Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:17]#[N:18].[Na+].O=O.C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[C:17]([CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:16][N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)#[N:18]
Reactant: c1ccc(N2CCc3ccccc3C2)cc1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: O=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#CC1c2ccccc2CCN1c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
N-phenyl-1,2,3,4-tetrahydroisoquinoline (1 mmol), RuCl3-nH2O (0.05 mmol) and sodium cyanide (1.2 mmol) were charged into a 25-ml side-arm flask, the interior of the reacting container was replaced by oxygen, and an oxygen balloon was attached to supply oxygen at 1 atm. Then, 1.7 ml of a mixed solvent of methanol-acetic acid (volume ratio 3/1) was added thereto at room temperature. Reaction was effected by stirring the mixed liquid at 60° C. for 4 hours. After the reaction mixture liquid was made alkaline with the addition of saturated sodium bicarbonate aqueous solution, the mixture was extracted with 10 ml ethyl acetate once and with 5 ml ethyl acetate twice. The extracted liquid thus obtained was washed with saturated saline solution, and dried over sodium sulfate, thereby obtaining an ethyl acetate solution of 1-cyano-N-phenyl-1,2,3,4-tetrahydroisoquinoline. After this solution was concentrated under reduced pressure, the mixture was analyzed by a 1H NMR internal standard method, which revealed the conversion rate of N-phenyl-1,2,3,4-tetrahydroisoquinoline being 91% with a yield of 1-cyano-N-phenyl-1,2,3,4-tetrahydroisoquinoline being 79% (vs. N-phenyl-1,2,3,4-tetrahydroisoquinoline). By using silica gel chromatography, 1-cyano-N-phenyl-1,2,3,4-tetrahydroisoquinoline was isolated at a yield of 76%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1OS(C(F)(F)F)(=O)=O)[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:4][C:1]([C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:14]=1[C:30]1[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=1[F:28])([CH3:2])[CH3:3]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(C)(C)C)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: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 926.5 %

Procedure:
To a stirred solution of 8.7 (0.100 g, 0.29 mmol) in DMF (2.00 mL, 26 mmol) at 23° C., was added 2-fluoro-5-methoxyphenylboronic acid (available from Aldrich) (0.100 g, 0.59 mmol), potassium carbonate (0.12 g, 0.88 mmol), followed by tetrakis(triphenylphosphine)palladium (0.034 g, 0.029 mmol). The mixture was heated to 100° C. After 2 hours, the reaction was cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (3×50 mL) and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-15% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 8.8 as a colorless oil (0.85 g, 71%). MS ESI (pos.) m/e: 317.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[NH2:25])C1C=CC=CC=1.C([O-])(=O)C.[NH4+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(N)CC1

Procedure:
A solution of N-(tert-butoxycarbonyl)-hexahydro-1H-azepin-4-one (0.5 g, 2.34 mmoles), O-benzylhydroxylamine hydrochloride (0.41 g, 2.57 mmoles) and ammonium acetate (0.45 g, 5.86 mmoles) in methanol (10 mL) was refluxed for 1.2 hours. The solvent was evaporated in vacuo and the crude oxime was purified by flash column chromatography (hexanes:ethyl acetate 100:0 to 50:50). The product was taken in 4N NH3 in methanol (10 mL) and added 10% by weight Pd/C (100 mg) and stirred over H2 at balloon pressure for twelve hours. The reaction was filtered through a pad of celite and filtrate evaporated in vacuo to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20]([C:23]1[N:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[O:29][C:26]1[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[N:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cn1
Temperature: 90 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
A mixture of 2-(benzyloxy)-4-fluoro-1-nitrobenzene (21.0 g), 6-(methylsulfonyl)pyridin-3-ol (14.7 g) and potassium carbonate (12.2 g) in N,N-dimethylformamide (130 mL) was stirred at 90° C. for 5 h and then at 60° C. for 15 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed successively with water and brine, dried (MgSO4), filtered, and concentrated to give light yellow crystals, which were washed with ethyl acetate-hexane to give the title compound (28.0 g, 82%) as pale yellow crystals. MS 401 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[BH4-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COC(=O)CN=Cc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CNCc1ccc(OC)cc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 91.3 g (0.441 mol) of [(4-methoxy-benzylidene)-amino]-acetic acid methyl ester in 500 ml of THF and 1000 ml of MeOH, 20 g (0.529 mol) of sodium borohydride is added portionwise at −10 to 0° C. The reaction mixture is stirred for 30 min. at −10 to 0° C. and quenched with sat. NH4Cl. After adding of ice-water, the mixture is concentrated to ¼ of whole volume and extracted with AcOEt. The combined extracts are washed with H2O and brine, dried over MgSO4 and concentrated under reduced pressure to give (4-methoxybenzylamino)-acetic acid methyl ester; NMR (CDCl3): 1.87 (br s, 1H), 3.41 (s, 2H), 3.73 (s, 3H), 3.74 (s, 2H), 3.8 (s, 3H), 6.86 (d, 2H, J=8.56 Hz), 7.24 (d, 2H, J=8.56 Hz).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:18][CH2:19][C:20]1([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:16])[C:2]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][C:20]2([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][CH2:11]1
Reactant: COC(=O)CC1(CCBr)CCCCC1
Reactant: Cc1cc(C)c(NC2CCNCC2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1(CCN2CCC(Nc3c(C)cc(C)cc3C)CC2)CCCCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 52.7 %

Procedure:
A suspension of 4-(mesitylamino)piperidine (250 mg, 1.15 mmol), methyl [1-(2-bromoethyl)cyclohexyl]acetate (371 mg, 1.38 mmol) and potassium carbonate (318 mg, 2.3 mmol) in N,N-dimethylformamide (3 mL) was stirred at 80° C. for 10 hours. Chloroform (10 mL) was added to the reaction mixture, the insoluble portion was filtered out, and the filtrate was concentrated under reduced pressure. The residue was dissolved in xylene (10 mL) and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (10 g Merck Art 9385, hexane:ethyl acetate=7:3-chloroform:methanol=10:1) to obtain the title compound as a brown oil (243 mg) (53% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][O:28][C:29]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([CH:40]=2)=[CH:38][C:37]([O:41][CH3:42])=[CH:36][CH:35]=3)=[O:30])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH2:27][O:28][C:29]([C:31]4[CH:32]=[N:33][C:34]5[C:39]([CH:40]=4)=[CH:38][C:37]([O:41][CH3:42])=[CH:36][CH:35]=5)=[O:30])[CH2:23][CH2:22]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](N)CC3)cc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NCc4ccc5c(c4)OCCO5)CC3)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,3-Dihydro-benzo[1,4]dioxine-6-carbaldehyde (188 mg, 1.14 mmol, 1.8 eq) is added at room temperature to a stirred solution of the trifluoroacetic acid salt of 6-methoxy-quinoline-3-carboxylic acid trans-4-amino-cyclohexylmethyl ester (200 mg, 0.64 mmol, 1.0 eq) in 1,2-dichloroethane (10 mL), followed by sodium triacetoxyborohydride (1.35 g, 6.36 mmol, 10.0 eq). After 18 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and a saturated sodium hydrogen carbonate aqueous solution (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-methoxy-quinoline-3-carboxylic acid trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-cyclohexylmethyl ester as a white powder (123 mg, 40% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1I)[C:15]#[N:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([NH:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:21]([NH:24][C:25](=[CH:30][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:26]([O:28][CH3:29])=[O:27])(=[O:23])[CH3:22]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)OC(C)(C)C)NC(C)=O
Temperature: 115 °C
Reaction time: 4 h

Procedure:
18.0 g (46.4 mmol) of 3-[2-(t-butoxycarbonylamino)ethoxy]-4-iodobenzonitrile was dissolved in 200 ml of dimethylformamide (DMF). 13.3 g (92.8 mmol) of methyl 2-acetamidoacrylate, 2.82 g (9.28 mmol) of tris(2-methylphenyl)phosphine, 1.04 g (4.64 mmol) of palladium (II) acetate and 12.9 ml (92.8 mmol) of triethylamine were added to the obtained solution, and they were stirred at 115° C. for 4 hours. The solvent was evaporated to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9]CC2C=CC=CC=2)=[O:8])=[CH:5][C:4]=1[N:19]([CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[S:20]([CH3:23])(=[O:22])=[O:21]>CO.C(Cl)(Cl)Cl.[Pd]>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:19]([CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1N(CCN1CCOCC1)S(C)(=O)=O
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)O)cc1N(CCN1CCOCC1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
Benzyl 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzoate (1.5 g, 3.34 mmol) was dissolved in MeOH (20 ml), then Pd/C 5% (0.33 mmol, 702 mg) was added, and the mixture was hydrogenated in a Parr apparatus (H2:35 psi) for 30 minutes. The reaction was diluted with CHCl3 (300 ml) and MeOH (300 ml) to dissolve the product that precipitated in MeOH, and the catalyst was filtered over a celite pad, and the solvent is evaporated under vacuum, to yield 700 mg of white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH:25]=[CH2:26].CCOC(C)=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:26][CH:25]=[CH2:24])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(O)ccc1OCc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step A (75.4 mmol) in 100 mL of DMF was added potassium carbonate (20.8 g, 150.7 mmol), followed by allyl bromide (11.7 mL, 135 mmol). The reaction was warmed to 60° C. and stirred for one hour. The solution was poured into EtOAc and washed with water, saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (20-30% EtOAc/hexane) to provide the titled product, along with unreacted starting material (4.39 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][N:12]3[C:7](=[C:8]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:26]=1>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:26]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccc(Cl)cc3c12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2

Procedure:
363 mg of methyl 10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate were hydrogenated at room temperature in 50 ml of ethyl acetate in the presence of 36 mg of 10 percent palladium/carbon. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel and the product was crystallized from methanol. There was obtained methyl 10-chloro-6,7-dihydro-4-oxo-3 -phenyl-4H-benzo[a]quinolizine-1-carboxylate of m.p. 138°-139°.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][C@H:17]4[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]4)[C:12]4[CH:30]=[CH:31][N:32]=[CH:33][C:11]=4[C:10]=3[C:9](=[O:34])[NH:8][CH:7]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]#[C:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][C@H:17]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]4)[C:12]4[CH:30]=[CH:31][N:32]=[CH:33][C:11]=4[C:10]=3[C:9](=[O:34])[NH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2nc3c(C#CC4CC4)c[nH]c(=O)c3c3cnccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]cc(C#CC2CC2)c2nc(N[C@H]3CCCNC3)c3ccncc3c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (3S)-3-{[4-(cyclopropylethynyl)-1-oxo-1,2-dihydropyrido[4,3-c]-1,6-naphthyridin-6-yl]amino}piperidine-1-carboxylate (100 mg, 0.218 mmol) in dichloromethane (2 mL), trifluoroacetic acid (2000 26.0 mmol) was added. After stirring at room temperature for 10 min, the mixture was quenched with aqueous sodium hydrogen carbonate (saturated). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford 4-(cyclopropylethynyl)-6-[(3S)-piperidin-3-ylamino]pyrido[4,3-c]-1,6-naphthyridin-1(2H)-one as a yellow solid. 1H NMR (500 MHz, C2D6SO) δ 10.97 (s, 1H), 8.74 (d, 1H), 8.29 (d, 1H), 8.06 (d, 1H), 7.61 (s, 1H), 4.42 (m, 1H), 3.03 (m, 2H), 2.74 (m, 1H), 2.16 (t, 2H), 1.66 (m, 2H), 0.84 (m, 6H). LRMS (APCI) calc'd for (C21H22N5O) [M+H]+, 360.2; found 360.1.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](C2C=CC=C(F)C=2)[C:8]([C:18]([O-:20])=[O:19])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].[OH2:23]>>[C:1]([C:5]1[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][O:23][CH2:1][CH2:5]2)[C:8]([C:18]([OH:20])=[O:19])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ncc(C(=O)[O-])c(-c2cccc(F)c2)n1
Reactant: O
Agent: [Li]O
Product: CC(C)(C)c1ncc(C(=O)O)c(N2CCOCC2)n1
Yield: 194.8 %

Procedure:
Using a procedure to Example B40, 2-tert-butyl-4-(3-fluorophenyl)pyrimidine-5-carboxylate (0.27 g, 0.89 mmol) was treated with LiOH—H2O (86 mg, 3.57 mmol) to afford 2-tert-butyl-4-morpholinopyrimidine-5-carboxylic acid (0.23 g, 92% yield). MS (ESI) m/z: 275.0 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].Br[C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1>CN(C)C=O.[Cu]>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:14]2[CH:28]=[CH:27][C:17]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:10][C:7]4[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=4)=[CH:22][CH:21]=3)=[O:19])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: CC(C)c1ccc(O)cc1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(Oc2ccc(C(=O)c3ccc(Oc4ccc(C(C)C)cc4)cc3)cc2)cc1

Procedure:
To a solution of 4-isopropylphenol (20.4 g.) in 30 ml of dimethylformamide was added slowly a slurry of sodium hydride, 60% in mineral oil (6.0 g.) in 150 ml of dimethylformamide. When the reaction was complete, 8.5 g. of 4,4'-dibromobenzophenone and 1.0 g. dendritic copper powder were added and the reaction mixture heated to reflux and held at reflux for 24 hours. The solvent was removed under vacuum and the residue poured into ice-water. The crude product was recrystallized from ethanol to give the desired compound, mp 104-105° C. Structure was confirmed by IR, NMR, C-13 NMR and MS.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:16][CH2:15][CH:12]1[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1)(=[O:27])=[O:26]
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(C(=O)c2ccccc2)CC1
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
7.5 g (0.0342 mol) of 1-benzoyl-4-hydroxymethyl-piperidine were dissolved in 170 ml of dichlormethane and 17 ml (0.122 mol) of triethylamine, cooled to 0° and treated with a solution of 3.14 ml (0.0404 mol) of methanesulfonyl chloride in 20 ml of dichloromethane. The mixture was stirred at 0° for 1/2 hr. Then, 100 ml of 1N aqueous HCI were added, the mixture was stirred for 5 min., the organic phase was washed with 1N aqueous HCI, with saturated bicarbonate solution and with saturated sodium chloride solution and dried over sodium sulfate. 10.2 g (100%) of 1-benzoylpiperidin-4-ylmethyl methanesulfonate were obtained as yellow crystals; m.p. 87°-90°.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1O
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Temperature: 0 °C

Procedure:
mixture of 4-hydroxy-6-nitroquinoline-3-carbonitrile (11.0 g) and 50 mL of POCl3 was heated at reflux for 7 hours. The volatile materials were removed under vacuum at 70° C. The residue was stirred at 0° C. with methylene chloride and H2O, and solid K2CO3 was carefully added until the pH was 8-9. After stirring for 30 min at rt, the organic layer was separated, washed with H2O, dried and evaporated under vacuum to give a crude solid. Purification on a silica gel column gave the 4-chloro-6-nitroquinoline-3-carbonitrile (Compound 17) as an off-white solid (4.2 g).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.[OH:13][CH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[NH2:12][C:4]1[CH:3]=[C:2]([C:19]2[CH:20]=[C:15]([CH2:14][OH:13])[CH:16]=[CH:17][CH:18]=2)[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Product: Cc1cc2nc(N)cc(-c3cccc(CO)c3)n2n1

Procedure:
The titled compound was prepared using a procedure analogous to that described in connection with Example 15 except that 2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J) and 3-(hydroxymethyl)phenylboronic acid were used as starting materials. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.40 (s, 3H), 4.79 (s, 2H), 4.90 (br, 2H), 6.03 (s, 1H), 6.09 (s, 1H), 7.51-7.54 (m, 2H), 7.82-7.85 (m, 1H), 7.94 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:53]Br)=[N:51][CH:52]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:53][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:19][CH2:20][C@H:21]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:51][CH:52]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: BrCc1ccc(OCc2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCc2ccccc2)cn1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To a solution of 360 mg of di-tert-butyl (5S)-2-(benzyloxycarbonyl)-5-[(tert-butoxy-carbonyl)amino]hexanedioate (0.71 mmol; see example 12f) in N,N-dimethyl formamide (10 mL) was added under argon atmosphere 26 mg of sodium hydride (60% in oil, 0.64 mmol). The resulting mixture was stirred at room temperature for 30 minutes. A solution of 197 mg 5-(benzyloxy)-2-(bromomethyl)pyridine (prepared according to example 17a; 0.71 mmol) in N,N-dimethylformamide (5 mL) was added, and the mixture was stirred at 60° C. for one hour. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was purified by preparative HPLC (method A) to give 327 mg of the title compound (65% yield).