, 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27](O)=[O:28]>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:32]([F:33])=[C:24]([Cl:23])[CH:25]=1
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(F)c(Cl)c2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.15 mmol) was used in general procedure 2 with 3-chloro-4-fluorobenzoic acid (0.167 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(3-chloro-4-fluorobenzamido)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide. MS (Q1) 486.1 (M)+
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[C:12]([CH2:28][CH3:29])=[N:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[OH:38][C:32]([C:34]([F:37])([F:36])[F:35])=[O:33].[OH:38][C:32]([C:34]([F:37])([F:36])[F:35])=[O:33].[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH:14]=[C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([CH2:28][CH3:29])=[N:11]2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CCc1nn(Cc2ccc(S(C)(=O)=O)cc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nn(Cc2ccc(S(C)(=O)=O)cc2)cc1C1CCNCC1

Procedure:
4-((1-(4-Methylsulfonylbenzyl)-3-ethyl)-(1H)-pyrazol-4-yl)-N-t-butoxylcarbonylpiperidine from Step C was treated with TFA for 1 h and evaporated to afford the title, compound as the TFA salt.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)n1nc(-c2ccc(N)cc2)c2c(N)ncnc21
Agent: Cl
Solvent: O=CO
Product: Nc1ccc(-c2n[nH]c3ncnc(N)c23)cc1
Reaction time: 0.5 h

Procedure:
1-tert-butyl-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (9 mg, 0.032 mmol) was dissolved in a solution of formic acid (1 mL) and conc. HCl (0.2 mL) and heated to reflux. The reaction was allowed to proceed 30 min., then concentrated in vacuo and the products purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 227.1, found 227.3.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=2)O1>>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([C:32]5[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cnc(N)nc3)cc1OCC2
Yield: 73 %

Procedure:
Following the same procedure as for 182, 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 194 and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine provided 223 in 73% yield. LS/MS (ESI+): m/z 389 (M+H). 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.45 (d, J=8.4, 1H), 7.93 (d, J=9.7, 2H), 7.46 (dd, J=8.5, 1.9, 1H), 7.35 (d, J=1.8, 1H), 6.86 (s, 1H), 5.91 (hept, J=6.4, 1H), 4.61-4.44 (m, 4H), 1.50 (d, J=6.6, 6H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1)=[O:6].[F:25][C:26]([F:41])([F:40])[C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[N:34]=2)[CH:30]=[CH:31][CH:32]=1.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>C1COCC1.CN(C=O)C.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]>[CH3:24][C:23]1[CH:22]=[CH:21][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:39][C:35]1[N:34]=[C:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:41])([F:25])[F:40])[CH:28]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccc(C(=O)Nc2ccc(CCN3CCCC3)cc2)cc1Br
Reactant: Nc1nccc(-c2cccc(C(F)(F)F)c2)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(CCN3CCCC3)cc2)cc1Nc1nccc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C

Procedure:
A mixture of 3-bromo-4-methyl-N-(4-(2-(pyrrolidin-1-yl)ethyl)phenyl)benzamide (59 mg, 0.13 mmol) and 4-(3-(trifluoromethyl)phenyl)pyrimidin-2-amine (31 mg, 0.13 mmol), KOBut (22 mg, 0.2 mmol), Pd2(dba)3 (4.6 mg, 0.005 mmol) and Xantphos (4.6 mg, 0.008 mmol) in a microwave reaction vessel was suspended in 1 mL of THF. The reaction mixture was heated in a microwave at 150° C. for 90 min. After cooling, the mixture was diluted with DMF, and then filtered with a 0.45 μm microfilter. The obtained filtrate was separated by a semi-preparative HPLC. Collected product fraction was lyophilized to give pure product as a while powder. MS (ESI+) m/z 546.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([OH:13])=O.Cl.[CH3:15][NH:16][O:17][CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13]
Reactant: CNOC
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
3-(2,4-Difluoro-phenyl)-acrylic acid (9.5 g, 51.4 mmol) prepared in Step 1, N,O-dimethylhydroxylamine hydrochloride (6.5 g, 66.8 mmol), HOBT (7.6 g, 56.5 mmol), EDAC (10.8 g, 56.5 mmol) and diisopropylethylamine (9.8 mL, 56.5 mmol) were added to dichloromethane (250.0 mL). The reaction mixture stirred at room temperature for 24 hours, quenched with a saturated solution of ammonium chloride, and then extracted with dichloromethane. The extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 10.1 g of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.Cl.[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][NH:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH:31]3[C:36]([O:38][CH3:39])=[O:37])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.Cl>O1CCOCC1>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][NH:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:32][CH:31]3[C:36]([O:38][CH3:39])=[O:37])=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: COC(=O)C1CNCCC1NCc1ccc2c(c1)OCCO2
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1CN(CCn2c(=O)ccc3ccc(OC)cc32)CCC1NCc1ccc2c(c1)OCCO2

Procedure:
As similarly to Example 1, to 0.10 g of methyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidine-3-carboxylate obtained from (7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde and methyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidine-3-carboxylate hydrochloride, 1.0 mL of 6 mol/L hydrochloric acid and 1.0 mL of dioxane were added. The reaction mixture was stirred under reflux with heating for 3 hours. The solvent was removed, acetonitrile was added, and resulting solid was filtered to afford 54 mg of 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-1-(2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidine-3-carboxylic acid hydrochloride as a brown solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35]C(C)(C)C)[CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>CO>[NH2:20][CH2:19][CH2:18][N:17]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])[CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCN(CCCN1CCC(Cc2ccccc2)CC1)Cc1ccccc1OC(C)(C)C
Agent: N
Solvent: CO
Product: NCCN(CCCN1CCC(Cc2ccccc2)CC1)Cc1ccccc1O
Yield: 60 %

Procedure:
The same procedure as described for compound L24a was applied to compound 26 (0.7 g, 1.3 mmol) Purification was carried out on a silica gel TLC plate that was developed in with a 6% methanolic NH3 (7 M NH3 in methanol/94% CH2Cl2. The product was isolated as pale yellow oil (60%). 1H NMR (CDCl3) δ 7.257 (t, 2H, Ar), 7.163 (m, 2H, Ar), 7.118 (d, 2H, Ar), 6.952 (d, 1H, Ar), 6.801 (d, 1H, Ar), 6.757 (t, 1H, Ar), 3.724 (s, 2H, —CH2—), 2.867 (q, 4H, —CH2—CH—), 2.553 (m, 4H, —CH2—CH2—), 2.511 (d, 2H, —CH2—), 2.278 (t, 2H, —CH2—), 1.837 (ddd, 2H, —CH2—), 1.725 (p, 2H, —CH2—), 1.608 (d, 2H, —CH2—), 1.500 (m, 1H, —CH—), 1.275 (m, 2H, —CH2—). Mass Spec.=382.29 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:15]C)=[O:14])[N:4]=1.[OH-].[K+]>O.C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])[N:6]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(OC(C(=O)O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5 g (16 mmol) Methyl 2-(4,6-dimethoxy-2-pyrimidinyloxy)-2-phenylacetate was dissolved in 50 ml water/ethanol (1:1) and treated with 0.9 g potassium hydroxide. After stirring for 16 hours at room temperature, the mixture was extracted with ethyl acetate. The aqueous phase was acidified with 10% hydrochloric acid until it was pH 2 and extracted with ethyl acetate. After drying over magnesium sulphate, the ethyl acetate phase was concentrated the solid residue recrystallised from diisopropyl ether/ethyl acetate mixture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([O:39][CH3:40])[C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>CO.Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[N:24][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[C:22]([O:39][CH3:40])[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cnc1N1CCNCC1
Yield: 68.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)piperazine-1-carboxylate (91 mg, 0.156 mmol) was deprotected in methanol/HCl in dioxane (5/5 ml) to afford 52 mg (56% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.727-8.722 (d, 1H), 8.626-8.622 (d, 1H), 8.29 (s, 1H), 8.19-8.18 (d, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.75-7.74 (d, 1H), 7.37-7.35 (q, 1H), 7.12-7.10 (d, 1H), 7.02-6.99 (m, 2H), 5.44 (s, 2H), 4.03 (s, 3H), 3.78-3.74 (t, 4H), 3.39-3.32 (m, 4H). MS: m/z=484.3 (M+1), HPLC: 97.58% in method A.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]=[CH:11][CH:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C>>[CH:11]([CH:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH2:10]
Reactant: C=CC(O)CCCCCC
Reactant: O=Cc1ccc(O)cc1
Product: C=CC(CCCCC)Oc1ccc(C=O)cc1

Procedure:
By the method of example 13, 4-hydroxybenzaldehyde and 1-nonen-3-ol are coupled under Mitsunobu conditions, producing 4-((1-ethenylhexyl)oxy)benzaldehyde. By the methods described in example 1, this benzaldehyde is chain-extended and condensed with glyoxylic acid to provide the title compound as a colorless oil after chromatography, which solidifies on standing giving a colorless solid, mp 46°-50°.