Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][C:12]([OH:14])=O)[N:10]=[C:4]2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.CN(C)C=O.[N:32]1([C:38]2[CH:39]=[C:40]3[C:45](=[CH:46][CH:47]=2)[NH:44][C:43](=[O:48])[CH:42]=[CH:41]3)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CS(C)=O.C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][C:12]([N:35]3[CH2:36][CH2:37][N:32]([C:38]4[CH:39]=[C:40]5[C:45](=[CH:46][CH:47]=4)[NH:44][C:43](=[O:48])[CH:42]=[CH:41]5)[CH2:33][CH2:34]3)=[O:14])[N:10]=[C:4]2[CH:3]=1
Reactant: O=c1ccc2cc(N3CCNCC3)ccc2[nH]1
Reactant: Cc1ccn2cc(CC(=O)O)nc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1ccn2cc(CC(=O)N3CCN(c4ccc5[nH]c(=O)ccc5c4)CC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
A mixture of 7-methylimidazo[1,2-a]pyridine-2-acetic acid (571 mg), 1,1'-carbonyldiimidazole (535 mg), N,N-dimethylformamide (4.5 ml) and chloroform (7.5 ml) was stirred for 1 hour at ambient temperature. A solution of 6-(1-piperazinyl)-2(1H)-quinolinone (933 mg), triethylamine (607 mg) and dimethylsulfoxide (20 ml) was added thereto and the mixture was stirred for 2 hours at the same temperature. The resulting precipitates were collected, washed with chloroform,.and dissolved in 15% solution of methanol in chloroform (30 ml) and 5% hydrochloric acid (5 ml). The mixture was adjusted to pH 9 with a saturated aqueous solution of potassium carbonate. The separated organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to a column chromatography on silica gel (60 g) and eluted with 10% solution of methanol in chloroform. The fractions containing the object compound were combined and concentrated. The residue was pulverized with diethyl ether and dried to give 6 -[4-(7-methylimidazo[1,2-a]pyridin-2-ylacetyl)-1-piperazinyl]-2(lH)-quinolinone (0.45 g).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[CH:4][N:3]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].[H-].[Na+]>CC(N(C)C)=O>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:2]2[C:7]([O:8][CH3:9])=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:20][CH:21]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(CO)cc1
Reactant: COc1cncnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cncnc1OCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 4-chloro-5-methoxypyrimidine (1.5 g, 10.3 mmol) described in Journal of the Chemical Society (1960), 4590, and 4-t-butylbenzylalcohol (2.55 g, 15.6 mmol) in dimethylacetamide (10 mL) was added sodium hydride (0.625 g, 15.6 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-(4-t-butylbenzyloxy)-5-methoxypyrimidine (2.16 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCO>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Solvent: CCO
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(Br)cc1Cl

Procedure:
A 500 mL round-bottomed flask was charged with 4-bromo-2-chlorobenzene-1-sulfonyl chloride (10.0 g, 34.5 mmol, Sigma-Aldrich, St. Louis, Mo.), ferric chloride (2.80 g, 17.2 mmol), and 200 mL of benzene. The mixture was heated at reflux for 12 h then diluted with water (100 mL) and extracted with CH2Cl2 (2×300 mL). The combined organic layers were dried (MgSO4) and concentrated to give a brown solid that was slurried with EtOH (100 mL) to give 4-bromo-2-chloro-1-(phenylsulfonyl)benzene (7.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:24]([CH3:23])(=[O:26])=[O:25])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)OCc1ccnc(Cl)c1
Reaction time: 0.17 h
Yield: 107.2 %

Procedure:
To a 0° C. solution of (2-chloro-pyridin-4-yl)-methanol (2.00 g, 13 mmol) (prepared from the corresponding carboxylic acid according to the procedure in U.S. Pat. No. 6,218,537), ethyl acetate (30 mL) and triethylamine (2.9 mL, 21 mmol) was added drop wise methansulfonyl chloride (1.4 mL, 18 mmol). The solution was stirred for 10 minutes and then water (5 mL) was added. The reaction mixture was extracted with three 30 mL portions of ethyl acetate, the organics combined and washed with water (30 mL) and brine (30 mL), dried on sodium sulfate, and concentrated to a crude oil. Pentane was added to the residue and stirred at 0° C. The precipitate was collected and dried in vacuo to give methanesulfonic acid 2-chloro-pyridin-4-ylmethyl ester (3.09 g, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:38])([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:17][CH:16]=2)=[CH:11][N:10]=1)[C:3]([O:5]C)=[O:4].[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C.[Cl-].[Na+].O>[CH3:1][C:2]([CH3:38])([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:35])[CH3:37])[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=3)=[CH:19][CH:20]=2)=[CH:11][N:10]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cc2)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(COc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cc2)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
In ethanol (10 mL) was dissolved methyl 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}pyridin-2-yl]oxy]-propanoate (490 mg), 2N aqueous sodium hydroxide solution (2.2 mL) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction mixture was ice-cooled and neutralized with 2N hydrochloric acid (2.2 mL), then, ethyl acetate and saturated brine were added to the mixture, and the liquids were separated. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 97:3) to obtain 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-pyridin-2-yl)oxy]propanoic acid (287 mg).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:20]([OH:22])=O)[C:14]4[C:19]([C:10]3=[CH:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:34]2C=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.N1CCCCC1.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]1([C:7]2[N:11]3[CH:12]=[C:13]([C:20]([N:30]4[CH2:36][CH2:37][CH2:38][CH2:33][CH2:34]4)=[O:22])[C:14]4[C:19]([C:10]3=[CH:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cn2c(-c3ccccc3)ncc2c2ccccc12
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C(c1cn2c(-c3ccccc3)ncc2c2ccccc12)N1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product from part 9 (95 mg), BOP (220 mg), piperidine (56 mg) and TEA (67 mg) in 2 ml of DMF is stirred at room temperature for 18 hours. The mixture is added to aqueous NaHCO3 solution and extracted with EtOAc. The organic layer is washed with brine and water, dried (Na2SO4), filtered and concentrated to afford a foam. Purification on a silica gel column, eluting with 5% methanol in methylene chloride, gives the title compound. 1H NMR (CDCl3) δ 1.38–1.50 and 1.60–1.80 (6H, m), 3.18–3.36 (2H, m), 3.65–3.95 (2H, m), 7.40–7.60 (6H, m), 7.75 (2H, d), 7.95 (1H, s), 8.05 (1H, s), 8.10 (1H, d). The hydrochloride salt was prepared by treating the free base in EtOAc with a solution of hydrogen chloride in ether and collecting by filtration.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CS(C)=O.ClCCl>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([O:15][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][N:7]=2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C1CCC(c2ccc(Cl)nc2)=NN1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-c3ccc(=O)[nH]n3)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To 6-(6-chloro-pyridin-3-yl)-4,5-dihydro-2H-pyridazin-3-one (3 g, 14.4 mmol) in DMSO (40 mL) was added 4-hydroxy-boc-piperidine (2.9 g, 14.4 mmol), followed by 1M KtOBu (19 mL). After overnight stirring at 100° C. open to air, the reaction was cooled, diluted with dichloromethane and washed several times with water/brine, dried over sodium sulfate, and concentrated under vacuum to obtain 4.9 g crude product (92%); MS m/z 373 (M+H).
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1.ClCCl>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([NH:2][CH3:1])[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CNc1cc(OC)ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
83.5 mL (167.0 mmol) of a 2 molar solution of methylamine in THF are added dropwise to 14.3 g (83.56 mmol) 3-fluoro-4-nitro-anisol and 12.71 g (92.02 mmol) potassium carbonate in 200 mL dichloromethane. The mixture is stirred overnight and then combined with water. The organic phase is washed successively with water and ammonium chloride solution, dried and evaporated down. The yellow solid remaining is stirred with hexane. Yield: 12.7 g (84%); mass spectroscopy: [M+H]+=183.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Mg].II.Br[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31]([C:36]([O:38]C)=[O:37])[CH:30]=[CH:29]2>C1COCC1.[Cl-].[Zn+2].[Cl-].O>[CH3:1][C:2]([C:13]1[CH:18]=[C:17]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([C:36]([OH:38])=[O:37])[CH:30]=[CH:29]3)[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(C)(C)c1cc(Br)ccc1OC
Reactant: COC(=O)c1ccc2cc(Br)ccc2c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCC(C)(C)c1cc(-c2ccc3cc(C(=O)O)ccc3c2)ccc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 16 g (45 mmol) of 2-(1,1-dimethyldecyl)-4-bromo anisole in 60 ml of THF is slowly added to 1.3 g (54 mmol) of magnesium and a crystal of iodine. The mixture is slightly heated at the beginning of the addition until the reaction of formation of the Grignard is initiated. Then the remainder of the solution containing the brominated derivative is added in a manner to maintain a regular reflux. Once the addition is complete, the mixture is stirred for 30 minutes at 50° C. and then cooled to ambient temperature. 7.4 g (54 mmol) of zinc chloride in solution in 50 ml of THF are added. The mixture is stirred for 30 minutes at ambient temperature, 6.6 g (25 mmol) of methyl 6-bromo-2-naphthoate are added and then 175 mg of NiCl2 /DPPE complex. The mixture is stirred for 3 hours at ambient temperature at which point 250 ml of water are added. The THF is evaporated under reduced pressure and the residue is extracted with dichloromethane, dried and the solvent evaporated. The residue is purified by passage through a silica column (eluant: mixture of 60% dichloromethane and 40% hexane). On evaporation, a solid is obtained which is recrystallized twice in hexane to give the methyl ester of 6-[3-(1,1-dimethyldecyl)-4-methoxyphenyl]-2-naphthoic acid: 7.05 g (61%). Melting point: 92° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:19])[N:4]([CH2:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:3]1=[O:30].[Li+].CC([N-]C(C)C)C.[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[CH:42][CH:41]=1>C1COCC1.CC(=O)OCC.O>[Cl:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]([OH:45])[C:11]2[C:6]3[C:5](=[O:19])[N:4]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:3](=[O:30])[N:2]([CH3:1])[C:7]=3[N:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:42][CH:41]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccnc3)cnc21
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cccnc3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
To a solution of 1-methyl-6-(pyridin-3-yloxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (400 mg, 0.97 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 1.94 mL, 3.88 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-chlorobenzaldehyde (273.5 mg, 1.94 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at −78° C. for 30 min. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl) (hydroxy)methyl)-1-methyl-6-(pyridin-3-yloxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (71 mg, 13.2% yield) as an oil. LCMS: [MH+-THP] 469 and TR=1.499 min.
Reaction SMILES: O.[OH-].[Li+:3].[O:4]1[CH:9]([C:10]([O:12]CC)=[O:11])[CH2:8][NH:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2>O.O1CCOCC1>[O:4]1[CH:9]([C:10]([O-:12])=[O:11])[CH2:8][NH:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.[Li+:3]
Reactant: CCOC(=O)C1CNc2ccccc2O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])C1CNc2ccccc2O1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of lithium hydroxide monohydrate (1.43 g, 34.2 mmol) in water (50 mL) was added to a solution of ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (3.55 g, 17.1 mmol) in dioxane (50 mL), and the mixture was stirred at 25° C. for 21 h. The reaction mixture was concentrated to afford the title compound. MS m/z: 180 (M+1 of acid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC)(OC)(OC)[CH3:11]>>[CH3:10][C:11]1[O:9][C:3]2[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=2[N:1]=1
Reactant: COC(C)(OC)OC
Reactant: Nc1cc(Br)ccc1O
Product: Cc1nc2cc(Br)ccc2o1

Procedure:
A solution of 2-amino-4-bromophenol (1 g, 5.32 mmol) in trimethyl orthoacetate (20 mL) was refluxed for 1.5 hours. The reaction was then cooled and the solvent removed under reduced pressure to give 1.1 g of title compound.
Reaction SMILES: [C:1]12([C:9](Cl)=[O:10])[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1>>[C:20]1([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][C@H:13]([NH:12][C:9]([C:1]34[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]3)[CH2:3][CH2:2]4)=[O:10])[CH2:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C12CCC(CC1)CC2
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C12CCC(CC1)CC2

Procedure:
Bicyclo[2.2.2]octane-1-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)bicyclo[2.2.2]octane-1-carboxamide.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.C(Cl)(Cl)Cl>O>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][Cl:19])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1)N1CCC(CCl)CC1
Yield: 90 %

Procedure:
4-Hydroxymethylpyridine is hydrogenated in methanol at 140° C. under 200 atmospheres of hydrogen pressure in the presence of ruthenium oxide, producing 4-hydroxymethylpiperidine, b.p. 126°-130° C./14 mm Hg; m.p. 55°-56° C. Reaction with benzoyl chloride produces N-benzoyl-4-hydroxymethylpiperidine (m.p. 83°-85° C.). A mixture of 135.0 g of N-benzoyl-4-hydroxymethyl-piperidine, 90 ml of thionyl chloride and 900 ml of chloroform is heated under reflux for 4 hours. Thereafter, the reaction mixture is mixed with water, while cooling with ice, and the organic phase is washed neutral with an aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate and evaporated. There are obtained 132.0 g (90% of theory) of N-benzoyl-4-chloromethylpiperidine; m.p. 68°-70° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:13]([O:22][CH2:23][CH3:24])(=[O:21])/[CH:14]=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2)=[CH:14][C:13]([O:22][CH2:23][CH3:24])=[O:21])[CH3:20]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: Cc1ccc2cc(Br)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C(=O)OCC)c1ccc2nc(C)ccc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-bromo-2-methylquinoline (2.89 g) in DMF (70 mL) at room temperature, diethyl maleate (4.85 mL), palladium acetate (0.15 g), tri(o-tolyl)phosphine (0.39 g) and potassium carbonate (3.59 g) were subsequently added then the reaction mixture was warmed to 100° C. and stirring continued overnight. After cooling, the reaction mixture was quenched with water and extracted twice with diethyl ether. The combined organic layers were collected, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with cyclohexane-ethyl acetate from 100 to 60%) to give 4 g of the title compound as a slightly yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=3[N:23]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:16]3[CH2:17][CH2:18][N:19]([C:32]4[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34][N:33]=4)[CH2:20][CH2:21][C:22]=3[N:23]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNCC3)cc1
Reactant: Cc1cc(Cl)ncn1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2cc(C)ncn2)CC3)cc1
Yield: 36 %

Procedure:
The compound op was prepared following the general procedure in Example 2, substituting 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea with (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-d]azepin-2-yl)phenyl)urea and substituting 2-Chloropyrimidine with 4-Chloro-6-methylpyrimidine. The desired product op (36% yield) was obtained as white powder: 1H NMR (500 MHz, DMSO) δ 8.70 (s, 1H), 8.42 (s, 1H), 8.20 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 6.80 (s, 1H), 6.19 (t, J=5.5 Hz, 1H), 4.10-3.62 (m, 9H), 3.52 (dd, J=11.0, 3.6 Hz, 1H), 3.21-3.02 (m, 5H), 2.88 (m, 2H), 2.28 (s, 3H), 1.12 (d, J=6.4 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); LC-MS m/z=503 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([O:17]CC)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH3:22]>>[CH3:1][N:2]1[CH2:21][CH2:20][C:5]2[N:6]([CH2:14][C:15]([NH2:22])=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: N
Product: Cc1ccc2c(c1)c1c(n2CC(N)=O)CCN(C)C1
Reaction time: 0.25 h

Procedure:
Ethyl 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetate (0.5 g, 1.75 mmol) was taken in 4 ml aqueous ammonia and microwaved at 120° C. for 5 min using Initiator (Biotage Microwave). The solid product precipitated out after the reaction was filtered through Buchner funnel and washed with 10% sodium bicarbonate (10 ml×2) followed by demineralised water (10 ml×2) wash. Product was vacuum dried and was taken in 5 ml ethanolic HCl, stirred for 15 minutes, concentrated in vacuo to afford 13 mg of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetamide as HCl salt. 1H NMR (DMSO) 10.2 (bs, 1H), 7.62 (s, 1H), 7.21-7.3 (m, 3H), 6.9 (d, 1H), 4.75 (s, 2H), 4.45-4.51 (m, 1H), 4.21-4.25 (m, 1H), 3.12-3.17 (m, 4H), 2.97 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][CH2:34][C:35]2[NH:44][C:38]3=[N:39][CH:40]=[C:41](I)[CH:42]=[C:37]3[N:36]=2)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:41]3[CH:42]=[C:37]4[N:36]=[C:35]([CH2:34][CH2:33][C:29]5[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=[CH:31][N:30]=5)[NH:44][C:38]4=[N:39][CH:40]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: CN(c1ccc(Cl)cc1)S(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N(C)c5ccc(Cl)cc5)cc4)cnc3[nH]2)c1
Temperature: 90 °C
Yield: 32.6 %

Procedure:
A mixture of 0.541 g of N-(4-chlorophenyl)-N-methyl-4-bromo-benzenesulfonamide, 0.42 g of bis-(pinacolato)-diboron, 0.025 g of 1,1′-bisdiphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenylphosphino)-ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 115° under N2 for 6 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30-25:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate gives 0.17 g of the title compound as a solid of m.p. 191-192° C. The mass spectrum shows the molecular peak MH+ at 534.3 Da.