Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2].C(=O)(O)[O-].[Na+].[N:53]#[C:54]Br>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:39])([F:37])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=3)[C:22]([N:40]3[CH2:45][CH2:44][N:43]([C:54]#[N:53])[CH2:42][CH2:41]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:46][CH3:47])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCNCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCN(C#N)CC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 13 h
Yield: 88.2 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(piperazin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg) is dissolved in ethanol (3 ml), and thereto are added sodium bicarbonate (76.4 mg) and cyanogen bromide (35 mg). The mixture is stirred at room temperature for 13 hours, and partitioned by adding water and diethyl ether to the reaction solution. The resulting mixture is washed with saturated brine, then dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=4:1→3:2) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-[5-(4-cyanopiperazin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (183 mg). MS (m/z): 693 [M+H]+.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([NH:20][C:21]4[S:22][CH:23]=[CH:24][N:25]=4)=[O:19])=[CH:17][C:12]3=[N:11][C:10]=2[CH:26]([CH3:28])[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.NC1SCCN=1>>[CH:1]1([O:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([NH:20][C:21]4[S:22][CH2:23][CH2:24][N:25]=4)=[O:19])=[CH:17][C:12]3=[N:11][C:10]=2[CH:26]([CH3:28])[CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)c1nc2cc(C(=O)Nc3nccs3)ccn2c1COC1CCCCC1
Agent: NC1=NCCS1
Product: CC(C)c1nc2cc(C(=O)NC3=NCCS3)ccn2c1COC1CCCCC1

Procedure:
Compound 25 (8.9 mg, yield 14%) was obtained in the same manner as in step 4 of Example 21, using 3-cyclohexyloxymethyl-2-isopropyl[1,2-a]pyridine-7-carboxylic acid obtained in step 3 of Example 21, and 2-amino-4,5-dihydrothiazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:8]([F:13])(F)[C:9](O)=O>ClCCl>[F:13][C:8]1[CH:5]=[CH:4][C:3]([C:5]2[CH:4]=[C:3]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]3)[CH:2]=[N:1][CH:6]=2)=[CH:2][CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: c1ccncc1
Solvent: ClCCl
Product: Fc1ccc(-c2cncc(C3CCCCN3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The above-described pyridine derivative (1.25 g, 3.5 mmol) was dissolved in a mixture of dichloromethane (10 mL) and trifluoroacetic acid (10 mL) and this was stirred at 25° C. for 18 h. The solvents were removed in vacuo and the crude material dissolved in ethyl acetate (50 mL). Saturated sodium carbonate solution (30 mL) was added and the organic layer separated. The aqueous phase was extracted with two further portions of ethyl acetate (2×30 mL), the combined organic extracts washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel with ethyl acetate, then methanol:ethyl acetate (1:9) as eluant to afford 5-(4-fluorophenyl)-3-(2-piperidinyl)pyridine, 940 mg, 100%. NMR (CDCl3, 300 MHz): δ 8.69 (d, J=2 Hz, 1 H), 8.55 (d, J=2 Hz, 1 H), 7.93 (t, J=2 Hz, 1 H), 7.56 (m, 2 H), 7.16 (app. tm, J=9 Hz, 2 H), 3.18 (d, J=12 Hz, 1 H), 2.83 (td, J=12, 3 Hz, 1 H), 2.61 (bs exch., 1 H), 1.92 (m, 2 H), 1.45-1.75 (m, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25][CH2:26][C:27]3[N:31]([CH2:32][CH2:33][CH3:34])[CH:30]=[N:29][N:28]=3)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:43])C=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH2:26][C:27]3[N:31]([CH2:32][CH2:33][CH3:34])[CH:30]=[N:29][N:28]=3)=[O:43])=[CH:21][CH:20]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCn1cnnc1CSc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Solvent: C1CCOC1
Product: CCCn1cnnc1CS(=O)c1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
A mixture of (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-(4-{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]thio}phenyl)acrylamide (96 mg), m-chloroperbenzoic acid (40 mg) and tetrahydrofuran (3 ml) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated and purified by HPLC to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-(4-{[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}phenyl)acrylamide (36 mg, 37%) as pale-yellow crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[N:8][C:7]=2[CH:22]=1.[OH-].[Na+]>C(O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[N:8][C:7]=2[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(OCc2nc3cc(F)ccc3s2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(OCc2nc3cc(F)ccc3s2)cc1
Temperature: 25 °C
Yield: 73.3 %

Procedure:
1.5 ml of concentrated hydrochloric acid were carefully added to a solution of 2.33 g of O-(5-fluorobenzothiazol-2-ylmethyl)-4-nitrophenol [prepared as described in step (a) above] in 47 ml of ethanol with stirring at room temperature and then 3.63 g of stannous chloride were added in small portions to the resulting mixture. The reaction mixture was then stirred at room temperature for 30 minutes, at the end of which time 3 ml of concentrated hydrochloric acid were added and the mixture was stirred for a further 1.5 hours at room temperature. The reaction mixture was then heated to 50° C. and stirred at this temperature for 4 hours. The reaction mixture was then cooled in an ice-water bath and 10% aqueous sodium hydroxide solution was added to said solution to adjust the pH to 10. The resulting mixture was then extracted with ethyl acetate and the resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure and the resulting residue was recrystallized from a mixed solvent of methylene chloride and hexane to give 1.54 g (yield 73%) of the title compound as a solid having a melting point of 125° to 128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[C:14](=O)([O-])[O-].[Na+].[Na+].O.C(OCC)(=O)C>CN(C)C=O.CI>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Nc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a suspension of 4-amino-2-nitrobenzoic acid (200 mg, 1.10 mmol) synthesized in accordance with the synthesis method described in WO96/35666 and sodium carbonate (349 mg, 3.29 mmol) in dimethylformamide (5.5 mL), methyl iodide (0.21 ml) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and extraction was carried out with ethyl acetate, and the combined organic layer was washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution, followed by drying over anhydrous sodium sulfate. By concentrating the obtained organic layer, 216 mg of the desired product was obtained as a yellow solid (yield 100%).
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2(CC)CC2)=C[CH:14]=1.[Li]CCCC.CN(C=O)C>>[CH2:13]([C:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1)[CH3:14]
Reactant: CCC1(c2ccc(Br)cc2)CC1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CCC1(c2ccc(C=O)cc2)CC1
Yield: 81 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 1-bromo-4-(1-ethylcyclopropyl)-benzene (208 mg, 0.92 mmol), n-BuLi (635 μl, 1.6M solution in hexane, 1.02 mmol) and DMF (144 μl, 1.85 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-(1-ethylcyclopropyl)-benzaldehyde (130 mg, 81%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 9.97 (s, 1H), 7.80 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz, 2H), 1.65 (q, J=7.5 Hz, 2H), 0.86 (t, J=7.5 Hz, 3H), 0.89-0.82 (m, 2H), 0.79-0.75 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:6][C:5]2=1.C(N1C(=O)C2C(CCC3NC4C(C=32)=CC=CC=4)C1=O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6][C:5]2=1
Reactant: CCOC(=O)C1Cc2[nH]c3ccc(Cl)cc3c2CC1C(=O)OCC
Agent: O=C1C2CCc3[nH]c4ccccc4c3C2C(=O)N1Cc1ccccc1
Product: CCOC(=O)c1cc2[nH]c3ccc(Cl)cc3c2cc1C(=O)OCC

Procedure:
Diethyl 6-chloro-1,2,3,4-tetrahydrocarbazole-2,3-dicarboxylate was subjected instead of the N-benzyl-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide to the same reaction as in Reference Example 1 (3), to obtain diethyl 6-chlorocarbazole-2,3-dicarboxylate as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].Cl[C:22]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([NH:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(O)C>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][NH:33][C:26]2[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:22]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])[N:23]=[CH:24][N:25]=2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1c(Cl)ncnc1NCc1ccc(OC)cc1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(NCc2ccc(OC)cc2)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Yield: 82 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one was treated with ethyl 4-chloro-6-((4-methoxybenzyl)amino)pyrimidine-5-carboxylate (6 mg, 0.02 mmol), N,N-diisopropylethylamine (16 μl, 0.09 mmol) and ethanol as a solvent according to the method described in Example 17. The solvent was concentrated and the solid was suspended in ethanol and filtered. The white solid obtained was washed with ether and dried in the oven to give 281 mg (82% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([NH2:13])=O)=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]#[N:13])=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(N)=O)cc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
To a slurry of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxamide (0.4488 g, 1.43 mmol) in tetrahydrofuran (20 ml) at 5° C. is added triethylamine (0.5 ml, 3.58 mmol) and trifluoroacetic acid anhydride (0.26 ml, 1.79 mmol). The cooling bath is removed and the reaction allowed to warm to room temperature and stir for 16 hours. The contents are partitioned between water and methylene chloride, and the organic layer is separated, dried over magnesium sulfate, filtered and concentrated to a solid, which is chromatographed on silica gel (9:1 dichloromethane:toluene) to afford 386.9 mg (92%) of title compound as a solid: mp 141.7-142.9° C. IR (KBr) 2985, 2214, 1610, 1498, 1479, 1260, 1033 cm-1 ; 1H NMR (CDCl3): δ7.82 (d, 2 H, J=8.9 Hz), 7.81 (d, 1 H, J=8.8 Hz), 7.28 (d, 1 H, J=2.2 Hz), 7.12 (dd, 1 H, J=8.9, 2.2 Hz), 7.02 (d, 2 H, J=8.9 Hz), 3.90 (s, 3 H), 3.88 (s, 3 H); 13C NMR (CDCl3): d 161.1, 158.5, 155.5, 131.0, 138.5, 133.1, 129.4, 124.3, 123.0, 115.8, 114.7, 104.9, 100.2, 55.8, 55.5. Anal. Calcd. for C17H13NO2S: C, 69.13; H, 4.44; N, 4.74; S, 10.85. Found: C, 68.86; H, 4.66; N, 4.52; S, 10.76.
Reaction SMILES: [CH:1]1([C:4](=[O:20])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[C:9]=2[S:16]([CH3:19])(=[O:18])=[O:17])=[O:7])[CH2:3][CH2:2]1.[CH:21](OCC)(OCC)[O:22][CH2:23][CH3:24]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:20])[C:5](=[CH:21][O:22][CH2:23][CH3:24])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[C:9]=2[S:16]([CH3:19])(=[O:18])=[O:17])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: CS(=O)(=O)c1c(C(=O)CC(=O)C2CC2)ccc(F)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(F)c(F)c1S(C)(=O)=O)C(=O)C1CC1
Yield: 112.1 %

Procedure:
A mixture of 3-cyclopropyl-1-(3,4-difluoro-2-methylsulphonylphenyl)propane-1,3-dione (0.85 g) and triethyl orthoformate (1.04 g) in acetic anhydride was stirred and heated at reflux for 4 hours. It was evaporated to dryness and the residue was treated with toluene and re-evaporated to give 3-cyclopropyl-1-(3,4-difluoro-2-methylsulphonylphenyl)-2-ethoxymethylenepropane-1,3-dione (1.13 g) as a brown oil which was not purified further.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:23]=[C:22]([CH3:24])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([CH3:25])[CH:9]=2)[N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:23]=[C:22]([CH3:24])[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[N+:18]([O-:33])[CH:19]=[CH:20][CH:21]=3)=[C:10]([CH3:25])[CH:9]=2)[N:4]=1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1cccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCc1ccc[n+]([O-])c1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of 3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine (1 g, 2.6 mmol) in 50 ml of methylene chloride cooled to 0° C. was added 0.67 g (3.9 mmol) of m-chloroperoxybenzoic acid, and the mixture was allowed to stir overnight. The mixture was washed with saturated sodium bicarbonate, the organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 1 g (98%) of 3-[3-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-propyl]-pyridine-N-oxide, as a yellow oil which crystallized (yellow flakes) on standing, m.p. 84°-86°C.
Reaction SMILES: [CH2:1]([O-:8])[CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7].[Na+].Cl.Cl[CH2:12][CH2:13][N:14]([CH2:18][CH2:19]Cl)[CH2:15][CH2:16]Cl.Cl>>[CH2:13]([N:14]([CH2:18][CH2:19][O:8][CH2:1][CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:15][CH2:16][O:8][CH2:1][CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:12][O:8][CH2:1][CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: ClCCN(CCCl)CCCl
Reactant: CCCCOCC[O-]
Agent: Cl
Agent: [Na+]
Product: CCCCOCCOCCN(CCOCCOCCCC)CCOCCOCCCC
Temperature: 130 °C

Procedure:
When all of the water of the reaction has been eliminated, 55 g of tris(2-chloroethyl)amine hydrochloride are introduced. The mixture is heated at 130° C. for 5 hours, then cooled. Excess sodium alcoholate is then neutralized with a 10% aqueous solution of hydrochloric acid. The 3-oxaheptan-1-ol is removed by distillation and the sodium chloride is removed by filtration. The desired product, tris(3,6-dioxadecyl)amine, is distilled (192° C. under 0.1 mmHg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:25])[C:7](=[O:24])[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=1.[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CC([O-])(C)C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C(O[Pd]OC(=O)C)(=O)C>[C:35]([O:34][C:32]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:25])[C:7](=[O:24])[N:8]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:9]=2)[CH2:28][CH2:27]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(Br)cc3N21
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Yield: 33.7 %

Procedure:
To a mixture of 6-bromo-4-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #1, Step E, 0.5 g, 1.173 mmol), tert-butyl piperazine-1-carboxylate (0.655 g, 3.52 mmol) and sodium 2-methylpropan-2-olate (0.225 g, 2.345 mmol) in toluene (50 mL) was added dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.224 g, 0.469 mmol) and diacetoxypalladium (0.026 g, 0.117 mmol) and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 3-20% EtOAc in petroleum ether) to give 4-[4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.210 g, 33%). 1H NMR (400 MHz, CDCl3) δ 6.92 (d, J=8.8 Hz, 1H), 6.56 (dd, J=2.6, 8.7 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 5.18-5.05 (m, 2H), 4.73 (q, J=6.6 Hz, 1H), 4.65-4.52 (m, 2H), 3.67 (t, J=8.4 Hz, 2H), 3.63-3.57 (m, 4H), 3.04 (d, J=4.0 Hz, 4H), 1.58 (s, 5H), 1.51-1.46 (m, 12H), 1.03-0.94 (m, 2H), 0.02 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([NH2:32])=[CH:30][C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:28][N:27]=2)[CH2:22][CH2:21]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[N:23]1([C:26]2[C:31]([NH:32][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)[C:3]=3[CH3:19])=[CH:30][C:29]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:28][N:27]=2)[CH2:22][CH2:21][O:20][CH2:25][CH2:24]1
Reactant: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cccnc2)nc2cc(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-7-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (95 mg, 0.35 mmol), 2,5-dimorpholinopyridin-3-amine (92 mg, 0.35 mmol) and a 4.0M solution of HCl in dioxane (0.017 mL, 0.07 mmol) in NMP (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinyl-3-pyridinyl)-7-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinamine was obtained. 1H NMR (400 MHz, chloroform-d) δ ppm 8.87 (1H, d, J=2.7 Hz), 8.73 (1H, dd, J=5.1, 2.0 Hz), 7.99 (1H, dt, J=7.8, 2.0 Hz), 7.74-7.89 (2H, m), 7.62 (1H, d, J=2.7 Hz), 7.49 (1H, dd, J=8.0, 4.9 Hz), 7.31 (1H, ddd, J=9.3, 7.9, 2.7 Hz), 6.80 (1H, s), 6.21 (1H, d, J=2.7 Hz), 3.89-3.99 (4H, m), 3.75 (4H, ddd, J=4.3, 2.7, 2.3 Hz), 3.23 (4H, t, J=4.9 Hz), 2.87-3.01 (4H, m), 2.31 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: I[C:2]1[C:7]2[O:8][C:9]3[C:14]([Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH:27]=[CH2:28]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH2:31]([O:30][C:26](=[O:29])[CH:27]=[CH:28][C:2]1[C:7]2[O:8][C:9]3[C:14]([Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:32]
Reactant: C[Si](C)(C)c1cccc2c1oc1c(I)cccc12
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C=Cc1cccc2c1oc1c([Si](C)(C)C)cccc12
Yield: 92.9 %

Procedure:
An oven-dried, 100 mL round-bottomed flask was cooled under Ar and charged with 4-iodo-6-trimethylsilyldibenzofuran (5) (3.82 g, 10.4 mmol), palladium acetate (49.2 mg, 2.1 mol %), and tri-ortho-tolylphosphine (0.162 g, 5.1 mol %). The flask was fitted with a condenser and the system was alternately evacuated under high vacuum and flushed with Ar (4 cycles). Acetonitrile (16.5 mL), triethylamine (4.36 mL, 31.1 mmol), and ethyl acrylate (3.39 mL, 31.3 mmol) were added through the condenser and the mixture was heated to 85÷C in an oil bath. The reaction mixture was cooled to room temperature when the palladium precipitated after 2 hours. The mixture was concentrated under reduced pressure to give a yellow-brown solid which was then partitioned between CH2Cl2 (120 mL) and H2O (150 mL). The aqueous layer was extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by flash chromatography (95:5 hexanes:ethyl acetate) to afford the pure compound (3.27 g, 93%) as an oil which solidified upon standing to afford beige solid: mp 48-52° C.; 1H NMR (d6-acetone) d 8.16 (d, Jo=7.6, 2H, Ar H1 and H9), 7.98 (d, J=16.2, 1H, --CHCHCO2Et), 7.77 (dd, Jo=7.0, Jp=0.6, 1H, Ar H3), 7.64 (dd, Jo=7.2, Jm=1.3, 1H, Ar H7), 7.44 (td, Jo=7.6, Jm=1.6, 2H, Ar H2 and H8), 7.20 (d, J=16.2, 1H, --CHCHCO2Et), 4.28 (q, J=7.1, 2H, --CO2CH2CH3), 1.34 (t, J=7.1, 3H, --CO2CH2CH3), 0.52 (s, 8H, --Si(CH3)3); 13C NMR (d6-acetone) d 167.51, 139.99, 134.60, 134.32, 129.78, 126.14, 124.59, 124.55, 124.08, 123.89, 123.36, 123.25, 122.98, 120.74, 61.27, 14.99, -0.56; EIMS m/z 338.1349, M+ calcd for C20H22O3Si 338.1338.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[CH2:34][C:35](Cl)=[O:36].C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[Cl:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[CH2:34][C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1)=[O:36]
Reactant: COc1ccc(CC(=O)Cl)c(Cl)c1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: COc1ccc(CC(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)c(Cl)c1
Yield: 96.2 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, (3), and 2-chloro-4-methoxyphenylacetyl chloride (0.237 mmol), the title compound (76 mg, yield 48%) was obtained in the same manner as that of Example 1, (4).