Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3]I.[OH:5][C:6]([C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=1)([CH3:10])[CH:7]([CH3:9])[CH3:8]>>[CH3:3][O:5][C:6]([C:11]1[CH:24]=[CH:23][C:22]2[C:13](=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[CH:17][CH:16]=[N:15]3)[N:12]=1)([CH3:10])[CH:7]([CH3:9])[CH3:8]
Reactant: CI
Reactant: CC(C)C(C)(O)c1ccc2ccc3cccnc3c2n1
Agent: [H-]
Agent: [Na+]
Product: COC(C)(c1ccc2ccc3cccnc3c2n1)C(C)C
Yield: 100.3 %

Procedure:
By employing General Procedure II, NaH (0.020 g, 0.74 mmol), methyl iodide (0.046 mL, 0.74 mmol), and the corresponding 1-hydroxy-1,2-dimethylpropyl phenanthroline (0.052 g, 0.185 mmol), prepared as described by Example 4, were reacted to yield 0.052 g (70% yield) of the title methyl ether as a colorless oil: 1H NMR (300 MHz, CDCl3) δ9.24 (dd, J=4.40, 1.80 Hz, Hp9), 8.24 (dd, J=8.10, 1.80 Hz, Hp7), 8.11 (d, J=8.40 Hz, Hp4), 7.88 (d, J=8.40 Hz, Hp3), 7.81 and 7.74 (two d, J=8.80 Hz, Hp5 and Hp6), 7.60 (dd, J=8.10, 4.50 Hz, Hp8), 3.17 (s, OCH3), 2.25 (sep, J=6.80 Hz, CH(CH3)CH3),1.88 (s, CH3), 1.00 (d, J=6.60 Hz, CH(CH3)CH3), 0.71 (d, J=6.90 Hz, CH(CH3)CH3); 13C NMR (75 MHz) δ165.28, 150.46, 146.51, 145.13, 136.07, 135.76, 128.87, 127/39, 126.46, 126.07, 122.49, 121.06, 84.40, 51.25 39.10, 17.72, 17.43, 16.64; IR (CHCl3 2961 (C—H Ar), 2928 (CH), 866.4 (C—H Ar) cm−1; HRMS m/e Calcd for C18H21N2O (MH+): 281.1654, found 281.1651.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:27][O:28][CH3:29]>C(Cl)(Cl)Cl>[CH3:27][O:28][CH2:29][N:3]1[CH:4]=[CH:5][S:1][C:2]1=[N:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=1
Reactant: COCCl
Reactant: COC(=O)c1cccc(Nc2nccs2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COCn1ccsc1=Nc1cccc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of 4.85 g (20.6 mmol) of methyl 6-(thiazol-2-ylamino)-pyridine-2-carboxylate, 7.20 ml (41.2 mmol) of N,N-diisopropylethylamine and 100 ml of chloroform was added 2.35 ml (30.9 mmol) of chloromethylmethyl ether followed by stirring at room temperature for 1 hour. The reaction mixture was washed with 100 ml of water for three times and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to about 20 ml in total and the resulting solid was filtered. The resulting solid was washed with ether and dried in vacuo to give 6.38 g (20.6 mmol) of the title compound as a white solid.
Reaction SMILES: [CH:1](=[C:3](/[N:13]=[C:14]([Br:17])[CH:15]=[CH2:16])\[C:4](=[O:12])[CH2:5][CH2:6][CH:7](OC)[O:8]C)/[CH3:2].CC(C)=O>O>[CH:1](=[C:3](/[N:13]=[C:14]([Br:17])[CH:15]=[CH2:16])\[C:4](=[O:12])[CH2:5][CH2:6][CH:7]=[O:8])/[CH3:2]
Reactant: C=CC(Br)=N/C(=C\C)C(=O)CCC(OC)OC
Solvent: CC(C)=O
Solvent: O
Product: C=CC(Br)=N/C(=C\C)C(=O)CCC=O
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of N-[1-Eth-(Z)-ylidene-5,5-dimethoxy-2-oxo-pentyl]acrylimidoyl bromide (7.0 g, 28.9 mmol) in a solution of acetone (30 mL) and water (1.5 mL) at room temperature, is added Amberlyse-15 (20 g). After mechanical shacking for 3 hr at room temperature, the reaction mixture is filtered. The resin beads were washed with acetone (contain 10% of Et3N). The combined organic layers were concentrated and purified by chromatography (Hexane/EtOAc:70/30) to yield N-[1-Eth-(Z)-ylidene-2,5-dioxo-pentyl]-acrylimidoyl bromide (5.18 g, 88.1%) as light yellow liquid. M/Z=421, 243.9 [M+1]
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[C:18](O)(=[O:20])[CH3:19].C(OC(=O)C)(=O)C>CCOCC>[C:18]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)O)c(=O)[nH]2)cc1

Procedure:
A mixture of 11.5 g (50 mmol) of 6-(4-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 200 ml of acetic acid, and 10.5 ml (110 mmol) of acetic anhydride is heated at reflux for 4.5 hrs. The mixture is cooled and diluted with 150 ml of ether. The solid is filtered, washed with ether, and dried at 60° to give 13.6 g of 6-[4-(acetylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp>260°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:47]=[CH:48][C:49]=1[O:50][CH3:51])[CH2:28][O:29][C:30]([NH:32][C:33]1[NH:34][C:35](=[O:46])[C:36]2[N:37]=[CH:38][N:39]([CH2:42][C:43](O)=[O:44])[C:40]=2[N:41]=1)=[O:31]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:43](=[O:44])[CH2:42][N:39]1[CH:38]=[N:37][C:36]2[C:35](=[O:46])[NH:34][C:33]([NH:32][C:30]([O:29][CH2:28][C:27]3[CH:47]=[CH:48][C:49]([O:50][CH3:51])=[C:25]([O:24][CH3:23])[CH:26]=3)=[O:31])=[N:41][C:40]1=2)[CH3:2]
Reactant: COc1ccc(COC(=O)Nc2nc3c(ncn3CC(=O)O)c(=O)[nH]2)cc1OC
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(=O)[nH]c(NC(=O)OCc3ccc(OC)c(OC)c3)nc21
Yield: 68.1 %

Procedure:
The title compound (2.48 g, 68%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [2-N-(3,4-dimethoxybenzyloxycarbonyl)-guanin-9-yl]-acetic acid (2.02 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 8.26 (dd, 1H), 8.14 (dd, 1H), 7.80 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (m, 2H), 7.04 (s, 1H), 6.95 (m, 2H), 5.15 (s, 2H), 5.09 (s, 1.2H), 4.90 (s, 0.8H), 4.42 (s, 0.8H), 4.16 (q, 0.8H), 4.06 (s, 1.2H), 4.03 (q, 1.2H), 3.74 (s, 3H), 3.73 (s, 3H), 3.62 (t, 1.2H), 3.43 (t, 1.2H), 3.39 (t, 0.8H), 3.20 (t, 0.8H), 1.21 (t, 1.2H), 1.13 (t, 1.8H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[C:3]=1[N+:17]([O-])=O.C(OC([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([NH2:36])[CH:34]=2)[C:29](=[O:37])[NH:28]1)=O)(C)(C)C.C(N(C(C)C)CC)(C)C>C1COCC1>[NH2:17][C:3]1[C:2]([NH:36][C:33]2[CH:34]=[C:35]3[C:30]([C:29](=[O:37])[NH:28][NH:27]3)=[CH:31][CH:32]=2)=[N:7][CH:6]=[N:5][C:4]=1[NH:8][C:9]1[NH:10][N:11]=[C:12]([CH:14]2[CH2:16][CH2:15]2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Nc1cc(C2CC2)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Nc1c(Nc2ccc3c(=O)[nH][nH]c3c2)ncnc1Nc1cc(C2CC2)n[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 33.6 %

Procedure:
To a solution of (6-chloro-5-nitro-pyrimidin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (50 mg, 0.18 mmol) in anhydrous THF (2 mL) was added 6-amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (67 mg, 0.27 mmol) and diisopropylethylamine (23 mg, 0.18 mmol). The mixture was stirred at RT for 14 hrs and the solvents were removed under vacuum. The residue was dissolved in CH2Cl2 (3 mL) and treated with TFA (2 mL) at RT for 2 hrs. After removal of the solvents via evaporation, the residue was reduced by hydrogen (50 psi) in MeOH (10 mL) in the presence of Pd/C (10%, 50 mg) for 3 hrs. The solution was filtered via celite, the filtrate was evaporated under vacuum, and the residue was purified by HPLC to give the desired product as white solid (22 mg). NMR (500 MHz, DMSO-d6) δ11.16 (br, 1H), 9.92 (br, 1H), 8.98 (s, 1H), 8.27 (s, 1H), 7.67 (s, 1H), 7.55 (d, 1H), 7.08 (d, 1H), 5.95 (s, 1H), 2.00 (m, 1H), 1.06 (m, 2H), 0.81 (m, 2H) ppm. MS (ES+): m/e=364.3 (M+H); LC/Method A/2.45 min.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=1)=O.Cl.[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][NH2:25])[CH:20]=[CH:19][C:18]=12.N1C=CC=CC=1>C(O)C>[N:14]1[O:15][N:16]=[C:17]2[CH:22]=[C:21]([CH2:23][O:24][N:25]=[C:2]([C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[CH:5]=3)[CH3:1])[CH:20]=[CH:19][C:18]=12
Reactant: NOCc1ccc2nonc2c1
Reactant: COc1ccc(C(C)=O)cc1O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(C)=NOCc2ccc3nonc3c2)cc1O
Temperature: 25 °C
Yield: 90.2 %

Procedure:
A solution of 3-hydroxy-4-methoxyacetophenone (0.070 g, 0.421 mmol), (benzo[c][1,2,5]oxadiazol-5-yl)methoxyamine hydrochloride (0.126 g, 0.625 mmol) and pyridine (0.16 ml, 1.98 mmol) in ethanol (6 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a yellow oil which was diluted with water. The resultant suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water, dried over magnesium sulphate, filtered and concentrated to a yellow oil. The crude product was purified by column chromatography (SiO2), eluting with 8:2 petrol/ethyl acetate, to give a slightly sticky solid which was further triturated with petroleum spirit (40-60°), to give 1-(3-hydroxy-4-methoxyphenyl)ethanone-O -[(benzo[c][1,2,5]oxadiazol-5-yl)methyl]oxime (CP9-33) as a light yellow solid (0.119 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Br:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Br:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([C:15]#[C:16][CH3:17])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[CH:22][CH:21]=1
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(O)cc1
Reactant: BrCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc(CBr)cc2)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution ethyl (3S)-3-(4-hydroxyphenyl)hex-4-ynoate (0.1 g, 0.43 mmol) and 1,4-bis(bromomethyl)benzene (0.227 g, 0.861 mmol) in DMF (5 mL) is added Cs2CO3 (0.28 g, 0.861 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature over 2 h. The reaction mixture is diluted with water (25 mL) and extracted with EtOAc (3×10 mL). The combined organic layer is washed with water (10 mL×3) and saturated brine solution (10 mL), dried, filtered, and evaporated to dryness. The crude product is purified by silica gel chromatography, eluting with hexane:ethyl acetate (9.0:1.0) to give the title compound (0.1 g, 55.9%). ESI/MS m/z (M+H)+ 415.4.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[N:9]=1)(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(Cl)n1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(-c2cccnc2)n1

Procedure:
By carrying out the operation analogously to example 41, starting from 6-chloro-2-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation XIII, and 3-pyridineboronic acid, the desired product is obtained in the form of a cream powder (yield=38%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:29][CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH:44]3[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]3)[CH:38]=2)[CH:34]=[CH:35][CH:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:27][CH3:28])=[C:10]([CH2:19][NH:20][C:21](=[O:26])[CH2:22][C:23]([NH:29][CH2:30][C:31]3[CH:32]=[C:33]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH:44]5[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]5)[CH:38]=4)[CH:34]=[CH:35][CH:36]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CC3CCNCC3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.2 %

Procedure:
To the solution of 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (0.0779 g, 0.200 mmol) in DCM (1 mL) was added 1,1-dimethylethyl 4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-1-piperidinecarboxylate (0.0837 g, 0.220 mmol), HBTU (0.0910 g, 0.240 mmol), TEA (0.0563 mL, 0.400 mmol) and was stirred at room temperature for 16 hours. The reaction mixture was concentrated on Glas-Col evaporator, purified by Gilson HPLC and concentrated with Biotachi evaporator. The crude product was dissolved in DCM (0.6 mL) and TFA (0.2 mL) was added. The resultant mixture was left at room temperature for 1 hour before being concentrated on Glas-Col evaporator, purified by Gilson HPLC (with 0.1% TFA) and basified with amine cartridge to afford the title compound 0.0329 g (25.24%). LC-MS m/z 652 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.38 (t, J=7.65 Hz, 3H) 1.49 (t, J=7.28 Hz, 5H) 1.72-1.85 (m, 2H) 1.87-2.02 (m, 5H) 2.69 (d, J=6.78 Hz, 2H) 2.94 (td, J=12.80, 2.26 Hz, 2H) 3.05 (q, J=7.53 Hz, 2H) 3.37 (d, J=12.55 Hz, 2H) 3.59 (td, J=11.48, 2.13 Hz, 2H) 3.92 (dt, J=1.80, 3.51 Hz, 2H) 4.19-4.30 (m, 1H) 4.42-4.50 (m, 4H) 4.52 (s, 2H) 7.19 (d, J=7.53 Hz, 1H) 7.27-7.32 (m, 1H) 7.37 (td, J=7.59, 3.14 Hz, 2H) 7.44-7.52 (m, 3H) 7.57 (s, 1H) 8.24 (s, 1H).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:35]4C(=O)C5=CC=CC=C5C4=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:35][CH2:34][CH2:33][C:29]1[CH:28]=[C:27]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:15]2=[O:26])[CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cccc(Cl)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCN3C(=O)c4ccccc4C3=O)c2)C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(Cl)c1N1Cc2cnc(Nc3ccccc3)nc2N(c2cccc(CCN)c2)C1=O
Yield: 15.5 %

Procedure:
A solution of 250 mg (0.4 mmol) of 7-anilino-3-(2-chloro-6-methylphenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 10 ml of ethanol was treated with 0.5 ml of hydrazine hydrate. After 18 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. Trituration of the residue with hexane followed by filtration afforded 30 mg (15%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2-chloro-6-methylphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 192° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:36].O>C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:36])=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A solution of tert-butyl 2-{2-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (15.47 g, 37.3 mmol) in 150 mL of CHCl3 was treated with 3-chloroperoxybenzoic acid (MCPBA, 70%, 15.12 g, 61.3 mmol). After stirring for 1.5 h, the reaction mixture was treated with water (100 mL) and CHCl3 (50 mL) and the layers were separated. The organic portion was washed with 2% Na2CO3 solution (2×), H2O and brine then dried over Na2SO4 and concentrated to give 16.06 g of tert-butyl 2-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:20][NH2:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:37])([F:36])[C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][C:33](=N)[NH2:34])[CH:28]=[CH:29][CH:30]=1>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]3[NH:34][C:33]([CH2:32][CH2:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:37])[F:36])[CH:26]=4)=[N:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: N=C(N)CCc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1n(Cc2nnc(CCc3cccc(C(F)(F)F)c3)[nH]2)nc(-c2ccc(Cl)cc2)n1C1CC1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
50 mg (0.16 mmol) of the compound from Example 21A were taken up in 1 ml of DMF, 62 mg (0.24 mmol) of 3-[3-(trifluoromethyl)phenyl]propaneimidamide hydrochloride were added and the mixture was stirred in a microwave oven at 180° C. for 1 h. After cooling, the reaction mixture was diluted with methanol and the solution was directly separated by preparative HPLC [Method 19]. This gave 11 mg (14% of theory) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2].[F:16][C:17]([F:44])([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:16][C:17]([F:44])([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:42])([F:41])[F:43])=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:15][CH2:14][CH2:13][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[O:27])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
2.50 g (11.8 mmol) of 2-(2,4-dinitrophenyl)ethanol, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-di-methylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloro-methane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yields 5.11 g (71%) of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:25])=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:10]3[CH2:9][C:8](=O)[NH:7][C:6]=2[CH:24]=1.B.CO>O1CCCC1>[Cl:1][C:2]1[C:3]([Cl:25])=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH:10]3[CH2:9][CH2:8][NH:7][C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2c3cc(Cl)c(Cl)cc3NC(=O)CC2C1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2c3cc(Cl)c(Cl)cc3NCCC2C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 15B (168 mg, 0.435 mmol) in tetrahydrofuran (1.5 mL) was added borane in tetrahydrofuran (1.74 mL, 1 M solution). The resulting mixture was heated to 80° C. overnight. Methanol was then added, and the mixture was heated at 80° C. for 1 hour to destroy excess borane. The reaction was then cooled to room temperature and 1 M HCl was added. The mixture was allowed to stir for another 30 minutes. Aqueous sodium bicarbonate was slowly added to the mixture until the solution was basic (pH=8). Ethyl acetate was then added, and the water layer was separated and washed two times with additional ethyl acetate. The organic layers thus obtained were combined and concentrated. The crude material was purified by silica gel chromatography eluting with a gradient of 0% to 30% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.88 (s, 1 H), 6.70 (s, 1 H), 5.75 (d, J=5.55 Hz, 1 H), 3.61-3.79 (m, 1 H), 3.36-3.58 (m, 2 H), 2.95-3.23 (m, 5 H), 2.82-2.94 (m, 1 H), 1.80-1.97 (m, 1 H), 1.56-1.74 (m, 1 H), 1.41 (s, 9 H); MS (DCI+) m/z 372.2 (M+H)+.