Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH:6]([NH:13][C:14]([C:16]1[C:25](=[O:26])[N:24]2[C:19]([CH:20]=[C:21](Cl)[CH:22]=[CH:23]2)=[CH:18][CH:17]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(NC[CH2:38][CH2:39][NH2:40])(OC(C)(C)C)=O.C([N:43](CC)CC)C>N1C=CC=CC=1>[NH2:43][CH2:38][CH2:39][NH:40][C:21]1[CH:22]=[CH:23][N:24]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[C:16]([C:14]([NH:13][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:5][C:4]([OH:3])=[O:28])=[O:15])[C:25]2=[O:26]
Reactant: CCOC(=O)CC(NC(=O)c1ccc2cc(Cl)ccn2c1=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCN(CC)CC
Solvent: c1ccncc1
Product: NCCNc1ccn2c(=O)c(C(=O)NC(CC(=O)O)c3ccccc3)ccc2c1
Temperature: 60 °C
Yield: 95.1 %

Procedure:
To solution of (+/−)-3-[(8-Chloro-4-oxo-4H-quinolizine-3-carbonyl)-amino]-3-phenyl-propionic acid ethyl ester (32 mg, 0.080 mmol) in anhydrous pyridine (0.7 ml) at room temperature were sequentially added N-Boc-1,3-diaminopropane (30.9 mg, 0.19 mmol)and triethylamine (31.4 μl, 0.23 mmol). The resulting mixture was heated at 60° C. for 18 h. The solvent was removed under vacuum and the resulting residue subjected to a silica gel chromatography (EtOAc to EtOAc: MeOH=9:1) to give the desired product as yellowish solid (30 mg, 73%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:15](NC1(C(O)=O)CCCCCC1)=[O:16].[OH-:33].[Li+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:15]([OH:16])=[O:33]
Reactant: [OH-]
Reactant: COc1ccc(C(=O)NC2(C(=O)O)CCCCCC2)cc1OCCc1cc(C)ccc1F
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1OCCc1cc(C)ccc1F
Reaction time: 0.33 h

Procedure:
The compound of step 1 (530 mg, 1.66 mmol) was dissolved in dioxane (8.3 ml). Lithium hydroxide (8.3 ml of an aqueous 1 M solution) was added and the mixture was kept for 20 min at 60° C. After cooling, the mixture was partitioned between an excess of 2 N hydrochloric acid and EA and the aqueous phase extracted with EA. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was stirred overnight with a mixture of diethyl ether and HEP, filtered, and the solid was dried in vacuo to give 500 mg of the title compound.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([CH2:12][C:13](=O)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26].O>C(O)(=O)C>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]2[N:21]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=[O:26])[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:7]=2[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(C)(C)C1CCC(=O)C(CC(=O)c2ccccc2)C1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C1CCc2c(cc(-c3ccccc3)n2-c2cccc(C(=O)O)c2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
A solution of 4-tert-butyl-2-(2-oxo-2-phenylethyl)-cyclohexanone (0.219 gm) in glacial acetic acid (3.0 mL) in a 25-mL round-bottomed flask, under nitrogen, was fitted with a heating mantle and reflux condenser. To this solution was added 3-aminobenzoic acid (0.138 gm), which was then heated at 110 C for 3 hr. The solution was cooled to ambient temperature, 8 mL water was added, and the suspension was stirred 18 hr under nitrogen. The solid was filtered, washed with water, and recrystallized in acetonitrile to provide 0.123 gm of the pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[CH:9].[F:10][C:11]([F:32])([F:31])[C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:15][N:16]1[C:20]([Cl:21])=[C:19]([CH:22]=[O:23])[N:18]=[N:17]1.O.Cl>C1COCC1.C[Mg]Br>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:14]([CH:13]=[C:12]([C:11]([F:10])([F:32])[F:31])[CH:26]=1)[CH2:15][N:16]1[C:20]([Cl:21])=[C:19]([CH:22]([OH:23])[C:9]#[C:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:18]=[N:17]1
Reactant: C#Cc1ccccc1Cl
Reactant: O=Cc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OC(C#Cc1ccccc1Cl)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Reaction time: 0.67 h

Procedure:
Dissolve 1-chloro-2-ethynyl-benzene (22.1 g, 162 mmol) in THF (300 mL) and slowly add methyl magnesium bromide (50 mL, 3.0 M in ether). Stir solution at RT for 40 min, then add a solution of 1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carbaldehyde (29.6 g, 82.8 mmol) in THF (160 ml). Stir resulting solution at RT for 2 h then pour into cold water (500 mL) and 1N HCl (150 mL) and extract with EtOAc (3×200 mL). Combine the organic phases and wash with saturated NaHCO3 (200 mL) and brine (200 mL) then dry, filter, and concentrate. Purify the crude material by triturating with 30% ether/hexanes to give the title compound. MS (IS) 494.0 (M+1), MS (ES−) 492.0 (M−1); 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.79 (s, 2H), 7.47 (dd, 1H, J=1.9, 7.3), 7.37 (dd, 1H, J=1.4, 7.9), 7.25 (dt, 1H, J=2.0, 7.3), 7.19 (dt, 1H, J=1.5, 7.3), 5.92 (d, 1H, J=6.7), 5.62 (s, 2H), 2.79 (d, 1H, J=6.4).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:33]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:23](=[O:24])[C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][NH:20][CH:19]=2)=[O:17])=[CH:11][C:10]=1[F:32].Cl>C1COCC1>[ClH:1].[NH2:33][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:23](=[O:24])[C:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)=[CH:21][NH:20][CH:19]=3)=[O:17])=[CH:11][C:10]=2[F:32])[CH:6]=[CH:5][N:4]=1
Reactant: O=C(Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: Cl
Solvent: C1CCOC1
Product: Nc1nccc(Oc2ccc(NC(=O)c3c[nH]cc(-c4ccc(F)cc4)c3=O)cc2F)c1Cl

Procedure:
The HCl salt of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (Example 3) is obtained by treating a solution of N-(4-(3-chloro-2-(diphenylmethyleneamino)pyridin-4-yloxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (Preparation 3G) in THF with excess aqueous HCl at room temperature. The volatiles are removed in vacuo to provide the desired compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7]2.[H-].[Na+].Cl[CH2:19][C:20]([NH2:22])=[O:21]>CN(C)C=O>[C:20]([CH2:19][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7]2)(=[O:21])[NH2:22]
Reactant: COC(=O)c1cc2cccc(O)c2n1C
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cccc(OCC(N)=O)c2n1C
Temperature: 25 °C
Yield: 84.4 %

Procedure:
After 0.50 g (2.44 mmol) of methyl 7-hydroxy-1-methyl-2-indolecarboxylate was added to a suspension of 0.01 g (2.44 mmol) of 60% sodium hydride in 25 ml of dimethyl-formamide, the mixture was stirred at room temperature until the mixture became a transparent solution. Then 0.25 g (2.68 mmols) of 2-chloroacetamide as added dropwise to the transparent solution at room temperature followed by stirring at 50° C. for an hour. The reaction mixture was poured onto ice water. The resulting mixture was then extracted three times with ethyl acetate. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 0.54 g (84.4%) of methyl 7-carbamoylmethoxy-1-methyl-2-indolecarboxylate.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[NH:6][CH:5]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:33](O)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[N:6]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c2ccc(Cl)cc12
Reactant: OCCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1cn(CCc2ccccc2)c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a mixture of 0.58 g (3 mmol) of 3-acetyl-5-chloroindole, 1.42 g (5.4 mmol) of triphenylphosphine and 0.66 g (5.4 mmol) of phenethyl alcohol in THF (12 ml) was added under ice-cooling, 1.09 g (5.4 mmol) of diisopropyl azodicarboxylate. After stirring for 3 hours at room temperature, the mixture was concentrated under reduced pressure. The obtained residue was chromatographed on silica gel (¼ ethyl acetate/toluene as eluant) to give 0.58 g of the titled compound as an oil. Yield: 65%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].Cl>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]2[O:12][C:13](=[O:14])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Cl)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-amino-4-chloro-6-nitrophenol (2.00 g, 10.6 mmol) in THF (50 mL) was added 1,1′-carbonyldiimidazole (2.06 g, 12.7 mmol) and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was poured into 1 N hydrochloric acid and the precipitate was isolated by filtration, washed with H2O, then hexanes, and dried in vacuo to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]([F:31])([CH3:30])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][C:21]=1[CH3:29]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][C:17]([F:31])([F:16])[CH3:30])=[C:21]([CH3:29])[CH:22]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)cnc1OCC(C)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(C)(F)F
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (340 mg, brown oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (390 mg, 1.4 mmol, Step-1 of Intermediate-1) and 1-(6-(2,2-difluoropropoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (374 mg, 1.4 mmol, Amine-56, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:9]([CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(NCCCn1ccnc1)c1cccs1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cccs1)N(CCCn1ccnc1)Cc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 4.7 g. of N-[3-(1H-imidazol-1-yl)propyl]-2-thiophene carboxamide, 40 ml. of dimethylformamide, and 0.96 g. of 50% sodium hydride in oil was stirred for 2 hours and 2.62 g. of benzyl bromide was added. The mixture was stirred for 24 hours, concentrated to remove the dimethyl formamide, diluted with water and methylene chloride, and the layers separated. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The oil was twice washed with hexane and again concentrated. The desired product was obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH2:16])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH:16][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccn2nc(C3(CN)CC3)nc12
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccn2nc(C3(CNC(=O)C(C)C)CC3)nc12
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere C-[1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropyl]-methylamine (0.05 g, 0.23 mmol) was dissolved in THF (1 mL) and Et3N (0.048 mL, 0.35 mmol). Isobutyryl chloride (0.03 mL, 0.29 mmol) was added. Stirring for 30 min. Aq. NaHCO3 and H2O was added. The aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to afford N-[1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-isobutyramide as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][O:18][CH2:19][C:20]1[N:25]=[C:24]([Cl:26])[N:23]=[C:22]([N:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)[C:21]=1[CH3:37]>CN(C)C=O>[ClH:26].[CH3:17][O:18][CH2:19][C:20]1[N:25]=[C:24]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=2[CH3:1])[N:23]=[C:22]([N:27]2[CH2:36][CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28]2)[C:21]=1[CH3:37]
Reactant: COCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Reactant: Cc1cc(F)ccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1nc(Nc2ccc(F)cc2C)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 58.3 %

Procedure:
After 2-methyl-4-fluoroaniline(0.51 g, 4.5 mmol) and triethylamine (0.63 ml, 4.5 mmol) were added to a solution of 6-methoxymethyl-5-methyl-2-chloro-4-(1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine(0.9 g, 3 mmol) in dimethylformamide (5 ml), 750 mg of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11]O)[CH:3]=1.C([O-])(O)=O.[Na+].O=S(Cl)[Cl:20]>>[Cl:20][CH2:11][C:4]1[CH:3]=[C:2]([F:1])[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1
Reactant: OCc1cc(F)c2c(c1)OCO2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1cc(CCl)cc2c1OCO2
Temperature: 25 °C
Yield: 92 %

Procedure:
To SOCl2 (20 mL) was added (7-fluoro-benzo[1,3]dioxol-5-yl)-methanol (0.80 g, 4.7 mmol) in portions at 0° C. The mixture was warmed to room temperature over 1 h and then was heated at reflux for 1 h. The excess SOCl2 was evaporated under reduced pressure to give the crude product, which was basified with saturated aqueous NaHCO3 to pH ˜7. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure to give 6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 92%), which was directly used in the next step.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH:18]=4)[CH:16]=[C:11]3[C:10]([CH3:31])=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:31][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH:18]=3)[CH:16]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4cccc(CN5CCN(C)CC5)c4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2ncc(-c3cccc(CN4CCN(C)CC4)c3)cc12
Temperature: 50 °C

Procedure:
To a solution of 1-(4-methoxybenzyl)-3-methyl-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridine (122) (30 mg, 0.136 mmol) dissolved in chloroform (25 mL) was added trifluoroacetic acid (6 mL) and the reaction mixture was heated at 50° C. for 12 h. After completion of the reaction the solvents were removed and diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform two times. The organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed. The crude was passed through 100-200 mesh silica gel eluting the compound at 7% MeOH/CHCl3 as pale yellow solid of 3-methyl-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-b]pyridine 123 obtained in 10 mg quantity. MS m/z 322.1 (M+H)+.
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=C(C)N=3)CC2)=O)=C(F)C=1.COC1C=CC(CN2CC(C)NC2=O)=CC=1.[F:42][C:43]1[CH:44]=[C:45]([N:66]2[CH:70]([CH3:71])[CH2:69][N:68](CC3C=CC(OC)=CC=3)[C:67]2=[O:81])[CH:46]=[CH:47][C:48]=1[C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[C:62]([CH3:63])=[CH:61][C:60]([CH3:64])=[C:59]([CH3:65])[N:58]=2)[CH2:53][CH2:52]1)=[O:50]>>[F:42][C:43]1[CH:44]=[C:45]([N:66]2[CH:70]([CH3:71])[CH2:69][NH:68][C:67]2=[O:81])[CH:46]=[CH:47][C:48]=1[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57]2[C:62]([CH3:63])=[CH:61][C:60]([CH3:64])=[C:59]([CH3:65])[N:58]=2)[CH2:55][CH2:56]1)=[O:50]
Reactant: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5nc(C)c(C)cc5C)CC4)c(F)c3)C2=O)cc1
Agent: COc1ccc(CN2CC(C)NC2=O)cc1
Agent: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)cc3F)CC2)nc1C

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (163 mg) described in Preparation Example 128 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 506, the title compound (79 mg) was obtained via 3-{3-fluoro-4-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-1-(4-methoxybenzyl)-4-methylimidazolidin-2-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH3:38][O:39][N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([O:39][CH3:38])[CH3:50])=[O:49])[CH2:48][CH2:47]3)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: CON(C)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-methoxy-N-methyl-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 16b) in an analogous manner as described in example 25. LR-MS: 725.3 [(M+H)+]
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]([CH3:44])[CH3:43])=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=4[F:40])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:40][C:33]1[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:32]=1[O:31][CH:28]1[CH2:27][CH2:26][N:25]([C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[NH:41][CH:42]([CH3:44])[CH3:43])[CH2:30][CH2:29]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CNCC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (51 mg, 0.082 mmol) and Pd(OH)2 on carbon (20 wt %, 5 mg, 7.12 μmol) in THF (820 μL) was stirred under an atmosphere of hydrogen gas (balloon) at rt. After 2 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (41.2 mg, 95%) as a yellow foam. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.88-1.98 (m, 2H), 2.05-2.14 (m, 2H), 2.94-3.03 (m, 4H), 3.35-3.43 (m, 2H), 3.54 (t, J=6.3 Hz, 2H), 3.76 (s, 3H), 4.10-4.21 (m, 3H), 4.32-4.39 (m, 1H), 6.67 (ddd, J=8.9, 3.0, 1.5 Hz, 1H), 6.74 (dd, J=12.8, 2.9 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 416.3.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][N:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:16][C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)=[CH:18][N:19]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)nc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)nc1
Yield: 42.3 %

Procedure:
The title compound was prepared from methyl 6-(2-(7-phenylheptanoyl)oxazol-5-yl)nicotinate (10 mg, 0.025 mmol) following General Procedure E. Preparative thin layer chromatography (2% AcOH/EtOAc) yielded the title compound as a white solid (4 mg, 40%): 1H NMR (THF-d8, 500 MHz) δ 9.18 (s, 1H), 8.41 (d, 1H, J=8.0 Hz), 7.97-7.94 (m, 2H), 7.22-7.09 (m, 5H), 3.08 (t, 2H, J=7.5 Hz), 2.61 (t, 2H, J=7.5 Hz), 1.74-1.69 (m, 2H), 1.67-1.61 (m, 2H), 1.47-1.40 (m, 4H); 13C NMR (THF-d8, 125 MHz) δ 185.6, 163.6, 156.7, 151.1, 149.8, 147.9, 141.0, 136.7, 126.7, 126.5, 125.0, 123.9, 117.7, 37.2, 34.3, 29.9, 27.6, 27.5, 22.2; MALDI-FTMS m/z 379.1645 (M+H+, C22H23N2O4, requires 379.1652).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([NH:9][C:17](=[O:18])[C:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][C:13]=1[O:20][CH3:21])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NCCc1ccccc1
Reactant: COc1cc(Br)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Br)ccc1C(=O)NCCc1ccccc1
Reaction time: 2 h
Yield: 90.1 %

Procedure:
Phenethylamine (0.79 mL, 6.31 mmol) was added slowly to a mixture of 4-Bromo-2-methoxy-1-benzenecarbonyl chloride (1.5 g, 6.01 mmol) and triethylamine (1.3 mL, 9.02 mmol) in dichloromethane (60 mL). After 2 hours, solvent was removed under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography using dichloromethane/ethyl acetate (97:3) as mobile to give N1-phenethyl-4-bromo-2-methoxybenzamide (1.81 g, 90%). 1H NMR (DMSO-d6) δ 2.83 (m, 2H), 3.50 (m, 2H), 3.84 (s, 3H), 7.31 (m, 7H), 7.65 (d, J=8.28 Hz, 1H), 8.15 (m, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1.Br[CH2:14][CH2:15][O:16][CH3:17].O1CCCC1.[H-].[Na+]>O.CN(C)C(=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[S:7][C:8]([CH2:11][O:12][CH2:14][CH2:15][O:16][CH3:17])=[CH:9][N:10]=1
Reactant: COCCBr
Reactant: OCc1cnc(C2OCCO2)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COCCOCc1cnc(C2OCCO2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
To a mixture of [2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]methanol (1.02 g), 1-bromo-2-methoxyethane (1.14 g), tetrahydrofuran (6 mL) and N,N-dimethylacetamide (6 mL) was slowly added sodium hydride (60%, oil, 0.28 g) at 0° C. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and the title compound (0.40 g, yield 29%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). MS: 246 (MH+).