Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH:30]2[CH2:34][CH2:33][O:32][CH2:31]2)[CH:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.N>C(Cl)Cl>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH:30]2[CH2:34][CH2:33][O:32][CH2:31]2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OC4CCOC4)c23)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OC4CCOC4)c23)c1
Yield: 148.5 %

Procedure:
Using an analogous procedure to that described in Example 20, 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-tetrahydrofuran-3-yloxyquinazoline (0.39 g) was reacted with trifluoroacetic acid (2.5 ml). The reaction mixture was evaporated and the residue was triturated under diethyl ether. The precipitate was isolated and the solid was dissolved in a mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was evaporated and the residue was purified by column chromatography on silica using a 97:3 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.47 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.2-2.3 (m, 1M, 2.3-2.5 (m, 1H), 3.8 (s, 3H), 3.75-3.9 (m, 1H), 3.9-4.0 (m, 2H), 4.2 (d, 1H), 5.5 (m, 1H), 6.8 (s, 1H), 6.92 (s, 1H), 7.02 (m, 1H), 7.55 (d, 1H), 7.6 (d, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 388 and 390.
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[C:22]([O:24][CH3:25])=[O:23])=[N:17][CH:18]=3)[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4]1)[CH3:2].N1C=CC=CC=1.[Cl:34][C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:34][C:35]([N:5]1[CH2:4][CH:3]([CH2:1][CH3:2])[O:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([CH3:26])([CH3:27])[C:22]([O:24][CH3:25])=[O:23])=[N:17][CH:18]=3)[CH:11]=[CH:12][C:6]1=2)=[O:37]
Reactant: CCC1CNc2ccc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)cc2O1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC1CN(C(=O)Cl)c2ccc(-c3ccc(OCC(C)(C)C(=O)OC)nc3)cc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of methyl 3-(5-(2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-10 (248.0 mg, 0.60 mmol) and dry pyridine (97.0 μL, 1.20 mmol) in anhydrous methylene chloride (3.0 mL) was added dropwise to a solution of triphosgene (71.2 mg, 0.24 mmol) in anhydrous methylene chloride (3.0 mL) at −20° C. under an atmosphere of argon. The reaction mixture was allowed to warm to room temperature over 30 mins and was stirred for 3 h at room temperature. It was then successively diluted with methylene chloride (25 mL), quenched with a 1 N aqueous solution of hydrogen chloride (1.0 mL), diluted with water (10 mL) and decanted. The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were washed with a 1 N aqueous solution of hydrogen chloride (20 mL), brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The light pink solid methyl 3-(5-(4-(chlorocarbonyl)-2-ethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)pyridin-2-yloxy)-2,2-dimethylpropanoate B-11 (265.0 mg, Yield=100%) was used for the next step without purification and stored at −20° C. under an atmosphere of nitrogen. MS (ESI) [M+1]+ 433.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5].[C:12]([NH:14][C:15]([NH2:17])=[NH:16])#[N:13].CCOCC>C1C(O)=CC=CC=1C>[ClH:2].[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][C:12]([NH:14][C:15]([NH2:17])=[NH:16])=[NH:13]
Reactant: CCc1cccc(Cl)c1N
Reactant: N#CNC(=N)N
Agent: Cl
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: CCc1cccc(Cl)c1NC(=N)NC(=N)N

Procedure:
A mixture of 3 g. (0.0156 mole) of 2-chloro-6-ethylaniline hydrochloride and 1.35 g. (0.016 mole) of cyanoguanidine in 25 ml of m-cresol is heated on a steam bath for 1 hour. The reaction mixture is then cooled and 250 ml of ether is added. The preciptate is filtered off and dissolved in 100 ml of warm water, charcoaled and filtered and cooled in an ice bath. 10% sodium hydroxide solution is then added to make the mixture strongly basic. The mixture is then filtered and washed with water. This is then dissolved in methanol, the pH is adjusted to 7 with methanolic hydrochloric acid and the mixture evaporated to dryness, triturated with ether and filtered to obtain 1-(2-chloro-6-ethylphenyl)biguanide hydrochloride (m.p. 209°-210°C).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[CH2:5]1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][CH:4]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6](=[O:14])[CH2:5]3)[CH2:16][CH2:17]2)=[CH:22]1
Reactant: O=C1CC(CCBr)c2ccccc2N1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2ccccc2N1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
A suspension of 4-(2-bromoethyl)-3,4-dihydro-2(1H)-quinolinone (II'-1) (500 mg, 1.97 mmol),3-(4-piperidinyl)-1H-indole (394.5 mg, 1.97 mmol) and sodium hydrogencarbonate (248.7 mg, 2.96 mmol) in dry dimethylformamide (5 ml) was allowed to react at 90 ° C. for 4 hours. Ice-water (50 ml) was poured into the reaction mixture and then the separated solid was filtered by aspiration. The residue was washed with water and dissolved in chloroform (50 ml). The solution was dried (anhydrous magnesium sulfate) and the solvent was distilled off. The residue was dissolved in developing solvent (chloroform: methanol=85:15) and purified by silica gel column chromatography (chloroform: methanol=85:15). After removing the first eluted impurity , a colorless solution was collected and the solvent distilled off to give the desired product (IV-1) (540 mg) as a pale yellow solid (yield 73.4%, mp 115°-117 ° C. (methanol/tetrahydrofuran/water).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)[NH:8][CH2:7][CH2:6][C:5]2=1.CCN(CC)CC.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C1COCC1>[C:29]([N:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)[NH:11][C:10]=2[CH:9]1[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3c1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCc2c([nH]c3ccc(C)cc23)C1c1cccc(O)c1
Reaction time: 1 h

Procedure:
To a solution of 6-methyl-1-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-beta-carboline (1 equiv) in THF was added Et3N (2.2 equiv) and acetic anhydride (1.2 equiv). After one hour, the solution was purified by prep-HPLC to give 3-(2-acetyl-6-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl)phenol 1.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:20]=[O:21].O>O1CCCC1>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:20]=[O:21])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)c2ccccc12
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
To a solution of 1,4-dibromonaphthalene (1.00 g, 3.50 mmol) in tetrahydrofuran (15 mL) were added n-butyllithium (1.6 mol/L; 3.1 mL) and dimethylformamide (0.54 mL, 7.0 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (8:1 hexane/ethyl acetate) to afford 4-bromo-1-naphthalenecarboxaldehyde (458 mg, 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]([CH3:36])([CH3:35])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31](O)=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:17][C:18]([CH3:36])([CH3:35])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2CC(C)(C)C)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2CC(C)(C)C)c1

Procedure:
1.74 g of compound 10 was obtained in a similar manner to those described in the Examples 1 and 2 using 3.16 g of ethyl 4-(2-aminophenoxy)butyrate and 1.93 g of 3-[1-(2,2-dimethylpropyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([OH:12])[CH:5]=1)[CH3:2].[C:15](OCC)(=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:5]=[C:6]2[C:7]([CH:8]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15](=[O:22])[O:12]2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(N(CC)CC)cc2oc1=O

Procedure:
--A solution of 4-diethylamino-2-hydroxy-benzaldehyde (29.8 g, 154 mmol) and diethyl malonate (23.8 ml, 157 mmol) in ethanol (185 ml) was treated with piperidine (1.37 ml, 13.9 mmol) and heated under reflux for 4 h. The solution was allowed to cools then concentrated under reduced pressure to approx. half-volume diluted with ether and washed with water, dilute aq. NaOH and water, dried and evaporated under reduced pressure. Trituration of the residue with EtOH (approx. 15 ml) gave yellow crystals which were recrystallised from EtOAc-light petroleum to give the ester 1 as bright yellow prisms (18 the m.p. 76-77° C. A sample recrystallised a second time had m.p. 77-78° C. (Found: C, 66.4; H, 6.7g N, 4.8. C16H9NO4 requires C, 66.4; H, 6.6; N, 4.8%). The discrepancy with the m.p. (87° C.) reported by Kendal et al. (GB 867,592), together with the sharp m.p. and satisfactory analytical result for the present sample suggests that the digits of the reported value may accidently have been transposed.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[C:5]([CH3:19])[NH:4][N:3]=1.Cl.[CH3:21]O>>[CH3:21][O:17][C:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:6]3[C:2]([NH2:1])=[N:3][NH:4][C:5]=3[CH3:19])[S:8][C:9]=2[CH:15]=1)=[O:18]
Reactant: CO
Reactant: Cc1[nH]nc(N)c1-c1nc2ccc(C(=O)O)cc2s1
Agent: Cl
Product: COC(=O)c1ccc2nc(-c3c(N)n[nH]c3C)sc2c1

Procedure:
A solution of 2-(3-amino-5-methyl-1H-pyrazol-4-yl)-benzothiazole-6-carboxylic acid (1.52 g, 5.5 mmol) in 500 mL of anhydrous methanol containing HCl gas was heated to reflux for 5 hrs. The excess methanol was removed by distillation and the solution was neutralized by the addition of a solution of saturated sodium carbonate. The resulting solids were isolated by filtration to yield 500 mg of the title compound as a yellow solid. MS (m/z, ES+): 289.1 (M+1,100%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)[O:17][C:16](=O)[C:13]2([CH2:15][CH2:14]2)[C:12](=[O:19])[O:11]1>C(O)C>[CH2:1]([N:8]1[CH2:15][CH2:14][CH:13]([C:12]([OH:19])=[O:11])[C:16]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: NCc1ccccc1
Solvent: CCO
Product: O=C(O)C1CCN(Cc2ccccc2)C1=O
Yield: 79.4 %

Procedure:
A mixture of benzylamine (0.962 mL; 8.82 mmol) and 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.5 g; 2.94 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 30 to 100% ethyl acetate in heptane with 5% acetic acid) to afford 0.512 g (79%) of 1-benzyl-2-oxopyrrolidine-3-carboxylic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:8][N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1
Reactant: O=Cc1ncc[nH]1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(CC1CCCN(Cc2ncc[nH]2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (21 mg, 0.061 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 2-imidazole carboxaldehyde (8.7 mg, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 20.3 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(1H-Imidazol-2-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 11 as a colorless oil (10.7 mg, 54%). LRMS 327.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=O)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:30]([NH:37][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@:9]1([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:15][C@H:14]2[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
(1R*,5S*,6R*)-8-Benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-one (Description 17; 5.0 g, 12.8 mmol), p-toluenesulfonic acid monohydrate (25 mg) and benzylamine (2.1 g, 20 mmol) in toluene (50mL) was heated at reflux under Dean Stark conditions for 24 hours, then cooled and the solvent removed in vacuo. The residue was dissolved in methanol (100 mL) and sodium cyanoborohydride (900 mg, 14 mmol) added. The solution formed was stirred at room temperature for 2 hours then concentrated to approximately ¼ volume. Water (500 mL) was added and the suspension formed was extracted with ethyl acetate (2×500 mL). The extracts were dried (MgSO4) and concentrated, before the residue was purified by silica chromatography to give the title compound (3.87 g, 8 mmol) as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=3)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:21][C:20]1[N:22]=[C:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[N:16]2[C:17]=1[CH:18]=[N:19][C:14]([NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[N:15]2
Reactant: COC(=O)c1ccc(C(=O)NC(C)c2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn2)cc1
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2nc(C)c3cnc(Nc4cc(OC)c(OC)c(OC)c4)nn23)cc1
Yield: 20.4 %

Procedure:
In a similar manner as described for Example 9, methyl 4-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}benzoate (Intermediate 30) (56 mg, 0.12 mmol), and 1,2,4-triazole (55 mg, 0.80 mmol) in pyridine (2 mL) and phosphorous oxychloride (0.037 mL, 0.40 mmol) gave methyl 4-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}benzoate (11 mg, 20%) as a yellow solid. 1H NMR (CD3OD): δ9.06 (s, 1H), 9.01 (s, 1H), 8.58 (d, J=7.87 Hz, 1H), 8.08 (d, J=7.87 Hz, 1H), 7.62 (t, J=7.87 Hz, 1H), 7.04 (s, 2H), 5.48 (s, 1H), 3.87 (s, 3.75 (s, 3H), 3.71 (s, 6H), 2.59 (s, 3H). MS m/z 449 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[NH:21][CH2:20][CH2:19][C:12]3(C(=O)CCC3=O)[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.[OH-:25].[Na+]>Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[CH2:11][C:12](=[O:25])[CH2:19][CH2:20][NH:21]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [OH-]
Reactant: O=C1CCC(=O)C12CCNC(Cc1ccc(F)c(F)c1)C2
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCNC(Cc2ccc(F)c(F)c2)C1
Temperature: 75 °C

Procedure:
A mixture of intermediate 12 (0.032 mol) in HCl, (6N; 90 ml) was stirred at 75° C., then cooled. CH2Cl2 was added and the mixture was alkalized with NaOH at a temperature below 20° C. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was dried, yielding 7.2 g of 2-[(3,4-difluorophenyl)methyl]-4-piperidinone (intermediate 13). In a similar way as described in procedure d) were prepared:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([Cl:17])[N:9]=1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:17][C:10]1[N:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=1
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
piperazine (1.38 g) was added to a stirred solution of 2,6-dichloro-3-nitropyridine (3.0 g, prepared according to J. Heterocyclic Chem. 1994, 31, 73) and diisopropylethylamine (3.0 ml) in dichloromethane (100 ml) at 0° C. under N2. The resulting solution was stirred at room temperature for 2 hours then poured into saturated aqueous sodium bicarbonate, extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (ethyl acetate:methanol 8:2) to afford 1-(6-Chloro-3-nitro-pyridin-2-yl)-piperazine (2.99 g) as a red solid. M.p. 50-53° C.; MS (ES+) 243/245 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19](Cl)=[O:20])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2.Cl.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].C(N(CC)CC)C>ClCCl>[F:23][C:24]([F:28])([F:27])[CH2:25][NH:26][C:19]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:20]
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
23 g (0.063 mol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid chloride are added dropwise to a solution of 9.35 g (0.069 mol) of 2,2,2-trifluoroethylamine-hydrochloride and 26 ml (0.188 mol) of triethylamine in 550 ml of dichloromethane at 0° C. under nitrogen and stirred for 2 hours at ambient temperature. The reaction mixture is extracted twice each with water, 1N hydrochloric acid and sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and the solvent is distilled off. The product is purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate=8:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][N:6]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29]/[CH:30]=[C:31]1/[C:32]2[CH:45]=[C:44]([C:46]([OH:49])([CH3:48])[CH3:47])[CH:43]=[CH:42][C:33]=2[O:34][CH2:35][C:36]2[N:41]=[CH:40][CH:39]=[CH:38][C:37]/1=2>C(#N)C.O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][N:6]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH:7]1[CH2:11][CH2:10][N:9]([CH2:28][CH2:29][CH:30]=[C:31]2[C:37]3[CH:38]=[CH:39][CH:40]=[N:41][C:36]=3[CH2:35][O:34][C:33]3[CH:42]=[CH:43][C:44]([C:46]([OH:49])([CH3:48])[CH3:47])=[CH:45][C:32]2=3)[CH2:8]1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Reactant: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 3-[(4-chloro-benzyl)-pyrrolidin-3-yl-amino]-propionic acid methyl ester (0.06 g, 0.2 mmol) in acetonitrile:water (3:1) was added potassium carbonate (0.056 g, 0.4 mmol) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.065 g, 0.17 mmol) and reaction stirred at 50° C. for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and dried over sodium sulfate. The crude product was purified by flash chromatography on silica using ethyl acetate/methanol (5%). 1H-NMR (CDCl3) δ: 1.40 (6H, s), 1.60 (1H, m), 1.80 (1H, m), 2.10-2.60 (8H, m), 3.20-3.40 (6H, m), 3.50 (2H, m; 2H, s), 5.20 (2H, br s), 6.15 (1H, t), 6.70 (1H, t), 7.18-7.42 (7H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 590 (M+1), UV retention time: 1.51 min.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([N:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:29])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][Mg]Br>O1CCCC1.C(OCCCC)CCC>[C:25]([C:23]1[N:24]=[C:19]([CH2:18][N:15]2[CH2:16][CH2:17][N:13]([C@@H:8]([C:9]([CH3:10])([CH3:12])[CH3:11])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:14]2=[O:29])[CH:20]=[CH:21][CH:22]=1)(=[O:27])[CH3:30]
Reactant: COC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A solution of the product from Example 17D (1.95 g, 4.815 mmol) in tetrahydrofuran (50 mL) at −78° C. was treated methylmagnesium bromide in butyl ether (5.7 mL, 1 M). The mixture was stirred 0.5 hours at −78° C., quenched with acetone (3 mL) and 10% citric acid. The reaction mixture was partitioned between ethyl acetate and 1 N NaHCO3, and the organic phase layer was decanted and concentrated. The residue was purified by flash chromatography on silica gel eluting with 25%-50% ethyl acetate in hexane give the title compound (1.6 g, 85% yield).