Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7](OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:17]1([C:24]2[CH:29]=[C:28](Cl)[N:27]=[C:26]([NH:31][C@H:32]3[CH2:36][CH2:35][N:34]([C:37](OC(C)(C)C)=O)[C@@H:33]3[CH2:44][CH2:45]C=O)[N:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:31][C@H:32]3[CH2:36][CH2:35][N:34]([CH:37]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C@@H:33]3[CH2:44][CH2:45][CH2:7][N:1]3[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]3)[N:25]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)cc(N3CCCCCC3)n2)[C@H]1CCC=O
Product: c1cc(N2CCCCCC2)nc(N[C@H]2CCN(C3CCCCC3)[C@@H]2CCCN2CCNCC2)n1

Procedure:
The same procedure as a series of reactions of Example 21→Example 16→Example 21→Example 20 was carried out, except that benzyl piperazine-1-carboxylate was used in place of the compound 20 and the compound 40 was used in place of cyclohexanone in the process of Example 21, to obtain the title compound (1.13 g) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>FC(F)(F)C1C=CC=CC=1.C(OCC)(=O)C.Cl>[Br:15][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)c(C(F)(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: O=C(O)c1ccc(CBr)cc1C(F)(F)F
Temperature: 90 °C

Procedure:
A suspension of 4-methyl-2-trifluoromethyl-benzoic acid (commercially available) (20.242 g), N-bromosuccinimide (“NBS”) (19.52 g) and 2,2′-azobis-(2-methylpropanenitrile) (“AIBN”) (0.859 g) in α,α,α-trifluorotoluene (160 ml) was heated to 90° C. for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature and then diluted with ethyl acetate (200 ml) and aqueous hydrochloric acid (1M) (100 ml). The phases were separated and the organic phase was washed with aqueous hydrochloric acid (1M) (100 ml) and brine (150 ml), dried over sodium sulfate and concentrated. The residue was triturated with dichloromethane (40 ml). The solids were isolated by filtration and dried to give 4-bromomethyl-2-trifluoromethyl-benzoic acid (5.01 g) as a white powder. The filtrate was concentrated, re-dissolved in heptane/dichloromethane (1:1) (40 ml) and the dichloromethane slowly evaporated to initiate crystallization. The solids were isolated by filtration, rinsed with pentane and dried to give a second fraction of 4-bromomethyl-2-trifluoromethyl-benzoic acid (7.00 g) as a white powder. 1H-NMR (CDCl3, 400 MHz): 11.5 (br s, 1H), 8.03-7.20 (m, 3H), 4.52 (s, 2H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:16])[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:16])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: Cc1cc(-c2ccc(F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (43 mg, 78%), MS (ISP) m/z=295.4 [(M+H)+], mp 257° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 10) (52 mg, 0.186 mmol) and commercially available 4-fluoro-phenylboronic acid (33.9 mg, 0.24 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4](=[N:11][CH2:12][CH2:13][OH:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC(Cl)(Cl)C([NH:24][CH2:25][C:26](O)=[O:27])=O.C1(N=C=NC2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO.O1CCCC1.O>[NH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4](=[N:11][CH2:12][CH2:13][OH:14])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:27]
Reactant: Nc1ccc(Br)cc1C(=NCCO)c1ccccc1
Reactant: O=C(O)CNC(=O)C(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: NCC(=O)Nc1ccc(Br)cc1C(=NCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.2g of 2-(2-amino-5-bromo-α-phenylbenzylideneamino)ethanol and 2.6g of trichloroacetylglycine in 50ml of dichloromethane is added 2.5g of N,N'-dicyclohexylcarbodiimide at 0° C., the temperature of the mixture is then raised gradually to room temperature and stirring is continued for 3 hours. After completion of the reaction, the precipitates formed in the reaction mixture is removed by filtration, and the solvent is evaporated from the filtrate to give 4.3g of a crystalline substance melting at 175°-176° C. The crystals are dissolved in a mixture of 80ml of methanol and 80ml of tetrahydrofuran, a solution of 4.0g of sodium carbonate in 80ml of water is added to this solution, and the mixture is stirred at room temperature overnight. After completion of the reaction, the solvent is evaporated from the reaction mixture, the residue extracted with dichloromethane, the extract washed with water, dried over anhydrous sodium sulfate, and the solvent is removed by distillation to give the desired product, which is recrystallized from ethyl acetate affording 0.96g of the desired product melting at 153°-154° C.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[CH:17]=[CH:16][C:15]3[C:19](=[O:22])[CH2:20][CH2:21][C:14]=3[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([O:23][CH3:24])=[CH:8][C:7]1=2.[Al+3].[Cl-].[Cl-].[Cl-].[C:30](Cl)([CH3:32])=[O:31].C([O-])([O-])=O.[Na+].[Na+]>C1([N+]([O-])=O)C=CC=CC=1.O>[C:30]([C:10]1[C:9]([O:23][CH3:24])=[CH:8][C:7]2[N:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:25])[C:18]3[CH:17]=[CH:16][C:15]4[C:19](=[O:22])[CH2:20][CH2:21][C:14]=4[C:13]=3[C:12]=2[CH:11]=1)(=[O:31])[CH3:32]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c3c4c(ccc3n(CCCN(C)C)c2c1)C(=O)CC4
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1cc2c(cc1C(C)=O)c1c3c(ccc1n2CCCN(C)C)C(=O)CC3
Reaction time: 0.67 h

Procedure:
A solution of compound 37 (0.84 g, 2.51 mmol) in PhNO2 (20 mL) was cooled in an ice bath. Then AlCl3 (1.7 g, 12.7 mmol, 5 eq.) and after that, AcCl (0.9 mL, 12.7 mmol, 5 eq.) were added. The mixture was kept for 40 min (LC/MS monitoring), diluted with water, neutralized with Na2CO3, extracted with CHCl3, and evaporated. The product was purified on a short thick column, eluent: CHCl3-MeOH 99:1→90:10. Yield of 38: 0.658 g (69%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CC(O)=[O:28].C([O-])([O-])=O.[Na+].[Na+].CCCCCC>Br.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:24]([NH2:25])=[O:28])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CC(=O)O
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 2 h

Procedure:
A suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (143 mg) in 25% hydrogen bromide solution of AcOH (1.5 ml) was stirred at 25-30° C. for 2 hours. The reaction mixture was poured into a mixture of Na2CO3 (2 g) and ice-water (30 g), extracted with CHCl3, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarboxamide as a solid (136 mg).
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][N:11]2[C@@H:15]([CH3:16])[C@@H:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)[O:13][C:12]2=[O:28])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[C:33]([O:36][CH3:37])=[N:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[C:3]([CH2:10][N:11]3[C@@H:15]([CH3:16])[C@@H:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=4)[O:13][C:12]3=[O:28])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=2)[C:33]([O:36][CH3:37])=[N:34][CH:35]=1
Reactant: COc1ncc(Cl)cc1B(O)O
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cccc(OC(F)(F)F)c3)[C@@H]2C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CC#N
Product: COc1ncc(Cl)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cccc(OC(F)(F)F)c2)[C@@H]1C
Temperature: 85 °C

Procedure:
(4S,5R)-3-{[5-Bromo-2-(methylthio)pyrimidin-4-yl]methyl}-4-methyl-5-[3-(trifluoromethoxy)phenyl]-1,3-oxazolidin-2-one (INTERMEDIATE 9, 345 mg, 0.721 mmol), 5-chloro-2-methoxypyridin-3-ylboronic acid (203 mg, 1.082 mmol) and K2CO3 (299 mg, 2.164 mmol) were added to a round bottom flask, which was then evacuated and charged with nitrogen 3 times. THF (4 mL) and water (0.4 mL) were then added. After evacuating and charging again with nitrogen, 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (47.0 mg, 0.072 mmol) was added and the reaction heated for 60 minutes at 85° C. LCMS showed complete conversion to product. The reaction was diluted with 5 mL acetonitrile and filtered through a 1 g C18 cartridge, eluting with 15 mL acetonitrile until the filtrate was colorless. The filtrate was then concentrated. Silica gel chromatography using a 0-30% ethyl acetate/hexanes linear gradient followed by an isocratic hold of 30% ethyl acetate/hexanes gave the title compound as a colorless oil. LCMS (M+H)+: 541.2.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][C@@H:12]([OH:28])[C@@H:13]2/[CH:16]=[CH:17]/[C@@H:18]([OH:27])[C:19]([CH3:26])([CH3:25])[CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[O:9]1)([OH:3])=[O:2].[N+](=[CH2:31])=[N-]>C(Cl)Cl>[CH3:31][O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:15][C@H:14]2[C@H:10]([CH2:11][C@@H:12]([OH:28])[C@@H:13]2/[CH:16]=[CH:17]/[C@@H:18]([OH:27])[C:19]([CH3:26])([CH3:25])[CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])[O:9]1)=[O:3]
Reactant: CC(C)=CCC(C)(C)[C@H](O)/C=C/[C@@H]1[C@H]2C[C@@H](CCCCC(=O)O)O[C@H]2C[C@H]1O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)CCCC[C@@H]1C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)(C)CC=C(C)C)[C@H](O)C[C@@H]2O1

Procedure:
A solution of 100 mg. of the carboxylic acid prepared in Example 30 in 10 ml. of methylene chloride is combined dropwise with an ethereal diazomethane solution at 0° until the yellow coloring is permanent. After 5 minutes the mixture is evaporated under vacuum and the residue filtered with methylene chloride/2% isopropanol over silica gel, thus obtaining 95 mg. of the title compound as an oil.
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:26](#[N:29])[CH:27]=[CH2:28].CCOC(C)=O>C1COCC1>[C:26]([CH2:27][CH2:28][N:23]1[CH2:22][CH2:21][CH:20]([N:4]([CH:1]2[CH2:2][CH2:3]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:25][CH2:24]1)#[N:29]
Reactant: C=CC#N
Reactant: C[C@](O)(c1ccc(C(=O)N(C2CCNCC2)C2CC2)cc1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@](O)(c1ccc(C(=O)N(C2CC2)C2CCN(CCC#N)CC2)cc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of (S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide prepared above in step c in Example 1 (73 mg, 0.20 mmol, 1.0 equiv.) in THF (0.70 mL) was treated with acrylonitrile (55 μL, 0.84 mmol, 4.2 equiv.). After being stirred for 24 h at 50° C., the reaction was diluted (EtOAc) and washed (1×1 N aqueous NaOH, and 1× brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 0-10% MeOH/CH2Cl2, gradient elution) gave the title compound as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.58 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 4.16-4.09 (m, 1H), 3.02-2.98 (m, 2H), 2.75-2.70 (m, 3H), 2.57-2.54 (m, 3H), 2.26-2.20 (m, 2H), 2.15-2.08 (m, 2H), 1.92-1.87 (m, 2H), 1.78 (s, 3H), 0.58-0.53 (m, 2H), 0.46-0.42 (m, 2H); MS(ESI) 410 [M+H]+.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[H-].[Na+].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12]Br>C1COCC1>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5]
Reactant: COC(CBr)OC
Reactant: C#CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCOCC(OC)OC
Temperature: 40 °C
Yield: 33.5 %

Procedure:
Pent-4-yn-1-ol (4.5 mL, 48 mmol) was dissolved in anhydrous THF (50 mL). Sodium hydride (60% w/w in mineral oil, 1.95 g, 49 mmol) was added portionwise over a 10 min period. The resulting slurry was heated at 40° C. for 30 min. and then allowed to cool to room temperature. 2-Bromoacetaldehyde dimethylacetal (5.67 mL, 48 mmol) was added and the reaction mixture was heated at 40° C. for 18 h, and it was quenched with water (2 mL). The resulting solution was concentrated and then partitioned between dichloromethane (2×100 mL) and 1N HCl (100 mL). The organic phases were then removed and washed with saturated NaHCO3 solution (100 mL), and saturated brine (100 mL); and then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product (2.91 g) was then chromatographed using a silica gel column and eluting under 10 psi of nitrogen pressure with dichloromethane; 2% v/v methanol in dichloromethane; and then 4% v/v methanol in dichloromethane. The appropriate fractions were combined and concentrated to give the title intermediate (2.78 g, 16.1 mmol, 33.5% yield—contained 0.5 molar equivalents of dichloromethane). NOTE: Due to the volatility of this intermediate, this compound should not be dried on a high vacuum line.
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:19][CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24].[C:27]1([O-:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Na+]>C1COCC1>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[O:33]([CH2:19][CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)([O-])CCCCCl
Reactant: [O-]c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])CCCCOc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of tetrabutylammonium-4-chlorobutylsulfonate in THF a solution of sodium phenolate in THF is added dropwise under cooling. After complete addition, the solution is allowed to warm to room temperature. The precipitate is filtered off and the remaining solution is concentrated with a rotary evaporator to yield tetrabutylammonium-4-phenoxybutylsulfonate.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH2:13][C:12](=O)[NH:11][C:10]2[N:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:9]1=2.C1C[O:23][CH2:22]C1>>[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([CH2:19][CH2:22][OH:23])[CH:17]=[CH:18][C:9]1=2
Reactant: Cc1ccc2c(n1)NC(=O)CN2C
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCNc2nc(CCO)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
LiAlH4 (214 mg, 5.64 mmol) was slowly added to 10 mL anhydrous THF in a round-bottom flask fitted with a stirbar and a condenser. After stirring for 10 minutes, a solution of 1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (500 mg, 2.82 mmol) in 5 mL anhydrous THF was added dropwise. Upon completion of the addition, the reaction mixture was refluxed for 16 hours. The reaction was cooled to room temperature and quenched with 1 M NaOH solution until the mixture had become a milky yellow color. The precipitate was filtered off and washed 3 times with CH2Cl2. The filtrate and washings were combined, washed with brine, dried over MgSO4. Filtered and concentrated under reduced pressure to give the desired product as light yellow oil, which solidified on standing. (420 mg, 91% yield). H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H), 2.80 (s, 3H), 3.17 (t, 2H), 3.58 (m, 2H), 6.36 (d, 1H), 6.56(d, 2H). Step 5. Synthesis of tert-butyl 1,6-dimethyl-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxylate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[CH:4]=1)[CH3:2].[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27](Cl)[CH:26]=[CH:25]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[C:27]([C:9]1[N:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]3=[N:11][CH:10]=1)[CH:26]=[CH:25]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc2cccc(OCc3ccccc3)c2n1
Reactant: CCc1ccn2ccnc2c1
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1ccn2c(-c3ccc4cccc(OCc5ccccc5)c4n3)cnc2c1
Yield: 112.8 %

Procedure:
A mixture of 7-ethylimidazo[1,2-a]pyridine (1.18 g, 8.06 mmol), 8-benzyloxy-2-chloroquinoline (2.17 g, 8.06 mmol), potassium carbonate (2.23 g, 16.2 mmol), palladium (II) acetate (90.5 mg, 0.40 mmol), tetrakis(triphenylphosphine)palladium (0) (466 mg, 0.40 mmol), 1,4-dioxane (33 ml) and water (0.33 ml) was heated under a nitrogen atmosphere overnight. The reaction mixture was diluted with water, extracted with CH2Cl2 and EtOAc, and the combined organic extracts were dried over Na2SO4, filtered and concentrated to afford the desired product (3.45 g) as a solid. MS APCI (+) m/z 380.2 (M+1) detected.
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([C:19]([O:21][CH3:22])=[O:20])=[C:4]1[CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.[C:30]1([C:36]2[CH:40]=[C:39]([CH:41]=O)[O:38][N:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[O:2]=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([C:19]([O:21][CH3:22])=[O:20])=[C:4]1[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:41][C:39]2[O:38][N:37]=[C:36]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:40]=2)[CH2:26][CH2:25]1
Reactant: O=Cc1cc(-c2ccccc2)no1
Reactant: COC(=O)c1c(CC2CCNCC2)c(=O)c2ccccc2n1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(CC2CCN(Cc3cc(-c4ccccc4)no3)CC2)c(=O)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of the compound prepared in Example 306 (83.0 mg) and the compound prepared in Example 7 (52.2 mg) in dichloromethane (5.0 mL) was added diisopropylethylamine (0.105 mL) and sodium triacetoxyborohydride (85.2 mg). The reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous solution of sodium hydrogen carbonate, brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=9:1) to obtain the title compound (72.0 mg) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10](Cl)(=[O:20])[C:11]1[CH:19]=[CH:18][CH:17]=[C:13]([C:14](Cl)=[O:15])[CH:12]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:10](=[O:20])[C:11]2[CH:19]=[CH:18][CH:17]=[C:13]([C:14]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1cccc(C(=O)NCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 27.4 %

Procedure:
4-Fluoro-benzylamine (1.25 g) is added to isophthaloyl dichloride (1.015 g) in toluene (100 mL). The reaction mixture is stirred at room temperature for 4 days. The product is filtered off and washed with toluene. Recrystallization from methanol gives the product (0.52 g), mp 190–191° C.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].IC.C([O:16][C:17]1[C:25]([CH3:26])=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[CH3:27])C1C=CC=CC=1.Cl>CN(C=O)C.O>[OH:16][C:17]1[C:25]([CH3:26])=[CH:24][C:20]([C:21]([O:23][CH3:1])=[O:22])=[CH:19][C:18]=1[CH3:27]
Reactant: Cc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(C)c(O)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
K2CO3 (3.0 g, 21 mmol) followed by iodomethane (1.2 mL, 20 mmol) were added to a solution of 4-benzyloxy-3,5-dimethyl-benzoic acid (5.0 g, 20 mmol) in DMF (100 mL) and the mixture was stirred at room temperature for 6 h. The solution was diluted with water and was acidified with 1% aq. HCl. The mixture was extracted with EtOAc (3×200 mL). The combined organics were washed with water (200 mL), dried over sodium sulfate, filtered, and concentrated. The residue was taken up in degassed 2-propanol (100 mL). Pd/C (10%, 500 mg) was added and the mixture was again degassed and was backfilled with Ar. The mixture was introduced to an atmosphere of H2 (balloon) and was stirred overnight. The solids were removed by filtration through Celite and the filtrate was concentrated in vacuo to provide methyl 4-hydroxy-3,5-dimethyl-benzoate (91%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.56 (s, 2H), 3.76 (s, 3H), 3.38 (s, 9H), 2.19 (s, 6H).
Reaction SMILES: [OH-].[K+].C(OC(=O)[NH:7][CH:8]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:9]1)C>C(O)C.O>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][C:10]3([CH2:9][CH:8]([NH2:7])[CH2:11]3)[CH2:16][CH2:15]2)=[N:18][CH:19]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CCOC(=O)NC1CC2(CCN(c3ccc(CC(C)C)cn3)CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Cc1ccc(N2CCC3(CC2)CC(N)C3)nc1
Temperature: 110 °C
Yield: 91.4 %

Procedure:
1.21 g (21.65 mmol) of potassium hydroxide are added, at room temperature, to a solution of 0.37 g (1.08 mmol) of ethyl[7-(5-isobutylpyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate in 5 mL of ethanol/water (1/1). The mixture is then heated at 110° C. for 15 hours. The resulting mixture is allowed to cool to room temperature and is then concentrated under reduced pressure. The reaction medium is taken up in saturated sodium chloride solution and dichloromethane, the aqueous phase is separated out and extracted with dichloromethane, and the combined organic phases are dried over sodium sulfate. After evaporating under reduced pressure and purifying on a column of silica gel, eluting with a 100/0/0 to 96/4/0.4 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.27 g of expected product is obtained in the form of a wax.