Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[O:37](S(C1C=CC(C)=CC=1)(=O)=O)[S:38]([C:41]1[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=1)(=O)=[O:39]>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:25]3[CH2:28][CH:27]([CH2:29][O:30][S:38]([C:41]4[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=4)(=[O:39])=[O:37])[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: Nc1nccn2c(C3CC(CO)C3)nc(-c3cccc(OCc4ccccc4)c3)c12
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CC(c3nc(-c4cccc(OCc5ccccc5)c4)c4c(N)nccn34)C2)cc1
Temperature: 25 °C

Procedure:
A solution of {3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol (23 mg, 0.057 mmol) in dry methylene chloride (3 mL) was charged with pyridine (0.1 mL) and Ts2O (21 mg, 0.063 mmol) at −20° C. under N2 atmosphere. The mixture was slowly warmed to rt overnight. The reaction was quenched with water (1 mL), diluted with ethyl acetate (20 mL), washed with sat. aq. NaHCO3 (10 mL) and brine (2×10 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with EtOAc:MeOH=98:2→96:4), yielding the title compound as a white solid. Partial trans isomer was removed by chromatography and the ratio of cis and trans isomers raised to 8:1; MS (ES, Pos.): m/z 555 [MH+]. 1H NMR (CDCl3, 400 MHz) δ 2.27-2.35 (m, 2H), 2.41 (s, 3H), 2.55-2.62 (m, 2H), 2.80 (m, 1H), 3.66 (m, 1H), 4.07 (d, J=6.7 Hz, 2H), 5.01 (br s, 2H, NH2), 5.15 (s, 2H), 7.02-7.85 (m, 15H). Anal. Calcd for C31H30N4O4S.1/3H2O: C, 66.41; H, 5.51; N, 9.99. Found: C, 66.43; H, 5.44; N, 10.07.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:19])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:3]([OH:19])[CH2:2][NH:1][CH:43]2[CH2:42][CH2:41][N:40]([C:37]3[CH:36]=[CH:35][C:34]([S:31]([NH:30][C:24]4[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:22]([O:21][CH3:20])[CH:23]=4)(=[O:32])=[O:33])=[CH:39][CH:38]=3)[CH2:45][CH2:44]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(=O)CC3)cc2)cc1OC
Reactant: NCC(O)COc1cccc2[nH]c3ccccc3c12
Product: COc1ccc(NS(=O)(=O)c2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c6ccccc6c45)CC3)cc2)cc1OC

Procedure:
The title compound was prepared from 1-Amino-3-(9H-carbazol-4-yloxy)-propan-2-ol and Reference Example 73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 58-64° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.80-1.95 (m, 2H), 2.60-2.90 (m, 5H), 3.62 (s, 3H), 3.64 (s, 3H), 3.60-3.80 (m, 2H), 4.00-4.20 (m, 3H), 6.40-7.50 (m, 12H), 7.95 (s, 1H), 8.20 (d, 1H), 11.30 (s, 1H); MS (ES) m/z: 631.1 (MH+); HRMS Calcd. for C34H39N4O6S (MH+): 631.2590. Found: 631.2595.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:9][CH:8]=2)([O-])=O.C(N(CC)CC)C>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccc(OCCN3CCCC3)cc2c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1cnc2ccc(OCCN3CCCC3)cc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Nitro-6-(2-(pyrrolidin-1-yl)ethoxy)quinoline (134 mg, 0.46 mmol) was dissolved in EtOAc (10 mL) and the solution was sparged with N2 for several minutes. Triethylamine (0.065 mL, 0.46 mmol) was then added followed by a catalytic amount of 10% Pd/C. Sparging with N2 was repeated after each addition. A balloon of H2 was connected to the reaction flask and the reaction mixture was stirred at room temperature under H2 atmosphere for 48 hours. The mixture was then filtered through a Celite pad and concentrated to obtain crude 3-amino-6-(2-(pyrrolidin-1-yl)ethoxy)quinoline, which was used as is in the next reaction. LC/MS (m/z): 258.1 (MH+), Rt 0.33 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:23]([C:30]1[N:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[O:33][C:34]=1[CH2:35]Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([C:30]1[N:31]=[C:32]([C:37]([CH3:40])([CH3:39])[CH3:38])[O:33][C:34]=1[CH2:35][N:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:10][CH2:11]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(C)(C)c1nc(Cc2ccccc2)c(CCl)o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(Cc2oc(C(C)(C)C)nc2Cc2ccccc2)CC1
Yield: 64 %

Procedure:
A suspension containing 2-methoxyphenylpiperazine (1.0 mmole), potassium carbonate (2.0 mmole), potassium iodide (0.5 mmole) and 4-benzyl-5-chloromethyl-2-tertbutyl oxazole (1.0 mmole) from example 4, was stirred in acetone (10 ml) at ambient temperature for three days. The solvent was removed in vacuo, water (50 ml) added and the product extracted into ethyl acetate (3×50 ml). The combined organics were washed with water (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product was purified by “flash” chromatography over silica gel to afford the titled compound as a colorless oil (0.64 mmole, 64% yield). This was transformed into its mono-fumarate salt, a white crystalline powder, using the procedure outlined in example 10 above.
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29]([NH:31][CH2:32][CH2:33][S:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[O:30])[CH2:8][S:9]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(N[C@H](C(NCCSC(=O)C)=O)CS)(=O)C.C(Cl)Cl.CCOCC.C(Cl)(Cl)Cl>CCCCCC>[C:1]([NH:6][C@H:7]([C:29]([NH:31][CH2:32][CH2:33][S:34][C:35](=[O:40])[C:36]([CH3:37])([CH3:39])[CH3:38])=[O:30])[CH2:8][SH:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)C(C)(C)C
Agent: CC(=O)N[C@@H](CS)C(=O)NCCSC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C(=O)N[C@@H](CS)C(=O)NCCSC(=O)C(C)(C)C

Procedure:
This compound is obtained by the S-detritylation of 16 (2.78 mmol). The protocol used is the same as that described in example 1 for the synthesis of I-152. After the various treatments, a gum is collected, which gum is purified by flash chromatography on a silica gel column (eluent: CH2Cl2/ether 22%). I-214 is isolated in the form of a gum which, after trituration in hexane, provides a colorless powder (Yd=70%). Rf (CH2Cl2/ether, 5/5): 0.46. M.p.=120-122° C. [α]D20=−25° (c 1.04, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:41])=[O:40]
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cc(Cl)ccc4Cl)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2,5-dichlorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 588.7 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[O:5][CH2:6][CH2:7][OH:8]>CO.O1CCCC1.[Pd]>[OH:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][C:11]([NH2:12])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(OCCO)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCCO)ccc1N
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, 2-(3-methyl-4-nitrophenoxy)ethanol (1.0 g, 5.3 mmol) was dissolved in methanol/tetrahydrofuran (30 mL/30 mL) and 10% palladium on carbon (0.37 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere for 4 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure to afford 4-(2-hydroxyethoxy)-2-methylaniline as solid (0.80 g, y. 90%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:74][C:75]([F:79])([F:78])[CH2:76][NH2:77]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:77][CH2:76][C:75]([F:79])([F:78])[F:74])=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: NCC(F)(F)F
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: CN(C)C=O
Solvent: ClCCl
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)NCC(F)(F)F
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 2,2,2-trifluoroethanamine (9.0 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2,2,2-trifluoroethanamine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2,2,2-trifluoroethyl)acetamide. (16 mg, 0.032 mmol, 23%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])(C)C.C(N(CC)CC)C.C(OC(Cl)=O)[C:22]1[CH:27]=[CH:26]C=[CH:24][CH:23]=1>C1COCC1.O.C(OCC)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:7])[C:4]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CCNCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 169.4 %

Procedure:
Commercially available N-tert-butyloxycarbonyl-piperazine (0.5 g, 2.68 mmol) was dissolved in 5 mL of THF:water (1:1) and cooled in an ice bath. Triethylamine (0.748 mL, 5.4 mmol), followed by benzyloxycarbonyl chloride (0.575 mL, 3.21 mmol) in diethyl ether was slowly added to the reaction mixture. It was stirred at 0° C. for 1.5 hours. Solvents were removed and 50 mL of ethyl acetate was added to the residue. The ethyl acetate layer was washed with saturated NaHCO3 (20 mL×3), brine (20 mL×3), and dried over anhydrous sodium sulfate. N-tert-butyloxycarbonyl-N;benzyloxycarbonyl-piperazine (1.0 g) was obtained after evaporated to dryness in quantitative yield. MS: M+NH4 =338. M+H+ =321. N-tert-butyloxycarbonyl-N'-benzyloxycarbonyl-piperazine (1.8 g, 3.13 mmol) was dissolved in 10 mL of 4N-HCl/dioxane. It was stirred at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath, 1N-NaOH solution was carefully added to the mixture to adjust pH above 10. Ethyl acetate (50 mL×3) was used to extract the compound. The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate. After removal of the solvent, 1.1 g of N-benzyloxycarbonyl-piperazine was obtained in quantitative yield. Following the procedure of Example 6, but replacing 1-benzylpiperazine with N-benzyloxycarbonyl-piperazine, provided the desired compound. The product of Example 3 (1.1 g, 1.06 mmol), N-benzyloxycarbonyl-piperazine (700 mg, 3.18 mmol), and triethylamine (0.44 mL, 3.15 mmol) in 5 mL of methylene chloride were used. 339 mg of pure compound (C-32-N-benzyloxycarbonyl-piperazinyl-C-24-TBDMS-Ascomycin) was isolated in 29% yield. MS (FAB) m/z: M+H=1108. M+K-1146. The above obtained product (329 mg, 0.297 mmol) was treated with 48%-HF (0.55 mL) in 10 mL of acetonitrile in the procedure described in Example 5. 316 mg of semi pure compound (C-32-N-benzyloxycarbonyl-piperazinyl-Ascomycin) was isolated. This was directly used for the next reaction without further purification. The obtained product (317 mg, 0.32 mmol) was carefully hydrogenated in 40 mL of methanol in the presence of 10%-palladium on charcoal until theoretical ammount of hydrogen gas was consumed. 290 mg of crude product was purified by reverse phase-HPLC. 117 mg of the pure title compound was obtained in 47% yield. MS (FAB) m/z: M+H=860. M+K=898. mp=132° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([S:10]([OH:13])(=[O:12])=O)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH-:24])=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]1>O1CCCC1.Cl>[ClH:1].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:10]([C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][C:4]=3[C:8]=2[CH3:9])(=[O:12])=[O:13])=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: Cc1c(S(=O)(=O)O)sc2ccc(Cl)cc12
Reactant: COc1ccc([NH-])cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)cc1N1CCNCC1

Procedure:
A stirred suspension of 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid (4-methoxy-3-(4-tert-butoxycarbonylpiperazin-1-yl)phenylamide (D10) (193 g) in tetrahydrofuran (820 ml) and concentrated hydrochloric acid (180 ml) was heated at reflux for 1.75 h after which time a solution was obtained. The solution was concentrated and the residue dissolved in hot ethanol (600 ml). Upon cooling, a solid precipitated which was filtered and recrystallised (ethanol/water 1:1) to give the title compound (E83) as a white solid, m.p. 276-280° C. (dec.) (142 g, 83%). δH (250 MHz, D6-dmso) 2.29 (3H, s), 2.90 (4H, br s), 3.01 (4H, br s), 3.55 (3H, s), 6.54-6.71 (3H. m), 7.42 (1H, d, J 8.8 Hz), 7.85 (1H, s), 7.93 (1H, d, J 8.8 Hz), 9.03 (2H, br s), 10.3 (1H, br s). MH+ 452.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]2[O:9][CH2:8][CH2:7][N:6]3[CH:13]=[C:14]([C:16]4[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=4)[N:15]=[C:5]3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N1CCN2CCN(CCCC)P1N(CCCC)CC2)CCC.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]([N:20]1[C:16]([C:14]2[N:15]=[C:5]3[C:4]4[CH:3]=[C:2]([N:28]5[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]5)[N:12]=[CH:11][C:10]=4[O:9][CH2:8][CH2:7][N:6]3[CH:13]=2)=[N:17][CH:18]=[N:19]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Cl)ncc1OCC2
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(N3CCN(C)CC3)ncc1OCC2

Procedure:
A mixture of 10-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[4,3-f][1,4]oxazepine (132 mg, 0.400 mmol), 1-methyl-piperazine (88.7 uL, 0.800 mmol), palladium acetate (44.9 mg, 0.200 mmol), 2,8,9-tri-1-butyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (71.0 uL, 0.200 mmol) and Sodium tert-butoxide (38.4 mg, 0.400 mmol) in 1,4-Dioxane (8.0 mL) was degassed. The reaction was microwaved on 200 watts, 120° C. for 30 minutes. The mixture was filtered and the filtrate concentrated in vacuum. The residue was partitioned between water and ethyl acetate. The organic extracts were washed with water, brine and dried over MgSO4 and concentrated in vacuum. The residue was purified on 4 g silica column using 5-10% gradient of methanol containing 1% of ammonia in DCM to give 234. Yield 50 mg (30%). MS: 395.2. 1H NMR (500 MHz, DMSO) δ 8.04 (s, 1H), 8.03 (s, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 5.69 (dt, J=13.3, 6.6, 1H), 4.61-4.53 (m, 2H), 4.49-4.41 (m, 2H), 3.41 (s, 4H), 2.45 (s, 4H), 2.23 (s, 3H), 1.50 (d, J=6.6, 6H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:23][C:24]1[O:25][CH:26]=[CH:27][C:28]=1[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl>[N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[N:10]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29]([C:28]4[CH:27]=[CH:26][O:25][C:24]=4[CH3:23])=[O:30])=[N:37][CH:36]=3)=[O:39])[CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Reactant: Cc1occc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1occc1C(=O)Nc1ccc(C(=O)N2Cc3cccnc3Nc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) solution of 0.296 g of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine and 624 μL of triethylamine in 3 ml of dichloromethane is added a solution of 6-[(2-methyl-3-furanylcarbonyl)amino]-3-pyridinecarbonyl chloride in 4 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and the solvent removed under vacuum. To the residue is added 1M NaHCO3 and the mixture extracted with ethyl acetate. The extract is washed with H2O, 1M NaHCO3 brine and dried (Na2SO4). The solvent is removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: [NH2:1][NH2:2].[OH:3][C:4]1[C:5]([C:10]([O:12]C)=O)=[N:6][CH:7]=[CH:8][CH:9]=1>C(O)C>[OH:3][C:4]1[C:5]([C:10]([NH:1][NH2:2])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ncccc1O
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1ncccc1O

Procedure:
Hydrazine (0.248 mL, 7.91 mmol) was added under argon to a solution of methyl 3-hydroxy-2-pyridinecarboxylate (808 mg, 5.28 mmol) in ethanol (25 mL). The reaction mixture was stirred at reflux overnight (yellow solution). After cooling, a solid which has crashed out was filtrered to afford the desired product in 826 mg as a yellow solid.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[C:9]([Cl:23])[CH:8]=1)C>C(O)(=O)C.Cl>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:10]1[C:11]([Cl:13])=[CH:12][C:7]([O:6][CH2:5][CH:4]=[O:3])=[CH:8][C:9]=1[Cl:23]
Reactant: CCOC(COc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1)OCC
Agent: Cl
Solvent: CC(=O)O
Product: O=CCOc1cc(Cl)c(OCc2ccccc2Cl)c(Cl)c1
Temperature: 0 °C
Yield: 100 %

Procedure:
Then, 0.85 g of 4-(2-chlorobenzyloxy)-3,5-dichlorophenoxyacetaldehyde diethyl acetal was dissolved in 10 ml of acetic acid, to which 1 ml of concentrated hydrochloric acid was added dropwise, while stirring under ice cooling. After stirring under ice cooling for 2 hours, the reaction mixture was poured into ice water, and extracted twice with diethyl ether. The combined ether layer was washed with water, dried with anhydrous magnesium sulfate, followed by removal of the solvent by distillation under reduced pressure, which afforded 0.70 g of 4-(2-chlorobenzyloxy)-3,5-dichlorophenoxyacetaldehyde in crude form.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1)=S.C(=O)([O-])[O-].[K+].[K+].N#CBr>C(#N)C>[CH2:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][N:16]([C:14]2[N:3]3[CH:4]=[CH:5][N:1]=[C:2]3[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:13]=2)[CH2:17][CH2:18]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)N1CCN(C(=S)Nc2ccccc2Cc2ncc[nH]2)CC1
Agent: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(C2=Nc3ccccc3Cc3nccn32)CC1
Temperature: 25 °C

Procedure:
To a solution of 8.9 g of 1-[2-(2-imidazolylmethyl)phenylthiocarbamoyl]-4-ethoxycarbonylpiperazine in 70 ml of acetonitrile, cooled to 0°, was added 2.4 g of solid potassium carbonate while stirring, followed by dropwise addition of a solution of 2.5 g of cyanogen bromide in 10 ml of acetonitrile; the mixture was allowed to warm up to room temperature overnight. The solids were filtered off, washed with ethyl acetate, and the filtrate was evaporated to dryness. The residue was dissolved in methylene chloride, the solution was washed with water, dried over MgSO4, decolorized with charcoal and evaporated to dryness. The residue was chromatographed with 250 g of silica gel using ethyl acetate-methanol (9:1) as eluant to give 5-(4-ethoxycarbonyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine, m.p. 137°-139°.
Reaction SMILES: Br[C:2]1[C:3](=[O:33])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:60]1[C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=[C:62](B(O)O)[CH:61]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]3)=[CH:7][CH:8]=2)[C:3](=[O:33])[C:2]=1[C:62]1[CH:61]=[N:60][C:69]2[C:64]([CH:63]=1)=[CH:65][CH:66]=[CH:67][CH:68]=2
Reactant: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(Br)=C3c2ccc(F)cc2F)CC1
Reactant: OB(O)c1cnc2ccccc2c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2ccc(F)cc2F)CC1
Yield: 83 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-[3-(4-(methylsulfonyl)piperazin-1-yl)propoxy]-1H-inden-1-one obtained in Step 1 of Example 108 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 3-quinolinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (83%).