Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:16](=[O:34])[N:17]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[N:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH2:27][CH2:26][C:25]=4[CH:29]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[CH:31]1([CH2:30][N:17]2[C:16](=[O:34])[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH2:27][CH2:26][C:25]=4[CH:29]=3)=[N:18]2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=c1c(CN2CCNCC2)cc(-c2ccc3c(c2)CCO3)nn1CC1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(4-tert-Butoxycarbonyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one (121 mg, 0.26 mmol) was dissolved in trifluoroacetic acid (1.1 mL) under cooling with ice-water, and the solution was stirred for 15 minutes at the same temperature. Water (10 mL) was added to the reaction mixture, and the resultant mixture was made alkaline with potassium carbonate, followed by extraction with chloroform. The organic layer was washed with saturated brine (20 mL) and dried over sodium sulfate anhydrate, and the solvent was removed under reduced pressure, to thereby yield 83 mg (87.4%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[C:17]2[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)=[O:5])[CH3:2]>[Pd].C(O)C.O1CCOCC1>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)COc1ccnc2c([N+](=O)[O-])cccc12
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccnc2c(N)cccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 65 %

Procedure:
A mixture of 4-ethoxycarbonylmethoxy-8-nitroquinoline (404 mg) and 10% palladium on carbon in ethanol (5 ml) and dioxane (5 ml) was stirred for 5 hours at ambient temperature under hydrogen atmosphere. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was pulverized with diethyl ether to give 8-amino-4-(ethoxycarbonylmethoxy)quinoline (234 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O>[C:26]([Si:23]([O:22][CH2:21][CH2:20][O:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:25])[CH3:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 51.8 %

Procedure:
To a solution of 3-methoxy-4-nitrophenol (1 g, 5.9 mmol) in anhydrous DMF (25 mL) were added K2CO3 (2.45 g, 17.7 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.7 g, 7.1 mmol) sequentially. The reaction mixture was heated at 70° C. for 20 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (0-20% EtOAc in hexanes) to give tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane as a light yellow oil (1.0 g, 52%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].O.[OH-].[Li+].Cl.O>C(OCC)(=O)C>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1cc(C(=O)OCC)ccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)c1cc(C(=O)O)ccc1O
Temperature: 25 °C

Procedure:
The title compound of Example 1 (500 mg) was heated at reflux for 24 hours with 230 mg of lithium hydroxide monohydrate. The reaction mixture was cooled to room temperature, then added to 20 ml of 1N HCl with stirring, followed by the addition of 10 ml of water and 10 ml of ethyl acetate. The mixture was filtered and the solid recrystallized from dimethylformamide to give the title compound, m.p. ca. 170° C. ##STR12##
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16]O)[CH2:5]1)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC#N>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][Br:19])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)N1CC(CCO)c2c(C)cc(C)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(=O)N1CC(CCBr)c2c(C)cc(C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
1-Acetyl-3-(2-hydroxyethyl)-4,6-dimethylindoline (7.0 g) and CBr4 (9.9 g) were dissolved in CH3CN (70 ml), and Ph3P (9.4 g) was added, which was followed by stirring at room temperature for 30 min. CH3CN was evaporated under reduced pressure. AcOEt (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: benzene/AcOEt=50/1-10/1) to give 5.4 g of 1-acetyl-3-(2-bromoethyl)-4,6-dimethyl-indoline.
Reaction SMILES: C(OCC([C:13]1[O:14][C:15]2[C:16](=[C:18]([C:37]#[N:38])[C:19]([CH3:36])=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:21]=2N2CC[C@H](N(C)C)C2)[N:17]=1)(C)C)C1C=CC=CC=1.O1CCOCC1.[ClH:45]>C(OCC)C>[ClH:45].[CH3:36][C:19]1[C:18]([C:37]#[N:38])=[C:16]2[N:17]=[CH:13][O:14][C:15]2=[CH:21][C:20]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)COCc3ccccc3)nc2c1C#N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1c(-c2ccccc2)cc2ocnc2c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 161.5 %

Procedure:
2-[2-(Benzyloxy)-1,1-dimethylethyl]-7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (#13) (150 mg, 0.295 mmol) was dissolved in diethyl ether (5 ml), a 1,4-dioxane solution of 4 N hydrogen chloride (111 μl, 0.442 mmol) was added, followed by stirring at room temperature for 10 minutes. The reaction liquid was concentrated under reduced pressure to obtain a pale pink, amorphous 2-[2-(benzyloxy)-1,1-dimethylethyl]-7-(3-dimethylamino)pyrrolidin-1-yl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile hydrochloride (129 mg). The hydrochloride (118 mg, 0.216 mmol) was dissolved in methanol (7 ml), and catalytically hydrogenated at room temperature under 5 atmospheres on 10%-palladium carbon (50% wet, 75 mg), for 30 minutes. The catalyst was separated by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, dried on anhydrous magnesium sulfate, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the entitled compound (48 mg, 53%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.[Cl:10][C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:12]=1[NH:18][C:19](=[O:30])[C@:20]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[C:21]([F:24])([F:23])[F:22]>C(OCC)C.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:10][C:11]1[CH:16]=[C:15]([NH:17][CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:14]=[CH:13][C:12]=1[NH:18][C:19](=[O:30])[C@:20]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[C:21]([F:24])([F:23])[F:22]
Reactant: CC(C)(C)OCC1CO1
Reactant: CC(=O)O[C@](C)(C(=O)Nc1ccc(N)cc1Cl)C(F)(F)F
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Product: CC(=O)O[C@](C)(C(=O)Nc1ccc(NCC(O)COC(C)(C)C)cc1Cl)C(F)(F)F
Reaction time: 40 h

Procedure:
t-Butyl glycidyl ether (0.19 ml) and copper(II) trifluoromethanesulphonate (0.018 g) were added to a solution of (R)-N-(2-chloro-4-aminophenyl)-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide (0.325 g) (Method 32) in diethyl ether (5 ml). The mixture was stirred for 40 hours then volatile material was removed by evaporation and the residue was purified by chromatography to give the title compound (0.141 g) as a foam; MS (ESP−): 453.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:14]12[CH2:24][CH:17]([CH:18]([O:20][CH2:21][CH2:22][OH:23])[CH2:19]1)[CH2:16][NH:15]2.C(N(CC)CC)C.C(O)C>>[CH:11]([C:10]1[C:3]2[C:2]([N:15]3[CH2:16][CH:17]4[CH2:24][CH:14]3[CH2:19][CH:18]4[O:20][CH2:21][CH2:22][OH:23])=[N:7][CH:6]=[N:5][C:4]=2[S:8][CH:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1csc2ncnc(Cl)c12
Reactant: OCCOC1CC2CC1CN2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)c1csc2ncnc(N3CC4CC3CC4OCCO)c12
Temperature: 50 °C

Procedure:
4-Chloro-5-isopropyl-thieno[2,3-d]pyrimidine (0.35 g, 1.6 mmol), 2-(2-azabicyclo[2.2.1]heptan-5-yloxy)ethanol (0.39 g, 2.5 mmol), triethylamine (0.50 g, 0.70 mL, 4.9 mmol) and ethanol (3.95 g, 5 mL, 85.6 mmol) were combined and heated to 50° C. overnight. The reaction mixture was concentrated in vacuo. The resulting residue was taken up in DCM, washed with water, dried over Na2SO4 and concentrated in vacuo to afford
Reaction SMILES: [C:1]12([NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([NH2:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.CCN(C(C)C)C(C)C.[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[N:24]1.[CH3:31][C:32]1[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]([NH:12][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][C:3]([NH:11][C:38]([C:35]5[CH:34]=[N:33][C:32]([CH3:31])=[CH:37][N:36]=5)=[O:39])([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:30])=[N:24]1
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: NC12CC3CC(C1)CC(N)(C3)C2
Reactant: Cn1ccc(C(=O)O)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnc(C(=O)NC23CC4CC(C2)CC(NC(=O)c2ccn(C)n2)(C4)C3)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of adamantane-1,3-diamine (20 mg, 0.1 mmol; Zerenex Molecular Ltd., Greater Manchester, UK) in DCM (2 mL) was added DIEA (26 mg, 0.15 mmol), 1-methyl-1H-pyrazole-3-carboxylic acid (14 mg, 0.11 mmol), 5-methyl-pyrazine-2-carboxylic acid (15 mg, 0.11 mmol) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (110 mg, 0.20 mmol). After stirring for 3 hours at rt, the reaction mixture was partitioned into dichloromethane and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a RP-HPLC/MS purification system (Gradient: acetonitrile in water, 25-95%, in 3.4 minutes with a cycle time of 5 min. A shallow gradient between 25-50% of acetonitrile was used between 0.75-3.3 min to separate close-eluting impurities. Flow rate: 100 mL/min. Mobile phase additive: 25 mM of ammonium formate. Column: Inertsil® C8, 30×50 mm, 5 μm particle size (GL Sciences, Tokyo, Japan)) to afford 15 mg (37%) of the title compound, 5-methyl-pyrazine-2-carboxylic acid {3-[(1-methyl-1H-pyrazole-3-carbonyl)-amino]-adamantan-1-yl}-amide, as a colorless oil. 1H NMR (400 MHz, CDCl3) δ9.22 (s, 1H), 8.34-8.33 (m, 1H), 7.67 (s, br, 1H), 7.33 (d, J=2.3 Hz, 1H), 6.76-6.72 (m, 2H), 3.89 (s, 3H), 2.64 (s, 3H), 2.54 (s, br, 2H), 2.37-2.09 (m, 10H), 1.73-1.68 (m, 2H). ESI-MS m/z: 395.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH:43]([OH:47])[CH2:44][CH2:45][CH3:46])[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:47][CH:43]([CH2:42][CH2:41][N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)[CH2:44][CH2:45][CH3:46])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCC(O)CCN1CCOCC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC(CCN1CCOCC1)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 93 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene. (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-morpholino-3-hexanol (49 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 81%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[N+:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[C:20]2Cl)([O-:14])=[O:13].Cl.C(=O)([O-])O.[Na+]>CN1C(=O)CCC1.O1CCOCC1>[N+:12]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[C:22]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:11])[CH:8]=3)[NH:3][C:2]=1[CH3:1])[CH:21]=[CH:20]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Reactant: Cc1ccc2[nH]c(C)cc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1ccc2[nH]c(C)c(-c3ccc4cccc([N+](=O)[O-])c4n3)c2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
2,5-Dimethylindole (300 mg) and 8-nitro-4-chloroquinoline (430 mg) were suspended in NMP (10 ml) containing 4M HCl in dioxane (2 drops) and maintained under a nitrogen atmosphere. The reaction was heated to 120° C. with stirring for 8 hours. When cooled, the mixture was basified with saturated sodium hydrogen carbonate solution and extracted into ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to give an oil. The oil was purified by flash column chromatography using 2:1 isohexane/ethyl acetate as eluent to give the sub-title compound (560 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:6](=[O:59])[N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]4[CH:28]=[C:29]5[C:56](=[CH:57][CH:58]=4)[C:33]4[NH:34][C:35]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42](=[O:55])[CH:43]([NH:50][C:51](=[O:54])[CH2:52][CH3:53])[CH:44]6[CH2:49][CH2:48][O:47][CH2:46][CH2:45]6)=[N:36][C:32]=4[CH2:31][CH2:30]5)[CH:23]=3)[CH:18]=2)=[CH:15][N:16]=1.[C:67](Cl)(=O)CC>>[CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:6]([N:7]1[CH2:11][CH2:10][CH2:9][CH:8]1[C:12]1[NH:13][C:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:27]4[CH:28]=[C:29]5[C:56](=[CH:57][CH:58]=4)[C:33]4[NH:34][C:35]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42](=[O:55])[CH:43]([NH:50][C:51]([CH:52]6[CH2:67][CH2:53]6)=[O:54])[CH:44]6[CH2:49][CH2:48][O:47][CH2:46][CH2:45]6)=[N:36][C:32]=4[CH2:31][CH2:30]5)[CH:23]=3)[CH:18]=2)=[CH:15][N:16]=1)=[O:59]
Reactant: CCC(=O)NC(C(=O)N1CCCC1c1nc2c([nH]1)-c1ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)c6ccccc6)[nH]5)ccc4c3)cc1CC2)C1CCOCC1
Reactant: CCC(=O)Cl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc(C6CCCN6C(=O)C(NC(=O)C6CC6)C6CCOCC6)[nH]c4-5)ccc3c2)[nH]1)c1ccccc1
Yield: 38 %

Procedure:
[2-(2-{5-[6-(2-{1-[2-(Cyclopropanecarbonyl-amino)-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-phenyl-ethyl]-carbamic acid methyl ester (0.01 g, 38%) was prepared following the procedure for [2-Oxo-1-phenyl-2-(2-{5-[6-(2-{1-[2-propionylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-ethyl]-carbamic acid methyl ester, substituting Cyclopropanecarbonyl chloride for Propionyl chloride. LCMS-ESI+: calc'd for C53H56N8O6: 900.43 (M+); Found: 902.07 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:17])[NH:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: NCC(=O)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)NCC(=O)c1ccc(F)cc1
Yield: 61.9 %

Procedure:
The title compound (0.77 g) was prepared from 2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (0.80 g) and 2-amino-1-(4-fluoro-phenyl)-ethanone (0.63 g) according to the method of description 20.
Reaction SMILES: [OH-:1].[K+].[C:3]([NH:6][C:7]1[C:8]([I:31])=[C:9]([C:23]([NH:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:24])[C:10]([I:22])=[C:11]([C:20]=1[I:21])[C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])(=[O:5])[CH3:4].B(O)(O)O.[O:36]1[CH2:38][CH:37]1[CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH:45]1[CH2:47][O:46]1.Cl>C(#N)C.O.O.CO>[OH:36][CH:37]([CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH:45]([OH:46])[CH2:47][N:6]([C:7]1[C:20]([I:21])=[C:11]([C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])[C:10]([I:22])=[C:9]([C:8]=1[I:31])[C:23]([NH:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:24])[C:3](=[O:1])[CH3:4])[CH2:38][N:6]([C:7]1[C:20]([I:21])=[C:11]([C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])[C:10]([I:22])=[C:9]([C:8]=1[I:31])[C:23]([NH:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:24])[C:3](=[O:5])[CH3:4]
Reactant: [OH-]
Reactant: C(COCC1CO1)OCC1CO1
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: Cl
Agent: OB(O)O
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC(=O)N(CC(O)COCCOCC(O)CN(C(C)=O)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To a stirred solution of water/methanol (4.9 ml, 2.5 ml) and potassium hydroxide (0.49 g, 8.7 mmol) at 40° C. was added 5-acetylamino-N,N′-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo isophthalamide (5.0 g, 6.7 mmol). To the clear solution was then added boric acid (0.29 g, 4.6 mmol). The mixture was cooled to room temperature and pH adjusted to 12.6. 2-{[2-(oxiran-2-ylmethoxy)ethoxy]methyl}-oxirane (0.40 g, 2.3 mmol) was added. The pH of the solution was adjusted to the interval 12.6-13. The reaction was left over weekend. To the solution was added HCl (18%) to pH 4. Salts were removed by treatment with ion exchanger AMB200C and IRA67. The solution was filtered from the resin and evaporated. The product was purified by preparative HPLC (column Phenomenex Luna C18(2) 10 μm 250×50.0 mm, solvents: A=water and B=acetonitrile; gradient 05-10% B over 60 min; flow 50.0 ml/min, UV detection at 214 nm and 254 nm), and obtained in 268 mg after lyophilisation, 7% yield. Analysis by LC-MS (column Agilent Zorbax SB-Aq 3.5 μm 3.0×100 mm, solvents: A=water/0.1% formic acid and B=acetonitrile/0.1% formic acid; gradient 0-30% B over 20 min; flow 0.3 ml/min, UV detection at 214 and 254 nm, ESI-MS) gave three isomeric peaks centred at 11.7 minutes with m/z 1668.5 (MH+) corresponding to the structure.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)(=[O:3])[NH2:2].[H-].[Na+].[Cl:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>CN(C=O)C>[ClH:16].[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]2[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1)(=[O:3])[NH2:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: NC(=O)c1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccc(C(N)=O)cc43)ncnc2cc1OCCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.4 %

Procedure:
A solution of 5-carbamoyloxindole (391 mg, 2.2 mmol) in DMF (5 ml) was added dropwise to sodium hydride (89 mg, 2.2 mmol, prewashed with hexane) in DMF (3.5 ml). The mixture was stirred for 20 minutes at ambient temperature and 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (250 mg, 0.74 mmol), (prepared as described for the starting material in Example 5), was added as a solid and the mixture was heated at 60° C. for 1 hour. The volatiles were removed by evaporation and the residue was partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH8.5 with 2M hydrochloric acid. The precipitate was collected by filtration, washed with water and dried under vacuum. The solid was dissolved in methylene chloride/methanol and 3M ethereal hydrogen chloride (2 ml) was added. The mixture was concentrated by evaporation and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(5-carbamoyloxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline hydrochloride (184 mg, 45%).
Reaction SMILES: [H-].[Na+].[I-].[Na+].[CH2:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1>CN(C)C=O.O>[CH2:5]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 67 h
Yield: 53 %

Procedure:
To a stirred mixture of about 39.7 g of about 50% sodium hydride, about 13.5 g of sodium iodide and about 208.58 g of tetradecylbromide in about 750 ml of dimethylformamide at about 0° C. was added a solution of about 125 g of ethyl p-hydroxybenzoate in about 400 ml of dimethylformamide over about 1/2 hour. The mixture was stirred at room temperature for about 67 hours and then poured into about 2 liters of water. The solid was collected, washed with water, mixed with hot (about 50° C.) ethyl acetate, washed with water and dried. The solvent was removed and the residue recrystallized from ethanol, giving about 144.57 g of the desired title compound, mp 34°-35° C.