Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1B(O)O>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.O>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)c(Br)c1
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(C(=O)OCC)c(-c2cc(C)ccc2C)c1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
Diethyl bromoterephthalate (46.2 g, 150 mmol), K2CO3 (41.5 g, 300 mmol), 140 ml of toluene and 140 ml of H2O were placed in a reaction vessel and argon was passed in for 30 minutes. 2,5-dimethylbenzeneboronic acid (24.8 9, 165 mmol) (cf. B3) and Pd(PPh3)4 (0.7 g, 0.6 mmol) were subsequently added under protective gas. The brownish mixture, which was turbid due to phase separation, was stirred vigorously under a blanket of protective gas at an internal temperature of 85° C. The reaction was complete after 24 hours (according to TLC). After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The product was obtained as a yellow oil in sufficient purity (greater than 97%). Yield: 48.7 g (99%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([O:24][CH3:25])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6]1.[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:31](O)=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[NH2:26][C:27]1[C:35]([Cl:36])=[CH:34][C:30]([C:31]([NH:3][CH2:4][C:5]2([O:24][CH3:25])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7][CH2:6]2)=[O:32])=[C:29]([O:37][CH3:38])[CH:28]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: COC1(CN)CCN(CCCCCC(=O)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1(OC)CCN(CCCCCC(=O)c2ccccc2)CC1
Yield: 49.5 %

Procedure:
4-Aminomethyl-4-methoxy-1-(6-oxo-6-phenylhexyl)piperidine dihydrochloride (2.25 g) as starting compound, triethylamine (2.4 ml), 4-amino-5-chloro-2-methoxybenzoic acid (1.16 g), 1-hydroxybenzotriazole (0.815 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.16 g) were reacted and treated in the same manner as in Example 270 to give 1.43 g of 4-amino-5-chloro-2-methoxy-N-((4-methoxy-1-(6-oxo-6-phenylhexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.O1CCCC1.[CH3:22][C:23]([CH3:25])=[O:24].[Cl-].[NH4+]>O1CCCC1.O>[CH3:22][C:23]([OH:24])([CH3:25])[CH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1ccc2ccccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc2ccccc2c1
Temperature: -69 °C
Reaction time: 12 h

Procedure:
2-Methylnaphthalene (7.11 g) was dissolved in tetrahydrofuran (100 ml) and the solution was cooled to −69° C. To the solution was added dropwise a 1.6M n-butyllithium-tetrahydrofuran solution (34 ml), and then a solution of acetone (4.41 ml) in tetrahydrofuran (4.41 ml). The reaction mixture was stirred for 12 hr while allowing to warm to room temperature. To the reaction mixture was added dropwise saturated ammonium chloride solution (6 ml), and the resulting mixture was poured into water (200 ml) and extracted with diethyl ether. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=85:15) to give the title compound (3.80 g).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([C:18]#[CH:19])[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>O1CCCC1>[F:10][C:11]([F:20])([F:21])[C:12]1[CH:13]=[C:14]([C:18]2[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#Cc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl chlorooximidoacetate (6.68 g, 44.09 mmol) in tetrahydrofuran (90 mL) in an ice bath was added 3-(trifluoromethyl)phenylacetylene (5.0 g, 29.39 mmol) slowly, followed by triethylamine (8.19 mL, 58.78 mmol) dropwise. The resulting mixture was stirred at room temperature overnight, which was then filtered through a layer of silica gel (top) and anhydrous Na2SO4 (bottom), and washed with ethyl acetate. The filtrate was washed with water, the organic layer dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:Hexanes=1:9) to afford ethyl 5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxylate.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[N:9]([CH:13]=[CH:14][N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][C:13]1[N:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[N:15][CH:14]=1
Reactant: c1ccc(-c2cccn3ccnc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Brc1cnc2c(-c3ccccc3)cccn12

Procedure:
Combine 2 g (10.3 mmol) of the product from Example 4 with 1.8 g (10.3 mmol) of N-bromosuccinimide in 50 ml of methylene chloride, and stir for 10 minutes at room temperature. Wash the reaction mixture with 50 ml of 10% potassium carbonate. Dry the methylene chloride layer over sodium sulfate, treat with charcoal, filter, and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.
Reaction SMILES: FCCC[O:5][C:6]1[CH:14]=[C:13]2C(CC3(CCC(=O)CC3)C2=O)=[CH:8][CH:7]=1.[F:22][C:23]([F:38])([F:37])[CH2:24][CH2:25][O:26][C:27]1[CH:35]=[C:34]2[C:30]([CH2:31][CH2:32][C:33]2=[O:36])=[CH:29][CH:28]=1.C(OC)(=O)C=C>>[F:22][C:23]([F:37])([F:38])[CH2:24][CH2:25][O:26][C:27]1[CH:35]=[C:34]2[C:30]([CH2:31][C:32]3([CH2:13][CH2:14][C:6](=[O:5])[CH2:7][CH2:8]3)[C:33]2=[O:36])=[CH:29][CH:28]=1
Reactant: O=C1CCC2(CC1)Cc1ccc(OCCCF)cc1C2=O
Reactant: O=C1CCc2ccc(OCCC(F)(F)F)cc21
Solvent: C=CC(=O)OC
Product: O=C1CCC2(CC1)Cc1ccc(OCCC(F)(F)F)cc1C2=O
Yield: 58 %

Procedure:
The title compound (854 mg, 58% yield) was prepared using the method described for Intermediate 63 starting from 6-(3,3,3-trifluoropropoxy)-2,3-dihydro-1H-inden-1-one (Intermediate 47, 1.08 g, 4.42 mmol) and methyl acrylate (878 μL, 9.73 mmol): 1H NMR (500 MHz, CDCl3) δ ppm 1.82-1.92 (m, 2H), 2.17-2.27 (m, 2H), 2.42-2.53 (m, 2H), 2.60-2.75 (m, 4H), 3.14-3.20 (m, 2H), 4.22-4.27 (m, 2H), 7.19-7.22 (m, 1H), 7.25 (dd, 1H), 7.41 (d, 1H): MS (ES+) m/z 327 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:15]=[C:14]2[C:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)=[N:4]1)[CH3:2].CN(CCN(C)C)C.C([Li])CCC.Cl.CN([CH:34]=[O:35])C>C(#N)C.C1COCC1>[CH2:1]([N:3]1[C:15]([CH:34]=[O:35])=[C:14]2[C:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)=[N:4]1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCn1cc2c(n1)c(=O)[nH]c1ccccc12
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: CCn1nc2c(=O)[nH]c3ccccc3c2c1C=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, a mixture of 2-ethyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one (10 g, 46.8 mmol), N,N,N,N-tetramethylethylenediamine (31 mL), and THF (520 mL) was chilled to 0° C. A solution of n-butyllithium in hexanes (56 mL of 2.5 M) was added dropwise. After the addition was complete the reaction mixture was stirred for 5 minutes and then DMF (72 mL) was added dropwise. The reaction mixture was warmed to ambient temperature and stirred for 1 hour. 1 N hydrochloric acid was added and the reaction mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to about half the original volume and then diluted with water and extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a dark yellow oil. The oil was combined with acetonitrile and stirred for 20 minutes. A bright yellow solid was isolated by filtration to provide 4 g of 2-ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-1-carbaldehyde as a yellow powder. An additional 3 g of material was isolated from the mother liquor.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[I:19]I.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C>[I:19][C:13]1[C:12](=[O:15])[NH:11][C:10](=[O:16])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[CH:14]=1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]1
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)cc1I
Temperature: 80 °C
Yield: 160.9 %

Procedure:
To a suspension of 1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 113) (5.09 g) in acetonitrile (75 ml) were added iodine (3.03 g) and cerium ammonium nitrate (6.54 g) and the resulting mixture was stirred at 80° C. for thirty minutes. The resulting mixture was cooled to 0° C. and thereto were then added ethyl acetate (150 ml), saturated saline (50 ml) and 5% sodium hydrogen sulfite solution (100 ml) so as to separate the layer. Furthermore, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with 5% aqueous sodium hydrogen sulfite solution and saturated saline. The resulting mixture was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the residue were added ethyl acetate (50 ml) and hexane (100 ml) and the resulting mixture was stirred for fifteen minutes, and the precipitated solids were then collected by filtration and washed with hexane to afford 5-iodo-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (7.34 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:21][C:22]1[C:27](Cl)=[N:26][C:25]([Cl:29])=[CH:24][N:23]=1)(=[O:20])=[O:19]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][O:6][C:27]2[C:22]([NH:21][S:18]([C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=3[Cl:10])(=[O:20])=[O:19])=[N:23][CH:24]=[C:25]([Cl:29])[N:26]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Nc1ncc(Cl)nc1Cl)c1cccc(Cl)c1Cl
Reactant: OCc1cccc(Br)c1
Product: O=S(=O)(Nc1ncc(Cl)nc1OCc1cccc(Br)c1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 31b using 3-bromobenzylalcohol (1.3 g) and 2,3-dichloro-N-(3,5-dichloro-2-pyrazinyl)benzenesulphonamide (Example 74) (1.1 g). Yield is 1.1 g.
Reaction SMILES: C[O-].[Na+].CO.[CH3:6][C:7]12[C:15](=[O:16])[CH2:14][CH2:13][CH:12]1[CH:11]([O:17][CH2:18][C:19](=[O:29])[CH2:20][CH2:21][CH2:22][C:23]1([CH3:28])[O:27][CH2:26][CH2:25][O:24]1)[C:10](=O)[CH2:9][CH2:8]2>C1(C)C=CC=CC=1>[CH3:6][C:7]12[C:15](=[O:16])[CH2:14][CH2:13][CH:12]1[CH:11]1[C:10]([CH2:9][CH2:8]2)=[C:20]([CH2:21][CH2:22][C:23]2([CH3:28])[O:27][CH2:26][CH2:25][O:24]2)[C:19](=[O:29])[CH2:18][O:17]1
Reactant: CC1(CCCC(=O)COC2C(=O)CCC3(C)C(=O)CCC23)OCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1(CCC2=C3CCC4(C)C(=O)CCC4C3OCC2=O)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 25% (w/w) solution of sodium methoxide in methanol (2.71 mL, 12.8 mmol, 1 eq) was added to the stirred solution of 7a-Methyl-4-[5-(2-methyl-[1,3]dioxolan-2-yl)-2-oxo-pentyloxy]-hexahydro-indene-1,5-dione (4.5 g, 12.8 mmol, 1 eq) in toluene (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then the reaction was quenched with a 10:1 (v/v) of ammonium chloride/potassium bisulfate solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layer was dried with magnesium sulfate. The resulting solution was then filtered and concentrated to yield the title compound as an oil, which was used in the next step without further purification.
Reaction SMILES: C[CH:2](NC=O)[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].[C:20](#[N:22])[CH3:21]>>[CH3:2][CH:3]1[N:22]=[CH:20][C:21]2[S:5][CH:6]=[CH:7][C:8]=2[CH2:4]1
Reactant: CC#N
Reactant: CC(Cc1cccs1)NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC1Cc2ccsc2C=N1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 6.6 g (33.1 mmol) N-(1-methyl-2-thiphen-2-yl-ethyl)-formamide in 200 ml acetonitrile is cooled in the ice bath and slowly combined with a solution of 6.1 ml (66.3 mmol) phosphorus oxychloride in 50 ml acetonitrile. The mixture is first of all stirred for a further three hours in the ice bath and then for 16 hours at RT. Then it is poured onto 200 ml of water, made alkaline with 9 g of solid sodium hydroxide and extracted three times with ethyl acetate. The combined organic phases are combined with activated charcoal and sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Mg]Br)=[CH:9][CH:8]=1.[CH3:15][C:16]1([CH3:35])[CH2:21][CH2:20][C:19](=[O:22])/[C:18](=[CH:23]/[O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])/[CH2:17]1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH3:15])([CH3:35])[CH2:17]/[C:18]/2=[CH:23]\[O:24][Si:25]([CH:26]([CH3:28])[CH3:27])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])=[CH:9][CH:8]=1
Reactant: CC(C)[Si](O/C=C1\CC(C)(C)CCC1=O)(C(C)C)C(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[Si](O/C=C1\CC(C)(C)CCC1(O)c1ccc(Cl)cc1)(C(C)C)C(C)C
Temperature: -2.5 °C
Reaction time: 1 h

Procedure:
To EXAMPLE 2 (26 g, as a solution in toluene) was added to anhydrous tetrahydrofuran (65 mL). The resulting mixture was cooled to −5 to 0° C. A separate flask was charged with anhydrous tetrahydrofuran (65 mL) and a 1 M solution of (4-chlorophenyl)magnesium bromide (172 mL, 2.05 equiv). The reagent mixture was cooled to −5 to 0° C. The mixture of EXAMPLE 2 in toluene was slowly added to the Grignard reagent, maintaining a reaction temperature below 5° C. The reaction was monitored by HPLC and was determined to be complete in about one hour. The reaction mixture was quenched slowly with methanol (91 mL), maintaining an internal temperature below 5° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]=[O:15].[CH3:16][Mg]Br.CCOCC>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([OH:15])[CH3:16]
Reactant: O=Cc1nc2ccc(F)cn2c(=O)c1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1nc2ccc(F)cn2c(=O)c1Br
Temperature: 9 °C
Reaction time: 1.5 h

Procedure:
To a stirring suspension of 3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carbaldehyde (2.3555 g, 8.691 mmol) in THF (86.91 mL) was added methyl-magnesium bromide 3 M in Et2O (4.345 mL, 13.04 mmol) dropwise at 0° C. and the mixture was allowed to warm to 9° C. over 1.5 h. After 1.5 h, the reaction was quenched with satd aq NH4Cl (50 mL) and water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (100 mL×1), brine (100 mL×1), dried over Na2SO4, filtered, and concd under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 100% gradient of EtOAc in hexane over 25 min and 100% isocratic of EtOAc in hexane for 4 min as eluent to give 3-bromo-7-fluoro-2-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92-8.97 (1 H, m), 8.14 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.83-7.90 (1 H, m), 5.26 (1 H, d, J=6.7 Hz), 5.09 (1 H, qd, J=6.5, 6.3 Hz), 1.38 (3 H, d, J=6.7 Hz); Mass Spectrum (ESI) m/e=286.9 [M+1 (79Br)] and 289.0 [M+1 (81Br)].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]([OH:18])=O)[N:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:48][C:47]=1[O:58][C:59]([F:62])([F:61])[F:60].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH2:57][CH2:56][N:55]([C:16](=[O:18])[CH2:15][N:8]3[C:9]4=[N:10][CH:11]=[CH:12][CH:13]=[C:14]4[C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[N:7]3)[CH2:54][CH2:53]2)=[CH:48][C:47]=1[O:58][C:59]([F:62])([F:60])[F:61]
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: FC(F)(F)Oc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2ncc[nH]2)c2cccnc21)N1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A vial was charged with 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid (55 mg, 0.226 mmol), HBTU (125 mg, 0.33 mmol), 1-(4-Chloro-3-trifluoromethoxy-phenyl)-piperazine dihydrochloride (177 mg, 0.50 mmol), anhydrous DMF (2.0 mL), and DIPEA (0.4 mL). The vial was capped, heated to 45° C., and stirred overnight. The following day, the volatiles were removed in vacuo and separation by preparative hplc (reverse phase, acetonitrile-water gradient) gave 1-[4-(4-Chloro-3-trifluoromethoxy-phenyl)-piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-ethanone. MS (ES) [M+H]+ found: 506.4
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Br:12]Br>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([Br:12])=[CH:6][N:7]=1
Reactant: BrBr
Reactant: COC(=O)c1nccnc1N
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1nc(Br)cnc1N
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
Methyl 3-amino-2-pyrazine-carboxylate (10 g, 65.3 mmol) was dissolved in glacial acetic acid (50 mL) by warming to approximately 45° C. To the warm solution was added bromine (3.7 mL) in acetic acid (5 mL) dropwise and the resulting mixture was stirred at room temperature for 20 minutes. The solution was diluted with water (300 mL) and then stirred at room temperature for 30 minutes, which resulted in a precipitate. The precipitate was then filtered, washed with water and dried to afford methyl 3-amino-6-bromo-2-pyrazine-carboxylate as a yellow solid (14.2 g, 94%). 1H NMR (300 MHz, CDCl3) δ3.99 (s, 3H), 8.30 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 53.02, 123.49, 124.85, 150.24, 154.70, 166.04.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3]([O-:5])=[O:4].[Na+].[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1)[CH:9]([CH3:11])[CH3:10].O.S(=O)(=O)(O)O>C1COCC1>[CH2:8]([C:12]1[CH:17]=[CH:16][C:15]([CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:14][CH:13]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Cc1ccc([Mg]Br)cc1
Reactant: CC(Br)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reaction time: 0.21 h
Yield: 10.2 %

Procedure:
A suspension of 1.75 g of sodium α-bromopropionate in 20 ml of THF was added to 15 ml of a 0.67 M solution of p-isobutylphenyl magnesium bromide in THF. The mixture was heated under reflux for 1 hour, and then cooled. Then, 15 ml of water and then 5 ml of 20% sulfuric acid were added. The mixture was stirred for 10 to 15 minutes, and extracted with diethyl ether. The extract was washed with water, and then, extracted with a 1 N aqueous solution of potassium carbonate. The extract was washed with diethyl ether. The resulting aqueous layer was added to a mixture of 10 ml of concentrated hydrochloric acid and 20 ml of water, and the mixture was extracted with diethyl ether. The extract was washed with water, dried, concentrated and purified by silica gel column chromatography to give 0.21 g (yield 10.2%) of α-(p-isobutylphenyl)propionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 88.3 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)pyrrolidin-3-ylcarbamate (417 mg, 1.5 mmol) to afford the desired product (488 mg, 88%) as a yellow solid: ESI MS m/z 552 [C27H30BrN5O3+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2.[Cl:19][C:20]1[CH:21]=[C:22]([SH:27])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]3)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=C1CCc2cc(OCCCCCBr)ccc2N1
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: O=C1CCc2cc(OCCCCCSc3ccc(Cl)c(Cl)c3)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(5-bromopentoxy)-3,4-dihydro-carbostyril (m.p.: 97°-98° C.) and 3,4-dichloro-thiophenol.
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[O:20])[CH2:15][N:16]=1)=[CH:8]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)CC2CN=C(c3cc4cccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)S2)CC1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (80 mg), N-methylpiperazine (25 μL), 1H-1,2,3-benzotriazol-1-ol (35 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (50 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow crystals were recrystallized from ethyl acetate-hexane to give the title compound (59 mg, yield: 62%) as colorless crystals.