Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][N:2]=1.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.[ClH:54].C(N=C=NCCCN(C)C)C>ClCCl>[ClH:54].[ClH:54].[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[N:2][CH:3]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1ccnnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3ccnnc3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 117.8 %

Procedure:
0.25 g of 4-pyridazine-carboxylic acid (2.01 mmol) and 0.7 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.01 mmol) were dissolved in 25 ml of dichloromethane. 1.04 g of diisopropylethylamine (8.04 mmol), 0.19 g of hydroxybenzotriazole (HOBt, 1.4 mmol), and 0.46 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.4 mmol) were added at 0° C. and the reaction mixture was stirred for 16 h at room temperature. 0.09 g of hydroxybenzotriazole and 0.23 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride were added and the reaction mixture was stirred 5 h. 25 ml of dichloromethane were added, the organic layer was washed with aqueous saturated sodium chloride, the aqueous phase re-extracted once with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (10%). Fractions containing the product were combined, the solvent evaporated, and the residue re-dissolved in 20 ml of ethyl acetate. Treatment with 3.3 ml of 1 N hydrochloride acid in diethyl ether yielded 0.69 g of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16]C(OCC2C=CC=CC=2)=O)[C:11]1=[O:27])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O.[Pd]>[C:1]([O:5][C:6](=[O:28])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]1=[O:27])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(NC(=O)OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(N)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of (S)-2-(3-Benzyloxycarbonylamino-2-oxo-2H-pyridin-1-yl)-butyric acid tert-butyl ester (2.48 g, 6.43 mmol) in a mixture of MeOH (15 mL) and EtOAc (15 mL) was added 10% Pd/C (250 mg). The mixture was degassed and stirred at room temperature for 90 minutes under an atmosphere of hydrogen (balloon pressure). The reaction mixture was filtered through a short pad of silica which was then flushed with MeOH. The combined filtrates were evaporated under reduced pressure to afford the title compound as a white solid (1.62 g, 100%); 1H NMR (400 MHz, CDCl3) δ 0.91 (3H, t), 1.44 (9H, s), 1.91 (1H, m), 2.21 (1H, m), 4.24 (2H, br s), 5.50 (1H, dd), 6.11 (1H, t), 6.53 (1H, d), 6.77 (1H, d)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][CH:3]=1.[CH2:11]([OH:13])[CH3:12].S(=O)(=O)(O)[OH:15].C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:13][CH2:11][CH3:12])=[O:15])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=S(=O)(O)O
Reactant: N#CCc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1ccc(Cl)nc1

Procedure:
22.0 g (144 mmol) of (6-chloropyridin-3-yl)acetonitrile are added to a mixture of 270 ml of ethanol and 101 ml conc. sulfuric acid, and the mixture is stirred under reflux for 24 h. With stirring, the reaction mixture is then slowly added dropwise to a mixture of 350 g of sodium bicarbonate and 1 liter of water. The aqueous phase is extracted with dichloromethane (five times 400 ml each). The combined organic phases are dried over sodium sulfate, filtered and freed from the solvent using a rotary evaporator. This gives 23.1 g (80% of theory) of the title compound, which is reacted without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:20][NH2:21]>C(Cl)Cl.CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([NH:21][CH3:20])=[O:6]
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-nitrobenzoic acid (17.7 g) and oxalyl chloride (2 equiv.) in 250 mL of anhydrous CH2Cl2 was added a few drops of DMF, and the mixture was stirred for 2 hrs at room temperature. It was concentrated in vacuo, then reconcentrated in vacuo twice from 400 mL of toluene to remove excess oxalyl chloride. The residue was dissolved in 100 mL of anhydrous THF. In a separated flask methylamine (3 equiv.) was dissolved in 100 ml of anhydrous THF and cooled to 0° C. Then the acid chloride solution was added dropwise, causing a white solid to precipitate. The mixture was allowed to stir at room temperature for 16 hrs, and the solids were removed by filtration. The filtrate was concentrated in vacuo to provide a white solid, which was triturated with diethyl ether, collected by filtration to yield 3-bromo-N-methyl-5-nitrobenzamide. NMR (300 MHz, DMSO-d6) δ 9.92 (m, 1H), 8.64 (s, 1H), 8.53 (s, 1H), 8.43 (s, 1H), 2.81 (d, 3H, J=7 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[N:16])[CH2:11][CH2:10]1.[C:17]1([S:23]([N:26]2[C:30]3=[N:31][CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[C:34](Cl)=[C:29]3[CH:28]=[CH:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:17]1([S:23]([N:26]2[C:30]3=[N:31][CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[C:34]([NH:8][C@H:9]4[CH2:14][CH2:13][C@H:12]([C:15]#[N:16])[CH2:11][CH2:10]4)=[C:29]3[CH:28]=[CH:27]2)(=[O:24])=[O:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#C[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: N#C[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1

Procedure:
A mixture of trans 4-amino-cyclohexanecarbonitrile trifluoroacetic acid salt (6.36 g, 26.7 mmol), 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (8.21 g, 24.3 mmol) and diisopropylethylamine (12.5 mL, 73.0 mmol) in propan-2-ol (200 mL) was heated at reflux for 3 hours. The cooled mixture was filtered and the precipitate washed with propan-2-ol to afford 9.04 g (87%) of trans 4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanecarbonitrile as a bright yellow solid. LCMS (Method Q, ESI): RT=4.15 min, m+H=426.0; 1H NMR (400 MHz, CDCl3) δ: 9.11 (s, 1H), 9.07 (d, 1H), 8.20 (m, 2H), 7.63 (m, 2H), 7.53 (m, 2H), 6.67 (d, 1H), 4.06 (m, 1H), 2.66 (m, 1H), 2.24 (m, 4H), 1.83 (m, 2H), 1.58 (m, 2H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:22]([CH3:23])[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]2[N:11]=1)[CH3:2].I([O-])(=O)(=O)=[O:25].[Na+].CO>O.C1COCC1>[CH2:1]([S:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:22]([CH3:23])[C:13]2=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]2[N:11]=1)=[O:25])[CH3:2]
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCS(=O)c1ccccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 76.4 %

Procedure:
A mixture of 2-(2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.25 g), sodium periodate (0.24 g), methanol (6 ml), water (2 ml), and THF (0.8 ml) was stirred at roam temperature for 20 minutes, and then heated to 50° C., and stirred with heating for further 1.5 hours. To the ice-cooled reaction mixture, water was added. The precipitated crystal was collected by filtration. The obtained crystal was dissolved in ethyl acetate, and washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution, then saturated brine, sequentially. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was washed with hexane to give 0.20 g of 2-(2-ethylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 5).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.Cl[CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[N:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Reactant: ClCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 9.7 %

Procedure:
A suspension of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), 1-(3-chloropropyl)piperidine (0.12 g, 0.72 mmol) and potassium carbonate (0.125 g, 0.9 mmol) in DMF (5 ml) was stirred at 95° C. for 2 hours. After cooling, the precipitate was filtered. The filtrate was diluted with methylene chloride and purified by column chromatography eluting with methanol/ethyl acetate/methylene chloride (1/4/5) followed by methanol/methylene chloride (1/9) followed by methanol saturated with ammonia/methylene chloride (1/9). The fractions containing the expected product were combined and evaporated to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)cinnoline (27 mg, 10%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C=O.[CH3:15][S:16]([O-:18])=[O:17].[Na+].[CH2:20](N(CC)CC)C>O>[OH:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[CH2:15][S:16]([CH3:20])(=[O:18])=[O:17]
Reactant: Cc1ccc2c(O)ccnc2c1
Reactant: CCN(CC)CC
Reactant: CS(=O)[O-]
Agent: C=O
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(O)c(CS(C)(=O)=O)cnc2c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a soluttion of 7-methyl-4-hydroxyquinoline (2.63 g.) in water (55 ml.) were added aqueous formaldehyde (37%, 3.5 ml.), sodium methanesulphinate (6.39 g.) and triethylamine (4 ml.). The mixture was heated with stirring on the steam bath for 60 hours, cooled to room temperature, and filtered. The solid residue was washed with water and dried to give the novel compound 4-hydroxy-7-methyl-3-methylsulphonylmethylquinoline, m.p. 285°-290°.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[F:20][C:21]1([F:35])[C:25](=[CH2:26])[CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22]1=[O:34].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:35][C:21]1([F:20])[C:25](=[CH2:26])[CH2:24][N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:22]1([C:19]1[C:14]([F:13])=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:34]
Reactant: C=C1CN(C(=O)OC(C)(C)C)C(=O)C1(F)F
Reactant: Fc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CN(C(=O)OC(C)(C)C)C(O)(c2cccnc2F)C1(F)F
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of diisopropylamine (23.9 g) in anhydrous tetrahydrofuran (175 mL) was added dropwise a 1.61 mol/L hexane solution (136 mL) of n-butyllithium at −78° C., and the mixture was stirred at the same temperature for 15 min. To the obtained solution was added dropwise a solution of 2-fluoropyridine (21.9 g) in anhydrous tetrahydrofuran (25 mL) at the same temperature over 30 min, and the mixture was stirred for 2 hr. To the obtained suspension was added dropwise a solution of tert-butyl 3,3-difluoro-4-methylene-2-oxopyrrolidine-1-carboxylate (25.0 g) in anhydrous tetrahydrofuran (50 mL) at the same temperature, and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=2:1). The obtained crystals were washed with diisopropyl ether to give the title compound as colorless crystals (yield 23.7 g, 67%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[O:10]1[CH2:14][CH2:13][O:12][CH:11]1[CH2:15][CH2:16][NH2:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[Br:1][C:2]1[C:7]([CH2:8][NH:17][CH2:16][CH2:15][CH:11]2[O:12][CH2:13][CH2:14][O:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1cccnc1Br
Reactant: NCCC1OCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Brc1ncccc1CNCCC1OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromopyridine-3-carbaldehyde (3.53 g, 19.0 mmol, 1.0 eq) (Melnyk et al., Synthetic Commun. 23(19):2727-2730, 1993) in 1,2-dichloroethane (50 mL) was added 2-(1,3-dioxolan-2-yl)ethylamine (TCI-GR, 2.67 g, 22.8 mmol, 1.2 eq), sodium triacetoxyborohydride (Aldrich, 1.61 g, 76 mmol, 4.0 eq) and glacial acetic acid (1.14 g, 19 mmol, 1.0 eq). The reaction mixture was stirred under nitrogen at room temperature for 2 h. The reaction was quenched with 1.0 N aqueous NaOH to about pH 8 and the solution was extracted with EtOAc (200 mL×3). The organic extracts were washed with saturated NaCl, dried with MgSO4, filtered and concentrated. Flash column chromatography (silica gel, 0-10% EtOAc-Hexane) afforded the title compound as a colorless oil. MS m/z 377 (Br=79, M+H), 379 (Br=81, M+H).
Reaction SMILES: CC(OC(C)=O)=O.[CH3:8][S:9][C:10]1[NH:15][C:14](=[O:16])[CH:13]=[CH:12][N:11]=1.C1C(=O)N([Cl:24])C(=O)C1>CC(O)=O>[Cl:24][C:13]1[C:14](=[O:16])[NH:15][C:10]([S:9][CH3:8])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1nccc(=O)[nH]1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSc1ncc(Cl)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 24 h
Yield: 48.5 %

Procedure:
To a mixture of HOAc (500 mL) and Ac2O (10 mL) was added compound 2-(methylthio)pyrimidin-4(3H)-one (40 g, 0.28 mol). The resulting mixture was heated at 80° C. for 30 min to remove any moisture. Then NCS (49 g, 0.37 mol) was added at 50˜60° C. The resulting mixture was stirred at 50˜60° C. for 24 h. The mixture was then cooled to room temperature and was poured into ice-water (500 mL). The solid formed was collected and was treated with MeOH (100 mL) at reflux. Then the solid was filtered and dried on vacuum to give title compound (24 g, 48%) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]=1[C:4]([N:6]([CH2:14][CH3:15])[CH:7]([O:12][CH3:13])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5].[CH3:24][N:25](CCN(C)C)[CH3:26].[Li]C(C)(C)C.CCCCC.BrCCBr>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:24][N:25]([CH3:26])[C:19]1[CH:18]=[CH:17][C:16]([Si:20]([CH3:23])([CH3:22])[CH3:21])=[C:3]([CH:2]=1)[C:4]([N:6]([CH2:14][CH3:15])[CH:7]([O:12][CH3:13])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:5]
Reactant: CN(C)CCN(C)C
Reactant: CCN(C(=O)c1c(Cl)cccc1[Si](C)(C)C)C(OC)C(C)(C)C
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: BrCCBr
Product: CCN(C(=O)c1cc(N(C)C)ccc1[Si](C)(C)C)C(OC)C(C)(C)C
Temperature: -20 °C

Procedure:
A solution of the compound of Example 201 (0.72 g, 2.0 mmol) and TMEDA (1.20 mL, 8.0 mmol) in THF (30 mL) at -78° C. was treated with a solution of 1.7 M t-BuLi in pentane (5.6 mL, 9.6 mmol) and allowed to slowly warm to -20° C. over 4 h. The reaction was quenched with 1,2-dibromoethane (0.86 mL, 10 mmol), was diluted with sat NaHCO3, extracted with ether, the organic layers washed with brine, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by RC (ethyl acetate/hexanes) and recrystallization from pentane (-78° C.) to afford the title compound as a white solid (0.14 g, 20%). m.p. 96-98° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:10]1[CH:27]=[C:14]2[C:15]3[C:20]([CH2:21][CH2:22][N:13]2[C:12](=[O:28])[N:11]=1)=[CH:19][C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3>CC(O)C>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[O:25][CH3:26])[C:14]1=[CH:27][C:10](=[N:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[CH3:1])[NH:11][C:12](=[O:28])[N:13]1[CH2:22][CH2:21]2
Reactant: COc1cc2c(cc1OC)-c1cc(Cl)nc(=O)n1CC2
Reactant: Cc1ccccc1N
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3ccccc3C)[nH]c(=O)n1CC2
Temperature: 25 °C
Yield: 100.4 %

Procedure:
2-Methylaniline (5.44 ml, 51 mmol) and 2-chloro-9,10-dimethoxy-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one (5 g, 17 mmol) were suspended in propan-2-ol (400 ml) and heated at reflux, under nitrogen, for 24 h. After cooling to room temperature, the solution was concentrated in vacuo and the residue purified by flash column chromatography [dichloromethane/methanol (98:2-96:4)] to afford the title compound (6.2 g, quantitative yield) as a yellow/orange solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)[C:18]([CH3:31])=[C:17]([CH3:32])[N:16]=1>CN(C)C=O>[ClH:14].[CH3:31][C:18]1[C:19]([N:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[N:20][C:15]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:16][C:17]=1[CH3:32]
Reactant: C1CCNCC1
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCCCC2)nc(N2CCc3ccccc3C2)c1C
Product: Cl
Yield: 40.2 %

Procedure:
After piperidine(0.27 ml, 2.7 mmol) and triethylamine(0.38 ml, 2.7 mmol) were added to a solution of 2-chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl) pyrimidine(0.5 g, 1.8 mmol) in dimethylformamide, 260 mg of the titled compound was obtained in accordance with the same procedure as in Example 1.
Reaction SMILES: Cl.[C:2]12([NH2:12])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.Cl[C:21](OC(Cl)(Cl)Cl)=[O:22].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][NH2:45])[CH2:38][CH2:37]1>C(Cl)Cl>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:37][CH2:38][N:39]([CH2:42][CH2:43][CH2:44][NH:45][C:21]([NH:12][C:2]23[CH2:9][CH:8]4[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]4)[CH2:3]2)[CH2:11]3)=[O:22])[CH2:40][CH2:41]1
Reactant: COc1ccccc1N1CCN(CCCN)CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCCNC(=O)NC23CC4CC(CC(C4)C2)C3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 1-adamantanamine hydrochloride (1.25 gm, 0.0067 mol) and triethylamine (2.7 gm, 0.027 mol) in 25 ml of dry methylene chloride under a dry nitrogen atmosphere was added, dropwise, trichloromethyl chloroformate (1.33 gm, 0.0033 mol). The resulting suspension was refluxed for three hours, and then a solution of 3-[4-(2-methoxyphenyl)-1-piperazinyl]propylamine (1.64 gm, 0.0067 mol) in 15 ml of dry methylene chloride was added. The resulting mixture was allowed to stir at room temperature overnight. The reaction mixture was then diluted to 200 ml with methylene chloride, washed with 3% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The title compound (TLC on silica gel using a 20% methanol in ethyl acetate solvent system, RF=0.35) was isolated by gravity chromatography on silica gel and recrystallized from methylene chloride/hexane (1.65 gm, 53% of theory), mp.=181°-182° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[F-].[K+].[O:22]1[CH2:27][CH2:26]OCC1>O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:8]1([C:7]2[C:2]([C:8]3[CH:9]=[CH:10][C:26]([CH:27]=[O:22])=[CH:6][CH:7]=3)=[N:3][C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:5][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1nc(-c2ccccn2)ncc1-c1ccccc1
Reactant: C1COCCO1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: O
Product: O=Cc1ccc(-c2nc(-c3ccccn3)ncc2-c2ccccc2)cc1

Procedure:
4-Chloro-5-phenyl-2-pyridin-2-ylpyrimidine (4-2; 0.15 g, 0.56 mmol), (4-formylphenyl)boronic (0.126 g, 0.840 mmol), bis(tri-t-butylphosphine)palladium(0) (0.014 g, 0.028 mmol) and anhydrous KF (0.107 g, 1.85 mmol) were stirred in 2 ml anhydrous dioxane under N2. The reaction was heated to reflux. After 15 min an additional sample of bis(tri-t-butylphosphine)palladium(0) (0.014 g, 0.028 mmol) was added and the reaction was heated at reflux overnight. The reaction was cooled and diluted with water. The mixture was extracted 3× with DCM. The combined organic phases was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (dissolved sample in DCM, eluted with 98:2 DCM/EA) and provided an impure sample of 4-(5-phenyl-2-pyridin-2-ylpyrimidin-4-yl)benzaldehyde (4-3) that was used directly in the next transformation.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)#[N:11].N1CCCCC1>CO>[C:10]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=1)#[N:11]
Reactant: COC(=O)CC(=O)OC
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CO
Product: COC(=O)C(=Cc1ccc(C#N)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethyl malonate (5.04 g, 38.13 mmol), 4-cyanobenzaldehyde (5.00 g, 38.13 mmol) and piperidine (0.097 g, 1.1 mmol) are dissolved in methanol (150 ml). The reaction mixture is stirred for two days (48 hours) at room temperature. The solvent is removed in vacuo to afford a viscous oil which is recrystallised from methanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)[CH:3]=1.[N+](=[CH2:21])=[N-].C(OCC)C>CO.C1(C)C=CC=CC=1>[CH3:21][O:17][C:16]([CH:13]1[CH2:14][CH2:15][N:10]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([O:8][CH3:9])[N:5]=2)[CH2:11][CH2:12]1)=[O:18]
Reactant: C=[N+]=[N-]
Reactant: COc1nc(Cl)cc(N2CCC(C(=O)O)CC2)n1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)C1CCN(c2cc(Cl)nc(OC)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 1-(6-chloro-2-methoxy-pyrimidin-4-yl)-piperidine-4-carboxylic acid [131 mg, 0.48 mmol] in MeOH (1 mL) and toluene (1 mL) is added a solution of 2 M diazomethane in diethylether (0.48 mL, 0.96 mmol). The solution is stirred for 2 h at ambient temperature and concentrated. The residue is subjected to chromatography on silica gel eluting with 40% ethyl acetate:heptane to afford 1-(6-chloro-2-methoxy-pyrimidin-4-yl)-piperidine-4-carboxylic acid methyl ester [103 mg, 75%] as a solid.