Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[C:3]1=[O:13].[N+:14]([O-])([OH:16])=[O:15].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]([CH3:12])[N:8]=2)[C:3]1=[O:13]
Reactant: CC1CCN(c2ccn(C)n2)C1=O
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1CCN(c2nn(C)cc2[N+](=O)[O-])C1=O
Temperature: 0 °C

Procedure:
To a solution of 3-methyl-1-(1-methyl-1H-pyrazol-3-yl)pyrrolidin-2-one (97 mg) in acetic anhydride (1.2 mL) was added fuming nitric acid (45 μL) under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. The reaction mixture was poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (53 mg).
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[NH:17]([C:24]1[S:25][CH:26]=[C:27]([CH:29]=[CH:30][C:31](OCC)=[O:32])[N:28]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.CO>[NH:17]([C:24]1[S:25][CH:26]=[C:27]([CH:29]=[CH:30][CH2:31][OH:32])[N:28]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C=Cc1csc(Nc2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CO
Product: OCC=Cc1csc(Nc2ccccc2)n1
Temperature: -50 °C
Reaction time: 2 h

Procedure:
58 ml of a 1M hexane solution of diisobutyl aluminum hydride was added dropwise at -60° C. to a solution of 4 g of ethyl 3-(2-anilinothiazol-4-yl)acrylate (prepared by the procedure described in Preparation 48) in 40 ml of tetrahydrofuran. The resulting mixture was stirred at -50° C. for 2 hours, then the excess of the reducing reagent was decomposed with 90% aqueous methanol. The mixture was then neutralized with 3N hydrochloric acid and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate. the solvent was evaporated off under reduced pressure, giving crude 3-(2-anilinothiazol-4-yl)allyl alcohol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:6]=2[N:7]=1
Reactant: BrC1CCOCC1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1cnn2C1CCOCC1

Procedure:
Ethyl 6-bromo-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 equiv.) was suspended in acetonitrile and K2CO3 (1.5 equiv.) and 4-bromotetrahydro-2H-pyran (2 equiv.) was added to it. The reaction mixture was refluxed for 8 h. On completion, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13](=[O:20])[O:12]3)[C:5]=12.C([BH-](CC)CC)C.[Li+]>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]([OH:20])[O:12]3)[C:5]=12
Reactant: O=C1OC(Cc2cccn3ccnc23)c2ccccc21
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: ClCCl
Product: OC1OC(Cc2cccn3ccnc23)c2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of 3-(imidazo[1,2-a]pyridin-8-ylmethyl)isobenzofuran-1(3H)-one (80 mg, 0.3 mmol) in DCM (6 mL) at −78° C., was added lithium triethyl borohydride (1M/THF, 0.3 mL) dropwise. The reaction mixture was stirred at −78° C. for 30 min, diluted with DCM (\; 10 mL), and quenched with MeOH (1 mL) and 5% HCl (2 mL). The mixture was warmed up to rt and stirred for 1 h. The solvents were removed and the residue was purified on RP-HPLC using CH3CN and water as eluent to give 3-(imidazo[1,2-a]pyridin-8-ylmethyl)-1,3-dihydroisobenzofuran-1-ol (20 mg, 25%). 1H NMR (400 MHz, CD3OD) δ=8.56 (t, 1H), 8.97 (d, 1H), 7.74 (s, 1H), 7.45-7.32 (m, 5H), 7.07-7.00 (m, 1H), 6.38-6.30 (m, 1H), 5.84-5.80 (m, 0.5H), 5.56 (dd, 0.5H), 3.69 (t, 0.5H), 3.65 (t, 0.5H), 3.26 (dd, 0.5H), 3.13 (dd, 0.5H). LRMS (M+H+) m/z 267.1.
Reaction SMILES: CN(C)CCN.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][NH2:16])=[CH:11][CH:10]=1.C(O)(=O)C.[C:21]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCO>[Cl:35][C:33]1[CH:32]=[CH:31][C:30]([NH:36][S:37]([C:40]([F:43])([F:41])[F:42])(=[O:39])=[O:38])=[C:29]([C:21](=[N:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:34]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(Cl)cc1
Agent: CN(C)CCN
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C(=NOc1ccc(Cl)cc1)c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.9 %

Procedure:
N,N-Dimethylethylenediamine (82 μL, 0.75 mmol) was added to a suspension of O-(4-chlorophenyl)hydroxylamine hydrochloride (141 mg, 0.51 mmol) in EtOH (15 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (3 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (170 mg, 0.47 mmol) in EtOH (5 mL), and the reaction stirred for 63 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in CH2Cl2 (50 mL), washed with water (twice), brine, dried over MgSO4 and the solvent evaporated under reduced pressure. The residue was filtered through a pad of silica (eluting with CH2Cl2/PE, 3:7) and purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19 to 1:4) to afford N-{4-chloro-2-[(4-chlorophenoxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 164 (140 mg, 61%), as a orange-brown solid. M.p. 86-87° C. 1H n.m.r. (200 MHz, CDCl3) δ 10.99, br s, 1H; 7.73, d, J=8.8 Hz, 1H; 7.54, m, 3H; 7.43-7.27, m, 5H; 7.07, m, 1H; 7.01, m, 2H. O-(4-Chlorophenyl)hydroxylamine hydrochloride was prepared by the procedure described in Example 2C.
Reaction SMILES: [CH3:1][C@:2]1([OH:32])[C@@H:16]2[C:11](=[C:12]([OH:30])[C@:13]3(O)[C:20](=[O:21])[C:19]([C:22]([NH2:24])=[O:23])=[C:18]([OH:25])[C@@H:17]([N:26]([CH3:28])[CH3:27])[C@@H:14]3[CH2:15]2)[C:9](=[O:10])[C:8]2[C:7]([OH:31])=[CH:6][CH:5]=[CH:4][C:3]1=2>N.[Zn]>[CH3:1][C:2]1([OH:32])[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([OH:31])[C:8]=2[C:9]([OH:10])=[C:11]2[CH:16]1[CH2:15][CH:14]1[CH:17]([N:26]([CH3:28])[CH3:27])[C:18]([OH:25])=[C:19]([C:22]([NH2:24])=[O:23])[C:20](=[O:21])[CH:13]1[C:12]2=[O:30]
Reactant: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4[C@@](C)(O)[C@H]3C[C@@H]12
Agent: N
Agent: [Zn]
Product: CN(C)C1C(O)=C(C(N)=O)C(=O)C2C(=O)C3=C(O)c4c(O)cccc4C(C)(O)C3CC21
Yield: 20.7 %

Procedure:
A solution was prepared by dissolving 2 g of tetracycline in 50 ml of a 15% aqueous ammonia solution. To the resulting solution 4 g of zinc dust was added and the mixture was vigorously stirred. After being stirred for two (2) hours, the reaction mixture was filtered to remove excess zinc dust. The filtrate was neutralized with concentrated hydrochloric acid under ice-cooling. The precipitated solid was collected by filtration and then mixed with 450 ml of water. The mixture was adjusted to a pH of 1.8 by use of hydrochloric acid. The solution obtained was extracted with ether by liquid-liquid extraction method. The extract was concentrated to give 450 mg of crude product, which was recrystallized from dimethylformamide-methanol to yield 400 mg of 12a-deoxytetracycline (yield: 21%). HPLC revealed that this product was a mixture of two types of isomers, molecular weight FD mass [M]+ 428.
Reaction SMILES: [CH3:1][Mg+].[Br-].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[N:15][N:14]3[C:17](=[O:27])[N:18]([CH2:20][C:21](=[O:26])[CH2:22][O:23][CH2:24][CH3:25])[N:19]=[C:13]3[C:12]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:7][CH:6]=1.[NH4+].[Cl-]>>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[N:15][N:14]3[C:17](=[O:27])[N:18]([CH2:20][C:21]([OH:26])([CH3:1])[CH2:22][O:23][CH2:24][CH3:25])[N:19]=[C:13]3[C:12]=2[C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[CH:9][CH:10]=1
Reactant: C[Mg+]
Reactant: CCOCC(=O)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Product: CCOCC(C)(O)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
MeMgBr (0.03 mL, 0.08 mmol, 3.0 M in Et2O) was added to a solution of 7,8-bis(4-chlorophenyl)-2-(3-ethoxy-2-oxopropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, prepared as described in Example 30, (23 mg, 0.05 mmol) at −78° C. The reaction was stirred for 30 min. at −78° C. After this time, saturated aqueous NH4Cl (2 mL) was added to the reaction and the resultant solution was warmed to RT. The layers were separated and the aqueous layer was extracted with EtOAC (3×10 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude product was purified by reverse phase HPLC to give the title compound, 7,8-bis(4-chlorophenyl)-2-(3-ethoxy-2-hydroxy-2-methylpropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (4 mg, 16% yield) as a yellow oil. MS [M+H]+: found 473; 1H NMR (CDCl3, 400 MHz) δ 8.13 (s, 1H), 7.29-7.18 (m, 6H), 7.06-7.02 (m, 2H), 4.25 (d, 1H), 3.98 (d, 1H), 3.43 (q, 2H), 3.35 (d, 1H), 3.25 (d, 1H), 1.18 (s, 3H), 1.07 (t, 3H).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:18]=1/[CH:19]=[CH:20]/C=O>O1CCCC1.CCCCCC>[Cl:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:18]=1/[CH:19]=[CH:20]/[CH:8]1[O:7][C:1](=[O:6])[CH2:2][CH:3]([OH:4])[CH2:5]1
Reactant: COC(=O)CC(C)=O
Reactant: O=C/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CC(O)CC(/C=C/c2c(Cl)cc(Cl)cc2OCc2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 107.5 %

Procedure:
Methyl acetoacetate (9.56 g, 82.3 mmole) was added dropwise to a stirred suspension of sodium hydride (50% oil suspension) (3.95 g, 82.3 mmole) in anhydrous tetrahydrofuran at 0° C. under a nitrogen atmosphere. The resulting solution was stirred 15 minutes at 0° C. and then treated with a 1.6M solution (51.5 ml, 82.3 mmole) of n-butyllithium in hexane over 5 minutes. The resulting yellow solution was stirred 15 minutes at 0° C. and then treated with a solution of (E)-2,4-dichloro-6-phenylmethoxycinnamaldehyde (25.3 g, 82.3 mmole) in anhydrous tetrahydrofuran (150 ml). The resulting orange solution was stirred 15 minutes at 0° C. and then quenched by dropwise addition of 12N hydrochloric acid (ca. 20 ml). The reaction mixture was diluted with water (100 ml) and extracted with ether (3×300 ml). The organic extracts were combined, washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo leaving the title compound as a yellow oil (34.8 g, 100%): pmr (CDCl3) δ2.75 (2H, d), 3.45 (2H, s), 3.72 (3H, s), 4.71 (H, m), 5.50 (2H, s), 7.37 (5H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[N+:19]([O-])=O)[CH2:4]1>CO.[Pd]>[NH2:19][C:10]1[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:9]=1[N:5]1[CH2:6][CH2:7][CH2:8][C@H:3]([N:2]([CH3:22])[CH3:1])[CH2:4]1
Reactant: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1

Procedure:
(S)-N,N-Dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine (0.82 g, 2.6 mmol) was reduced with Pd/C (10%, 0.27 g) in 10 ml methanol in a manner similar to Example 124-Step 3 to give the title compound as an orange-red oil. MS (m/z): 288.2 (M+H)+. Calc'd for C14H20F3N3: 287.32.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[CH:69][C:70]([N:73]3[CH2:77][CH2:76][CH:75]([OH:78])[CH2:74]3)=[N:71][CH:72]=2)[C:56]=1[CH3:79].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[CH:69][C:70]([N:73]5[CH2:77][CH2:76][CH:75]([OH:78])[CH2:74]5)=[N:71][CH:72]=4)[C:56]=3[CH3:79])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(-c2ccc(N3CCC(O)C3)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
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(-c2ccc(N3CCC(O)C3)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (8.73 mg, 0.018 mmol), 2,5-dimorpholinopyridin-3-amine (0.036 g, 0.14 mmol), 1-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)pyrrolidin-3-ol (0.043 g, 0.11 mmol), Pd2dba3 (0.004 g, 0.005 mmol) and sodium tert-butoxide (0.027 g, 0.29 mmol) in toluene (1.1 mL) at 100° C. for 2.5 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)) to give the desired product 1-(5-(4-(2,5-dimorpholinopyridin-3-ylamino)-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)pyrrolidin-3-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (1H, d, J=2.2 Hz), 7.85 (1H, dd, J=8.8, 2.5 Hz), 7.74 (1H, d, J=6.1 Hz), 7.60 (1H, m), 7.56 (1H, d, J=2.5 Hz), 7.40 (1H, m), 6.58 (1H, d, J=9.2 Hz), 6.40 (1H, d, J=2.5 Hz), 5.00 (1H, m), 4.43 (1H, br. s.), 3.64-3.78 (8H, m), 3.55 (4H, m), 3.42 (4H, m), 3.00 (4H, d, J=4.9 Hz), 2.14 (3H, s), 1.95 (2H, br. s.). Mass Spectrum (ESI) m/e=604.3 (M+1).
Reaction SMILES: CN(C)C[CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=O.CN(CCN)C.C1(N2CCNCC2)C=CC=CC=1>O1CCCC1>[CH3:22][N:24]([CH3:25])[CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:14]1)=[O:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CCCNC(=O)N1CCN(c2ccccc2)CC1
Agent: CN(C)CCN
Agent: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccccc2)CC1
Yield: 43 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 5. A mixture of 5.7 g (0.035 mole) of 1,1'-carbonyldiimidazole, 3.0 g (0.034 mole) of unsym-dimethylethylenediamine and 4.9 g (0.03 mole) of 1-phenylpiperazine in a total of 200 ml of tetrahydrofuran gave 3.6 g (43%) of title compound as a white powder, m.p. 88°-90° C., after recrystallization from diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][O:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1ccc(CO)cc1
Reactant: COC(=O)Cc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1OCc1ccc(CCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 15 h
Yield: 59.8 %

Procedure:
To a mixture of [4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]phenyl]methanol (0.60 g), methyl 2-(2-hydroxyphenyl)acetate (0.35 g), triphenylphosphine (0.79 g) and tetrahydrofuran (50 mL) was dropwise added a solution (40%, 1.39 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. To the reaction mixture was added ethyl acetate, the mixture was washed successively with water, a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-[2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]benzyloxy]phenyl]acetate as a colorless oil (0.54 g, 58%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:44][C:45]1[CH:46]=[C:47]([S:51][C:52]2[C:57](O)=[CH:56][CH:55]=[CH:54][N:53]=2)[CH:48]=[CH:49][CH:50]=1>C1COCC1>[Br:44][C:45]1[CH:46]=[C:47]([S:51][C:52]2[C:57]([O:10][CH2:9][CH2:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:56][CH:55]=[CH:54][N:53]=2)[CH:48]=[CH:49][CH:50]=1
Reactant: Oc1cccnc1Sc1cccc(Br)c1
Reactant: OCCCc1cccnc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1cccc(Sc2ncccc2OCCCc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
3-(Pyridin-3-yl)-1-propanol (5.5 g, 40 mmol) and triphenylphosphine (10.5 g, 40 mmol) are dissolved in THF (120 ml), and thereto are added successively with stirring diisopropyl azodicarboxylate (6.1 g, 30 mmol) and 2-(3-bromophenylthio)-3-pyridinol (5.0 g, 18 mmol) obtained in Reference Example 1 under ice-cooling. The mixture is further stirred at room temperature for 30 minutes, and the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (300 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (150 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (200 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane), and recrystallized from diethyl ether to give the title compound (6.8 g) as colorless crystals, m.p. 75-76° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[O:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[C:21]([C:18]1[O:17][C:16]([CH2:15][NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:24])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1)([OH:23])=[O:22]
Reactant: COC(=O)c1cccc(NCc2ccc(C(=O)O)o2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: O=C(O)c1ccc(CNc2cccc(C(=O)O)c2C(=O)O)o1

Procedure:
3-[(5-Carboxy-furan-2-ylmethyl)-amino]-phthalic acid dimethyl ester (0.90 g, 2.70 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid the product of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)=[CH:17][C:16]=1I>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)=[CH:17][C:16]=1[C:13]#[C:12][C:9]1[N:8]=[N:7][C:6]([NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=1
Reactant: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(I)c4)[nH]c3c2)CC1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Product: CN1CCN(Cc2ccc3nc(-c4ccc(Cl)c(C#Cc5ccc(NC6CCC6)nn5)c4)[nH]c3c2)CC1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole in a manner similar to that described for in Example 1. The title compound was obtained as a pale yellow solid. Mp:161-163° C.; 1H NMR (300 MHz, CDCl3) δ: 8.13-8.15 (1 H, d, J=6.0 Hz), 7.95 (1 H, s), 7.62-7.65 (1 H, d, J=9.0 Hz), 7.65 (1 H, s), 7.36-7.39 (1 H, d, J=9.0 Hz), 7.29-7.32 (1 H, d, J=9.0 Hz), 7.18-7.21 (1 H, d, J=9.0 Hz), 6.63-6.66 (1 H, d, J=9.0 Hz), 5.80 (1 H, s), 4.28-4.30 (1 H, m), 3.63 (2 H, s), 2.63 (8 H, brs), 2.40-2.44 (2 H, m) 2.40 (3 H, s), 1.96-2.02 (2 H, m), 1.79-1.81 (2 H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C29H31ClN7: 512.2324. found: 512.2303.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:27][CH2:28][NH2:29]>>[NH2:29][CH2:28][CH2:27][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: NCCCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2F)CC1
Product: NCCn1cc(C(=O)N2CCC(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-ethylamine gave the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:6]([CH3:11])[CH2:7][C@H:8]([OH:10])[CH3:9])[CH:4]=[CH2:5].F[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[C:26]([CH3:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2>C1COCC1>[CH2:3]([N:6]([CH3:11])[CH2:7][C@@H:8]([CH3:9])[O:10][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[C:15]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[C:26]([CH3:38])[CH:25]=1)=[N:16][CH:17]=[N:18]2)[CH:4]=[CH2:5]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Reactant: C=CCN(C)C[C@@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Temperature: 65 °C
Yield: 51.1 %

Procedure:
Sodium hydride (960 mg, 60% dispersion in oil, 20 mmol) was added portion wise to an ice-cooled solution of (2R)-1-[allyl(methyl)amino]propan-2-ol (3.87 g, 30 mmol, obtained as described in Example 2.3, preparation of starting materials) and 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (3.6 g, 10 mmol) in THF (25 ml). The mixture was heated at 65° C. for 24 hours. After cooling, the solvents were evaporated under vacuum. The mixture was diluted with DCM, and washed with water and brine. The organic layer was dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2 to 4% methanol in DCM) to give 5-{(1R)-2-[allyl(methyl)amino]-1-methylethoxy}-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (2.4 g, 51%) as a brown oil; Mass spectrum: MH+ 470.